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Sample records for spontaneous complement activation

  1. Material properties in complement activation

    DEFF Research Database (Denmark)

    Moghimi, S. Moein; Andersen, Alina Joukainen; Ahmadvand, Davoud

    2011-01-01

    activation differently and through different sensing molecules and initiation pathways. The importance of material properties in triggering complement is considered and mechanistic aspects discussed. Mechanistic understanding of complement events could provide rational approaches for improved material design...

  2. Complement activation in experimental human malaria infection.

    NARCIS (Netherlands)

    Roestenberg, M.; McCall, M.B.B.; Mollnes, T.E.; Deuren, M. van; Sprong, T.; Klasen, I.S.; Hermsen, C.C.; Sauerwein, R.W.; Ven, A.J.A.M. van der

    2007-01-01

    The objective of this study was to investigate complement activation in uncomplicated, early phases of human malaria. Fifteen healthy volunteers were experimentally infected with Plasmodium falciparum malaria. Parasitemia and complement activation products were assessed. During blood stage

  3. Complement Activation and Inhibition in Wound Healing

    OpenAIRE

    Cazander, Gwendolyn; Jukema, Gerrolt N.; Nibbering, Peter H.

    2012-01-01

    Complement activation is needed to restore tissue injury; however, inappropriate activation of complement, as seen in chronic wounds can cause cell death and enhance inflammation, thus contributing to further injury and impaired wound healing. Therefore, attenuation of complement activation by specific inhibitors is considered as an innovative wound care strategy. Currently, the effects of several complement inhibitors, for example, the C3 inhibitor compstatin and several C1 and C5 inhibitors...

  4. HIV Coinfection Enhances Complement Activation During Sepsis

    NARCIS (Netherlands)

    Huson, Michaëla A. M.; Wouters, Diana; van Mierlo, Gerard; Grobusch, Martin P.; Zeerleder, Sacha S.; van der Poll, Tom

    2015-01-01

    Human immunodeficiency virus (HIV)-induced complement activation may play a role in chronic immune activation in patients with HIV infection and influence the complement system during acute illness. We determined the impact of HIV infection on the complement system in patients with asymptomatic HIV

  5. Complement Activation and Inhibition in Wound Healing

    Science.gov (United States)

    Cazander, Gwendolyn; Jukema, Gerrolt N.; Nibbering, Peter H.

    2012-01-01

    Complement activation is needed to restore tissue injury; however, inappropriate activation of complement, as seen in chronic wounds can cause cell death and enhance inflammation, thus contributing to further injury and impaired wound healing. Therefore, attenuation of complement activation by specific inhibitors is considered as an innovative wound care strategy. Currently, the effects of several complement inhibitors, for example, the C3 inhibitor compstatin and several C1 and C5 inhibitors, are under investigation in patients with complement-mediated diseases. Although (pre)clinical research into the effects of these complement inhibitors on wound healing is limited, available data indicate that reduction of complement activation can improve wound healing. Moreover, medicine may take advantage of safe and effective agents that are produced by various microorganisms, symbionts, for example, medicinal maggots, and plants to attenuate complement activation. To conclude, for the development of new wound care strategies, (pre)clinical studies into the roles of complement and the effects of application of complement inhibitors in wound healing are required. PMID:23346185

  6. Complement activation and inhibition: a delicate balance

    DEFF Research Database (Denmark)

    Sjöberg, A P; Trouw, L A; Blom, A M

    2009-01-01

    activation. Disturbances to the complement regulation on endogenous ligands can lead to diseases such as age-related macular degeneration, neurological and rheumatic disorders. A thorough understanding of these processes might be crucial to developing new therapeutic strategies....... proteins, pentraxins, amyloid deposits, prions and DNA, all bind the complement activator C1q, but also interact with complement inhibitors C4b-binding protein and factor H. This contrasts to the interaction between C1q and immune complexes, in which case no inhibitors bind, resulting in full complement...

  7. Kallikrein Cleaves C3 and Activates Complement.

    Science.gov (United States)

    Irmscher, Sarah; Döring, Nadia; Halder, Luke D; Jo, Emeraldo A H; Kopka, Isabell; Dunker, Christine; Jacobsen, Ilse D; Luo, Shanshan; Slevogt, Hortense; Lorkowski, Stefan; Beyersdorf, Niklas; Zipfel, Peter F; Skerka, Christine

    2017-12-14

    The human plasma contact system is an immune surveillance system activated by the negatively charged surfaces of bacteria and fungi and includes the kallikrein-kinin, the coagulation, and the fibrinolytic systems. Previous work shows that the contact system also activates complement, and that plasma enzymes like kallikrein, plasmin, thrombin, and FXII are involved in the activation process. Here, we show for the first time that kallikrein cleaves the central complement component C3 directly to yield active components C3b and C3a. The cleavage site within C3 is identical to that recognized by the C3 convertase. Also, kallikrein-generated C3b forms C3 convertases, which trigger the C3 amplification loop. Since kallikrein also cleaves factor B to yield Bb and Ba, kallikrein alone can trigger complement activation. Kallikrein-generated C3 convertases are inhibited by factor H; thus, the kallikrein activation pathway merges with the amplification loop of the alternative pathway. Taken together, these data suggest that activation of the contact system locally enhances complement activation on cell surfaces. The human pathogenic microbe Candida albicans activates the contact system in normal human serum. However, C. albicans immediately recruits factor H to the surface, thereby evading the alternative and likely kallikrein-mediated complement pathways. © 2017 S. Karger AG, Basel.

  8. Complement activation in chromosome 13 dementias

    DEFF Research Database (Denmark)

    Rostagno, A.; Revesz, T.; Lashley, T.

    2002-01-01

    experiments and enzyme-linked immunosorbent assays specific for the activation products iC3b, C4d, Bb, and C5b-9 indicated that ABri and ADan are able to fully activate the complement cascade at levels comparable to those generated by Aβ1–42. ABri and ADan specifically bound C1q with high affinity and formed...

  9. Complement activation by ceramide transporter proteins.

    Science.gov (United States)

    Bode, Gerard H; Losen, Mario; Buurman, Wim A; Veerhuis, Robert; Molenaar, Peter C; Steinbusch, Harry W M; De Baets, Marc H; Daha, Mohamed R; Martinez-Martinez, Pilar

    2014-02-01

    C1q is the initiator of the classical complement pathway and, as such, is essential for efficient opsonization and clearance of pathogens, altered self-structures, and apoptotic cells. The ceramide transporter protein (CERT) and its longer splicing isoform CERTL are known to interact with extracellular matrix components, such as type IV collagen, and with the innate immune protein serum amyloid P. In this article, we report a novel function of CERT in the innate immune response. Both CERT isoforms, when immobilized, were found to bind the globular head region of C1q and to initiate the classical complement pathway, leading to activation of C4 and C3, as well as generation of the membrane attack complex C5b-9. In addition, C1q was shown to bind to endogenous CERTL on the surface of apoptotic cells. These results demonstrate the role of CERTs in innate immunity, especially in the clearance of apoptotic cells.

  10. The Epidermal Growth Factor Receptor Is a Regulator of Epidermal Complement Component Expression and Complement Activation

    DEFF Research Database (Denmark)

    Abu-Humaidan, Anas H A; Ananthoju, Nageshwar; Mohanty, Tirthankar

    2014-01-01

    The complement system is activated in response to tissue injury. During wound healing, complement activation seems beneficial in acute wounds but may be detrimental in chronic wounds. We found that the epidermal expression of many complement components was only increased to a minor extent in skin...... wounds in vivo and in cultured keratinocytes after exposure to supernatant from stimulated mononuclear cells. In contrast, the epidermal expression of complement components was downregulated in ex vivo injured skin lacking the stimulation from infiltrating inflammatory cells but with intact injury......-induced epidermal growth factor receptor (EGFR)-mediated growth factor response. In cultured primary keratinocytes, stimulation with the potent EGFR ligand, TGF-α, yielded a significant downregulation of complement component expression. Indeed, EGFR inhibition significantly enhanced the induction of complement...

  11. Genetically Encoded Fluorescent Probe for Imaging Apoptosis in Vivo with Spontaneous GFP Complementation.

    Science.gov (United States)

    Nasu, Yusuke; Asaoka, Yoichi; Namae, Misako; Nishina, Hiroshi; Yoshimura, Hideaki; Ozawa, Takeaki

    2016-01-05

    Apoptosis plays a pivotal role in development and tissue homeostasis in multicellular organisms. Dysfunction of apoptosis is involved in many fatal diseases such as cancer. Visualization of apoptosis in living animals is necessary to understand the mechanism of apoptosis-related diseases. Here, we describe a genetically encoded fluorescent probe for imaging apoptosis in living multicellular organisms, based on spontaneous complementation of two fragments of a green fluorescent protein (GFP) variant (GFP OPT). The probe is designed for detection of mitochondria-mediated apoptosis during which a mitochondrial protein of Smac is released into cytosol. The Smac is connected with a carboxy-terminal fragment of GFP OPT (GFP11), whereas the remainder of GFP OPT (GFP(1-10)) is located in the cytosol. Under an apoptotic condition, the Smac is released from mitochondria into cytosol, allowing complementation of the GFP-OPT fragments and the emission of fluorescence. Live-cell imaging demonstrates that the probe enables detection of apoptosis in living cells with a high signal-to-background ratio. We applied the probe to living zebrafish, in which apoptotic cells were visualized with fluorescence. The technique provides a useful tool for the study of apoptosis in living animals, facilitating elucidation of the mechanisms of apoptosis-related diseases.

  12. Non-specific adsorption of complement proteins affects complement activation pathways of gold nanomaterials.

    Science.gov (United States)

    Quach, Quang Huy; Kah, James Chen Yong

    2017-04-01

    The complement system is a key humoral component of innate immunity, serving as the first line of defense against intruders, including foreign synthetic nanomaterials. Although gold nanomaterials (AuNMs) are widely used in nanomedicine, their immunological response is not well understood. Using AuNMs of three shapes commonly used in biomedical applications: spherical gold nanoparticles, gold nanostars and gold nanorods, we demonstrated that AuNMs activated whole complement system, leading to the formation of SC5b-9 complex. All three complement pathways were simultaneously activated by all the AuNMs. Recognition molecules of the complement system interacted with all AuNMs in vitro, except for l-ficolin, but the correlation between these interactions and corresponding complement pathway activation was only observed in the classical and alternative pathways. We also observed the mediating role of complement activation in cellular uptake of all AuNMs by human U937 promonocytic cells, which expresses complement receptors. Taken together, our results highlighted the potential immunological challenges for clinical applications of AuNMs that were often overlooked.

  13. Complement Activation by Ceramide Transporter Proteins

    NARCIS (Netherlands)

    Bode, G.H.; Losen, M.; Buurman, W.A.; Veerhuis, R.; Molenaar, P.C.; Steinbusch, H.W.M.; De Baets, M.H.; Daha, MR; Martinez-Martinez, P.

    2014-01-01

    C1q is the initiator of the classical complement pathway and, as such, is essential for efficient opsonization and clearance of pathogens, altered self-structures, and apoptotic cells. The ceramide transporter protein (CERT) and its longer splicing isoform CERTL are known to interact with

  14. Genetic Association of the Porcine C9 Complement Component with Hemolytic Complement Activity.

    Science.gov (United States)

    Khoa, D V A; Wimmers, K

    2015-09-01

    The complement system is a part of the natural immune regulation mechanism against invading pathogens. Complement activation from three different pathways (classical, lectin, and alternative) leads to the formation of C5-convertase, an enzyme for cleavage of C5 into C5a and C5b, followed by C6, C7, C8, and C9 in membrane attack complex. The C9 is the last complement component of the terminal lytic pathway, which plays an important role in lysis of the target cells depending on its self-polymerization to form transmembrane channels. To address the association of C9 with traits related to disease resistance, the complete porcine C9 cDNA was comparatively sequenced to detect single nucleotide polymorphisms (SNPs) in pigs of the breeds Hampshire (HS), Duroc (DU), Berlin miniature pig (BMP), German Landrace (LR), Pietrain (PIE), and Muong Khuong (Vietnamese potbelly pig). Genotyping was performed in 417 F2 animals of a resource population (DUMI: DU×BMP) that were vaccinated with Mycoplasma hyopneumoniae, Aujeszky diseases virus and porcine respiratory and reproductive syndrome virus at 6, 14 and 16 weeks of age, respectively. Two SNPs were detected within the third exon. One of them has an amino acid substitution. The European porcine breeds (LR and PIE) show higher allele frequency of these SNPs than Vietnamese porcine breed (MK). Association of the substitution SNP with hemolytic complement activity indicated statistically significant differences between genotypes in the classical pathway but not in the alternative pathway. The interactions between eight time points of measurement of complement activity before and after vaccinations and genotypes were significantly different. The difference in hemolytic complement activity in the both pathways depends on genotype, kind of vaccine, age and the interaction to the other complement components. These results promote the porcine C9 (pC9) as a candidate gene to improve general animal health in the future.

  15. Genetic Association of the Porcine C9 Complement Component with Hemolytic Complement Activity

    Directory of Open Access Journals (Sweden)

    D. V. A. Khoa

    2015-09-01

    Full Text Available The complement system is a part of the natural immune regulation mechanism against invading pathogens. Complement activation from three different pathways (classical, lectin, and alternative leads to the formation of C5-convertase, an enzyme for cleavage of C5 into C5a and C5b, followed by C6, C7, C8, and C9 in membrane attack complex. The C9 is the last complement component of the terminal lytic pathway, which plays an important role in lysis of the target cells depending on its self-polymerization to form transmembrane channels. To address the association of C9 with traits related to disease resistance, the complete porcine C9 cDNA was comparatively sequenced to detect single nucleotide polymorphisms (SNPs in pigs of the breeds Hampshire (HS, Duroc (DU, Berlin miniature pig (BMP, German Landrace (LR, Pietrain (PIE, and Muong Khuong (Vietnamese potbelly pig. Genotyping was performed in 417 F2 animals of a resource population (DUMI: DU×BMP that were vaccinated with Mycoplasma hyopneumoniae, Aujeszky diseases virus and porcine respiratory and reproductive syndrome virus at 6, 14 and 16 weeks of age, respectively. Two SNPs were detected within the third exon. One of them has an amino acid substitution. The European porcine breeds (LR and PIE show higher allele frequency of these SNPs than Vietnamese porcine breed (MK. Association of the substitution SNP with hemolytic complement activity indicated statistically significant differences between genotypes in the classical pathway but not in the alternative pathway. The interactions between eight time points of measurement of complement activity before and after vaccinations and genotypes were significantly different. The difference in hemolytic complement activity in the both pathways depends on genotype, kind of vaccine, age and the interaction to the other complement components. These results promote the porcine C9 (pC9 as a candidate gene to improve general animal health in the future.

  16. Complement activation, endothelial dysfunction, insulin resistance and chronic heart failure

    DEFF Research Database (Denmark)

    Bjerre, M.; Kistorp, C.; Hansen, T.K.

    2010-01-01

    Objectives. Patients with chronic heart failure (CHF) have an exaggerated immune response, endothelial damage/dysfunction, and increased risk of diabetes mellitus (DM). The inter-relationship(s) between indices of complement activation (soluble membrane attack complex, sMAC), inflammation (hs......, IR was an independent predictor of sMAC in the CHF group beta = 0.37 (p complement system and thus...

  17. The role of complement activation in thrombosis and hemolytic anemias.

    Science.gov (United States)

    Chapin, John; Terry, Hunter S; Kleinert, Dorothy; Laurence, Jeffrey

    2016-04-01

    The objective of this study was to describe complement activation in hemostatic and pathologic states of coagulation and in the acquired and congenital hemolytic anemias. We review published and emerging data on the involvement of the classic, alternative and lectin-based complement pathways in coagulation and the hemolytic anemias. The alternative pathway in particular is always "on," at low levels, and is particularly sensitive to hyper-activation in a variety of physiologic and pathologic states including infection, autoimmune disorders, thrombosis and pregnancy, requiring tight control predicated on a variety of soluble and membrane bound regulatory proteins. In acquired hemolytic anemias such as paroxysmal nocturnal hemoglobinuria (PNH) and cold agglutinin disease (CAD), the complement system directly induces red blood cell injury, resulting in intravascular and extravascular hemolysis. In congenital hemolytic anemias such as sickle cell disease and β-thalassemia, the complement system may also contribute to thrombosis and vascular disease. Complement activation may also lead to a storage lesion in red blood cells prior to transfusion. Complement pathways are activated in hemolytic anemias and are closely linked with thrombosis. In acquired disorders such as PNH and possibly CAD, inhibition of the alternative complement pathway improves clinical outcomes and reduces thrombosis risk. Whether complement inhibition has a similar role in congenital hemolytic anemias apart from the atypical hemolytic-uremic (aHUS)-type thrombotic microangiopathies remains to be determined. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Molecular mechanisms of complement activation, regulation and evasion

    NARCIS (Netherlands)

    Wu, J.

    2012-01-01

    The complement system of our immune defense can rapidly recognize and eliminate pathogens in blood. Activation of complement depends on enzymatic complexes, known as C3 convertases, which are short lived and dissociate irreversibly. Staphylococcus aureus secretes a small protein (named SCIN) that

  19. Functional analysis of Ficolin-3 mediated complement activation

    DEFF Research Database (Denmark)

    Hein, Estrid; Honoré, Christian; Skjoedt, Mikkel-Ole

    2010-01-01

    Ficolin-3 mediated complement activation that could be applicable for research and clinical use. Bovine serum albumin (BSA) was acetylated (acBSA) and chosen as a solid phase ligand for Ficolins in microtiter wells. Binding of Ficolins on acBSA was evaluated, as was functional complement activation...... was applied to the samples that inhibited interference from the classical pathway due to the presence of anti-BSA antibodies in some sera. We describe a novel functional method for measuring complement activation mediated by Ficolin-3 in human serum up to the formation of TCC. The assay provides......The recognition molecules of the lectin complement pathway are mannose-binding lectin and Ficolin -1, -2 and -3. Recently deficiency of Ficolin-3 was found to be associated with life threatening infections. Thus, we aimed to develop a functional method based on the ELISA platform for evaluating...

  20. Complement activation and interleukin response in major abdominal surgery.

    Science.gov (United States)

    Kvarnström, A L; Sarbinowski, R T; Bengtson, J-P; Jacobsson, L M; Bengtsson, A L

    2012-05-01

    The objective of this study was to evaluate whether major abdominal surgery leads to complement activation and interleukin response and whether the kind of anaesthesia influence complement activation and the release of inflammatory interleukins. The study design was prospective and randomised. Fifty patients undergoing open major colorectal surgery due to cancer disease or inflammatory bowel disease were studied. Twenty-five patients were given total intravenous anaesthesia (TIVA) with propofol and remifentanil, and 25 patients were given inhalational anaesthesia with sevoflurane and fentanyl. To determine complement activation (C3a and SC5b-9) and the release of pro- and anti-inflammatory interleukins (tumour necrosis factor-a (TNF-a)), interleukin-1b (IL-1b), IL-6, IL-8, IL-4 and IL-10), blood samples were drawn preoperatively, 60 minutes after start of surgery, 30 minutes after end of surgery and 24 hours postoperatively. Complement was activated and pro-inflammatory interleukins (IL-6 and IL-8) and anti-inflammatory interleukins (IL-10) were released during major colorectal surgery. There was no significant difference between TIVA and inhalational anaesthesia regarding complement activation and cytokine release. Major colorectal surgery leads to activation of the complement cascade and the release of both pro-inflammatory and anti-inflammatory cytokines. There are no significant differences between total intravenous anaesthesia (TIVA) with propofol and remifentanil and inhalational anaesthesia with sevoflurane and fentanyl regarding complement activation and the release of pro- and anti-inflammatory interleukins. © 2012 The Authors. Scandinavian Journal of Immunology © 2012 Blackwell Publishing Ltd. Scandinavian Journal of Immunology.

  1. Micrurus snake venoms activate human complement system and generate anaphylatoxins

    Directory of Open Access Journals (Sweden)

    Tanaka Gabriela D

    2012-01-01

    Full Text Available Abstract Background The genus Micrurus, coral snakes (Serpentes, Elapidae, comprises more than 120 species and subspecies distributed from the south United States to the south of South America. Micrurus snake bites can cause death by muscle paralysis and further respiratory arrest within a few hours after envenomation. Clinical observations show mainly neurotoxic symptoms, although other biological activities have also been experimentally observed, including cardiotoxicity, hemolysis, edema and myotoxicity. Results In the present study we have investigated the action of venoms from seven species of snakes from the genus Micrurus on the complement system in in vitro studies. Several of the Micrurus species could consume the classical and/or the lectin pathways, but not the alternative pathway, and C3a, C4a and C5a were generated in sera treated with the venoms as result of this complement activation. Micrurus venoms were also able to directly cleave the α chain of the component C3, but not of the C4, which was inhibited by 1,10 Phenanthroline, suggesting the presence of a C3α chain specific metalloprotease in Micrurus spp venoms. Furthermore, complement activation was in part associated with the cleavage of C1-Inhibitor by protease(s present in the venoms, which disrupts complement activation control. Conclusion Micrurus venoms can activate the complement system, generating a significant amount of anaphylatoxins, which may assist due to their vasodilatory effects, to enhance the spreading of other venom components during the envenomation process.

  2. Functional analysis of Ficolin-3 mediated complement activation

    DEFF Research Database (Denmark)

    Hein, Estrid; Honoré, Christian; Skjoedt, Mikkel-Ole

    2010-01-01

    assessed by C4, C3 and terminal complement complex (TCC) deposition. Serum Ficolin-3 bound to acBSA in a calcium dependent manner, while only minimal binding of Ficolin-2 and no binding of Ficolin-1 were observed. No binding to normal BSA was seen for any of the Ficolins. Serum C4, C3 and TCC deposition...... was applied to the samples that inhibited interference from the classical pathway due to the presence of anti-BSA antibodies in some sera. We describe a novel functional method for measuring complement activation mediated by Ficolin-3 in human serum up to the formation of TCC. The assay provides...

  3. Activation of the lectin complement pathway on human renal ...

    African Journals Online (AJOL)

    This study aimed to investigate the roles of high glucose and mannose-binding lectin (MBL) on the activation of the lectin complement pathway (LCP) on human renal glomerular endothelial cells (HRGECs) in vitro. Flow cytometry analysis, immunofluorescence staining and Western blot were used to detect the cell surface ...

  4. Regulation of mast cell activation by complement-derived peptides.

    Science.gov (United States)

    Erdei, Anna; Andrásfalvy, Márton; Péterfy, Hajna; Tóth, Gábor; Pecht, Israel

    2004-03-29

    It is known for more than 25 years that the complement-derived anaphylatoxic peptides, C3a, C4a and C5a are potent activators of basophils and certain types of mast cells. Although tissue distribution of receptors for C3a and C5a well exceeds myeloid cells, apparently they are not expressed on mucosal type mast cells, consequently these cells are not activated by C3a and C5a. Our results do however demonstrate that C3a and peptides related to this complement activation product are able to inhibit FcRI-clustering induced activation of mucosal type mast cells-such as RBL-2H3 cells and bone-marrow derived mast cells. Based on the current results we propose the presence of separate "activator" and "inhibitor" sequence motifs in C3a which are in balance under physiologic conditions.

  5. Yin and Yang: complement activation and regulation in Alzheimer's disease.

    Science.gov (United States)

    Shen, Yong; Meri, Seppo

    2003-08-01

    The spectrum of inflammatory diseases is nowadays considered to include diverse diseases of the central nervous system (CNS). Current evidence suggests that syndromes such as Alzheimer's disease (AD) have important inflammatory and immune components and may be amenable to treatment by anti-inflammatory and immunotherapeutic approaches. Compelling evidence has been reported that complement activation occurs in the brain with Alzheimer's disease, and that this contributes to the development of a local inflammatory state that is correlated with cognitive dysfunction. The complement system is a critical element of the innate immune system recognizing and killing, or targeting for destruction, otherwise pathogenic organisms. In addition to triggering the generation of a membranolytic complex, complement proteins interact with cell surface receptors to promote a local inflammatory response that contributes to the protection and healing of the host. Complement activation causes inflammation and cell damage, yet it is an essential component in trying to eliminate cell debris and potentially toxic protein aggregates. It is the balance of these seemingly competing events--the "Yin" and the "Yang"--that influences the ultimate state of neuronal function. Knowledge of the unique molecular interactions that occur in the development of Alzheimer's disease, the functional consequences of those interactions, and the proportional contribution of each element to this disorder, should facilitate the design of effective therapeutic strategies for this disease.

  6. Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE)

    DEFF Research Database (Denmark)

    Marquart, H V; Svendsen, A; Rasmussen, J M

    1995-01-01

    It has previously been reported that the expression of the complement receptors, CR1 on erythrocytes and blood leucocytes and CR2 on B cells, is reduced in patients with SLE, and that the reduced expression of CR1 on erythrocytes is related to disease activity. We have earlier demonstrated...... that normal B cells are capable of activating the alternative pathway (AP) of complement in a CR2-dependent fashion. In this study we have investigated whether disturbances in this activity may be related to the altered phenotype of SLE B cells. Flow cytometry was used to measure expression of complement...... activation by B cells in homologous serum. Finally, we demonstrated an inverse relationship between SLE disease activity index (SLEDAI) and the expression of complement receptor 2 (CR2) on SLE B cells. Thus, determination of CR2 on B cells may emerge as an additional laboratory tool in the assessment of SLE...

  7. Peptide Inhibitor of Complement C1 (PIC1 Rapidly Inhibits Complement Activation after Intravascular Injection in Rats.

    Directory of Open Access Journals (Sweden)

    Julia A Sharp

    Full Text Available The complement system has been increasingly recognized to play a pivotal role in a variety of inflammatory and autoimmune diseases. Consequently, therapeutic modulators of the classical, lectin and alternative pathways of the complement system are currently in pre-clinical and clinical development. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement and is referred to as Peptide Inhibitor of Complement C1 (PIC1. In this study, we determined that the lead PIC1 variant demonstrates a salt-dependent binding to C1q, the initiator molecule of the classical pathway. Additionally, this peptide bound to the lectin pathway initiator molecule MBL as well as the ficolins H, M and L, suggesting a common mechanism of PIC1 inhibitory activity occurs via binding to the collagen-like tails of these collectin molecules. We further analyzed the effect of arginine and glutamic acid residue substitution on the complement inhibitory activity of our lead derivative in a hemolytic assay and found that the original sequence demonstrated superior inhibitory activity. To improve upon the solubility of the lead derivative, a pegylated, water soluble variant was developed, structurally characterized and demonstrated to inhibit complement activation in mouse plasma, as well as rat, non-human primate and human serum in vitro. After intravenous injection in rats, the pegylated derivative inhibited complement activation in the blood by 90% after 30 seconds, demonstrating extremely rapid function. Additionally, no adverse toxicological effects were observed in limited testing. Together these results show that PIC1 rapidly inhibits classical complement activation in vitro and in vivo and is functional for a variety of animal species, suggesting its utility in animal models of classical complement-mediated diseases.

  8. Spontaneous Plasticity of Multineuronal Activity Patterns in Activated Hippocampal Networks

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    Atsushi Usami

    2008-01-01

    Full Text Available Using functional multineuron imaging with single-cell resolution, we examined how hippocampal networks by themselves change the spatiotemporal patterns of spontaneous activity during the course of emitting spontaneous activity. When extracellular ionic concentrations were changed to those that mimicked in vivo conditions, spontaneous activity was increased in active cell number and activity frequency. When ionic compositions were restored to the control conditions, the activity level returned to baseline, but the weighted spatial dispersion of active cells, as assessed by entropy-based metrics, did not. Thus, the networks can modify themselves by altering the internal structure of their correlated activity, even though they as a whole maintained the same level of activity in space and time.

  9. Cigarette smoke can activate the alternative pathway of complement in vitro by modifying the third component of complement.

    OpenAIRE

    Kew, R R; Ghebrehiwet, B; Janoff, A

    1985-01-01

    Cigarette smoking is associated with significant increases in the number of pulmonary mononuclear phagocytes and neutrophils. A potent chemoattractant for these cells is C5a, a peptide generated during complement (C) activation. We, therefore, investigated the possibility that cigarette smoke could activate the complement system in vitro. Our results show that factor(s) (mol wt less than 1,000) present in an aqueous solution of whole, unfiltered cigarette smoke can deplete the hemolytic capac...

  10. Spontaneous activity in peripheral diaphragmatic lymphatic loops.

    Science.gov (United States)

    Moriondo, Andrea; Solari, Eleonora; Marcozzi, Cristiana; Negrini, Daniela

    2013-10-01

    The spontaneous contractility of FITC-dextran-filled lymphatics at the periphery of the pleural diaphragm was documented for the first time "in vivo" in anesthetized Wistar rats. We found that lymphatic segments could be divided into four phenotypes: 1) active, displaying rhythmic spontaneous contractions (51.8% of 197 analyzed sites); 2) stretch-activated, whose contraction was triggered by passive distension of the vessel lumen (4.1%); 3) passive, which displayed a completely passive distension (4.5%); and 4) inert, whose diameter never changed over time (39.6%). Smooth muscle actin was detected by immunofluorescence and confocal microscopy in the vessel walls of active but also of inert sites, albeit with a very different structure within the vessel wall. Indeed, while in active segments, actin was arranged in a dense mesh completely surrounding the lumen, in inert segments actin decorated the vessels wall in sparse longitudinal strips. When located nearby along the same lymphatic loop, active, stretch-activated, and passive sites were always recruited in temporal sequence starting from the active contraction. The time delay was ∼0.35 s between active and stretch-activated and 0.54 s between stretch-activated and passive segments, promoting a uniform lymph flux of ∼150/200 pl/min. We conclude that, unlike more central diaphragmatic lymphatic vessels, loops located at the extreme diaphragmatic periphery do require an intrinsic pumping mechanism to propel lymph centripetally, and that such an active lymph propulsion is attained by means of a complex interplay among sites whose properties differ but are indeed able to organize lymph flux in an ordered fashion.

  11. Early Intra-Articular Complement Activation in Ankle Fractures

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    Hagen Schmal

    2014-01-01

    Full Text Available Cytokine regulation possibly influences long term outcome following ankle fractures, but little is known about synovial fracture biochemistry. Eight patients with an ankle dislocation fracture were included in a prospective case series and matched with patients suffering from grade 2 osteochondritis dissecans (OCD of the ankle. All fractures needed external fixation during which joint effusions were collected. Fluid analysis was done by ELISA measuring aggrecan, bFGF, IL-1β, IGF-1, and the complement components C3a, C5a, and C5b-9. The time periods between occurrence of fracture and collection of effusion were only significantly associated with synovial aggrecan and C5b-9 levels (P<0.001. Furthermore, synovial expressions of both proteins correlated with each other (P<0.001. Although IL-1β expression was relatively low, intra-articular levels correlated with C5a (P<0.01 and serological C-reactive protein concentrations 2 days after surgery (P<0.05. Joint effusions were initially dominated by neutrophils, but the portion of monocytes constantly increased reaching 50% at day 6 after fracture (P<0.02. Whereas aggrecan and IL-1β concentrations were not different in fracture and OCD patients, bFGF, IGF-1, and all complement components were significantly higher concentrated in ankle joints with fractures (P<0.01. Complement activation and inflammatory cell infiltration characterize the joint biology following acute ankle fractures.

  12. Genetic, molecular and functional analyses of complement factor I deficiency

    DEFF Research Database (Denmark)

    Nilsson, S.C.; Trouw, L.A.; Renault, N.

    2009-01-01

    Complete deficiency of complement inhibitor factor I (FI) results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI deficiency and three patie...

  13. Guinea pig complement potently measures vibriocidal activity of human antibodies in response to cholera vaccines.

    Science.gov (United States)

    Kim, Kyoung Whun; Jeong, Soyoung; Ahn, Ki Bum; Yang, Jae Seung; Yun, Cheol-Heui; Han, Seung Hyun

    2017-12-01

    The vibriocidal assay using guinea pig complement is widely used for the evaluation of immune responses to cholera vaccines in human clinical trials. However, it is unclear why guinea pig complement has been used over human complement in the measurement of vibriocidal activity of human sera and there have not been comparison studies for the use of guinea pig complement over those from other species. Therefore, we comparatively investigated the effects of complements derived from human, guinea pig, rabbit, and sheep on vibriocidal activity. Complements from guinea pig, rabbit, and human showed concentration-dependent vibriocidal activity in the presence of quality control serum antibodies. Of these complements, guinea pig complement was the most sensitive and effective over a wide concentration range. When the vibriocidal activity of complements was measured in the absence of serum antibodies, human, sheep, and guinea pig complements showed vibriocidal activity up to 40-fold, 20-fold, and 1-fold dilution, respectively. For human pre- and post-vaccination sera, the most potent vibriocidal activity was observed when guinea pig complement was used. In addition, the highest fold-increases between pre- and post- vaccinated sera were obtained with guinea pig complement. Furthermore, human complement contained a higher amount of V. cholerae- and its lipopolysaccharide-specific antibodies than guinea pig complement. Collectively, these results suggest that guinea pig complements are suitable for vibriocidal assays due to their high sensitivity and effectiveness to human sera.

  14. Complement activation in emergency department patients with severe sepsis.

    Science.gov (United States)

    Younger, John G; Bracho, David O; Chung-Esaki, Hangyul M; Lee, Moonseok; Rana, Gurpreet K; Sen, Ananda; Jones, Alan E

    2010-04-01

    This study assessed the extent and mechanism of complement activation in community-acquired sepsis at presentation to the emergency department (ED) and following 24 hours of quantitative resuscitation. A prospective pilot study of patients with severe sepsis and healthy controls was conducted among individuals presenting to a tertiary care ED. Resuscitation, including antibiotics and therapies to normalize central venous and mean arterial pressure (MAP) and central venous oxygenation, was performed on all patients. Serum levels of Factor Bb (alternative pathway), C4d (classical and mannose-binding lectin [MBL] pathway), C3, C3a, and C5a were determined at presentation and 24 hours later among patients. Twenty patients and 10 healthy volunteer controls were enrolled. Compared to volunteers, all proteins measured were abnormally higher among septic patients (C4d 3.5-fold; Factor Bb 6.1-fold; C3 0.8-fold; C3a 11.6-fold; C5a 1.8-fold). Elevations in C5a were most strongly correlated with alternative pathway activation. Surprisingly, a slight but significant inverse relationship between illness severity (by sequential organ failure assessment [SOFA] score) and C5a levels at presentation was noted. Twenty-four hours of structured resuscitation did not, on average, affect any of the mediators studied. Patients with community-acquired sepsis have extensive complement activation, particularly of the alternative pathway, at the time of presentation that was not significantly reversed by 24 hours of aggressive resuscitation.

  15. Circulating AIM Prevents Hepatocellular Carcinoma through Complement Activation

    Directory of Open Access Journals (Sweden)

    Natsumi Maehara

    2014-10-01

    Full Text Available Hepatocellular carcinoma (HCC is a widespread fatal disease and the third most common cause of cancer deaths. Here, we show the potent anti-HCC effect of the circulating protein AIM. As in adipocytes, AIM is incorporated into normal hepatocytes, where it interferes with lipid storage. In contrast, AIM accumulates on the HCC cell surface and activates the complement cascade via inactivating multiple regulators of complement activation. This response provokes necrotic cell death specifically in AIM-bound HCC cells. Accordingly, AIM−/− mice were highly susceptible to steatosis-associated HCC development, whereas no AIM+/+ mouse developed the disease despite comparable liver inflammation and fibrosis in response to a long-term high-fat diet. Administration of AIM prevented tumor development in AIM−/− mice, and HCC induction by diethylnitrosamine was more prominent in AIM−/− than wild-type mice. These findings could be the basis for novel AIM-based therapeutic strategies for HCC.

  16. Complement activation, endothelial dysfunction, insulin resistance and chronic heart failure

    DEFF Research Database (Denmark)

    Bjerre, M.; Kistorp, C.; Hansen, T.K.

    2010-01-01

    Objectives. Patients with chronic heart failure (CHF) have an exaggerated immune response, endothelial damage/dysfunction, and increased risk of diabetes mellitus (DM). The inter-relationship(s) between indices of complement activation (soluble membrane attack complex, sMAC), inflammation (hs......CRP), endothelial activation (soluble E-selectin, sEsel)), endothelial damage/dysfunction (von Willebrand factor, vWf) and insulin resistance (IR) and prognosis in CHF remains unknown. Design. We investigated the association(s) between plasma sMAC, hsCRP, sEsel, vWf and IR (assessed by homeostatic model assessment......, HOMA) in a prospective study including a total of 193 patients with CHF, and assessed whether high levels of these biomarkers had a prognostic impact. Biomarker levels in CHF patients were compared to 100 age-matched controls. Results. Plasma sMAC levels were elevated in patients with CHF due...

  17. Non-linear dynamics of the complement system activation.

    Science.gov (United States)

    Korotaevskiy, Andrey A; Hanin, Leonid G; Khanin, Mikhail A

    2009-12-01

    The complement system (CS) plays a prominent role in the immune defense. The goal of this work is to study the dynamics of activation of the classic and alternative CS pathways based on the method of mathematical modeling. The principal difficulty that hinders modeling effort is the absence of the measured values of kinetic constants of many biochemical reactions forming the CS. To surmount this difficulty, an optimization procedure consisting of constrained minimization of the total protein consumption by the CS was designed. The constraints made use of published data on the in vitro kinetics of elimination of the Borrelia burgdorferi bacteria by the CS. Special features of the problem at hand called for a significant modification of the general constrained optimization procedure to include a mathematical model of the bactericidal effect of the CS in the iterative setting. Determination of the unknown kinetic constants of biochemical reactions forming the CS led to a fully specified mathematical model of the dynamics of cell killing induced by the CS. On the basis of the model, effects of the initial concentrations of complements and their inhibitors on the bactericidal action of the CS were studied. Proteins playing a critical role in the regulation of the bactericidal action of the CS were identified. Results obtained in this work serve as an important stepping stone for the study of functioning of the CS as a whole as well as for developing methods for control of pathogenic processes.

  18. The distribution of and complementation relationships between spontaneous X-linked recessive lethal mutations recovered from crossing long-term laboratory stocks of Drosophila melanogaster

    International Nuclear Information System (INIS)

    Schalet, A.P.

    1986-01-01

    Drosophila melanogaster males from a wild-type laboratory stock, were mated with virgin females of the M-6 stock, and 149 spontaneous independent non-mosaically transmitted, as well as 8 incidentally detected, mosaically transmitted, X-linked recessive lethal mutations were recovered from 95 704 F 2 cultures. 152 mutations were mapped over the entire length of the X-chromosome by complementation and/or crossover tests. Although there were far too few spontaneous mutations to make a meaningful comparison of relative mutability on a locus-by-locus basis, those loci displaying a relatively higher X-ray mutability, when taken as a group, tend to display a relatively higher spontaneous mutability, and those loci displaying a relatively lower X-ray mutability, when taken as a group, tend to display a relatively lower spontaneous mutability. (Auth.)

  19. Spontaneous Activity Drives Local Synaptic Plasticity In Vivo

    NARCIS (Netherlands)

    Winnubst, Johan; Cheyne, Juliette E; Niculescu, Dragos; Lohmann, C.

    2015-01-01

    Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in

  20. Hepatitis C virus NS3/4A protease inhibits complement activation by cleaving complement component 4.

    Directory of Open Access Journals (Sweden)

    Seiichi Mawatari

    Full Text Available BACKGROUND: It has been hypothesized that persistent hepatitis C virus (HCV infection is mediated in part by viral proteins that abrogate the host immune response, including the complement system, but the precise mechanisms are not well understood. We investigated whether HCV proteins are involved in the fragmentation of complement component 4 (C4, composed of subunits C4α, C4β, and C4γ, and the role of HCV proteins in complement activation. METHODS: Human C4 was incubated with HCV nonstructural (NS 3/4A protease, core, or NS5. Samples were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then subjected to peptide sequencing. The activity of the classical complement pathway was examined using an erythrocyte hemolysis assay. The cleavage pattern of C4 in NS3/4A-expressing and HCV-infected cells, respectively, was also examined. RESULTS: HCV NS3/4A protease cleaved C4γ in a concentration-dependent manner, but viral core and NS5 did not. A specific inhibitor of NS3/4A protease reduced C4γ cleavage. NS3/4A protease-mediated cleavage of C4 inhibited classical pathway activation, which was abrogated by a NS3/4A protease inhibitor. In addition, co-transfection of cells with C4 and wild-type NS3/4A, but not a catalytic-site mutant of NS3/4A, produced cleaved C4γ fragments. Such C4 processing, with a concomitant reduction in levels of full-length C4γ, was also observed in HCV-infected cells expressing C4. CONCLUSIONS: C4 is a novel cellular substrate of the HCV NS3/4A protease. Understanding disturbances in the complement system mediated by NS3/4A protease may provide new insights into the mechanisms underlying persistent HCV infection.

  1. Complement factor C4 activation in patients with hereditary angioedema

    DEFF Research Database (Denmark)

    Åbom, Anne; Bygum, Anette; Koch, Claus

    2017-01-01

    , that C1-INH-HAE may potentially be overlooked, if screening is performed only by measurement of C4. It has been suggested that measurement of C4 activation products is better suited to avoid false negative results. Our aim was to investigate whether total antigenic C4 or non-functional C4c is a better......Objectives: Low complement factor C4 is usually considered a valuable screening tool for patients with the potentially life-threatening hereditary angioedema with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE). However, there are patients with C1-INH-HAE presenting with normal C4 levels. This means...... measure of the increased C4 activation in C1-INH-HAE patients. Design and methods: Two different monoclonal antibodies (mAb) to human C4 were produced: one had specificity for the β-chain of C4 and would thus react with both functional and non-functional C4, and the other was developed against the factor...

  2. Immune complement activation is attenuated by surface nanotopography

    Directory of Open Access Journals (Sweden)

    Elwing H

    2011-10-01

    Full Text Available Mats Hulander1, Anders Lundgren1, Mattias Berglin1, Mattias Ohrlander2, Jukka Lausmaa3,4, Hans Elwing1 1Department of Cell and Molecular Biology/Interface Biophysics, University of Gothenburg, Medicinaregatan 9E, Gothenburg, 2Bactiguard AB, Stockholm, 3SP Technical Research Institute, Boras, 4Biomatcell, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Abstract: The immune complement (IC is a cell-free protein cascade system, and the first part of the innate immune system to recognize foreign objects that enter the body. Elevated activation of the system from, for example, biomaterials or medical devices can result in both local and systemic adverse effects and eventually loss of function or rejection of the biomaterial. Here, the researchers have studied the effect of surface nanotopography on the activation of the IC system. By a simple nonlithographic process, gold nanoparticles with an average size of 58 nm were immobilized on a smooth gold substrate, creating surfaces where a nanostructure is introduced without changing the surface chemistry. The activation of the IC on smooth and nanostructured surfaces was viewed with fluorescence microscopy and quantified with quartz crystal microbalance with dissipation monitoring in human serum. Additionally, the ability of pre-adsorbed human immunoglobulin G (IgG (a potent activator of the IC to activate the IC after a change in surface hydrophobicity was studied. It was found that the activation of the IC was significantly attenuated on nanostructured surfaces with nearly a 50% reduction, even after pre-adsorption with IgG. An increase in surface hydrophobicity blunted this effect. The possible role of the curvature of the nanoparticles for the orientation of adsorbed IgG molecules, and how this can affect the subsequent activation of the IC, are discussed. The present findings are important for further understanding of how surface nanotopography affects complex protein

  3. Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE)

    DEFF Research Database (Denmark)

    Marquart, H V; Svendsen, A; Rasmussen, J M

    1995-01-01

    receptors and regulatory proteins on B cells from SLE patients, as well as the deposition of C3 fragments occurring in vivo or after in vitro AP activation. We have confirmed, for a proportion of the patients studied, reduced expression of CR1 and CR2 on B cells, and shown a consistency between low CR2...... activation by B cells in homologous serum. Finally, we demonstrated an inverse relationship between SLE disease activity index (SLEDAI) and the expression of complement receptor 2 (CR2) on SLE B cells. Thus, determination of CR2 on B cells may emerge as an additional laboratory tool in the assessment of SLE...

  4. The Role of Properdin in Zymosan- and Escherichia coli-Induced Complement Activation

    DEFF Research Database (Denmark)

    Harboe, Morten; Garred, Peter; Lindstad, Julie K

    2012-01-01

    Properdin is well known as an enhancer of the alternative complement amplification loop when C3 is activated, whereas its role as a recognition molecule of exogenous pathogen-associated molecular patterns and initiator of complement activation is less understood. We therefore studied the role...... of properdin in activation of complement in normal human serum by zymosan and various Escherichia coli strains. In ELISA, microtiter plates coated with zymosan induced efficient complement activation with deposition of C4b and terminal complement complex on the solid phase. Virtually no deposition of C4b...... or terminal complement complex was observed with mannose-binding lectin (MBL)-deficient serum. Reconstitution with purified MBL showed distinct activation in both readouts. In ELISA, normal human serum-induced deposition of properdin by zymosan was abolished by the C3-inhibiting peptide compstatin. Flow...

  5. Increased activity of the mannan-binding lectin complement activation pathway in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Ytting, H; Jensenius, J C; Christensen, Ib Jarle

    2004-01-01

    BACKGROUND: Postoperative bacterial infectious complications are frequent in patients with colorectal cancer (CRC), with subsequent increased recurrence rates and poor prognosis. Deficiency of the mannan-binding lectin (MBL) complement activation pathway may cause increased risk of infection...... in the colon or rectum, and disease stages according to Dukes' classification. No statistical difference (P=0.20) in frequency of MBL deficiency was found between the patients (20%) and the donors (27%). CONCLUSIONS: Overall, the MBL complement activation pathway is significantly increased in patients...

  6. Learning sculpts the spontaneous activity of the resting human brain

    OpenAIRE

    Lewis, Christopher M.; Baldassarre, Antonello; Committeri, Giorgia; Romani, Gian Luca; Corbetta, Maurizio

    2009-01-01

    The brain is not a passive sensory-motor analyzer driven by environmental stimuli, but actively maintains ongoing representations that may be involved in the coding of expected sensory stimuli, prospective motor responses, and prior experience. Spontaneous cortical activity has been proposed to play an important part in maintaining these ongoing, internal representations, although its functional role is not well understood. One spontaneous signal being intensely investigated in the human brai...

  7. Complement is activated by IgG hexamers assembled at the cell surface

    NARCIS (Netherlands)

    Diebolder, Christoph A.|info:eu-repo/dai/nl/325786771; Beurskens, Frank J.; De Jong, Rob N.; Koning, Roman I.; Strumane, Kristin; Lindorfer, Margaret A.; Voorhorst, Marleen; Ugurlar, Deniz; Rosati, Sara; Heck, Albert J. R.|info:eu-repo/dai/nl/105189332; Van De Winkel, Jan G. J.; Wilson, Ian A.; Koster, Abraham J.; Taylor, Ronald P.; Saphire, Erica Ollmann; Burton, Dennis R.; Schuurman, Janine; Gros, Piet|info:eu-repo/dai/nl/075243016; Parren, Paul W. H. I.

    2014-01-01

    Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent

  8. Targeting complement activation in brain-dead donors improves renal function after transplantation

    NARCIS (Netherlands)

    Damman, Jeffrey; Hoeger, Simone; Boneschansker, Leo; Theruvath, Ashok; Waldherr, Ruediger; Leuvenink, Henri G.; Ploeg, Rutger J.; Yard, Benito A.; Seelen, Marc A.

    Kidneys recovered from brain-dead donors have inferior outcomes after transplantation compared to kidneys from living donors. Since complement activation plays an important role in renal transplant related injury, targeting complement activation in brain-dead donors might improve renal function

  9. Membrane complement regulatory protein reduces the damage of transplanting autologous bone marrow mesenchymal stem cells by suppressing the activation of complement.

    Science.gov (United States)

    Xiao, Kai; Fang, Zhenhua; Gao, Xinfeng; Zhao, Jingjing; Huang, Ruokun; Xie, Ming

    2017-10-01

    There are few studies on the interaction of transplanting autologous bone marrow mesenchymal stem cells (BMSCs) and complement. In order to further explore the effect of complement on BMSCs, BMSCs were obtained from bone marrow of 20 cases clinical patients, and then experimented in vitro. The cytotoxicity of complement on the mesenchymal stem cells in autologous human serum (AHS) was measured by Europium cytotoxicity assay. The complement membrane attack complex (MAC) deposited on the membrane surface was detected by flow cytometry. Finally, the cytotoxicity on BMSCs was measured after mCRPs overexpression or knockdown. We found that more than 90% of cells derived from bone marrow were identified to be mesenchymal stem cells through detection of cell membrane surface markers by flow cytometry. BMSCs harvested from the 20 patients all had cytotoxicity after incubated with AHS, and the cytotoxicity was significant higher than that incubated with complement inactivated autologous human serum (iAHS). Complement attack complex (MAC) could be detected on the BMSCs incubated with AHS, which implied the complement activation. We also found that mCRPs CD55 and CD59 overexpressions can resist the cytotoxicity induced by complement activation, while mCRPs CD55 and CD59 knockdown can enhance the cytotoxicity. Thus, the results indicated that mCRPs could effectively protect BMSCs from attacking by complement by suppressing the activation of complement. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Electroluminescent TCC, C3dg and fB/Bb epitope assays for profiling complement cascade activation in vitro using an activated complement serum calibration standard.

    Science.gov (United States)

    van Vuuren, B Jansen; Bergseth, G; Mollnes, T E; Shaw, A M

    2014-01-15

    Electroluminescent assays for epitopes on the complement components C3dg, terminal complement complex (TCC) and factor B/Bb (fB/Bb) have been developed with capture and detection antibodies to produce detection limits C3dg=91±9ng/mL, TCC=3±0.1ng/mL and fB=55.7±0.1ng/mL. The assay performance was assessed against a series of zymosan and heat aggregated IgG (HAIgG) in vitro activations of complement using a calibrated activated complement serum (ACS) as calibration standard. The ACS standard was stable within 20% accuracy over a 6-month period with freeze-thaw cycles as required. Differential activation of the complement cascade was observed for TCC showing a pseudo-first order formation half-life of 3.5h after activation with zymosan. The C3dg activation fragment indicates a 10% total activation for both activation agents. The kinetic-epitope analysis for fB indicates that the capture epitope is on the fB/Bb protein fragment which can then become covered by the formation of C3bBb or C3bBbP complexes during the time course of the cascade. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Complement activation in Ghanaian children with severe Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Helegbe, Gideon K; Goka, Bamenla Q; Kurtzhals, Jørgen

    2007-01-01

    BACKGROUND: Severe anaemia (SA), intravascular haemolysis (IVH) and respiratory distress (RD) are severe forms of Plasmodium falciparum malaria, with RD reported to be of prognostic importance in African children with malarial anaemia. Complement factors have been implicated in the mechanism......55)] in children with discrete clinical forms of P. falciparum malaria. The relationship between the findings and clinical parameters including coma, haemoglobin (Hb) levels and RD were investigated. RESULTS: Of the 484 samples tested, 131(27%) were positive in DCT, out of which 115/131 (87.8%) were...... malaria, possibly through induction of erythrophagocytosis and haemolysis. In contrast to other studies, this study did not find association between levels of the complement...

  12. New perspectives on mannan-binding lectin-mediated complement activation

    DEFF Research Database (Denmark)

    Degn, Søren Egedal; Thiel, Steffen; Jensenius, Jens Christian

    2007-01-01

    The complement system is an important part of the innate immune system, mediating several major effector functions and modulating adaptive immune responses. Three complement activation pathways exist: the classical pathway (CP), the alternative pathway (AP), and the lectin pathway (LP). The LP...... picture of the complement system is more that of a small "scale-free" network where C3 acts as the main hub, than that of three linear pathways converging in a common terminal pathway....

  13. Direct evidence of complement activation in HELLP syndrome: a link to atypical hemolytic uremic syndrome

    OpenAIRE

    Vaught, Arthur J.; Gavriilaki, Eleni; Hueppchen, Nancy; Blakemore, Karin; Yuan, Xuan; Seifert, Sara M.; York, Sarah; Brodsky, Robert A.

    2016-01-01

    HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) is a severe variant of preeclampsia whose pathogenesis remains unclear. Recent evidence and clinical similarities suggest a link to atypical hemolytic uremic syndrome (aHUS), a disease of excessive activation of the alternative complement pathway effectively treated with a complement inhibitor, eculizumab. Therefore, we utilized a functional complement assay, the modified Ham test, to test sera of women with ...

  14. Solution Structures of Complement C2 and its C4 Complexes Propose Pathway Specific Mechanisms for Control and Activation of the Complement Proconvertases

    DEFF Research Database (Denmark)

    Mortensen, Sofia; Jensen, Jan Kristian; Andersen, Gregers Rom

    2016-01-01

    The lectin (LP) and classical (CP) pathways are two of the three main activation cascades of the complement system. These pathways start with recognition of different pathogen- or danger-associated molecular patterns and include identical steps of proteolytic activation of complement component C4...

  15. Activity and activation of the complement system in patients being operated on for cancer of the colon

    DEFF Research Database (Denmark)

    Baatrup, G; Qvist, N; Junker, A

    1994-01-01

    OBJECTIVE: To find out if there was any local activation of complement in the vicinity of a colonic cancer, and any fluctuation in the function of the complement system during operation. DESIGN: Prospective study. SETTING: One university and two district hospitals in Denmark. SUBJECTS: 29 selected...... patients undergoing emergency and elective operations for colonic cancer. INTERVENTIONS: Measurements of systemic and local complement fixation capacity and complement activation in samples of serum or plasma taken before, during, and after operation. MAIN OUTCOME MEASURES: Changes in complement fixation...

  16. Complement activation by cholesterol crystals triggers a subsequent cytokine response

    DEFF Research Database (Denmark)

    Niyonzima, Nathalie; Halvorsen, Bente; Sporsheim, Bjørnar

    2017-01-01

    may under certain circumstances drive processes leading to adverse inflammation. One example is cholesterol crystals (CC) that accumulate in the vessel wall during early phases of atherogenesis and represent an important endogenous danger signal promoting inflammation. CC is recognized by the lectin...... of inflammation processes before downstream release of cytokines including IL-1β. Another therapeutic candidate can be broad-acting 2-hydroxypropyl-β-cyclodextrin, a compound that targets several mechanisms such as cholesterol efflux, complement gene expression, and the NLRP3 pathway. In summary, emerging...

  17. The Emerging Role of Complement Lectin Pathway in Trypanosomatids: Molecular Bases in Activation, Genetic Deficiencies, Susceptibility to Infection, and Complement System-Based Therapeutics

    Directory of Open Access Journals (Sweden)

    Ingrid Evans-Osses

    2013-01-01

    Full Text Available The innate immune system is evolutionary and ancient and is the pivotal line of the host defense system to protect against invading pathogens and abnormal self-derived components. Cellular and molecular components are involved in recognition and effector mechanisms for a successful innate immune response. The complement lectin pathway (CLP was discovered in 1990. These new components at the complement world are very efficient. Mannan-binding lectin (MBL and ficolin not only recognize many molecular patterns of pathogens rapidly to activate complement but also display several strategies to evade innate immunity. Many studies have shown a relation between the deficit of complement factors and susceptibility to infection. The recently discovered CLP was shown to be important in host defense against protozoan microbes. Although the recognition of pathogen-associated molecular patterns by MBL and Ficolins reveal efficient complement activations, an increase in deficiency of complement factors and diversity of parasite strategies of immune evasion demonstrate the unsuccessful effort to control the infection. In the present paper, we will discuss basic aspects of complement activation, the structure of the lectin pathway components, genetic deficiency of complement factors, and new therapeutic opportunities to target the complement system to control infection.

  18. Rivaroxaban limits complement activation compared with warfarin in antiphospholipid syndrome patients with venous thromboembolism.

    Science.gov (United States)

    Arachchillage, D R J; Mackie, I J; Efthymiou, M; Chitolie, A; Hunt, B J; Isenberg, D A; Khamashta, M; Machin, S J; Cohen, H

    2016-11-01

    Essentials Complement activation has a pathogenic role in thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Complement activation markers were elevated in anticoagulated thrombotic APS patients. Complement activation decreased in APS patients switching from warfarin to rivaroxaban. Background Complement activation may play a major role in the pathogenesis of thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Aims To establish whether rivaroxaban, a direct factor Xa inhibitor, limits complement activation compared with warfarin in APS patients with previous venous thromboembolism (VTE). Methods A total of 111 APS patients with previous VTE, on warfarin target INR 2.5, had blood samples taken at baseline and at day 42 after randomization in the RAPS (Rivaroxaban in Antiphospholipid Syndrome) trial. Fifty-six patients remained on warfarin and 55 switched to rivaroxaban. Fifty-five normal controls (NC) were also studied. Markers of complement activation (C3a, C5a, terminal complement complex [SC5b-9] and Bb fragment) were assessed. Results APS patients had significantly higher complement activation markers compared with NC at both time-points irrespective of the anticoagulant. There were no differences between the two patient groups at baseline, or patients remaining on warfarin at day 42. In 55 patients randomized to rivaroxaban, C3a, C5a and SC5b-9 were lower at day 42 (median (ng mL -1 ) [confidence interval] 64 [29-125] vs. 83 [35-147], 9 [2-15] vs. 12 [4-18] and 171 [56-245] vs. 201 [66-350], respectively) but levels of Bb fragment were unchanged. There were no correlations between rivaroxaban levels and complement activation markers. Conclusions APS patients with previous VTE on warfarin exhibit increased complement activation, which is likely to occur via the classical pathway and is decreased by rivaroxaban administration

  19. Voluntary breath holding affects spontaneous brain activity measured by magnetoencephalography

    NARCIS (Netherlands)

    Schellart, N. A.; Reits, D.

    1999-01-01

    Spontaneous brain activity was measured by multichannel magnetoencephalography (MEG) during voluntary breath holds. Significant changes in the activity are limited to the alpha rhythm: 0.25 Hz frequency increase and narrowing of the peak. The area of alpha activity shifts slightly toward (fronto-)

  20. Spontaneous Electrical Activity in the Nervous System and its ...

    African Journals Online (AJOL)

    The present study was carried out to examine the effects of biogenic amines on the spontaneous electrical activity of the nervous system in the silkworm Bombyx mori. The activity recorded from different segments of the ventral nerve cord differed in the frequency and number of spike categories firing. The activity was highest ...

  1. Activation of the classical pathway of complement by tobacco glycoprotein (TGP).

    Science.gov (United States)

    Koethe, S M; Nelson, K E; Becker, C G

    1995-07-15

    Tobacco glycoprotein (TGP), a polyphenol-rich glycoprotein isolated from tobacco leaves, activates the classical complement pathway through a mechanism that appears to involve direct interaction with C1q. A binding site on C1q for TGP can be localized by competitive inhibition with DNA to a region located in the junction between the collagen-like and globular regions of the molecule. A protein with activity similar to TGP has also been isolated from cigarette smoke condensate (TGP-S); it shares a binding site on C1q with TGP and has similar functional activity, with the exception that complement activation does not proceed to formation of a C3 cleaving enzyme. The ability of TGP and TGP-S to activate complement can be partially duplicated using polyphenols associated with tobacco leaf and smoke, i.e., chlorogenic acid and rutin. These polyphenols also compete with TGP for a binding site on immobilized C1q, suggesting that the polyphenol portion of TGP is critical for activation of complement. These results provide an additional mechanism for complement activation by cigarette products that, in vivo, could result in a localized complement depletion, generation of biologically active complement cleavage products, and initiation of an inflammatory response.

  2. Classical complement pathway activation in the kidneys of women with preeclampsia

    NARCIS (Netherlands)

    Penning, Marlies; Chua, Jamie S.; Van Kooten, Cees; Zandbergen, Malu; Buurma, Aletta; Schutte, Joke; Bruijn, Jan Anthonie; Khankin, Eliyahu V.; Bloemenkamp, Kitty; Karumanchi, S. Ananth; Baelde, Hans

    2015-01-01

    A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Because the kidney is highly susceptible to complement activation, we hypothesized that preeclampsia is associated with

  3. Complement activation by carbon nanotubes and its influence on the phagocytosis and cytokine response macrophages

    NARCIS (Netherlands)

    Pondman, K.M.; Sobik, M.T.; Nayak, A.; Tsolaki, A.G.; Jäkel, A.; Flahaut, E.; Hampel, S.; ten Haken, Bernard; Sim, R.B.; Kishore, U.D.

    2014-01-01

    Carbon nanotubes (CNTs) have promised a range of applications in biomedicine. Although influenced by the dispersants used, CNTs are recognized by the innate immune system, predominantly by the classical pathway of the complement system. Here, we confirm that complement activation by the CNT used

  4. Mesoscale Architecture Shapes Initiation and Richness of Spontaneous Network Activity.

    Science.gov (United States)

    Okujeni, Samora; Kandler, Steffen; Egert, Ulrich

    2017-04-05

    Spontaneous activity in the absence of external input, including propagating waves of activity, is a robust feature of neuronal networks in vivo and in vitro The neurophysiological and anatomical requirements for initiation and persistence of such activity, however, are poorly understood, as is their role in the function of neuronal networks. Computational network studies indicate that clustered connectivity may foster the generation, maintenance, and richness of spontaneous activity. Since this mesoscale architecture cannot be systematically modified in intact tissue, testing these predictions is impracticable in vivo Here, we investigate how the mesoscale structure shapes spontaneous activity in generic networks of rat cortical neurons in vitro In these networks, neurons spontaneously arrange into local clusters with high neurite density and form fasciculating long-range axons. We modified this structure by modulation of protein kinase C, an enzyme regulating neurite growth and cell migration. Inhibition of protein kinase C reduced neuronal aggregation and fasciculation of axons, i.e., promoted uniform architecture. Conversely, activation of protein kinase C promoted aggregation of neurons into clusters, local connectivity, and bundling of long-range axons. Supporting predictions from theory, clustered networks were more spontaneously active and generated diverse activity patterns. Neurons within clusters received stronger synaptic inputs and displayed increased membrane potential fluctuations. Intensified clustering promoted the initiation of synchronous bursting events but entailed incomplete network recruitment. Moderately clustered networks appear optimal for initiation and propagation of diverse patterns of activity. Our findings support a crucial role of the mesoscale architectures in the regulation of spontaneous activity dynamics. SIGNIFICANCE STATEMENT Computational studies predict richer and persisting spatiotemporal patterns of spontaneous activity in

  5. Spatial diversity of spontaneous activity in the cortex

    Directory of Open Access Journals (Sweden)

    Andrew Yong-Yi Tan

    2015-09-01

    Full Text Available The neocortex is a layered sheet across which a basic organization is thought to widely apply. The variety of spontaneous activity patterns is similar throughout the cortex, consistent with the notion of a basic cortical organization. However, the basic organization is only an outline which needs adjustments and additions to account for the structural and functional diversity across cortical layers and areas. Such diversity suggests that spontaneous activity is spatially diverse in any particular behavioral state. Accordingly, this review summarizes the laminar and areal diversity in cortical activity during fixation and slow oscillations, and the effects of attention, anesthesia and plasticity on the cortical distribution of spontaneous activity. Among questions that remain open, characterizing the spatial diversity in spontaneous membrane potential may help elucidate how differences in circuitry among cortical regions supports their varied functions. More work is also needed to understand whether cortical spontaneous activity not only reflects cortical circuitry, but also contributes to determining the outcome of plasticity, so that it is itself a factor shaping the functional diversity of the cortex.

  6. The Stability of Complement-Mediated Bactericidal Activity in Human Serum against Salmonella

    Science.gov (United States)

    O’Shaughnessy, Colette M.; Cunningham, Adam F.; MacLennan, Calman A.

    2012-01-01

    The complement cascade includes heat-labile proteins and care is required when handling serum in order to preserve its functional integrity. We have previously used a whole human serum bactericidal assay to show that antibody and an intact complement system are required in blood for killing of invasive isolates of Salmonella. The aim of the present study was to evaluate the conditions under which human serum can be stored and manipulated while maintaining complement integrity. Serum bactericidal activity against Salmonella was maintained for a minimum of 35 days when stored at 4°C, eight days at 22°C and 54 hours at 37°C. Up to three freeze-thaw cycles had no effect on the persistence of bactericidal activity and hemolytic complement assays confirmed no effect on complement function. Delay in the separation of serum for up to four days from clotted blood stored at 22°C did not affect bactericidal activity. Dilution of serum resulted in an increased rate of loss of bactericidal activity and so serum should be stored undiluted. These findings indicate that the current guidelines concerning manipulation and storage of human serum to preserve complement integrity and function leave a large margin for safety with regards to bactericidal activity against Salmonella. The study provides a scheme for determining the requirements for serum handling in relation to functional activity of complement in other systems. PMID:23145102

  7. Strong complement activation after acute ischemic stroke is associated with unfavorable outcomes

    DEFF Research Database (Denmark)

    Széplaki, Gábor; Szegedi, Róbert; Hirschberg, Kristóf

    2009-01-01

    OBJECTIVE: According to data from animal models, complement activation plays a major role in the brain injury after acute ischemic stroke. Scarce findings are, however, available on the detection of complement activation products in stroke patients. METHODS: We have measured plasma levels...... of the five complement activation products (C1rC1sC1inh, C4d, C3a, C5a and SC5b-9) in samples of 26 patients with ischemic stroke upon admission. Twenty-six patients with severe carotid atherosclerosis served as patient controls. RESULTS: Levels of two activation products (SC5b-9 and C4d)) were significantly...... elevated in the plasma of stroke patients, SC5b-9 levels, exhibited significant positive correlation with the clinical severity of stroke, the severity of neurological deficit, as well as with the level of functional disability. CONCLUSION: These findings suggest that complement activation plays an active...

  8. Increased activity of the mannan-binding lectin complement activation pathway in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Ytting, H; Jensenius, Jens Christian; Christensen, I J

    2004-01-01

    BACKGROUND: Postoperative bacterial infectious complications are frequent in patients with colorectal cancer (CRC), with subsequent increased recurrence rates and poor prognosis. Deficiency of the mannan-binding lectin (MBL) complement activation pathway may cause increased risk of infection......: Serum MBL concentrations and MBL/MASP activity were determined using immunofluorometric assays. The levels are presented as the median, inter-quartile range and range. RESULTS: Serum MBL levels were significantly (P cancer (1384 (400-2188) ng/mL) (median...... in the colon or rectum, and disease stages according to Dukes' classification. No statistical difference (P=0.20) in frequency of MBL deficiency was found between the patients (20%) and the donors (27%). CONCLUSIONS: Overall, the MBL complement activation pathway is significantly increased in patients...

  9. Structural insight into the recognition of complement C3 activation products by integrin receptors

    DEFF Research Database (Denmark)

    Bajic, Goran

    2015-01-01

    The complement system is the major effector of innate immunity. It is the body’s first defense against pathogens recognizing and tagging them for subsequent elimination. Complement is a germline-encoded system of more than 50 circulating and membrane-bound proteins that recognize molecular patterns...... on one side and to host cell receptors on the other. This elicits inflammatory responses directing immune cells to the place of infection, tagging of pathogens for phagocytosis, their subsequent lysis and stimulation of adaptive immunity. The C3 molecule is cleaved into a large fragment C3b and a small...... fragment C3a called anaphylatoxin. Complement leads to opsonization as the proteolytic fragment C3b becomes covalently linked to the activator surface through a reactive thioester. Self-surfaces are protected by complement regulators, whereas complement activation vividly amplifies on pathogens...

  10. Direct evidence of complement activation in HELLP syndrome: A link to atypical hemolytic uremic syndrome.

    Science.gov (United States)

    Vaught, Arthur J; Gavriilaki, Eleni; Hueppchen, Nancy; Blakemore, Karin; Yuan, Xuan; Seifert, Sara M; York, Sarah; Brodsky, Robert A

    2016-05-01

    HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) is a severe variant of pre-eclampsia whose pathogenesis remains unclear. Recent evidence and clinical similarities suggest a link to atypical hemolytic uremic syndrome, a disease of excessive activation of the alternative complement pathway effectively treated with a complement inhibitor, eculizumab. Therefore, we used a functional complement assay, the modified Ham test, to analyze sera of women with classic or atypical HELLP syndrome, pre-eclampsia with severe features, normal pregnancies, and healthy nonpregnant women. Sera were also evaluated using levels of the terminal product of complement activation (C5b-9). We tested the in vitro ability of eculizumab to inhibit complement activation in HELLP serum. Increased complement activation was observed in participants with classic or atypical HELLP compared with those with normal pregnancies and nonpregnant controls. Mixing HELLP serum with eculizumab-containing serum resulted in a significant decrease in cell killing compared with HELLP serum alone. We found that HELLP syndrome is associated with increased complement activation as assessed with the modified Ham test. This assay may aid in the diagnosis of HELLP syndrome and could confirm that its pathophysiology is related to that of atypical hemolytic uremic syndrome. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  11. Pseudomonas aeruginosa alkaline protease blocks complement activation via the classical and lectin pathways.

    Science.gov (United States)

    Laarman, Alexander J; Bardoel, Bart W; Ruyken, Maartje; Fernie, Job; Milder, Fin J; van Strijp, Jos A G; Rooijakkers, Suzan H M

    2012-01-01

    The complement system rapidly detects and kills Gram-negative bacteria and supports bacterial killing by phagocytes. However, bacterial pathogens exploit several strategies to evade detection by the complement system. The alkaline protease (AprA) of Pseudomonas aeruginosa has been associated with bacterial virulence and is known to interfere with complement-mediated lysis of erythrocytes, but its exact role in bacterial complement escape is unknown. In this study, we analyzed how AprA interferes with complement activation and whether it could block complement-dependent neutrophil functions. We found that AprA potently blocked phagocytosis and killing of Pseudomonas by human neutrophils. Furthermore, AprA inhibited opsonization of bacteria with C3b and the formation of the chemotactic agent C5a. AprA specifically blocked C3b deposition via the classical and lectin pathways, whereas the alternative pathway was not affected. Serum degradation assays revealed that AprA degrades both human C1s and C2. However, repletion assays demonstrated that the mechanism of action for complement inhibition is cleavage of C2. In summary, we showed that P. aeruginosa AprA interferes with classical and lectin pathway-mediated complement activation via cleavage of C2.

  12. Uncovering intrinsic modular organization of spontaneous brain activity in humans.

    Directory of Open Access Journals (Sweden)

    Yong He

    Full Text Available The characterization of topological architecture of complex brain networks is one of the most challenging issues in neuroscience. Slow (<0.1 Hz, spontaneous fluctuations of the blood oxygen level dependent (BOLD signal in functional magnetic resonance imaging are thought to be potentially important for the reflection of spontaneous neuronal activity. Many studies have shown that these fluctuations are highly coherent within anatomically or functionally linked areas of the brain. However, the underlying topological mechanisms responsible for these coherent intrinsic or spontaneous fluctuations are still poorly understood. Here, we apply modern network analysis techniques to investigate how spontaneous neuronal activities in the human brain derived from the resting-state BOLD signals are topologically organized at both the temporal and spatial scales. We first show that the spontaneous brain functional networks have an intrinsically cohesive modular structure in which the connections between regions are much denser within modules than between them. These identified modules are found to be closely associated with several well known functionally interconnected subsystems such as the somatosensory/motor, auditory, attention, visual, subcortical, and the "default" system. Specifically, we demonstrate that the module-specific topological features can not be captured by means of computing the corresponding global network parameters, suggesting a unique organization within each module. Finally, we identify several pivotal network connectors and paths (predominantly associated with the association and limbic/paralimbic cortex regions that are vital for the global coordination of information flow over the whole network, and we find that their lesions (deletions critically affect the stability and robustness of the brain functional system. Together, our results demonstrate the highly organized modular architecture and associated topological properties in

  13. Complement activation cascade triggered by PEG-PL engineered nanomedicines and carbon nanotubes: The challenges ahead

    DEFF Research Database (Denmark)

    Moghimi, S.M.; Andersen, Alina Joukainen; Hashemi, S.H.

    2010-01-01

    reactions to certain PEG-PL engineered nanomedicines in both experimental animals and man. These reactions are classified as pseudoallergy and may be associated with cardiopulmonary disturbance and other related symptoms of anaphylaxis. Recent studies suggest that complement activation may be a contributing......, but not a rate limiting factor, in eliciting hypersensitivity reactions to such nanomedicines in sensitive individuals. This is rather surprising since PEGylated structures are generally assumed to suppress protein adsorption and blood opsonization events including complement. Here, we examine the molecular...... basis of complement activation by PEG-PL engineered nanomedicines and carbon nanotubes and discuss the challenges ahead....

  14. Cyclodextrin Reduces Cholesterol Crystal-Induced Inflammation by Modulating Complement Activation

    DEFF Research Database (Denmark)

    Bakke, Siril S; Aune, Marie H; Niyonzima, Nathalie

    2017-01-01

    Cholesterol crystals (CC) are abundant in atherosclerotic plaques and promote inflammatory responses via the complement system and inflammasome activation. Cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (BCD) is a compound that solubilizes lipophilic substances. Recently we have shown...

  15. Structural insight into the recognition of complement C3 activation products by integrin receptors

    DEFF Research Database (Denmark)

    Bajic, Goran

    2015-01-01

    The complement system is the major effector of innate immunity. It is the body’s first defense against pathogens recognizing and tagging them for subsequent elimination. Complement is a germline-encoded system of more than 50 circulating and membrane-bound proteins that recognize molecular patterns...... associated with microbes and apoptotic or necrotic cells. Complement not only protects against pathogens but also maintains body homeostasis. Activation of complement leads to cleavage of the complement proteins C4, C3 and C5, and their fragments have effector functions through binding to pathogen surfaces...... on one side and to host cell receptors on the other. This elicits inflammatory responses directing immune cells to the place of infection, tagging of pathogens for phagocytosis, their subsequent lysis and stimulation of adaptive immunity. The C3 molecule is cleaved into a large fragment C3b and a small...

  16. Behavioral Modulation by Spontaneous Activity of Dopamine Neurons

    Directory of Open Access Journals (Sweden)

    Toshiharu Ichinose

    2017-12-01

    Full Text Available Dopamine modulates a variety of animal behaviors that range from sleep and learning to courtship and aggression. Besides its well-known phasic firing to natural reward, a substantial number of dopamine neurons (DANs are known to exhibit ongoing intrinsic activity in the absence of an external stimulus. While accumulating evidence points at functional implications for these intrinsic “spontaneous activities” of DANs in cognitive processes, a causal link to behavior and its underlying mechanisms has yet to be elucidated. Recent physiological studies in the model organism Drosophila melanogaster have uncovered that DANs in the fly brain are also spontaneously active, and that this activity reflects the behavioral/internal states of the animal. Strikingly, genetic manipulation of basal DAN activity resulted in behavioral alterations in the fly, providing critical evidence that links spontaneous DAN activity to behavioral states. Furthermore, circuit-level analyses have started to reveal cellular and molecular mechanisms that mediate or regulate spontaneous DAN activity. Through reviewing recent findings in different animals with the major focus on flies, we will discuss potential roles of this physiological phenomenon in directing animal behaviors.

  17. Activation capacity of the alternative and classic complement pathways in patients operated on for colorectal cancer

    DEFF Research Database (Denmark)

    Zimmermann-Nielsen, Erik; Iversen, Lene H; Svehag, Sven-Erik

    2002-01-01

    PURPOSE: Tumor cells may suppress activation of the host's complement system, and the functional state of the complement system may be a prognostic marker of outcome in patients with malignancies. Serial plasma samples from patients undergoing intended curative surgery for colorectal cancer were...... analyzed for complement factor C3 activation capacity. METHODS: Samples were collected from 91 patients with colorectal cancer and 13 with benign colorectal diseases before surgery and 1, 2, and 7 days after surgery, between 8 and 13 days after surgery, and 3, 6, 12, 18, 24, 36, 48, and 60 months after...... surgery. The samples were analyzed with an enzyme-linked immunosorbent assay that measured C3 activation capacity by the alternative and classic complement pathways. Cancer patients were compared according to Dukes stage, type of surgery performed, transfusion of blood, development of infection, venous...

  18. A novel method for direct measurement of complement convertases activity in human serum.

    Science.gov (United States)

    Blom, A M; Volokhina, E B; Fransson, V; Strömberg, P; Berghard, L; Viktorelius, M; Mollnes, T E; López-Trascasa, M; van den Heuvel, L P; Goodship, T H; Marchbank, K J; Okroj, M

    2014-10-01

    Complement convertases are enzymatic complexes that play a central role in sustaining and amplification of the complement cascade. Impairment of complement function leads directly or indirectly to pathological conditions, including higher infection rate, kidney diseases, autoimmune- or neurodegenerative diseases and ischaemia-reperfusion injury. An assay for direct measurement of activity of the convertases in patient sera is not available. Existing assays testing convertase function are based on purified complement components and, thus, convertase formation occurs under non-physiological conditions. We designed a new assay, in which C5 blocking compounds enabled separation of the complement cascade into two phases: the first ending at the stage of C5 convertases and the second ending with membrane attack complex formation. The use of rabbit erythrocytes or antibody-sensitized sheep erythrocytes as the platforms for convertase formation enabled easy readout based on measurement of haemolysis. Thus, properties of patient sera could be studied directly regarding convertase activity and membrane attack complex formation. Another advantage of this assay was the possibility to screen for host factors such as C3 nephritic factor and other anti-complement autoantibodies, or gain-of-function mutations, which prolong the half-life of complement convertases. Herein, we present proof of concept, detailed description and validation of this novel assay. © 2014 British Society for Immunology.

  19. Patterns of Spontaneous Magnetoencephalographic Activity in Schizophrenic Patients

    OpenAIRE

    Siekmeier, Peter J.; Stufflebeam, Steven M.

    2010-01-01

    Magnetoencephalography (MEG) non-invasively measures the magnetic fields produced by the brain. Pertinent research articles from 1993 to 2009 that measured spontaneous, whole-head MEG activity in schizophrenic patients were reviewed. Data on localization of oscillatory activity and correlation of these findings with psychotic symptoms are summarized. While the variety of measures used by different research groups makes a quantitative meta-analysis difficult, it appears that MEG activity in pa...

  20. Modulating spontaneous brain activity using repetitive transcranial magnetic stimulation

    NARCIS (Netherlands)

    van der Werf, Y.D.; Sanz-Arigita, E.J.; Menning, S.; van den Heuvel, O.A.

    2010-01-01

    Background: When no specific stimulus or task is presented, spontaneous fluctuations in brain activity occur. Brain regions showing such coherent fluctuations are thought to form organized networks known as 'resting-state' networks, a main representation of which is the default mode network.

  1. Presynaptic Spontaneous Activity Enhances the Accuracy of Latency Coding

    Czech Academy of Sciences Publication Activity Database

    Leváková, Marie; Tamborrino, M.; Košťál, Lubomír; Lánský, Petr

    2016-01-01

    Roč. 28, č. 10 (2016), s. 2162-2180 ISSN 0899-7667 R&D Projects: GA MŠk 7AMB15AT010; GA ČR(CZ) GA15-08066S Institutional support: RVO:67985823 Keywords : neural coding * first-spike latency * spontaneous activity Subject RIV: FH - Neurology Impact factor: 1.938, year: 2016

  2. Classical Complement Pathway Activation in the Kidneys of Women With Preeclampsia.

    Science.gov (United States)

    Penning, Marlies; Chua, Jamie S; van Kooten, Cees; Zandbergen, Malu; Buurma, Aletta; Schutte, Joke; Bruijn, Jan Anthonie; Khankin, Eliyahu V; Bloemenkamp, Kitty; Karumanchi, S Ananth; Baelde, Hans

    2015-07-01

    A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Because the kidney is highly susceptible to complement activation, we hypothesized that preeclampsia is associated with renal complement activation. We performed a nationwide search for renal autopsy material in the Netherlands using a computerized database (PALGA). Renal tissue was obtained from 11 women with preeclampsia, 25 pregnant controls, and 14 nonpregnant controls with hypertension. The samples were immunostained for C4d, C1q, mannose-binding lectin, properdin, C3d, C5b-9, IgA, IgG, and IgM. Preeclampsia was significantly associated with renal C4d-a stable marker of complement activation-and the classical pathway marker C1q. In addition, the prevalence of IgM was significantly higher in the kidneys of the preeclamptic women. No other complement markers studied differed between the groups. Our findings in human samples were validated using a soluble fms-like tyrosine kinase 1 mouse model of preeclampsia. The kidneys in the soluble fms-like tyrosine kinase 1-injected mice had significantly more C4 deposits than the control mice. The association between preeclampsia and renal C4d, C1q, and IgM levels suggests that the classical complement pathway is involved in the renal injury in preeclampsia. Moreover, our finding that soluble fms-like tyrosine kinase 1-injected mice develop excess C4 deposits indicates that angiogenic dysregulation may play a role in complement activation within the kidney. We suggest that inhibiting complement activation may be beneficial for preventing the renal manifestations of preeclampsia. © 2015 American Heart Association, Inc.

  3. Anopheles midgut epithelium evades human complement activity by capturing factor H from the blood meal.

    Science.gov (United States)

    Khattab, Ayman; Barroso, Marta; Miettinen, Tiera; Meri, Seppo

    2015-02-01

    Hematophagous vectors strictly require ingesting blood from their hosts to complete their life cycles. Exposure of the alimentary canal of these vectors to the host immune effectors necessitates efficient counteractive measures by hematophagous vectors. The Anopheles mosquito transmitting the malaria parasite is an example of hematophagous vectors that within seconds can ingest human blood double its weight. The innate immune defense mechanisms, like the complement system, in the human blood should thereby immediately react against foreign cells in the mosquito midgut. A prerequisite for complement activation is that the target cells lack complement regulators on their surfaces. In this work, we analyzed whether human complement is active in the mosquito midgut, and how the mosquito midgut cells protect themselves against complement attack. We found that complement remained active for a considerable time and was able to kill microbes within the mosquito midgut. However, the Anopheles mosquito midgut cells were not injured. These cells were found to protect themselves by capturing factor H, the main soluble inhibitor of the alternative complement pathway. Factor H inhibited complement on the midgut cells by promoting inactivation of C3b to iC3b and preventing the activity of the alternative pathway amplification C3 convertase enzyme. An interference of the FH regulatory activity by monoclonal antibodies, carried to the midgut via blood, resulted in increased mosquito mortality and reduced fecundity. By using a ligand blotting assay, a putative mosquito midgut FH receptor could be detected. Thereby, we have identified a novel mechanism whereby mosquitoes can tolerate human blood.

  4. Anopheles midgut epithelium evades human complement activity by capturing factor H from the blood meal.

    Directory of Open Access Journals (Sweden)

    Ayman Khattab

    2015-02-01

    Full Text Available Hematophagous vectors strictly require ingesting blood from their hosts to complete their life cycles. Exposure of the alimentary canal of these vectors to the host immune effectors necessitates efficient counteractive measures by hematophagous vectors. The Anopheles mosquito transmitting the malaria parasite is an example of hematophagous vectors that within seconds can ingest human blood double its weight. The innate immune defense mechanisms, like the complement system, in the human blood should thereby immediately react against foreign cells in the mosquito midgut. A prerequisite for complement activation is that the target cells lack complement regulators on their surfaces. In this work, we analyzed whether human complement is active in the mosquito midgut, and how the mosquito midgut cells protect themselves against complement attack. We found that complement remained active for a considerable time and was able to kill microbes within the mosquito midgut. However, the Anopheles mosquito midgut cells were not injured. These cells were found to protect themselves by capturing factor H, the main soluble inhibitor of the alternative complement pathway. Factor H inhibited complement on the midgut cells by promoting inactivation of C3b to iC3b and preventing the activity of the alternative pathway amplification C3 convertase enzyme. An interference of the FH regulatory activity by monoclonal antibodies, carried to the midgut via blood, resulted in increased mosquito mortality and reduced fecundity. By using a ligand blotting assay, a putative mosquito midgut FH receptor could be detected. Thereby, we have identified a novel mechanism whereby mosquitoes can tolerate human blood.

  5. Spontaneous neutrophil activation in HTLV-1 infected patients

    Directory of Open Access Journals (Sweden)

    Jaqueline B. Guerreiro

    Full Text Available Human T cell lymphotropic Virus type-1 (HTLV-1 induces lymphocyte activation and proliferation, but little is known about the innate immune response due to HTLV-1 infection. We evaluated the percentage of neutrophils that metabolize Nitroblue tetrazolium (NBT to formazan in HTLV-1 infected subjects and the association between neutrophil activation and IFN-gamma and TNF-alpha levels. Blood was collected from 35 HTLV-1 carriers, from 8 patients with HAM/TSP (HTLV-1- associated myelopathy; 22 healthy individuals were evaluated for spontaneous and lipopolysaccharide (LPS-stimulated neutrophil activity (reduction of NBT to formazan. The production of IFN-gamma and TNF-alpha by unstimulated mononuclear cells was determined by ELISA. Spontaneous NBT levels, as well as spontaneous IFN-gamma and TNF-alpha production, were significantly higher (p<0.001 in HTLV-1 infected subjects than in healthy individuals. A trend towards a positive correlation was noted, with increasing percentage of NBT positive neutrophils and levels of IFN-gamma. The high IFN-gamma producing HTLV-1 patient group had significantly greater NBT than healthy controls, 43±24% and 17±4.8% respectively (p< 0.001, while no significant difference was observed between healthy controls and the low IFN-gamma-producing HTLV-1 patient group (30±20%. Spontaneous neutrophil activation is another marker of immune perturbation resulting from HTLV-1 infection. In vivo activation of neutrophils observed in HTLV-1 infected subjects is likely to be the same process that causes spontaneous IFN-gamma production, or it may partially result from direct IFN-gamma stimulation.

  6. Complement factor H protects mice from ischemic acute kidney injury but is not critical for controlling complement activation by glomerular IgM.

    Science.gov (United States)

    Goetz, Lindsey; Laskowski, Jennifer; Renner, Brandon; Pickering, Matthew C; Kulik, Liudmila; Klawitter, Jelena; Stites, Erik; Christians, Uwe; van der Vlag, Johan; Ravichandran, Kameswaran; Holers, V Michael; Thurman, Joshua M

    2018-02-01

    Natural IgM binds to glomerular epitopes in several progressive kidney diseases. Previous work has shown that IgM also binds within the glomerulus after ischemia/reperfusion (I/R) but does not fully activate the complement system. Factor H is a circulating complement regulatory protein, and congenital or acquired deficiency of factor H is a strong risk factor for several types of kidney disease. We hypothesized that factor H controls complement activation by IgM in the kidney after I/R, and that heterozygous factor H deficiency would permit IgM-mediated complement activation and injury at this location. We found that mice with targeted heterozygous deletion of the gene for factor H developed more severe kidney injury after I/R than wild-type controls, as expected, but that complement activation within the glomeruli remained well controlled. Furthermore, mice that are unable to generate soluble IgM were not protected from renal I/R, even in the setting of heterozygous factor H deficiency. These results demonstrate that factor H is important for limiting injury in the kidney after I/R, but it is not critical for controlling complement activation by immunoglobulin within the glomerulus in this setting. IgM binds to glomerular epitopes after I/R, but it is not a significant source of injury. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia

    NARCIS (Netherlands)

    de Beer, Friso; Lagrand, Wim; Glas, Gerie J.; Beurskens, Charlotte J. P.; van Mierlo, Gerard; Wouters, Diana; Zeerleder, Sacha; Roelofs, Joris J. T. H.; Juffermans, Nicole P.; Horn, Janneke; Schultz, Marcus J.

    2016-01-01

    Complement activation plays an important role in the pathogenesis of pneumonia. We hypothesized that inhibition of the complement system in the lungs by repeated treatment with nebulized plasma-derived human C1-esterase inhibitor reduces pulmonary complement activation and subsequently attenuates

  8. Spontaneous physical activity protects against fat mass gain

    OpenAIRE

    Teske, Jennifer A.; Billington, Charles J.; Kuskowski, Michael A.; Kotz, Catherine M.

    2011-01-01

    It is unclear whether elevated spontaneous physical activity (SPA, very low-intensity physical activity) positively influences body composition long-term. Objective We determined whether SPA and caloric intake were differentially related to the growth curve trajectories of body weight, FM and FFM between obesity resistant and Sprague-Dawley rats at specific age intervals. Design and Subjects Body composition, SPA and caloric intake were measured in selectively-bred obesity resistant and out-b...

  9. Single-Walled Carbon Nanotube Surface Control of Complement Recognition and Activation

    DEFF Research Database (Denmark)

    Andersen, Alina Joukainen; Robinson, Joshua T.; Dai, Hongjie

    2013-01-01

    circulation profiles of CNTs, activates the complement system differently, depending on the amphiphile structure. CNTs with linear poly(ethylene glycol) amphiphiles trigger the lectin pathway of the complement through both l-ficolin and mannan-binding lectin recognition. The lectin pathway activation, however......, did not trigger the amplification loop of the alternative pathway. An amphiphile with branched poly(ethylene glycol) architecture also activated the lectin pathway but only through l-ficolin recognition. Importantly, this mode of activation neither generated anaphylatoxins nor induced triggering...

  10. Complement activation, endothelial dysfunction, insulin resistance and chronic heart failure

    DEFF Research Database (Denmark)

    Bjerre, M.; Kistorp, C.; Hansen, T.K.

    2010-01-01

    CRP), endothelial activation (soluble E-selectin, sEsel)), endothelial damage/dysfunction (von Willebrand factor, vWf) and insulin resistance (IR) and prognosis in CHF remains unknown. Design. We investigated the association(s) between plasma sMAC, hsCRP, sEsel, vWf and IR (assessed by homeostatic model assessment...

  11. Complement activated granulocytes can cause autologous tissue destruction in man

    Directory of Open Access Journals (Sweden)

    E. Löhde

    1992-01-01

    Full Text Available Activation of polymorphonuclear granulocytes (PMNs by C5a is thought to be important in the pathogenesis of multiple organ failure during sepsis and after trauma. In our experiment exposure of human PMNs to autologous zymosan activated plasma (ZAP leads to a rapid increase in chemiluminescence. Heating the ZAP at 56°C for 30 min did not alter the changes, while untreated plasma induced only baseline activity. The respiratory burst could be completely abolished by decomplementation and preincubation with rabbit antihuman C5a antibodies. Observation of human omentum using electron microscopy showed intravascular aggregation of PMNs, with capillary thrombosis and diapedesis of the cells through endothelial junctions 90 s after exposure to ZAP. PMNs caused disruption of connections between the mesothelial cells. After 4 min the mesothelium was completely destroyed, and connective tissue and fat cells exposed. Native plasma and minimum essential medium did not induce any morphological changes. These data support the concept that C5a activated PMNs can cause endothelial and mesothelial damage in man. Even though a causal relationship between anaphylatoxins and organ failure cannot be proved by these experiments C5a seems to be an important mediator in the pathogenesis of changes induced by severe sepsis and trauma in man.

  12. Assembly and activation of alternative complement components on endothelial cell-anchored ultra-large von Willebrand factor links complement and hemostasis-thrombosis.

    Directory of Open Access Journals (Sweden)

    Nancy A Turner

    Full Text Available Vascular endothelial cells (ECs express and release protein components of the complement pathways, as well as secreting and anchoring ultra-large von Willebrand factor (ULVWF multimers in long string-like structures that initiate platelet adhesion during hemostasis and thrombosis. The alternative complement pathway (AP is an important non-antibody-requiring host defense system. Thrombotic microangiopathies can be associated with defective regulation of the AP (atypical hemolytic-uremic syndrome or with inadequate cleavage by ADAMTS-13 of ULVWF multimeric strings secreted by/anchored to ECs (thrombotic thrombocytopenic purpura. Our goal was to determine if EC-anchored ULVWF strings caused the assembly and activation of AP components, thereby linking two essential defense mechanisms.We quantified gene expression of these complement components in cultured human umbilical vein endothelial cells (HUVECs by real-time PCR: C3 and C5; complement factor (CF B, CFD, CFP, CFH and CFI of the AP; and C4 of the classical and lectin (but not alternative complement pathways. We used fluorescent microscopy, monospecific antibodies against complement components, fluorescent secondary antibodies, and the analysis of >150 images to quantify the attachment of HUVEC-released complement proteins to ULVWF strings secreted by, and anchored to, the HUVECs (under conditions of ADAMTS-13 inhibition. We found that HUVEC-released C4 did not attach to ULVWF strings, ruling out activation of the classical and lectin pathways by the strings. In contrast, C3, FB, FD, FP and C5, FH and FI attached to ULVWF strings in quantitative patterns consistent with assembly of the AP components into active complexes. This was verified when non-functional FB blocked the formation of AP C3 convertase complexes (C3bBb on ULVWF strings.AP components are assembled and activated on EC-secreted/anchored ULVWF multimeric strings. Our findings provide one possible molecular mechanism for clinical

  13. Complement activation in the injured central nervous system: another dual-edged sword?

    Directory of Open Access Journals (Sweden)

    Brennan Faith H

    2012-06-01

    Full Text Available Abstract The complement system, a major component of the innate immune system, is becoming increasingly recognised as a key participant in physiology and disease. The awareness that immunological mediators support various aspects of both normal central nervous system (CNS function and pathology has led to a renaissance of complement research in neuroscience. Various studies have revealed particularly novel findings on the wide-ranging involvement of complement in neural development, synapse elimination and maturation of neural networks, as well as the progression of pathology in a range of chronic neurodegenerative disorders, and more recently, neurotraumatic events, where rapid disruption of neuronal homeostasis potently triggers complement activation. The purpose of this review is to summarise recent findings on complement activation and acquired brain or spinal cord injury, i.e. ischaemic-reperfusion injury or stroke, traumatic brain injury (TBI and spinal cord injury (SCI, highlighting the potential for complement-targeted therapeutics to alleviate the devastating consequences of these neurological conditions.

  14. [In vitro effects of antiallergic eyedrops on complement activation induced by particulate matter].

    Science.gov (United States)

    Blondin, C; Cholley, B; Haeffner-Cavaillon, N; Goldschmidt, P

    2003-04-01

    Recent decades have been marked by an increasing number of patients suffering from ocular allergic-like symptoms without being associated with an increase in IgE levels. These symptoms include heaviness of the lid, foreign body sensation, burning, stinging and photophobia. Both epidemiological studies and controlled human exposure clinical studies have shown cause-effect relationships between allergic-like symptoms and environmental factors such as outdoor air pollutants or poor indoor air quality. An ocular surface subclinical inflammation is thought to be responsible for pseudoallergic, pollution-related conjunctivitis. The complement system is considered as one of the major effector mechanisms involved in initiation of the subclinical inflammation that leads to IgE-independent eye irritation. To study the capability of nine antiallergic eyedrops commonly used in the treatment of allergic conjunctivitis to inhibit complement activation induced in vitro by pollutants. Normal human serum obtained from healthy individuals was used as a source of complement. Activation of complement was assessed using the complement hemolytic 50% (CH50) assay, in the absence or the presence of antiallergic eyedrops and in the absence or the presence of various stimuli, including sand, common house dust, eye mascara, and Dactylis glomerata pollen extract. Zymosan was used as a standardized complement activator. The following eyedrops were studied: Naabak (4.9% N-acetyl aspartic acid-glutamic acid, NAAGA, sodium salt), Almide (lodoxamide 0.1%), Levophta (0.05% levocabastine), Emadine (0.05% emedastine), Tilavist (2% nedocromil), Allergodil (0.05% azelastine), Patanol (olopatadine), and Zaditen (0.025% ketotifen). Effects of preservative-free lodoxamide and ketotifen were also assessed and compared to those of the preserved formulations. A solution of 0.01% benzalkonium chloride (BAC), the most widely used preservative in topical eyedrops, was also tested. Zymosan-induced activation of

  15. Depressed activation of the lectin pathway of complement in hereditary angioedema

    DEFF Research Database (Denmark)

    Varga, L; Széplaki, G; Laki, J

    2008-01-01

    ) in three complement activation pathways. Functional activity of the CP, LP and AP were measured in the sera of 68 adult patients with hereditary angioedema (HAE) and 64 healthy controls. In addition, the level of C1q, MBL, MBL-associated serine protease-2 (MASP-2), C4-, C3- and C1INH was measured...... by standard laboratory methods. MBL-2 genotypes were determined by polymerase chain reaction. Besides the complement alterations (low CP and C1INH activity, low C4-, C1INH concentrations), which characterize HAE, the level of MASP-2 was also lower (P = 0.0001) in patients compared with controls. Depressed LP...

  16. Colostral whey concentrate supplement increases complement activity in the sera of neonatal calves.

    Science.gov (United States)

    Rokka, S; Korhonen, B H; Nousiainen, J; Marnila, P

    2001-08-01

    We evaluated the effect of a commercial bovine colostral whey on the complement-mediated immune responses of calves. Two groups of neonatal calves were fed, in addition to whole milk (WM) and pooled colostrum (PC), different amounts of a commercial immunoglobulin concentrate made from pooled colostral whey (Ig-C) for the first two feedings post natum. The control group was fed WM and PC only. Serum samples were obtained at the ages of 2, 7, 14 and 30 d. Bacteriolytic activity against complement-sensitive Escherichia coli JM103 and opsonic activity against complement-lysis-resistant E. coli IH3080 strains were studied, as well as the levels of C3 complement component and E. coli JM103 specific antibodies in the sera. Groups fed Ig-C had 2-3 times higher bacteriolytic activity than the control group of both the classic (P complement activities of serum can be increased substantially by feeding colostral whey concentrate to calves during their first days of life.

  17. Hemodialysis leukopenia. Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes.

    Science.gov (United States)

    Craddock, P R; Fehr, J; Dalmasso, A P; Brighan, K L; Jacob, H S

    1977-01-01

    Acute leukopenia occurs in all patients during the first hour of hemodialysis with cellophanemembrane equipment. This transient cytopenia specifically involves granulocytes and monocytes, cells which share plasma membrane reactivity towards activated complement components. The present studies document that complement is activated during exposure of plasma to dialyzer cellophane, and that upon reinfusion of this plasma into the venous circulation, granulocyte and monocyte entrapment in the pulmonary vasculature is induced. During early dialysis, conversion of both C3 and factor B can be demonstrated in plasma as it leaves the dialyzer. Moreover, simple incubation of human plasma with dialyzer cellophane causes conversion of C3 and factor B, accompanied by depletion of total hemolytic complement and C3 but sparing of hemolytic C1. Reinfusion of autologous, cellophane-incubated plasma into rabbits produces selective granulocytopenia and monocytopenia identical to that seen in dialyzed patients. Lungs from such animals reveal striking pulmonary vessel engorgement with granulocytes. The activated complement component(s) responsible for leukostasis has an approximate molecular weight of 7,000-20,000 daltons. Since it is generated in C2-deficient plasma and is associated with factor B conversion, it is suggested that activation of complement by dialysis is predominantly through the altermative pathway. Images PMID:856872

  18. Complement activation by the amyloid proteins A beta peptide and beta 2-microglobulin

    DEFF Research Database (Denmark)

    Nybo, Mads; Nielsen, E H; Svehag, S E

    1999-01-01

    Complement activation (CA) has been reported to play a role in the pathogenesis of Alzheimer's disease (AD). To investigate whether CA may contribute to amyloidogenesis in general, the CA potential of different amyloid fibril proteins was tested. CA induced by A beta preparations containing soluble...... protein, protofilaments and some fibrils or only fibrils in a solid phase system (ELISA) was modest with a slow kinetics compared to the positive delta IgG control. Soluble A beta induced no detectable CA in a liquid phase system (complement consumption assay) while fibrillar A beta caused CA at 200 mg....../ml and higher concentrations. Soluble beta 2-microglobulin (beta 2M) purified from peritoneal dialysates was found to be as potent a complement activator as A beta in both solid and liquid phase systems while beta 2M purified from urine exhibited lower activity, a difference which may be explained...

  19. Determination of alternative pathway of complement activity in mouse serum using rabbit erythrocytes

    NARCIS (Netherlands)

    Dijk, H. van; Rademaker, P.M.; Willers, J.M.N

    1980-01-01

    Rabbit, mouse and sheep erythrocytes expressing different concentrations of membrane sialic acid were used to study possible modes of activation of the alternative complement (C) pathway in mouse, human and guinea pig serum. Mouse erythrocytes activated only human serum, whereas rabbit erythrocytes

  20. Soluble and immobilized graphene oxide activates complement system differently dependent on surface oxidation state.

    Science.gov (United States)

    Wibroe, Peter P; Petersen, Søren V; Bovet, Nicolas; Laursen, Bo W; Moghimi, S Moein

    2016-02-01

    Graphene oxide (GO) is believed to become applicable in biomedical products and medicine, thereby necessitating appropriate safety evaluation dependent on their applications and the route of administration. We have examined the effect of GO form (in solution versus immobilized) and oxidation state on two related elements of innate immunity: the complement system and interleukin-6 (IL-6) release in human blood. In solution, there was a decrease in GO-mediated complement activation with decreasing surface oxygen content (and altered oxygen functionality), whereas with immobilized GO complement response were reversed and increased with decreasing oxygen content. GO solutions, at concentrations below complement activating threshold, did not induce IL-6 release from human blood leukocytes, and further dampened lipopolysaccharide-induced IL-6 release in the whole blood. The latter effect became more profound with GO's having higher oxygen content. This protective role of GO solutions, however, disappeared at higher concentrations above complement-activating threshold. We discuss these results in relation to GO surface structure and properties, and implications for local administration and development of GO-based implantable devices. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Hemolytic plate assay for quantification of active human complement component C3 using methylamine-treated plasma as complement source

    DEFF Research Database (Denmark)

    Ploug, M; Jessen, T E; Welinder, K. G.

    1985-01-01

    erythrocytes. Plasma treated with methylamine supplies the essential complement components other than C3. The lytic reaction is complete in 5 h at 37 degrees C and is unchanged by incubation overnight. The dose-response curve, i.e., lysis diameter versus logarithm of C3 concentration, is linear within 0...

  2. Citrem Modulates Internal Nanostructure of Glyceryl Monooleate Dispersions and Bypasses Complement Activation

    DEFF Research Database (Denmark)

    Wibroe, Peter P; Mat Azmi, Intan Diana Binti; Nilsson, Christa

    2015-01-01

    Lyotropic non-lamellar liquid crystalline (LLC) aqueous nanodispersions hold a great promise in drug solubilization and delivery, but these nanosystems often induce severe hemolysis and complement activation, which limit their applications for safe intravenous administration. Here, we engineer......, modulates the internal nanostructure of LLC dispersions from a biphasic H2/L2 feature to a neat L2 phase, where the latter resembles 'thread-like' swollen micelles. Citrem stabilization totally overcomes hemolysis and complement activation, thus realizing the potential of the engineered LLC aqueous...

  3. Activation of the lectin pathway of complement in experimental human keratitis with Pseudomonas aeruginosa.

    Science.gov (United States)

    Osthoff, Michael; Brown, Karl D; Kong, David C M; Daniell, Mark; Eisen, Damon P

    2014-01-01

    Pseudomonas aeruginosa (P. aeruginosa) microbial keratitis (MK) is a sight-threatening disease. Previous animal studies have identified an important contribution of the complement system to the clearance of P. aeruginosa infection of the cornea. Mannose-binding lectin (MBL), a pattern recognition receptor of the lectin pathway of complement, has been implicated in the host defense against P. aeruginosa. However, studies addressing the role of the lectin pathway in P. aeruginosa MK are lacking. Hence, we sought to determine the activity of the lectin pathway in human MK caused by P. aeruginosa. Primary human corneal epithelial cells (HCECs) from cadaveric donors were exposed to two different P. aeruginosa strains. Gene expression of interleukin (IL)-6, IL-8, MBL, and other complement proteins was determined by reverse transcription-polymerase chain reaction (RT-PCR) and MBL synthesis by enzyme-linked immunosorbent assay and intracellular flow cytometry. MBL gene expression was not detected in unchallenged HCECs. Exposure of HCECs to P. aeruginosa resulted in rapid induction of the transcriptional expression of MBL, IL-6, and IL-8. In addition, expression of several complement proteins of the classical and lectin pathways, but not the alternative pathway, were upregulated after 5 h of challenge, including MBL-associated serine protease 1. However, MBL protein secretion was not detectable 18 h after challenge with P. aeruginosa. MK due to P. aeruginosa triggers activation of MBL and the lectin pathway of complement. However, the physiologic relevance of this finding is unclear, as corresponding MBL oligomer production was not observed.

  4. Ensemble spontaneous activity alterations detected by CISA approach.

    Science.gov (United States)

    Boudaoud, Sofiane; Rix, Hervé; Meste, Olivier; Cazals, Yves

    2007-01-01

    In this paper, we propose a method for detecting alterations in the Ensemble Spontaneous Activity (ESA), a random signal representing the composite spontaneous contribution of the auditory nerve recorded on the round window. The proposed method is based on shape analysis of the ESA amplitude histogram. For this task, we use a recent approach, the Corrected Integral Shape Averaging (CISA). Using this approach, a shape clustering algorithm is proposed to classify healthy and pathological ESA signals generated by a recent ESA model. This model allows a precise simulation of neural mechanisms occurring in the auditory nerve. The obtained results demonstrate that this shape analysis is very sensitive for detecting a small number of fibers with correlated firing, supposed to occur during a particular type of tinnitus. In comparison, the classical spectral index fails in this detection.

  5. Complement Activation Induces Neutrophil Adhesion and Neutrophil-Platelet Aggregate Formation on Vascular Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Magdalena Riedl

    2017-01-01

    Discussion: Therefore, our findings of (i neutrophils adhering to complement-activated endothelial cells, (ii the formation of neutrophil-platelet aggregates on endothelial cells, and (iii the ability of aHUS serum to induce similar effects identify a possible role for neutrophils in aHUS manifestation.

  6. Ficolin-3-mediated lectin complement pathway activation in patients with subarachnoid hemorrhage

    DEFF Research Database (Denmark)

    Zanier, Elisa R; Zangari, Rosalia; Munthe-Fog, Lea

    2014-01-01

    OBJECTIVES: To assess the involvement of ficolin-3, the main initiator of the lectin complement pathway (LCP), in subarachnoid hemorrhage (SAH) pathology and outcome. METHODS: In this preliminary exploratory study, plasma concentration of ficolin-3 and of ficolin-3-mediated functional LCP activity...

  7. Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin

    DEFF Research Database (Denmark)

    Pilely, Katrine; Rosbjerg, Anne; Genster, Ninette

    2016-01-01

    Cholesterol crystals (CC) play an essential role in the formation of atherosclerotic plaques. CC activate the classical and the alternative complement pathways, but the role of the lectin pathway is unknown. We hypothesized that the pattern recognition molecules (PRMs) from the lectin pathway bind...

  8. Spontaneous cortical activity is transiently poised close to criticality.

    Directory of Open Access Journals (Sweden)

    Gerald Hahn

    2017-05-01

    Full Text Available Brain activity displays a large repertoire of dynamics across the sleep-wake cycle and even during anesthesia. It was suggested that criticality could serve as a unifying principle underlying the diversity of dynamics. This view has been supported by the observation of spontaneous bursts of cortical activity with scale-invariant sizes and durations, known as neuronal avalanches, in recordings of mesoscopic cortical signals. However, the existence of neuronal avalanches in spiking activity has been equivocal with studies reporting both its presence and absence. Here, we show that signs of criticality in spiking activity can change between synchronized and desynchronized cortical states. We analyzed the spontaneous activity in the primary visual cortex of the anesthetized cat and the awake monkey, and found that neuronal avalanches and thermodynamic indicators of criticality strongly depend on collective synchrony among neurons, LFP fluctuations, and behavioral state. We found that synchronized states are associated to criticality, large dynamical repertoire and prolonged epochs of eye closure, while desynchronized states are associated to sub-criticality, reduced dynamical repertoire, and eyes open conditions. Our results show that criticality in cortical dynamics is not stationary, but fluctuates during anesthesia and between different vigilance states.

  9. Spontaneous activity in the statoacoustic ganglion of the chicken embryo.

    Science.gov (United States)

    Jones, T A; Jones, S M

    2000-03-01

    Statoacoustic ganglion cells in the mature bird include neurons that are responsive to sound (auditory) and those that are not (nonauditory). Those that are nonauditory have been shown to innervate an otolith organ, the macula lagena, whereas auditory neurons innervate the basilar papilla. In the present study, single-unit recordings of statoacoustic ganglion cells were made in embryonic (E19, mean = 19.2 days of incubation) and hatchling (P6-P14, mean = 8.6 days posthatch) chickens. Spontaneous activity from the two age groups was compared with developmental changes. Activity was evaluated for 47 auditory, 11 nonauditory, and 6 undefined eighth nerve neurons in embryos and 29 auditory, 26 nonauditory, and 1 undefined neurons in hatchlings. For auditory neurons, spontaneous activity displayed an irregular pattern [discharge interval coefficient of variation (CV) was >0.5, mean CV for embryos was 1.46 +/- 0.58 and for hatchlings was 1.02 +/- 0.25; means +/- SD]. Embryonic discharge rates ranged from 0.05 to 97.6 spikes per second (sp/s) for all neurons (mean 18.6 +/- 16.9 sp/s). Hatchling spontaneous rates ranged from 1.2 to 185.2 sp/s (mean 66.5 +/- 39.6 sp/s). Discharge rates were significantly higher for hatchlings (P embryonic auditory neurons displayed long silent periods between irregular bursts of neural activity, a feature not seen posthatch. All regular bursting discharge patterns were correlated with heart rate in both embryos and hatchlings. Preferred intervals were visible in the time interval histograms (TIHs) of only one embryonic neuron in contrast to 55% of the neurons in posthatch animals. Generally, the embryonic auditory TIH displayed a modified quasi-Poisson distribution. Nonauditory units generally displayed regular (CV 0.5) activity and Gaussian and modified-Gaussian TIHs. Long silent periods or bursting patterns were not a characteristic of embryonic nonauditory neurons. CV varied systematically as a function of discharge rate in nonauditory

  10. Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements

    OpenAIRE

    Putterman, Chaim; Furie, Richard; Ramsey-Goldman, Rosalind; Askanase, Anca; Buyon, Jill; Kalunian, Kenneth; Chatham, W Winn; Massarotti, Elena; Kirou, Kyriakos; Jordan, Nicole; Blanco, Irene; Weinstein, Arthur; Chitkara, Puja; Manzi, Susan; Ahearn, Joseph

    2014-01-01

    Objective To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE). Methods The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using soli...

  11. Classical complement pathway activation in the nasal tissue of patients with chronic rhinosinusitis.

    Science.gov (United States)

    Van Roey, Griet A; Vanison, Christopher C; Wu, Jeffanie; Huang, Julia H; Suh, Lydia A; Carter, Roderick G; Norton, James E; Shintani-Smith, Stephanie; Conley, David B; Welch, Kevin C; Peters, Anju T; Grammer, Leslie C; Harris, Kathleen E; Hulse, Kathryn E; Kato, Atsushi; Stevens, Whitney W; Kern, Robert C; Schleimer, Robert P; Tan, Bruce K

    2017-07-01

    Complement plays a major role in inflammatory diseases, but its involvement and mechanisms of activation in patients with chronic rhinosinusitis (CRS) are not known. After earlier studies discovering autoantibodies in patients with CRS, we sought to investigate the nature, extent, and location of complement activation in nasal tissue of patients with CRS. Specifically, we were interested in whether antibody-mediated activation through the classical pathway was a major mechanism for complement activation in patients with CRS. Nasal tissue was obtained from patients with CRS and control subjects. Tissue homogenates were analyzed for complement activation products (ELISA-C5b-9, C4d, activated C1, and C5a) and major complement-fixing antibodies (Luminex). Tissue sections were stained for C5b-9, C4d, and laminin. Antibodies were purified with protein A/G columns from nasal polyps (NP), matching patient serum, and control serum and assayed for basement membrane binding by means of ELISA. C5b-9 levels were significantly increased in NP tissue compared with uncinate tissue (UT) of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and those with chronic rhinosinusitis without nasal polyps (CRSsNP; P < .01). Similarly, C4d levels were increased in NPs compared with UT of patients with CRSwNP, patients with CRSsNP, and control subjects (P < .05). Activated C1 levels were also increased in NP tissue compared with UT of patients with CRSsNP and control subjects (P < .05) and correlated with levels of C5a (P < .01), local immunoglobulins (especially IgM, P < .0001), and anti-double-stranded DNA IgG (P < .05). Immunofluorescence showed that C5b-9 and C4d deposition occurred linearly along the epithelial basement membrane. NP tissue extracts had significantly more anti-basement membrane antibodies than sera from patients with CRSwNP and control subjects (P < .0001). Levels of C5b-9, C4d, and activated C1 were significantly increased locally in NP tissue

  12. Human Secretory IgM Antibodies Activate Human Complement and Offer Protection at Mucosal Surface.

    Science.gov (United States)

    Michaelsen, T E; Emilsen, S; Sandin, R H; Granerud, B K; Bratlie, D; Ihle, O; Sandlie, I

    2017-01-01

    IgM molecules circulate in serum as large polymers, mainly pentamers, which can be transported by the poly-Ig receptor (pIgR) across epithelial cells to mucosal surfaces and released as secretory IgM (SIgM). The mucosal SIgM molecules have non-covalently attached secretory component (SC), which is the extracellular part of pIgR which is cleaved from the epithelial cell membrane. Serum IgM antibodies do not contain SC and have previously been shown to make a conformational change from 'a star' to a 'staple' conformation upon reaction with antigens on a cell surface, enabling them to activate complement. However, it is not clear whether SIgM similarly can induce complement activation. To clarify this issue, we constructed recombinant chimeric (mouse/human) IgM antibodies against hapten 5-iodo-4-hydroxy-3-nitro-phenacetyl (NIP) and in addition studied polyclonal IgM formed after immunization with a meningococcal group B vaccine. The monoclonal and polyclonal IgM molecules were purified by affinity chromatography on a column containing human SC in order to isolate joining-chain (J-chain) containing IgM, followed by addition of excess amounts of soluble SC to create SIgM (IgM J+ SC+). These SIgM preparations were tested for complement activation ability and shown to be nearly as active as the parental IgM J+ molecules. Thus, SIgM may offer protection against pathogens at mucosal surface by complement-mediated cell lysis or by phagocytosis mediated by complement receptors present on effector cells on mucosa. © 2016 The Foundation for the Scandinavian Journal of Immunology.

  13. Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment.

    Science.gov (United States)

    Natoli, Riccardo; Fernando, Nilisha; Dahlenburg, Tess; Jiao, Haihan; Aggio-Bruce, Riemke; Barnett, Nigel L; Chao de la Barca, Juan Manuel; Tcherkez, Guillaume; Reynier, Pascal; Fang, Johnny; Chu-Tan, Joshua A; Valter, Krisztina; Provis, Jan; Rutar, Matt

    2018-01-01

    Systemic increases in reactive oxygen species, and their association with inflammation, have been proposed as an underlying mechanism linking obesity and age-related macular degeneration (AMD). Studies have found increased levels of oxidative stress biomarkers and inflammatory cytokines in obese individuals; however, the correlation between obesity and retinal inflammation has yet to be assessed. We used the leptin-deficient (ob/ob) mouse to further our understanding of the contribution of obesity to retinal oxidative stress and inflammation. Retinas from ob/ob mice were compared to age-matched wild-type controls for retinal function (electroretinography) and gene expression analysis of retinal stress ( Gfap ), oxidative stress ( Gpx3 and Hmox1 ), and complement activation ( C3 , C2 , Cfb , and Cfh ). Oxidative stress was further quantified using a reactive oxygen species and reactive nitrogen species (ROS and RNS) assay. Retinal microglia and macrophage migration to the outer retina and complement activation were determined using immunohistochemistry for IBA1 and C3, respectively. Retinas and sera were used for metabolomic analysis using QTRAP mass spectrometry. Retinal function was reduced in ob/ob mice, which correlated to changes in markers of retinal stress, oxidative stress, and inflammation. An increase in C3-expressing microglia and macrophages was detected in the outer retinas of the ob/ob mice, while gene expression studies showed increases in the complement activators ( C2 and Cfb ) and a decrease in a complement regulator ( Cfh ). The expression of several metabolites were altered in the ob/ob mice compared to the controls, with changes in polyunsaturated fatty acids (PUFAs) and branched-chain amino acids (BCAAs) detected. The results of this study indicate that oxidative stress, inflammation, complement activation, and lipid metabolites in the retinal environment are linked with obesity in ob/ob animals. Understanding the interplay between these

  14. An assay for the mannan-binding lectin pathway of complement activation

    DEFF Research Database (Denmark)

    Petersen, Steen Vang; Thiel, S; Jensen, L

    2001-01-01

    the C1 complex, whereas the carbohydrate-binding activity of MBL and the integrity of the MBL complex is maintained under hypertonic conditions. In the assay described here, the specific C4b-depositing capacity of the MBL pathway was determined by incubating serum diluted in buffer containing 1 M NaCl...... deposited on the mannan-coated surface. However, we also found a threefold variation in C4b-depositing capacity between individuals with similar MBL concentrations. The assay permits for the determination of MBL complex activity in serum and plasma samples and may thus be used to evaluate the clinical......The mannan-binding lectin (MBL) pathway of complement activation has been established as the third pathway of complement activation. MBL is a carbohydrate-binding serum protein, which circulates in complex with serine proteases known as mannan-binding lectin associated serine proteases (MASPs...

  15. Recruitment of Perisomatic Inhibition during Spontaneous Hippocampal Activity In Vitro.

    Directory of Open Access Journals (Sweden)

    Anna Beyeler

    Full Text Available It was recently shown that perisomatic GABAergic inhibitory postsynaptic potentials (IPSPs originating from basket and chandelier cells can be recorded as population IPSPs from the hippocampal pyramidal layer using extracellular electrodes (eIPSPs. Taking advantage of this approach, we have investigated the recruitment of perisomatic inhibition during spontaneous hippocampal activity in vitro. Combining intracellular and extracellular recordings from pyramidal cells and interneurons, we confirm that inhibitory signals generated by basket cells can be recorded extracellularly, but our results suggest that, during spontaneous activity, eIPSPs are mostly confined to the CA3 rather than CA1 region. CA3 eIPSPs produced the powerful time-locked inhibition of multi-unit activity expected from perisomatic inhibition. Analysis of the temporal dynamics of spike discharges relative to eIPSPs suggests significant but moderate recruitment of excitatory and inhibitory neurons within the CA3 network on a 10 ms time scale, within which neurons recruit each other through recurrent collaterals and trigger powerful feedback inhibition. Such quantified parameters of neuronal interactions in the hippocampal network may serve as a basis for future characterisation of pathological conditions potentially affecting the interactions between excitation and inhibition in this circuit.

  16. Soluble IgM links apoptosis to complement activation in early alcoholic liver disease in mice.

    Science.gov (United States)

    Smathers, Rebecca L; Chiang, Dian J; McMullen, Megan R; Feldstein, Ariel E; Roychowdhury, Sanjoy; Nagy, Laura E

    2016-04-01

    Ethanol feeding in mice activates complement via C1q binding to apoptotic cells in the liver; complement contributes to ethanol-induced inflammation and injury. Despite the critical role of C1q in ethanol-induced injury, the mechanism by which ethanol activates C1q remains poorly understood. Secretory IgM (sIgM), traditionally considered to act as an anti-microbial, also has critical housekeeping functions, facilitating clearance of apoptotic cells, at least in part through activation of C1q. Therefore, we hypothesized that (1) ethanol-induced apoptosis in the liver recruits sIgM, facilitating the activation of C1q and complement and (2) C1INH (C1 esterase inhibitor), which inhibits C1 functional activity, prevents complement activation and decreases ethanol-induced liver injury. Female C57BL/6 wild-type, C1qa(-/-), BID(-/-) and sIgM(-/-) mice were fed ethanol containing liquid diets or pair-fed control diets. C1INH or vehicle was given via tail vein injection to ethanol- or pair-fed wild-type mice at 24 and 48h prior to euthanasia. Ethanol exposure increased apoptosis in the liver, as well as the accumulation of IgM in the liver. In the early stages of ethanol feeding, C1q co-localized with IgM in the peri-sinusoidal space of the liver and accumulation of IgM and C3b was dependent on ethanol-induced BID-dependent apoptosis. sIgM(-/-) mice were protected from both ethanol-induced activation of complement and early ethanol-induced liver injury when compared to wild-type mice. Treatment with C1INH also decreased hepatic C3b deposition and ethanol-induced injury. These data indicate that sIgM contributes to activation of complement and ethanol-induced increases in inflammatory cytokine expression and hepatocyte injury in the early stages of ethanol-induced liver injury. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Using an in vitro xenoantibody-mediated complement-dependent cytotoxicity model to evaluate the complement inhibitory activity of the peptidic C3 inhibitor Cp40.

    Science.gov (United States)

    Wang, Junxiang; Wang, Lu; Xiang, Ying; Ricklin, Daniel; Lambris, John D; Chen, Gang

    2016-01-01

    Simple and reliable methods for evaluating the inhibitory effects of drug candidates on complement activation are essential for preclinical development. Here, using an immortalized porcine aortic endothelial cell line (iPEC) as target, we evaluated the feasibility and effectiveness of an in vitro xenoantibody-mediated complement-dependent cytotoxicity (CDC) model for evaluating the complement inhibitory activity of Cp40, a potent analog of the peptidic C3 inhibitor compstatin. The binding of human xenoantibodies to iPECs led to serum dilution-dependent cell death. Pretreatment of the human serum with Cp40 almost completely inhibited the deposition of C3 fragments and C5b-9 on the cells, resulting in a dose-dependent inhibition of CDC against the iPECs. Using the same method to compare the effects of Cp40 on complement activation in humans, rhesus and cynomolgus monkeys, we found that the inhibitory patterns were similar overall. Thus, the in vitro xenoantibody-mediated CDC assay may have considerable potential for future clinical use. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Fcγ and Complement Receptors and Complement Proteins in Neutrophil Activation in Rheumatoid Arthritis: Contribution to Pathogenesis and Progression and Modulation by Natural Products

    Directory of Open Access Journals (Sweden)

    Adriana Balbina Paoliello-Paschoalato

    2015-01-01

    Full Text Available Rheumatoid arthritis (RA is a highly disabling disease that affects all structures of the joint and significantly impacts on morbidity and mortality in RA patients. RA is characterized by persistent inflammation of the synovial membrane lining the joint associated with infiltration of immune cells. Eighty to 90% of the leukocytes infiltrating the synovia are neutrophils. The specific role that neutrophils play in the onset of RA is not clear, but recent studies have evidenced that they have an important participation in joint damage and disease progression through the release of proteolytic enzymes, reactive oxygen species (ROS, cytokines, and neutrophil extracellular traps, in particular during frustrated phagocytosis of immune complexes (ICs. In addition, the local and systemic activation of the complement system contributes to the pathogenesis of RA and other IC-mediated diseases. This review discusses (i the participation of Fcγ and complement receptors in mediating the effector functions of neutrophils in RA; (ii the contribution of the complement system and ROS-dependent and ROS-independent mechanisms to joint damage in RA; and (iii the use of plant extracts, dietary compounds, and isolated natural compounds in the treatment of RA, focusing on modulation of the effector functions of neutrophils and the complement system activity and/or activation.

  19. An overview of the synergy and crosstalk between pentraxins and collectins/ficolins: their functional relevance in complement activation.

    Science.gov (United States)

    Ma, Ying Jie; Lee, Bok Luel; Garred, Peter

    2017-04-21

    The complement system is an innate immune defense machinery comprising components that deploy rapid immune responses and provide efficient protection against foreign invaders and unwanted host elements. The complement system is activated upon recognition of pathogenic microorganisms or altered self-cells by exclusive pattern recognition molecules (PRMs), such as collectins, ficolins and pentraxins. Recent accumulating evidence shows that the different classes of effector PRMs build up a co-operative network and exert synergistic effects on complement activation. In this review, we describe our updated view of the crosstalk between previously unlinked PRMs in complement activation and the potential pathogenic effects during infection and inflammation.

  20. Core shell methyl methacrylate chitosan nanoparticles: In vitro mucoadhesion and complement activation

    Directory of Open Access Journals (Sweden)

    F Atyabi

    2011-10-01

    Full Text Available Background and the purpose of the study: Studies show that chitosan nanoparticles increase mucoadhesivity and penetration of large molecules across mucosal surface. The aim of the present study was to investigate the use of thiolated chitosan in the development of polysaccharide-coated nanoparticles in order to confer specific functionality to the system. Methods: Methyl methacrylate nanoparticles were coated with thiolated chitosan using a radical polymerization method. Thiolation was carried out using glutathione (GSH to improve mucoadhesivity and permeation enhancing properties of chitosan. Mucoadhesion studies were carried out by calculating the amount of mucin adsorbed on nanoparticles in a specific period of time. Complement consumption was assessed in human serum (HS by measurement of the hemolytic capacity of the complement system after contact with nanoparticles.   Results:   The FT-IR and 1HNMR spectra both confirmed the synthesis and showed the conjugation of thiolated chitosan to methyl methacrylate (MMA homopolymer. Nanoparticles were spherical having a mean diameter within the range of about 334-650 nm and their positive zeta potential values indicated the presence of the cationic polysaccharide at the nanoparticle surface. Increasing the amount of thiolated chitosan led to mucoadhesivity and complement activation. However there was not dose dependent correlation between these phenomenons and the absence of thiolated chitosan led to particles with larger size, and without ability to activate complement process. Major conclusion: It can be concluded that nanoparticles could be used for the mucosal delivery of peptides and proteins. Results show that the thiolated chitosan had higher mucoadhesion and complement activation than unmodified chitosan.

  1. Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation

    Science.gov (United States)

    Liszewski, M. Kathryn; Kolev, Martin; Le Friec, Gaelle; Leung, Marilyn; Bertram, Paula G.; Fara, Antonella F.; Subias, Marta; Pickering, Matthew C.; Drouet, Christian; Meri, Seppo; Arstila, T. Petteri; Pekkarinen, Pirkka T.; Ma, Margaret; Cope, Andrew; Reinheckel, Thomas; Rodriguez de Cordoba, Santiago; Afzali, Behdad; Atkinson, John P.; Kemper, Claudia

    2013-01-01

    Summary Complement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While “tonic” intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance. PMID:24315997

  2. Characterization of the third component of complement (C3) after activation by cigarette smoke

    International Nuclear Information System (INIS)

    Kew, R.R.; Ghebrehiwet, B.; Janoff, A.

    1987-01-01

    Activation of lung complement by tobacco smoke may be an important pathogenetic factor in the development of pulmonary emphysema in smokers. We previously showed that cigarette smoke can modify C3 and activate the alternative pathway of complement in vitro. However, the mechanism of C3 activation was not fully delineated in these earlier studies. In the present report, we show that smoke-treated C3 induces cleavage of the alternative pathway protein, Factor B, when added to serum containing Mg-EGTA. This effect of cigarette smoke is specific for C3 since smoke-treated C4, when added to Mg-EGTA-treated serum, fails to activate the alternative pathway and fails to induce Factor B cleavage. Smoke-modified C3 no longer binds significant amounts of [ 14 C]methylamine (as does native C3), and relatively little [ 14 C]methylamine is incorporated into its alpha-chain. Thus, prior internal thiolester bond cleavage appears to have occurred in C3 activated by cigarette smoke. Cigarette smoke components also induce formation of noncovalently associated, soluble C3 multimers, with a Mr ranging from 1 to 10 million. However, prior cleavage of the thiolester bond in C3 with methylamine prevents the subsequent formation of these smoke-induced aggregates. These data indicate that cigarette smoke activates the alternative pathway of complement by specifically modifying C3 and that these modifications include cleavage of the thiolester bond in C3 and formation of noncovalently linked C3 multimers

  3. Decreased material-activation of the complement system using low-energy plasma polymerized poly(vinyl pyrrolidone) coatings

    DEFF Research Database (Denmark)

    Andersen, Thomas E; Palarasah, Yaseelan; Skjødt, Mikkel-Ole

    2011-01-01

    In the current study we investigate the activation of blood complement on medical device silicone rubber and present a plasma polymerized vinyl pyrrolidone (ppVP) coating which strongly decreases surface-activation of the blood complement system. We show that uncoated silicone and polystyrene...... are both potent activators of the complement system, measured both as activated, deposited C3b and quantifying fluid-phase release of the cleavage fragment C3c. The ppVP coated silicone exhibits approximately 90% reduced complement activation compared to untreated silicone. Quartz crystal microbalance...... of differences in the adsorbed protein layer composition. The alternative and classical complement pathways are barely detectable on ppVP while the lectin pathway through MBL/ficolin-2 deposition remains active on ppVP suggesting this pathway is responsible for the remaining subtle activation on the ppVP coated...

  4. Arthrogenicity of type II collagen monoclonal antibodies associated with complement activation and antigen affinity.

    Science.gov (United States)

    Koobkokkruad, Thongchai; Kadotani, Tatsuya; Hutamekalin, Pilaiwanwadee; Mizutani, Nobuaki; Yoshino, Shin

    2011-11-04

    The collagen antibody-induced arthritis (CAIA) model, which employs a cocktail of monoclonal antibodies (mAbs) to type II collagen (CII), has been widely used for studying the pathogenesis of autoimmune arthritis. In this model, not all mAbs to CII are capable of inducing arthritis because one of the initial events is the formation of collagen-antibody immune complexes on the cartilage surface or in the synovium, and subsequent activation of the complement by the complexes induces arthritis, suggesting that a combination of mAbs showing strong ability to bind mouse CII and activate the complement may effectively induce arthritis in mice. In the present study, we examined the relationship between the induction of arthritis by the combination of IgG2a (CII-6 and C2A-12), IgG2b (CII-3, C2B-14 and C2B-16) and IgM (CM-5) subclones of monoclonal antibodies (mAb) of anti-bovine or chicken CII and the ability of mAbs to activate complement and bind mouse CII. DBA/1J mice were injected with several combinations of mAbs followed by lipopolysaccharide. Furthermore, the ability of mAbs to activate the complement and bind mouse CII was examined by ELISA. First, DBA/1J mice were injected with the combined 4 mAbs (CII-3, CII-6, C2B-14, and CM-5) followed by lipopolysaccharide, resulting in moderate arthritis. Excluding one of the mAbs, i.e., using only CII-3, CII-6, and C2B-14, induced greater inflammation of the joints. Next, adding C2A-12 but not C2B-16 to these 3 mAbs produced more severe arthritis. A combination of five clones, consisting of all 5 mAbs, was less effective. Histologically, mice given the newly developed 4-clone cocktail had marked proliferation of synovial tissues, massive infiltration by inflammatory cells, and severe destruction of cartilage and bone. Furthermore, 4 of the 6 clones (CII-3, CII-6, C2B-14, and C2A-12) showed not only a strong cross-reaction with mouse CII but also marked activation of the complement in vitro. The combination of 4 mAbs showing

  5. Arthrogenicity of type II collagen monoclonal antibodies associated with complement activation and antigen affinity

    Directory of Open Access Journals (Sweden)

    Mizutani Nobuaki

    2011-11-01

    Full Text Available Abstract Background The collagen antibody-induced arthritis (CAIA model, which employs a cocktail of monoclonal antibodies (mAbs to type II collagen (CII, has been widely used for studying the pathogenesis of autoimmune arthritis. In this model, not all mAbs to CII are capable of inducing arthritis because one of the initial events is the formation of collagen-antibody immune complexes on the cartilage surface or in the synovium, and subsequent activation of the complement by the complexes induces arthritis, suggesting that a combination of mAbs showing strong ability to bind mouse CII and activate the complement may effectively induce arthritis in mice. In the present study, we examined the relationship between the induction of arthritis by the combination of IgG2a (CII-6 and C2A-12, IgG2b (CII-3, C2B-14 and C2B-16 and IgM (CM-5 subclones of monoclonal antibodies (mAb of anti-bovine or chicken CII and the ability of mAbs to activate complement and bind mouse CII. Methods DBA/1J mice were injected with several combinations of mAbs followed by lipopolysaccharide. Furthermore, the ability of mAbs to activate the complement and bind mouse CII was examined by ELISA. Results First, DBA/1J mice were injected with the combined 4 mAbs (CII-3, CII-6, C2B-14, and CM-5 followed by lipopolysaccharide, resulting in moderate arthritis. Excluding one of the mAbs, i.e., using only CII-3, CII-6, and C2B-14, induced greater inflammation of the joints. Next, adding C2A-12 but not C2B-16 to these 3 mAbs produced more severe arthritis. A combination of five clones, consisting of all 5 mAbs, was less effective. Histologically, mice given the newly developed 4-clone cocktail had marked proliferation of synovial tissues, massive infiltration by inflammatory cells, and severe destruction of cartilage and bone. Furthermore, 4 of the 6 clones (CII-3, CII-6, C2B-14, and C2A-12 showed not only a strong cross-reaction with mouse CII but also marked activation of the

  6. Copper is an endogenous modulator of neural circuit spontaneous activity.

    Science.gov (United States)

    Dodani, Sheel C; Firl, Alana; Chan, Jefferson; Nam, Christine I; Aron, Allegra T; Onak, Carl S; Ramos-Torres, Karla M; Paek, Jaeho; Webster, Corey M; Feller, Marla B; Chang, Christopher J

    2014-11-18

    For reasons that remain insufficiently understood, the brain requires among the highest levels of metals in the body for normal function. The traditional paradigm for this organ and others is that fluxes of alkali and alkaline earth metals are required for signaling, but transition metals are maintained in static, tightly bound reservoirs for metabolism and protection against oxidative stress. Here we show that copper is an endogenous modulator of spontaneous activity, a property of functional neural circuitry. Using Copper Fluor-3 (CF3), a new fluorescent Cu(+) sensor for one- and two-photon imaging, we show that neurons and neural tissue maintain basal stores of loosely bound copper that can be attenuated by chelation, which define a labile copper pool. Targeted disruption of these labile copper stores by acute chelation or genetic knockdown of the CTR1 (copper transporter 1) copper channel alters the spatiotemporal properties of spontaneous activity in developing hippocampal and retinal circuits. The data identify an essential role for copper neuronal function and suggest broader contributions of this transition metal to cell signaling.

  7. Collectin-11/MASP complex formation triggers activation of the lectin complement pathway--the fifth lectin pathway initiation complex

    DEFF Research Database (Denmark)

    Ma, Ying Jie; Skjoedt, Mikkel-Ole; Garred, Peter

    2013-01-01

    Collectins and ficolins are important in the clearance of endogenous and exogenous danger materials. A new human collectin-11 was recently identified in low concentration in serum in complex with mannose-binding lectin (MBL)/ficolin-associated serine proteases. Collectin-11 binds to carbohydrate...... complement complex on C. albicans. Moreover, spiking collectin-11-depleted serum, which did not mediate complement activation, with recombinant collectin-11 restored the complement activation capability. These results define collectin-11 as the fifth recognition molecule in the lectin complement pathway...

  8. Potassium humate inhibits complement activation and the production of inflammatory cytokines in vitro

    Energy Technology Data Exchange (ETDEWEB)

    van Rensburg, C.E.J.; Naude, P.J. [University of Pretoria, Pretoria (South Africa)

    2009-08-15

    The effects of brown coal derived potassium humate on lymphocyte proliferation, cytokine production and complement activation were investigated in vitro. Potassium humate increased lymphocyte proliferation of phytohaemaglutinin A (PHA) and pokeweed mitogen (PWM) stimulated mononuclear lymphocytes (MNL) in vitro from concentrations of 20 to 80 {mu} g/ml, in a dose dependant manner. On the other hand potassium humate, at 40 {mu} g/ml, significantly inhibited the release of TNF-alpha, IL-1 beta, IL-6 and IL-10 by PHA stimulated MNL. Regarding complement activation it was found that potassium humate inhibits the activation of both the alternative and classical pathways without affecting the stability of the red blood cell membranes. These results indicate that the anti-inflammatory potential of potassium humate could be partially due to the inhibition of pro-inflammatory cytokines responsible for the initiation of these reactions as well as inhibition of complement activation. The increased lymphocyte proliferation observed, might be due to increased IL-2 production as previously been documented.

  9. A novel method for direct measurement of complement convertases activity in human serum

    NARCIS (Netherlands)

    Blom, A.M.; Volokhina, E.B.; Fransson, V.; Stromberg, P.; Berghard, L.; Viktorelius, M.; Mollnes, T.E.; Lopez-Trascasa, M.; Heuvel, B. van den; Goodship, T.H.; Marchbank, K.J.; Okroj, M.

    2014-01-01

    Complement convertases are enzymatic complexes that play a central role in sustaining and amplification of the complement cascade. Impairment of complement function leads directly or indirectly to pathological conditions, including higher infection rate, kidney diseases, autoimmune- or

  10. Arthrogenicity of type II collagen monoclonal antibodies associated with complement activation and antigen affinity

    OpenAIRE

    Koobkokkruad, Thongchai; Kadotani, Tatsuya; Hutamekalin, Pilaiwanwadee; Mizutani, Nobuaki; Yoshino, Shin

    2011-01-01

    Abstract Background The collagen antibody-induced arthritis (CAIA) model, which employs a cocktail of monoclonal antibodies (mAbs) to type II collagen (CII), has been widely used for studying the pathogenesis of autoimmune arthritis. In this model, not all mAbs to CII are capable of inducing arthritis because one of the initial events is the formation of collagen-antibody immune complexes on the cartilage surface or in the synovium, and subsequent activation of the complement by the complexes...

  11. Patterns of spontaneous magnetoencephalographic activity in patients with schizophrenia.

    Science.gov (United States)

    Siekmeier, Peter J; Stufflebeam, Steven M

    2010-06-01

    Magnetoencephalography noninvasively measures the magnetic fields produced by the brain. Pertinent research articles from 1993 to 2009 that measured spontaneous, whole-head magnetoencephalography activity in patients with schizophrenia were reviewed. Data on localization of oscillatory activity and correlation of these findings with psychotic symptoms are summarized. Although the variety of measures used by different research groups makes a quantitative meta-analysis difficult, it appears that magnetoencephalography activity in patients may exhibit identifiable patterns, defined by topographic organization and frequency band. Specifically, 11 of the 12 studies showed increased theta (4-8 Hz) and delta (1-4 Hz) band oscillations in the temporal lobes of patients; of the 10 studies that examined the relationship between oscillatory activity and symptomatology, 8 found a positive correlation between temporal lobe theta activity and positive schizophrenic symptoms. Abnormally high frontal delta activity was not seen. These findings are analyzed in comparison with the electroencephalogram literature on schizophrenics, and possible confounds (e.g., medication effects) are discussed. In the future, magnetoencephalography might be used to assist in diagnosis or might be fruitfully used in conjunction with new neuroscience research approaches such as computational modeling, which may be able to link oscillatory activity and cellular-level pathology.

  12. Anti-complement activity of essential oils from red and black rice bran.

    Science.gov (United States)

    Chung, Ill-Min; Yeo, Min-A; Kim, Sun-Jin; Moon, Hyung-In

    2011-05-01

    The volatile essential oils from red and black rice bran were obtained by hydrodistillation using a clevenger-type apparatus, and the components of that oil were analyzed by capillary gas chromatography-mass spectroscopy (GC-MS). The present study involved characterizing the chemical compositions, their amounts and the anti-complement activities of red and black rice bran. The red rice bran essential oils yield was 0.031%, and GC-MS analysis revealed that its major constituents were (E)-β-ocimene (3.12%), nonanal (11.32%), (2E, 4E)-decadienal (2.54%), myristic acid (41.32%), geranyactone (2.41%) and methyl oleate (2.46%). The black rice bran essential oils yield was 0.053%, and GC-MS analysis revealed that its major constituents were nonanal (8.31%), acrylic acid (3.21%), 2-hydroxy-6-methylbenzaldehyde (2.81%), pelargonic acid (4.21%) and myrisitc acid (28.07%). The essential oils showed inhibitory activity against complement system with 50% inhibitory concentrations (IC(50)) values of 246 ppm (red rice bran) and 193 ppm (black rice bran). Also, myristic acid, nonanal, (E)-β-ocimene and pelargonic acid were tested against complement system. Pelargonic acid was shown to moderate activity (50% inhibitory concentration = 132 μM).

  13. Molluskan Hemocyanins Activate the Classical Pathway of the Human Complement System through Natural Antibodies.

    Science.gov (United States)

    Pizarro-Bauerle, Javier; Maldonado, Ismael; Sosoniuk-Roche, Eduardo; Vallejos, Gerardo; López, Mercedes N; Salazar-Onfray, Flavio; Aguilar-Guzmán, Lorena; Valck, Carolina; Ferreira, Arturo; Becker, María Inés

    2017-01-01

    Molluskan hemocyanins are enormous oxygen-carrier glycoproteins that show remarkable immunostimulatory properties when inoculated in mammals, such as the generation of high levels of antibodies, a strong cellular reaction, and generation of non-specific antitumor immune responses in some types of cancer, particularly for superficial bladder cancer. These proteins have the ability to bias the immune response toward a T h 1 phenotype. However, despite all their current uses with beneficial clinical outcomes, a clear mechanism explaining these properties is not available. Taking into account reports of natural antibodies against the hemocyanin of the gastropod Megathura crenulata [keyhole limpet hemocyanin (KLH)] in humans as well as other vertebrate species, we report here for the first time, the presence, in sera from unimmunized healthy donors, of antibodies recognizing, in addition to KLH, two other hemocyanins from gastropods with documented immunomodulatory capacities: Fisurella latimarginata hemocyanin (FLH) and Concholepas concholepas hemocyanin (CCH). Through an ELISA screening, we found IgM and IgG antibodies reactive with these hemocyanins. When the capacity of these antibodies to bind deglycosylated hemocyanins was studied, no decreased interaction was detected. Moreover, in the case of FLH, deglycosylation increased antibody binding. We evaluated through an in vitro complement deposition assay whether these antibodies activated the classical pathway of the human complement system. The results showed that all three hemocyanins and their deglycosylated counterparts elicited this activation, mediated by C1 binding to immunoglobulins. Thus, this work contributes to the understanding on how the complement system could participate in the immunostimulatory properties of hemocyanins, through natural, complement-activating antibodies reacting with these proteins. Although a role for carbohydrates cannot be completely ruled out, in our experimental setting

  14. Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction.

    Science.gov (United States)

    Fattahi, Fatemeh; Kalbitz, Miriam; Malan, Elizabeth A; Abe, Elizabeth; Jajou, Lawrence; Huber-Lang, Markus S; Bosmann, Markus; Russell, Mark W; Zetoune, Firas S; Ward, Peter A

    2017-09-01

    Polymicrobial sepsis in mice causes myocardial dysfunction after generation of the complement anaphylatoxin, complement component 5a (C5a). C5a interacts with its receptors on cardiomyocytes (CMs), resulting in redox imbalance and cardiac dysfunction that can be functionally measured and quantitated using Doppler echocardiography. In this report we have evaluated activation of MAPKs and Akt in CMs exposed to C5a in vitro and after cecal ligation and puncture (CLP) in vivo In both cases, C5a in vitro caused activation (phosphorylation) of MAPKs and Akt in CMs, which required availability of both C5a receptors. Using immunofluorescence technology, activation of MAPKs and Akt occurred in left ventricular (LV) CMs, requiring both C5a receptors, C5aR1 and -2. Use of a water-soluble p38 inhibitor curtailed activation in vivo of MAPKs and Akt in LV CMs as well as the appearance of cytokines and histones in plasma from CLP mice. When mouse macrophages were exposed in vitro to LPS, activation of MAPKs and Akt also occurred. The copresence of the p38 inhibitor blocked these activation responses. Finally, the presence of the p38 inhibitor in CLP mice reduced the development of cardiac dysfunction. These data suggest that polymicrobial sepsis causes cardiac dysfunction that appears to be linked to activation of MAPKs and Akt in heart.-Fattahi, F., Kalbitz, M., Malan, E. A., Abe, E., Jajou, L., Huber-Lang, M. S., Bosmann, M., Russell, M. W., Zetoune, F. S., Ward, P. A. Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction. © FASEB.

  15. Alternative complement pathway and factor B activities in rats with altered blood levels of thyroid hormone

    International Nuclear Information System (INIS)

    Bitencourt, C.S.; Duarte, C.G.; Azzolini, A.E.C.S.; Assis-Pandochi, A.I.

    2012-01-01

    Evaluating the activity of the complement system under conditions of altered thyroid hormone levels might help elucidate the role of complement in triggering autoimmune processes. Here, we investigated alternative pathway (AP) activity in male Wistar rats (180 ± 10 g) after altering their thyroid hormone levels by treatment with triiodothyronine (T3), propylthiouracil (PTU) or thyroidectomy. T3 and thyroxine (T4) levels were determined by chemiluminescence assays. Hemolytic assays were performed to evaluate the lytic activity of the AP. Factor B activity was evaluated using factor B-deficient serum. An anti-human factor B antibody was used to measure factor B levels in serum by radial immunodiffusion. T3 measurements in thyroidectomized animals or animals treated with PTU demonstrated a significant reduction in hormone levels compared to control. The results showed a reduction in AP lytic activity in rats treated with increasing amounts of T3 (1, 10, or 50 µg). Factor B activity was also decreased in the sera of hyperthyroid rats treated with 1 to 50 µg T3. Additionally, treating rats with 25 µg T3 significantly increased factor B levels in their sera (P < 0.01). In contrast, increased factor B concentration and activity (32%) were observed in hypothyroid rats. We conclude that alterations in thyroid hormone levels affect the activity of the AP and factor B, which may in turn affect the roles of AP and factor B in antibody production

  16. Optimizing complement-activating antibody-based cancer immunotherapy: a feasible strategy?

    Directory of Open Access Journals (Sweden)

    Maio Michele

    2004-06-01

    Full Text Available Abstract Passive immunotherapy with monoclonal antibodies (mAb targeted to specific tumor-associated antigens is amongst the most rapidly expanding approaches to biological therapy of cancer. However, until now a limited number of therapeutic mAb has demonstrated clinical efficacy in selected neoplasia. Results emerging from basic research point to a deeper characterization of specific biological features of neoplastic cells as crucial to optimize the clinical potential of therapeutic mAb, and to identify cancer patients who represent the best candidates to antibody-based immunotherapy. Focus on the tissue distribution and on the functional role of membrane complement-regulatory proteins such as Protectin (CD59, which under physiologic conditions protects tissues from Complement (C-damage, might help to optimize the efficacy of immunotherapeutic strategies based on C-activating mAb.

  17. Complement activation and its prognostic role in post-cardiac arrest patients

    DEFF Research Database (Denmark)

    Jenei, Z M; Zima, E; Csuka, D

    2014-01-01

    and then allowed to rewarm to normothermia. All patients underwent diagnostic coronary angiography. On admission, at 6 and 24 h, blood samples were taken from the arterial catheter. In these, complement products (C3a, C3, C4d, C4, SC5b9 and Bb) were measured by ELISA in blood samples. Patients were followed up...... for 30 days; 22 patients (47.8%) died by the end of this period. We observed that complement activation (determined as the C3a to C3 ratio) was higher in non-survivors than in survivors at each time point. In the multivariate Cox regression analysis, the C3a/C3 ratio determined 24 h after the initiation...

  18. Activation of the human complement system by cholesterol-rich and pegylated liposomes - Modulation of cholesterol-rich liposome-mediated complement activation by elevated serum LDL and HDL levels

    DEFF Research Database (Denmark)

    Moghimi, S.M.; Hamad, I.; Bunger, R.

    2006-01-01

    . Therefore, surface-associated lipoprotein particles (or apolipoproteins) seem to lessen liposome-induced adverse haemodynamic changes, possibly as a consequence of suppressed complement activation in vivo. PEGylated liposomes were also capable of activating the human complement system, and the presence...... of surface projected methoxypoly(ethylene glycol) chains did not interfere with generation of C3 opsonic fragments. We also show that poly(ethylene glycol) is not responsible for PEGylated liposome-mediated complement activation. The net anionic charge on the phosphate moiety of the phospholipid...

  19. Spontaneous recombinase activity of Cre-ERT2 in vivo.

    Science.gov (United States)

    Kristianto, Jasmin; Johnson, Michael G; Zastrow, Ryley K; Radcliff, Abigail B; Blank, Robert D

    2017-06-01

    Inducible Cre-ERT recombinase technology is widely used for gene targeting studies. The second generation of inducible Cre-ERT recombinase, hemizygous B6.129S-Tg(UBC-cre/ERT2)1Ejb/J (hereafter abbreviated as Cre-ERT2), a fusion of a mutated estrogen receptor and Cre recombinase, was engineered to be more efficient and specific than the original Cre-ERT. The putative mechanism of selective Cre-mediated recombination is Cre sequestration in the cytoplasm in the basal state with translocation to the nucleus only in the presence of tamoxifen. We utilized both a reporter mouse (B6.129 (Cg)-Gt(ROSA)26Sor tm4(ACTB-tdTomato,-EGFP)Luo /J) and endothelin converting enzyme-1 floxed transgenic mouse line to evaluate Cre-ERT2 activity. We observed spontaneous Cre activity in both settings. Unintended Cre activity is a confounding factor that has a potentially large impact on data interpretation. Thus, it is important to consider background Cre activity in experimental design.

  20. Complement activity of polysaccharides from three different plant parts of Terminalia macroptera extracted as healers do.

    Science.gov (United States)

    Zou, Yuan-Feng; Zhang, Bing-Zhao; Inngjerdingen, Kari Tvete; Barsett, Hilde; Diallo, Drissa; Michaelsen, Terje Einar; Paulsen, Berit Smestad

    2014-08-08

    Water decoctions of the root bark, stem bark and leaves of Terminalia macroptera are used by traditional healers in Mali to cure a wide range of illnesses, such as wounds, hepatitis, malaria, fever, cough and diarrhea as well as tuberculosis. Plant polysaccharides isolated from crude water extracts have previously shown effects related to the immune system. The aims of this study are comparing the properties of the polysaccharides among different plant parts, as well as relationship between chemical characteristics and complement fixation activities when the plant material has been extracted as the traditional healers do, with boiling water directly. Root bark, stem bark and leaves of Terminalia macroptera were extracted by boiling water, and five purified polysaccharide fractions were obtained by anion exchange chromatography and gel filtration. Chemical compositions were determined by GC of the TMS derivatives of the methyl-glycosides and the linkage determined after permethylation and GC-MS of the derived partly methylated alditol acetates. The bioactivity was determined by the complement fixation assay of the crude extracts and purified fractions. The acidic fraction TRBD-I-I isolated from the root bark was the most active of the fractions isolated. Structural studies showed that all purified fractions are of pectic nature, containing rhamnogalacturonan type I backbone. Arabinogalactan type II side chains were present in all fractions except TRBD-I-II. The observed differences in complement fixation activities among the five purified polysaccharide fractions are probably due to differences in monosaccharide compositions, linkage types and molecular sizes. The crude extracts from root bark and stem bark have similar total activities, both higher than those from leaves. The root bark, leaves and stem bark are all good sources for fractions containing bioactive polysaccharides. But due to sustainability, it is prefer to use leaves rather than the other two plant

  1. The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection

    DEFF Research Database (Denmark)

    Ali, Youssif M; Lynch, Nicholas J; Haleem, Kashif S

    2012-01-01

    The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation...... pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan...... to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse...

  2. Activation of the human complement system by cholesterol-rich and pegylated liposomes - Modulation of cholesterol-rich liposome-mediated complement activation by elevated serum LDL and HDL levels

    DEFF Research Database (Denmark)

    Moghimi, S.M.; Hamad, I.; Bunger, R.

    2006-01-01

    level of S-protein-bound form of the terminal complex (SC5b-9). However, liposome-induced rise of SC5b-9 was significantly suppressed when serum HDL cholesterol levels increased by 30%. Increase of serum LDL to levels similar to that observed in heterozygous familial hypercholesterolemia also suppressed......Intravenously infused liposomes may induce cardiopulmonary distress in some human subjects, which is a manifestation of "complement activation-related pseudoallergy." We have now examined liposome-mediated complement activation in human sera with elevated lipoprotein (LDL and HDL) levels, since...... abnormal or racial differences in serum lipid profiles seem to modulate the extent of complement activation and associated adverse responses. In accordance with our earlier observations, cholesterol-rich (45 mol% cholesterol) liposomes activated human complement, as reflected by a significant rise in serum...

  3. Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin

    Science.gov (United States)

    Foley, Jonathan H.; Walton, Bethany L.; Aleman, Maria M.; O'Byrne, Alice M.; Lei, Victor; Harrasser, Micaela; Foley, Kimberley A.; Wolberg, Alisa S.; Conway, Edward M.

    2016-01-01

    Thrombus formation leading to vaso-occlusive events is a major cause of death, and involves complex interactions between coagulation, fibrinolytic and innate immune systems. Leukocyte recruitment is a key step, mediated partly by chemotactic complement activation factors C3a and C5a. However, mechanisms mediating C3a/C5a generation during thrombosis have not been studied. In a murine venous thrombosis model, levels of thrombin–antithrombin complexes poorly correlated with C3a and C5a, excluding a central role for thrombin in C3a/C5a production. However, clot weight strongly correlated with C5a, suggesting processes triggered during thrombosis promote C5a generation. Since thrombosis elicits fibrinolysis, we hypothesized that plasmin activates C5 during thrombosis. In vitro, the catalytic efficiency of plasmin-mediated C5a generation greatly exceeded that of thrombin or factor Xa, but was similar to the recognized complement C5 convertases. Plasmin-activated C5 yielded a functional membrane attack complex (MAC). In an arterial thrombosis model, plasminogen activator administration increased C5a levels. Overall, these findings suggest plasmin bridges thrombosis and the immune response by liberating C5a and inducing MAC assembly. These new insights may lead to the development of strategies to limit thrombus formation and/or enhance resolution. PMID:27077125

  4. Zonulin as prehaptoglobin2 regulates lung permeability and activates the complement system.

    Science.gov (United States)

    Rittirsch, Daniel; Flierl, Michael A; Nadeau, Brian A; Day, Danielle E; Huber-Lang, Markus S; Grailer, Jamison J; Zetoune, Firas S; Andjelkovic, Anuska V; Fasano, Alessio; Ward, Peter A

    2013-06-15

    Zonulin is a protein involved in the regulation of tight junctions (TJ) in epithelial or endothelial cells. Zonulin is known to affect TJ in gut epithelial cells, but little is known about its influences in other organs. Prehaptoglobin2 has been identified as zonulin and is related to serine proteases (MASPs, C1qrs) that activate the complement system. The current study focused on the role of zonulin in development of acute lung injury (ALI) in C57BL/6 male mice following intrapulmonary deposition of IgG immune complexes. A zonulin antagonist (AT-1001) and a related peptide with permeability agonist activities (AT-1002) were employed and given intratracheally or intravenously. Also, zonulin was blocked in lung with a neutralizing antibody. In a dose-dependent manner, AT-1001 or zonulin neutralizing antibody attenuated the intensity of ALI (as quantitated by albumin leak, neutrophil accumulation, and proinflammatory cytokines). A similar pattern was found using the bacterial lipopolysaccharide model of ALI. Using confocal microscopy on sections of injured lungs, staining patterns for TJ proteins were discontinuous, reduced, and fragmented. As expected, the leak of blood products into the alveolar space confirmed the passage of 3 and 20 kDa dextran, and albumin. In contrast to AT-1001, application of the zonulin agonist AT-1002 intensified ALI. Zonulin both in vitro and in vivo induced generation of complement C3a and C5a. Collectively, these data suggest that zonulin facilitates development of ALI both by enhancing albumin leak and complement activation as well as increased buildup of neutrophils and cytokines during development of ALI.

  5. Zonulin as prehaptoglobin2 regulates lung permeability and activates the complement system

    OpenAIRE

    Rittirsch, Daniel; Flierl, Michael A.; Nadeau, Brian A.; Day, Danielle E.; Huber-Lang, Markus S.; Grailer, Jamison J.; Zetoune, Firas S.; Andjelkovic, Anuska V.; Fasano, Alessio; Ward, Peter A.

    2013-01-01

    Zonulin is a protein involved in the regulation of tight junctions (TJ) in epithelial or endothelial cells. Zonulin is known to affect TJ in gut epithelial cells, but little is known about its influences in other organs. Prehaptoglobin2 has been identified as zonulin and is related to serine proteases (MASPs, C1qrs) that activate the complement system. The current study focused on the role of zonulin in development of acute lung injury (ALI) in C57BL/6 male mice following intrapulmonary depos...

  6. New Perspectives on Spontaneous Brain Activity: Dynamic Networks and Energy Matter

    Science.gov (United States)

    Tozzi, Arturo; Zare, Marzieh; Benasich, April A.

    2016-01-01

    Spontaneous brain activity has received increasing attention as demonstrated by the exponential rise in the number of published article on this topic over the last 30 years. Such “intrinsic” brain activity, generated in the absence of an explicit task, is frequently associated with resting-state or default-mode networks (DMN)s. The focus on characterizing spontaneous brain activity promises to shed new light on questions concerning the structural and functional architecture of the brain and how they are related to “mind”. However, many critical questions have yet to be addressed. In this review, we focus on a scarcely explored area, specifically the energetic requirements and constraints of spontaneous activity, taking into account both thermodynamical and informational perspectives. We argue that the “classical” definitions of spontaneous activity do not take into account an important feature, that is, the critical thermodynamic energetic differences between spontaneous and evoked brain activity. Spontaneous brain activity is associated with slower oscillations compared with evoked, task-related activity, hence it exhibits lower levels of enthalpy and “free-energy” (i.e., the energy that can be converted to do work), thus supporting noteworthy thermodynamic energetic differences between spontaneous and evoked brain activity. Increased spike frequency during evoked activity has a significant metabolic cost, consequently, brain functions traditionally associated with spontaneous activity, such as mind wandering, require less energy that other nervous activities. We also review recent empirical observations in neuroscience, in order to capture how spontaneous brain dynamics and mental function can be embedded in a non-linear dynamical framework, which considers nervous activity in terms of phase spaces, particle trajectories, random walks, attractors and/or paths at the edge of the chaos. This takes us from the thermodynamic free-energy, to the realm

  7. Activation of complement by plicatic acid, the chemical compound responsible for asthma due to western red cedar (Thuja plicata).

    Science.gov (United States)

    Chan-Yeung, M; Giclas, P C; Henson, P M

    1980-05-01

    Plicatic acid, a low-molecular-weight compound responsible for western red cedar (Thuja plicata) asthma was tested for its ability to activate complement and to generate chemotactic activity from pooled normal human serum (NHS). Dose-dependent complement consumption was found as determined by hemolytic assay (CH50). Activation of complement by plicatic acid was also confirmed by the demonstration of conversion of C3 to C3b on immunoelectrophoresis. This activation was completely prevented by pretreating the serum with either edetate (EDTA) or ethylene glycol tetraacetic acid (EGTA), suggesting that complement was activated via the classical pathway. No conversion of factor B was seen in any of the samples. Leukocyte chemotactic activity was also generated when serum was incubated with plicatic acid. The consumption of C3 and CH50 was unimpaired in two samples of serum from patients with severe, untreated hypogammaglobulinemia and thus appears to be immunoglobulin independent. These observations suggest that plicatic acid could activate complement in vivo, thereby inducing an inflammatory response in the airways and contributing to the higher prevalence of industrial chronic bronchitis in exposed subjects. The pathogenetic role of complement activation in red cedar asthma has yet to elucidated.

  8. Functional structure of spontaneous sleep slow oscillation activity in humans.

    Directory of Open Access Journals (Sweden)

    Danilo Menicucci

    Full Text Available BACKGROUND: During non-rapid eye movement (NREM sleep synchronous neural oscillations between neural silence (down state and neural activity (up state occur. Sleep Slow Oscillations (SSOs events are their EEG correlates. Each event has an origin site and propagates sweeping the scalp. While recent findings suggest a SSO key role in memory consolidation processes, the structure and the propagation of individual SSO events, as well as their modulation by sleep stages and cortical areas have not been well characterized so far. METHODOLOGY/PRINCIPAL FINDINGS: We detected SSO events in EEG recordings and we defined and measured a set of features corresponding to both wave shapes and event propagations. We found that a typical SSO shape has a transition to down state, which is steeper than the following transition from down to up state. We show that during SWS SSOs are larger and more locally synchronized, but less likely to propagate across the cortex, compared to NREM stage 2. Also, the detection number of SSOs as well as their amplitudes and slopes, are greatest in the frontal regions. Although derived from a small sample, this characterization provides a preliminary reference about SSO activity in healthy subjects for 32-channel sleep recordings. CONCLUSIONS/SIGNIFICANCE: This work gives a quantitative picture of spontaneous SSO activity during NREM sleep: we unveil how SSO features are modulated by sleep stage, site of origin and detection location of the waves. Our measures on SSOs shape indicate that, as in animal models, onsets of silent states are more synchronized than those of neural firing. The differences between sleep stages could be related to the reduction of arousal system activity and to the breakdown of functional connectivity. The frontal SSO prevalence could be related to a greater homeostatic need of the heteromodal association cortices.

  9. Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Michael Huber

    2006-11-01

    Full Text Available BACKGROUND: To explore the possibility that antibody-mediated complement lysis contributes to viremia control in HIV-1 infection, we measured the activity of patient plasma in mediating complement lysis of autologous primary virus. METHODS AND FINDINGS: Sera from two groups of patients-25 with acute HIV-1 infection and 31 with chronic infection-were used in this study. We developed a novel real-time PCR-based assay strategy that allows reliable and sensitive quantification of virus lysis by complement. Plasma derived at the time of virus isolation induced complement lysis of the autologous virus isolate in the majority of patients. Overall lysis activity against the autologous virus and the heterologous primary virus strain JR-FL was higher at chronic disease stages than during the acute phase. Most strikingly, we found that plasma virus load levels during the acute but not the chronic infection phase correlated inversely with the autologous complement lysis activity. Antibody reactivity to the envelope (Env proteins gp120 and gp41 were positively correlated with the lysis activity against JR-FL, indicating that anti-Env responses mediated complement lysis. Neutralization and complement lysis activity against autologous viruses were not associated, suggesting that complement lysis is predominantly caused by non-neutralizing antibodies. CONCLUSIONS: Collectively our data provide evidence that antibody-mediated complement virion lysis develops rapidly and is effective early in the course of infection; thus it should be considered a parameter that, in concert with other immune functions, steers viremia control in vivo.

  10. Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner

    Science.gov (United States)

    Schafer, Dorothy P; Lehrman, Emily K; Kautzman, Amanda G; Koyama, Ryuta; Mardinly, Alan R; Yamasaki, Ryo; Ransohoff, Richard M; Greenberg, Michael E; Barres, Ben A; Stevens, Beth

    2012-01-01

    SUMMARY Microglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses. PMID:22632727

  11. Anti-complement activity in the saliva of phlebotomine sand flies and other haematophagous insects.

    Science.gov (United States)

    Cavalcante, R R; Pereira, M H; Gontijo, N F

    2003-07-01

    The saliva of haematophagous insects has a series of pharmacological activities which may favour blood feeding. In the present study, an inhibitory effect on the complement system was observed in salivary extracts obtained from the phlebotomine sand flies Lutzomyia longipalpis and Lu. migonei. Saliva from Lu. longipalpis was capable of inhibiting both the classical and alternative pathways, while that from Lu. migonei acted only on the former. Other haematophagous insect species were screened for inhibition of the classical pathway. The triatomine bugs Panstrongylus megistus, Triatoma brasiliensis and Rhodnius prolixus were also able to inhibit the classical pathway whereas the mosquito Aedes aegyti and flea Ctenocephalides felis were not. The activity of Lu. longipalpis saliva on the classical pathway was partially characterized. The inhibitor is a protein of Mr 10000-30000 Da, which is very resistant to denaturation by heat. The inhibition of the complement system by phlebotomine sand flies may have a role in the transmission of Leishmania to the vertebrate hosts. The inhibitor molecule is thus a promising component of a vaccine to target salivary immunomodulators.

  12. Protein adsorption and complement activation for di-block copolymer nanoparticles.

    Science.gov (United States)

    Vauthier, Christine; Persson, Bjorn; Lindner, Peter; Cabane, Bernard

    2011-02-01

    Four types of nanoparticles with core-diffuse shell structures have been synthesized through self-assembly of PICBA-Dextran block copolymers. These nanoparticles are designed to carry pharmaceutically active molecules into the human body through injection into the blood stream. In this work, we have determined how the characteristics of the diffuse shell influence the adsorption of three types of proteins: Bovine Serum Albumin (BSA), fibrinogen, and a protein from the complement system that triggers recognition and elimination by macrophages. We have determined the structural characteristics of the diffuse shells using Nuclear Magnetic Resonance (NMR), Small Angle Neutron Scattering (SANS) and Quasi-Elastic Light Scattering (QELS). We have measured the adsorption of Bovine Serum Albumin (BSA) through Immunodiffusion methods, and found that it adsorbed in substantial amounts even when the distance between dextran chains at the core-diffuse shell interface is quite short. We have observed the aggregation of the nanoparticles induced by fibrinogen, and found that it was prevented when the density of dextran chains protruding from the core surface was sufficiently high. Finally we have measured the activation of the complement system by the nanoparticles, and found that it was also limited by the surface density of dextran chains that protrude from the core and by their mesh size within the diffuse shell. 2010 Elsevier Ltd. All rights reserved.

  13. Tamsulosin modulates, but does not abolish the spontaneous activity in the guinea pig prostate gland.

    Science.gov (United States)

    Chakrabarty, Basu; Dey, Anupa; Lam, Michelle; Ventura, Sabatino; Exintaris, Betty

    2015-06-01

    To examine the effects of the α1A -adrenoceptor antagonist, tamsulosin, on spontaneous contractile and electrical activity in the guinea-pig prostate gland. The effects of tamsulosin (0.1 and 0.3 nM) were investigated in adult and ageing male guinea pig prostate glands using conventional tension recording and electrophysiological intracellular microelectrode recording techniques. Tamsulosin reduced spontaneous activity, and had different age-dependent effects on adult and ageing guinea pigs at different concentrations. 0.1 nM tamsulosin caused a significantly greater reduction of spontaneous contractile and electrical activity in ageing guinea pigs in comparison to adult guinea pigs. In contrast, 0.3 nM tamsulosin had a significantly greater reduction of spontaneous contractile and electrical activity in adult guinea pigs in comparison to ageing guinea pigs. This study demonstrates that tamsulosin can modulate spontaneous myogenic stromal contractility and the underlying spontaneous electrical activity; tamsulosin does not block spontaneous activity. This reduction in spontaneous activity suggests that downstream cellular mechanisms underlying smooth muscle tone are being targeted, and these may represent novel therapeutic targets to better treat benign prostatic hyperplasia. © 2014 Wiley Periodicals, Inc.

  14. IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis.

    Science.gov (United States)

    Cipolla, Ellyse; Fisher, Amanda J; Gu, Hongmei; Mickler, Elizabeth A; Agarwal, Manisha; Wilke, Carol A; Kim, Kevin K; Moore, Bethany B; Vittal, Ragini

    2017-12-01

    Interleukin 17A (IL-17A) and complement (C') activation have each been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have reported that IL-17A induces epithelial injury via TGF-β in murine bronchiolitis obliterans; that TGF-β and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates lung fibrosis. In the present study, we investigated the role of IL-17A in regulating C' in lung fibrosis. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that IL-17A (100 ng/ml; 24 h; n = 5 donor lungs) induces C' components (C' factor B, C3 , and GPCR kinase isoform 5), cytokines ( IL8 , -6 , and -1B ), and cytokine ligands ( CXCL1 , -2 , -3 , -5 , -6 , and -16 ). IL-17A induces protein and mRNA regulation of C' components and the synthesis of active C' 3a (C3a) in normal primary human alveolar type II epithelial cells (AECs). Wild-type mice subjected to IL-17A neutralization and IL-17A knockout ( il17a -/- ) mice were protected against bleomycin (BLEO)-induced fibrosis and collagen deposition. Further, BLEO-injured il17a -/- mice had diminished levels of circulating Krebs Von Den Lungen 6 (alveolar epithelial injury marker), local caspase-3/7, and local endoplasmic reticular stress-related genes. BLEO-induced local C' activation [C3a, C5a, and terminal C' complex (C5b-9)] was attenuated in il17a -/- mice, and IL-17A neutralization prevented the loss of epithelial C' inhibitors (C' receptor-1 related isoform Y and decay accelerating factor), and an increase in local TUNEL levels. RNAi-mediated gene silencing of il17a in fibrotic mice arrested the progression of lung fibrosis, attenuated cellular apoptosis (caspase-3/7) and lung deposition of collagen and C' (C5b-9). Compared to normals, plasma from IPF patients showed significantly higher hemolytic activity. Our findings demonstrate that limiting complement activation by

  15. Retinal pigment epithelial cells upregulate expression of complement factors after co-culture with activated T cells

    DEFF Research Database (Denmark)

    Juel, Helene Bæk; Kaestel, Charlotte; Folkersen, Lasse

    2011-01-01

    In this study we examined the effect of T cell-derived cytokines on retinal pigment epithelial (RPE) cells with respect to expression of complement components. We used an in vitro co-culture system in which CD3/CD28-activated human T cells were separated from the human RPE cell line (ARPE-19......) by a membrane. Differential gene expression in the RPE cells of complement factor genes was identified using gene arrays, and selected gene transcripts were validated by q-RT-PCR. Protein expression was determined by ELISA and immunoblotting. Co-culture with activated T cells increased RPE mRNA and/or protein...... expression of complement components C3, factors B, H, H-like 1, CD46, CD55, CD59, and clusterin, in a dose-dependent manner. Soluble factors derived from activated T cells are capable of increasing expression of complement components in RPE cells. This is important for the further understanding...

  16. Increased activity of the complement system in cerebrospinal fluid of the patients with Non-HIV Cryptococcal meningitis.

    Science.gov (United States)

    Shen, Lei; Zheng, Jianming; Wang, Yan; Zhu, Mengqi; Zhu, Haoxiang; Cheng, Qi; Li, Qian

    2017-01-04

    Cryptococcal meningitis (CM) has been known to lead to significant morbidity and mortality. The relative contribution of the complement system in protection and pathogenesis during CM remains largely unknown. The purpose of this study was to evaluate the baseline complement component profiles in human cerebrospinal fluid (CSF) and plasma from non-HIV patients with CM, and therefore to provide insights of possible roles of the complement system in CM. CSF and blood samples from forty two CM patients not infected with HIV and thirteen non-CM control patients (Ctrl) were retrospectively selected and evaluated from the patients admitted to the hospital with a suspected diagnosis of CM. CSF and blood samples were collected at the admission. Enzyme-linked immunosorbent assay (ELISA) for complement components, cytokine IL-12 and western blot for C3 activation were performed on CSF and plasma samples. The levels of complement C1q, factor B (FB), mannose binding lectin (MBL), C2, C3, C4, C5, C4 binding protein (C4BP), Factor I (FI), Factor H (FH), sC5b-9 in CSF and plasma samples were compared. Pearson's correlation coefficients were calculated on variables between complement components and the levels of total protein in the CSF samples. Our data demonstrated that the CSF levels of complement components of C1q, FB, MBL as well as complement pathway factors sC5b-9 and complement regulator FH were all elevated in patients with CM as compared to the controls, CSF C3 breakdown products iC3b were found in both CSF and plasma samples of the CM patients. A positive correlation was found between the levels of CSF protein and MBL, C1q or FB. The activity of the complement system in CSF was increased in non-HIV patients with CM. C1q, MBL and FB are the important participants in the complement activation in CM. The relative contribution of each of the specific complement pathways and complement cascades in protection and inflammation resolution against CM warrant further investigation.

  17. Spontaneous physical activity protects against fat mass gain.

    Science.gov (United States)

    Teske, J A; Billington, C J; Kuskowski, M A; Kotz, C M

    2012-04-01

    It is unclear whether elevated spontaneous physical activity (SPA, very low-intensity physical activity) positively influences body composition long term. We determined whether SPA and caloric intake were differentially related to the growth curve trajectories of body weight, fat mass (FM) and fat-free mass (FFM) between obesity resistant and Sprague-Dawley rats at specific age intervals. Body composition, SPA and caloric intake were measured in selectively-bred obesity-resistant and out-bred Sprague-Dawley rats from 1 to 18 months. Data from development throughout maturation were analyzed by longitudinal growth curve modeling to determine the rate and acceleration of body weight, FM- and FFM-gain. Obesity-resistant rats had a lower rate of FM gain overall, a lower acceleration in body weight early in life, significantly greater SPA and lower cumulative caloric intake. Greater SPA in obesity-resistant rats was significantly associated with a lower rate of FM gain overall and lower acceleration in body weight early in life. Obesity resistant rats lost less FFM compared with Sprague-Dawley rats despite that obesity-resistant rats had a lower acceleration in FFM gain early in life. Obesity-resistant rats gained less FM and more FFM per gram body weight and were less energy efficient than Sprague-Dawley rats. Caloric intake was significantly and positively related to body weight, FM and FFM gain in both groups. Circadian patterns of caloric intake were group and age-dependent. Our data demonstrate that elevated and sustained SPA during development and over the lifespan are related to the reduced the rate of FM gain and may preserve FFM. These data support the idea that SPA level is a reproducible marker that reliably predicts propensity for obesity in rats, and that elevated levels of SPA maintained during the lifespan promote a lean phenotype.

  18. Noise-induced effects on multicellular biopacemaker spontaneous activity: Differences between weak and strong pacemaker cells

    Science.gov (United States)

    Aghighi, Alireza; Comtois, Philippe

    2017-09-01

    Self-organization of spontaneous activity of a network of active elements is important to the general theory of reaction-diffusion systems as well as for pacemaking activity to initiate beating of the heart. Monolayer cultures of neonatal rat ventricular myocytes, consisting of resting and pacemaker cells, exhibit spontaneous activation of their electrical activity. Similarly, one proposed approach to the development of biopacemakers as an alternative to electronic pacemakers for cardiac therapy is based on heterogeneous cardiac cells with resting and spontaneously beating phenotypes. However, the combined effect of pacemaker characteristics, density, and spatial distribution of the pacemaker cells on spontaneous activity is unknown. Using a simple stochastic pattern formation algorithm, we previously showed a clear nonlinear dependency of spontaneous activity (occurrence and amplitude of spontaneous period) on the spatial patterns of pacemaker cells. In this study, we show that this behavior is dependent on the pacemaker cell characteristics, with weaker pacemaker cells requiring higher density and larger clusters to sustain multicellular activity. These multicellular structures also demonstrated an increased sensitivity to voltage noise that favored spontaneous activity at lower density while increasing temporal variation in the period of activity. This information will help researchers overcome the current limitations of biopacemakers.

  19. Possible role of complement activation in renal impairment in trichloroethylene-sensitized guinea pigs

    International Nuclear Information System (INIS)

    Yu, Jun-Feng; Leng, Jing; Shen, Tong; Zhou, Cheng-Fan; Xu, Hui; Jiang, Tao; Xu, Shu-Hai; Zhu, Qi-Xing

    2012-01-01

    Recent studies have revealed that trichloroethylene (TCE) can induce occupational medicamentosa-like dermatitis (OMLD) with multi-system injuries, including liver, kidney and skin injuries, which can subsequently cause multiple organ failure later. But the mechanism of immune dysfunction leading to organ injury was rarely clarified. The present study was initiated to analyze the influence of trichloroethylene on renal injury and study the relevant mechanism in guinea pigs. Guinea pig maximization test (GPMT) was carried out. Inflammation on the guinea pigs’ skin was scored. Kidney function, urine protein and ultra-structural change of kidney were determined by biochemical detection and electron microscope. Deposition of complement 3 and membrane attack complex (MAC, C5b-9) were determined by immunohistochemistry. Erythema and edema of skin impairment were observed in TCE sensitized groups, and sensitization rate was 63.16%. Through electron microscope, tubular epithelial cell mitochondrial swelling, vacuolar degeneration and atrophy of microvillus were observed in TCE sensitized groups. The parameters of urease and urinary protein elevated markedly, and a high degree of C3 and MAC deposition was found in the renal tubular epithelial cells in TCE sensitized groups. By demonstrating that TCE and its metabolites can cause the deposition of C3 and MAC in renal epithelial cells, we found that activated complement system may be the mechanism of the acceleration and the development of TCE-induced kidney disease.

  20. Spontaneous sigh rates during sedentary activity: watching television vs reading.

    Science.gov (United States)

    Hark, William T; Thompson, William M; McLaughlin, Timothy E; Wheatley, Lisa M; Platts-Mills, Thomas A E

    2005-02-01

    Spontaneous sighs are thought to play an important role in preventing atelectasis and in regulating airway tone. Recent studies have provided a mechanism by which expansion of the lungs could cause relaxation of smooth muscle. To investigate breathing patterns during 2 forms of sedentary behavior: reading and watching television. Breathing patterns were monitored for 1 to 2 hours to document respiratory rates and sigh rates. Each participant was monitored while reading and while watching a movie on videotape. During the first experiment (17 controls), metabolic rates were also measured. In the second experiment (18 controls and 9 patients with mild-to-moderate asthma), only breathing patterns were monitored. There were no significant differences in respiratory or metabolic rates between the 2 activities. In contrast, in the first experiment, 13 of 17 controls had lower sigh rates while watching a videotape than while reading (P < .01). In the second experiment, the sigh rate was significantly lower overall while watching a videotape (mean, 13.7 sighs per hour; range, 1.8-26.0 sighs per hour) than while reading (mean, 19.3 sighs per hour; range, 7.7-30.0 sighs per hour) (P < .001). A similar decrease was observed in patients with asthma (P < .01). Given that many children and adults watch television for 5 or more hours per day, breathing patterns during this time may be relevant to lung function. Our results demonstrate that prolonged periods of watching a videotape are associated with lower sigh rates than while reading. Further research is needed to determine whether these changes are relevant to increased bronchial reactivity.

  1. Distinct polymer architecture mediates switching of complement activation pathways at the nanosphere-serum interface: implications for stealth nanoparticle engineering.

    Science.gov (United States)

    Hamad, Islam; Al-Hanbali, Othman; Hunter, A Christy; Rutt, Kenneth J; Andresen, Thomas L; Moghimi, S Moein

    2010-11-23

    Nanoparticles with surface projected polyethyleneoxide (PEO) chains in "mushroom-brush" and "brush" configurations display stealth properties in systemic circulation and have numerous applications in site-specific targeting for controlled drug delivery and release as well as diagnostic imaging. We report on the "structure-activity" relationship pertaining to surface-immobilized PEO of various configurations on model nanoparticles, and the initiation of complement cascade, which is the most ancient component of innate human immunity, and its activation may induce clinically significant adverse reactions in some individuals. Conformational states of surface-projected PEO chains, arising from the block copolymer poloxamine 908 adsorption, on polystyrene nanoparticles trigger complement activation differently. Alteration of copolymer architecture on nanospheres from mushroom to brush configuration not only switches complement activation from C1q-dependent classical to lectin pathway but also reduces the level of generated complement activation products C4d, Bb, C5a, and SC5b-9. Also, changes in adsorbed polymer configuration trigger alternative pathway activation differently and through different initiators. Notably, the role for properdin-mediated activation of alternative pathway was only restricted to particles displaying PEO chains in a transition mushroom-brush configuration. Since nanoparticle-mediated complement activation is of clinical concern, our findings provide a rational basis for improved surface engineering and design of immunologically safer stealth and targetable nanosystems with polymers for use in clinical medicine.

  2. Contribution of the complement Membrane Attack Complex to the bactericidal activity of human serum.

    Science.gov (United States)

    Berends, Evelien T M; Mohan, Sarbani; Miellet, Willem R; Ruyken, Maartje; Rooijakkers, Suzan H M

    2015-06-01

    Direct killing of Gram-negative bacteria by serum is usually attributed to the Membrane Attack Complex (MAC) that is assembled upon activation of the complement system. In serum bactericidal assays, the activity of the MAC is usually blocked by a relatively unspecific method in which certain heat-labile complement components are inactivated at 56°C. The goal of this study was to re-evaluate MAC-driven lysis towards various Gram-negative bacteria. Instead of using heat-treatment, we included the highly specific C5 cleavage inhibitor OmCI to specifically block the formation of the MAC. Using a C5 conversion analysis tool, we monitored the efficacy of the inhibitor during the incubations. Our findings indicate that 'serum-sensitive' bacteria are not necessarily killed by the MAC. Other heat-labile serum factors can contribute to serum bactericidal activity. These unidentified factors are most potent at serum concentrations of 10% and higher. Furthermore, we also find that some bacteria can be killed by the MAC at a slower rate. Our data demonstrate the requirement for the use of specific inhibitors in serum bactericidal assays and revealed that the classification of serum-sensitive and resistant strains needs re-evaluation. Moreover, it is important to determine bacterial viability at multiple time intervals to differentiate serum susceptibility between bacterial species. In conclusion, these data provide new insights into bacterial killing by the humoral immune system and may guide future vaccine development studies for the treatment of pathogenic serum-resistant bacteria. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Peptide Inhibitor of Complement C1 Inhibits the Peroxidase Activity of Hemoglobin and Myoglobin

    Directory of Open Access Journals (Sweden)

    Pamela S. Hair

    2017-01-01

    Full Text Available Hemoglobin is the natural carrier of oxygen in red blood cells (RBCs. While intracellular hemoglobin provides life-sustaining oxygen transport, extracellular free hemoglobin displays toxicity due to inherent peroxidase activity generating reactive oxygen species that subsequently react with the hemoglobin molecule to produce toxic heme degradation products resulting in free radicals, oxidative stress damage, and lipid peroxidation. We have recently demonstrated that Peptide Inhibitor of Complement C1 (PIC1 inhibits peroxidase activity of the heme-based enzyme myeloperoxidase. To elucidate whether PIC1 could inhibit peroxidase activity of hemoglobin, we evaluated the consequence of PIC1 on RBC lysates, methemoglobin, and myoglobin using tetramethylbenzidine (TMB as an oxidation target. PIC1 reversibly and dose-dependently prevented TMB oxidation to tetramethylbenzidine diimine by RBC lysates, methemoglobin, and myoglobin, having comparable activity to the inhibitor 4-aminobenzoic acid hydrazide. PIC1 inhibited TMB oxidation of RBC lysates similar to L-cysteine suggesting that the two cysteine residues contained in PIC1 may mediate peroxidase activity. PIC1 also inhibited heme destruction by NaOCl for RBC lysates, hemoglobin, and myoglobin as assayed by preservation of the Soret absorbance peak in the presence of NaOCl and reduction in free iron release. In conclusion, PIC1 inhibits peroxidase activity of hemoglobin and myoglobin likely via an antioxidant mechanism.

  4. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement

    DEFF Research Database (Denmark)

    Frederiksen, Pernille Dorthea; Thiel, Steffen; Larsen, Claus Bindslev

    2005-01-01

    Ficolins play a role in the innate immune defence as pathogen-associated molecular pattern recognition molecules. Three ficolins are found in humans: H-ficolin, L-ficolin and M-ficolin. L-ficolin and H-ficolin circulate in blood in complexes with mannan-binding lectin-associated serine proteases...... (MASPs) and are capable of activating the complement system. L-ficolin shows affinity for acetylated compounds and binds to various capsulated strains of bacteria. H-ficolin has been shown to bind Aerococcus viridans. Less is known about M-ficolin, but it is thought to be present only on monocytes. We...... system. We developed a monoclonal rat anti-human-M/L-ficolin antibody and verified by flow cytometric analysis the presence of ficolin on the surface of peripheral blood monocytes....

  5. Investigation of the activation of the temporalis and masseter muscles in voluntary and spontaneous smile production.

    Science.gov (United States)

    Steele, Jessica E; Woodcock, Ian R; Murphy, Adrian D; Ryan, Monique M; Penington, Tony J; Coombs, Christopher J

    2018-03-06

    Masticatory muscles or their nerve supply are options for facial reanimation surgery, but their ability to create spontaneous smile has been questioned. This study assessed the percentage of healthy adults who activate the temporalis and masseter muscles during voluntary and spontaneous smile. Healthy volunteer adults underwent electromyography (EMG) studies of the temporalis and masseter muscles during voluntary and spontaneous smile. Responses were repeated three times and recorded as negative, weakly positive, or strongly positive according to the activity observed. The best response was used for analysis. Thirty healthy adults (median age: 34 years, range: 25-69 years) participated. Overall, 92% of the masseter muscles were activated during voluntary smile (22% strong, 70% weak). Seventy-seven percent of the masseter muscles were activated in spontaneous smile (12% strong, 65% weak). The temporalis muscle was activated in 62% of responses in voluntary smile (15% strong, 47% weak) and in 45% of responses in spontaneous smile (13% strong, 32% weak). No significant difference was found for males vs females or closed vs open mouth smiles. There was no significant difference in responses between voluntary and spontaneous smiles for the temporalis and masseter muscles, and their use in voluntary smile did not predict activity in spontaneous smile. Our study has shown that masseter and temporalis are active in a high proportion of healthy adults during voluntary and spontaneous smiles. Further work is required to determine the relationship between preoperative donor muscle activation and postoperative spontaneous smile, and whether masticatory muscle activity can be upregulated with appropriate training. Copyright © 2018. Published by Elsevier Ltd.

  6. Bothrops asper snake venom and its metalloproteinase BaP-1 activate the complement system. Role in leucocyte recruitment.

    Science.gov (United States)

    Farsky, S H; Gonçalves, L R; Gutiérrez, J M; Correa, A P; Rucavado, A; Gasque, P; Tambourgi, D V

    2000-01-01

    The venom of the snake Bothrops asper, the most important poisonous snake in Central America, evokes an inflammatory response, the mechanisms of which are not well characterized. The objectives of this study were to investigate whether B. asper venom and its purified toxins--phospholipases and metalloproteinase--activate the complement system and the contribution of the effect on leucocyte recruitment. In vitro chemotaxis assays were performed using Boyden's chamber model to investigate the ability of serum incubated with venom and its purified toxins to induce neutrophil migration. The complement consumption by the venom was evaluated using an in vitro haemolytic assay. The importance of complement activation by the venom on neutrophil migration was investigated in vivo by injecting the venom into the peritoneal cavity of C5-deficient mice. Data obtained demonstrated that serum incubated with crude venom and its purified metalloproteinase BaP-1 are able to induce rat neutrophil chemotaxis, probably mediated by agent(s) derived from the complement system. This hypothesis was corroborated by the capacity of the venom to activate this system in vitro. The involvement of C5a in neutrophil chemotaxis induced by venom-activated serum was demonstrated by abolishing migration when neutrophils were pre-incubated with antirat C5a receptor antibody. The relevance of the complement system in in vivo leucocyte mobilization was further demonstrated by the drastic decrease of this response in C5-deficient mice. Pre-incubation of serum with the soluble human recombinant complement receptor type 1 (sCR 1) did not prevent the response induced by the venom, but abolished the migration evoked by metalloproteinase-activated serum. These data show the role of the complement system in bothropic envenomation and the participation of metalloproteinase in the effect. Also, they suggest that the venom may contain other component(s) which can cause direct activation of C5a. PMID:11200361

  7. Bothrops asper snake venom and its metalloproteinase BaP–1 activate the complement system. Role in leucocyte recruitment

    Directory of Open Access Journals (Sweden)

    Sandra H. P. Farsky

    2000-01-01

    Full Text Available The venom of the snake Bothrops asper, the most important poisonous snake in Central America, evokes an inflammatory response, the mechanisms of which are not well characterized. The objectives of this study were to investigate whether B. asper venom and its purified toxins – phospholipases and metalloproteinase – activate the complement system and the contribution of the effect on leucocyte recruitment. In vitro chemotaxis assays were performed using Boyden's chamber model to investigate the ability of serum incubated with venom and its purified toxins to induce neutrophil migration. The complement consumption by the venom was evaluated using an in vitro haemolytic assay. The importance of complement activation by the venom on neutrophil migration was investigated in vivo by injecting the venom into the peritoneal cavity of C5-deficient mice. Data obtained demonstrated that serum incubated with crude venom and its purified metalloproteinase BaP–1 are able to induce rat neutrophil chemotaxis, probably mediated by agent(s derived from the complement system. This hypothesis was corroborated by the capacity of the venom to activate this system in vitro. The involvement of C5a in neutrophil chemotaxis induced by venom-activated serum was demonstrated by abolishing migration when neutrophils were pre-incubated with antirat C5a receptor antibody. The relevance of the complement system in in vivo leucocyte mobilization was further demonstrated by the drastic decrease of this response in C5-deficient mice. Pre-incubation of serum with the soluble human recombinant complement receptor type 1 (sCR 1 did not prevent the response induced by the venom, but abolished the migration evoked by metalloproteinase-activated serum. These data show the role of the complement system in bothropic envenomation and the participation of metalloproteinase in the effect. Also, they suggest that the venom may contain other component(s which can cause direct activation

  8. Spontaneous activity in the developing mammalian retina: Form and function

    Science.gov (United States)

    Butts, Daniel Allison

    Spontaneous neuronal activity is present in the immature mammalian retina during the initial stages of visual system development, before the retina is responsive to light. This activity consists of bursts of action potentials fired by retinal ganglion cells, and propagates in a wavelike manner across the inner plexiform layer of the retina. Unlike waves in other neural systems, retinal waves have large variability in both their rate and direction of propagation, and individual waves only propagate across small regions of the retina. The unique properties of retinal activity arise from dynamic processes within the developing retina, and produce characteristic spatiotemporal properties. These spatiotemporal properties are of particular interest, since they are believed to play a role in visual system development. This dissertation addresses the complex spatiotemporal patterning of the retinal waves from two different perspectives. First, it proposes how the immature circuitry of the developing retina generates these patterns of activity. In order to reproduce the distinct spatiotemporal properties observed in experiments, a model of the immature retinal circuitry must meet certain requirements, which are satisfied by a coarse-grained model of the developing retina that we propose. Second, this dissertation addresses how the particular spatiotemporal patterning of the retinal waves provides information to the rest of the visual system and, as a result, can be used to guide visual system development. By measuring the properties of this information, we place constraints on the developmental mechanisms that use this activity, and show how the particular spatiotemporal properties of the retinal waves provide this information. Together, this dissertation demonstrates how the apparent complexity of retinal wave patterning can be understood both through the immature circuitry that generates it, and through the developmental mechanisms that may use it. The first three

  9. Specific, sensitive, precise, and rapid functional chromogenic assay of activated first complement component (C1) in plasma

    DEFF Research Database (Denmark)

    Munkvad, S; Jespersen, J; Sidelmann, Johannes Jakobsen

    1990-01-01

    We present a new functional assay for the first complement component (C1) in plasma, based on its activation by inhibition of the C1-esterase inhibitor (C1-inh) when monospecific antiserum to C1-inh is added to the plasma. After maximal activation, we can determine the concentration of activated ...

  10. Heterocomplexes of Mannose-binding Lectin and the Pentraxins PTX3 or Serum Amyloid P Component Trigger Cross-activation of the Complement System

    DEFF Research Database (Denmark)

    Ma, Y. J.; Doni, A.; Skjoedt, M.-o.

    2011-01-01

    The long pentraxin 3 (PTX3), serum amyloid P component (SAP), and C-reactive protein belong to the pentraxin family of pattern recognition molecules involved in tissue homeostasis and innate immunity. They interact with C1q from the classical complement pathway. Whether this also occurs via...... complement pathways via recruitment of C1q, whereas SAP-enhanced complement activation occurs via a hitherto unknown mechanism. Taken together, MBL-pentraxin heterocomplexes trigger cross-activation of the complement system....

  11. Complement component C3 and butyrylcholinesterase activity are associated with neurodegeneration and clinical disability in multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Shahin Aeinehband

    Full Text Available Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE, an enzyme hydrolyzing acetylcholine (ACh, a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL, a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE and BuChE, in cerebrospinal fluid (CSF from patients with MS (n = 48 and non-inflammatory controls (n = 18. C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

  12. Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation

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    Huber-Lang Markus

    2006-07-01

    Full Text Available Abstract Background Neuroprotective strategies for prevention of the neuropathological sequelae of traumatic brain injury (TBI have largely failed in translation to clinical treatment. Thus, there is a substantial need for further understanding the molecular mechanisms and pathways which lead to secondary neuronal cell death in the injured brain. The intracerebral activation of the complement cascade was shown to mediate inflammation and tissue destruction after TBI. However, the exact pathways of complement activation involved in the induction of posttraumatic neurodegeneration have not yet been assessed. In the present study, we investigated the role of the alternative complement activation pathway in contributing to neuronal cell death, based on a standardized TBI model in mice with targeted deletion of the factor B gene (fB-/-, a "key" component required for activation of the alternative complement pathway. Results After experimental TBI in wild-type (fB+/+ mice, there was a massive time-dependent systemic complement activation, as determined by enhanced C5a serum levels for up to 7 days. In contrast, the extent of systemic complement activation was significantly attenuated in fB-/- mice (P fB-/- vs. fB+/+; t = 4 h, 24 h, and 7 days after TBI. TUNEL histochemistry experiments revealed that posttraumatic neuronal cell death was clearly reduced for up to 7 days in the injured brain hemispheres of fB-/- mice, compared to fB+/+ littermates. Furthermore, a strong upregulation of the anti-apoptotic mediator Bcl-2 and downregulation of the pro-apoptotic Fas receptor was detected in brain homogenates of head-injured fB-/- vs. fB+/+ mice by Western blot analysis. Conclusion The alternative pathway of complement activation appears to play a more crucial role in the pathophysiology of TBI than previously appreciated. This notion is based on the findings of (a the significant attenuation of overall complement activation in head-injured fB-/- mice, as

  13. The paralogous salivary anti-complement proteins IRAC I and IRAC II encoded by Ixodes ricinus ticks have broad and complementary inhibitory activities against the complement of different host species.

    Science.gov (United States)

    Schroeder, Hélène; Daix, Virginie; Gillet, Laurent; Renauld, Jean-Christophe; Vanderplasschen, Alain

    2007-02-01

    Several observations suggest that inhibition of the host complement alternative pathway by Ixodes tick saliva is crucial to achieve blood feeding. We recently described two paralogous anti-complement proteins called Ixodes ricinus anti-complement (IRAC) proteins I and II co-expressed in I. ricinus salivary glands. Phylogenetic analyses suggested that these sequences were diversifying by a process of positive Darwinian selection, possibly leading to molecules with different biological properties. In the present study, we tested the hypothesis that each paralogue may have different inhibitory activities against the complement of different natural host species, thereby contributing to broaden the host range of I. ricinus ticks. IRAC I and IRAC II were tested against the complement of eight I. ricinus natural host species (six mammals and two birds). The results demonstrate that IRAC I and IRAC II have broad and complementary inhibition activities against the complement of different host species. This report is the first description of paralogous anti-complement molecules encoded by a pathogen with broad and complementary inhibitory activities against the complement of different host species.

  14. Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration

    Science.gov (United States)

    Johnson, Lincoln V.; Forest, David L.; Banna, Christopher D.; Radeke, Carolyn M.; Maloney, Michelle A.; Hu, Jane; Spencer, Christine N.; Walker, Aimee M.; Tsie, Marlene S.; Bok, Dean; Radeke, Monte J.; Anderson, Don H.

    2011-01-01

    We introduce a human retinal pigmented epithelial (RPE) cell-culture model that mimics several key aspects of early stage age-related macular degeneration (AMD). These include accumulation of sub-RPE deposits that contain molecular constituents of human drusen, and activation of complement leading to formation of deposit-associated terminal complement complexes. Abundant sub-RPE deposits that are rich in apolipoprotein E (APOE), a prominent drusen constituent, are formed by RPE cells grown on porous supports. Exposure to human serum results in selective, deposit-associated accumulation of additional known drusen components, including vitronectin, clusterin, and serum amyloid P, thus suggesting that specific protein–protein interactions contribute to the accretion of plasma proteins during drusen formation. Serum exposure also leads to complement activation, as evidenced by the generation of C5b-9 immunoreactive terminal complement complexes in association with APOE-containing deposits. Ultrastructural analyses reveal two morphologically distinct forms of deposits: One consisting of membrane-bounded multivescicular material, and the other of nonmembrane-bounded particle conglomerates. Collectively, these results suggest that drusen formation involves the accumulation of sub-RPE material rich in APOE, a prominent biosynthetic product of the RPE, which interacts with a select group of drusen-associated plasma proteins. Activation of the complement cascade appears to be mediated via the classical pathway by the binding of C1q to ligands in APOE-rich deposits, triggering direct activation of complement by C1q, deposition of terminal complement complexes and inflammatory sequelae. This model system will facilitate the analysis of molecular and cellular aspects of AMD pathogenesis, and the testing of new therapeutic agents for its treatment. PMID:21969589

  15. Abnormal Complement Activation and Inflammation in the Pathogenesis of Retinopathy of Prematurity

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    Sonika Rathi

    2017-12-01

    Full Text Available Retinopathy of prematurity (ROP is a neurovascular complication in preterm babies, leading to severe visual impairment, but the underlying mechanisms are yet unclear. The present study aimed at unraveling the molecular mechanisms underlying the pathogenesis of ROP. A comprehensive screening of candidate genes in preterms with ROP (n = 189 and no-ROP (n = 167 was undertaken to identify variants conferring disease susceptibility. Allele and genotype frequencies, linkage disequilibrium and haplotypes were analyzed to identify the ROP-associated variants. Variants in CFH (p = 2.94 × 10−7, CFB (p = 1.71 × 10−5, FBLN5 (p = 9.2 × 10−4, CETP (p = 2.99 × 10−5, and CXCR4 (p = 1.32 × 10−8 genes exhibited significant associations with ROP. Further, a quantitative assessment of 27 candidate proteins and cytokines in the vitreous and tear samples of babies with severe ROP (n = 30 and congenital cataract (n = 30 was undertaken by multiplex bead arrays and further validated by western blotting and zymography. Significant elevation and activation of MMP9 (p = 0.038, CFH (p = 2.24 × 10−5, C3 (p = 0.05, C4 (p = 0.001, IL-1ra (p = 0.0019, vascular endothelial growth factor (VEGF (p = 0.0027, and G-CSF (p = 0.0099 proteins were observed in the vitreous of ROP babies suggesting an increased inflammation under hypoxic condition. Along with inflammatory markers, activated macrophage/microglia were also detected in the vitreous of ROP babies that secreted complement component C3, VEGF, IL-1ra, and MMP-9 under hypoxic stress in a cell culture model. Increased expression of the inflammatory markers like the IL-1ra (p = 0.014, MMP2 (p = 0.0085, and MMP-9 (p = 0.03 in the tears of babies at different stages of ROP further demonstrated their potential role in disease progression. Based on these findings, we conclude that increased complement activation in the

  16. The Immunobiology of Immunoglobulin G4 and Complement Activation Pathways in IgG4-Related Disease.

    Science.gov (United States)

    Kawa, Shigeyuki

    2017-01-01

    High serum immunoglobulin (Ig) G4 concentration and abundant IgG4-bearing plasma cell infiltration are characteristic features in autoimmune pancreatitis (AIP). AIP is also complicated with a variety of other organ involvements that commonly share marked IgG4-bearing plasma cell infiltration, suggesting the existence of a systemic disease associated with IgG4 currently recognized as IgG4-related disease (IgG4-RD). However, it is controversial whether IgG4 plays a role in the pathogenesis of AIP or IgG4-RD through such characteristic attributes as Fab-arm exchange and rheumatoid factor (RF)-like activity. Hypocomplementemia has been observed in AIP and several other IgG4-RDs. Muraki et al. reported that complements C3 and C4 were decreased in 36 % of patients with AIP, which implicated the complement activation system in disease pathogenesis. AIP patients with a high level of immune complexes showed serum elevation of IgG4-type immune complexes in an active disease stage, elevated serum IgG1 concentration, and decreased C3 and C4 values. This inferred that while IgG4 may have had little contribution to complement activation, IgG1 played a prominent role via the classical pathway. On the other hand, Sugimoto et al. observed that polyethylene glycol-precipitated immune complexes from patients with IgG4-RD and hypocomplementemia had the ability to activate the complement system through both the classical and the mannose-binding lectin pathways and that IgG4 might participate in the complement activation system. Thus, debate continues on which complement activation systems are working in AIP and IgG4-RD and whether they are associated with the pathogenesis of these conditions.

  17. DELTAMETHRIN AND PERMETHRIN DECREASE SPONTANEOUS ACTIVITY IN NEURONAL NETWORKS IN VITRO.

    Science.gov (United States)

    Effects of pyrethroid insecticides on spontaneous electrical activity were investigated in primary cultures of cortical or spinal cord neurons grown on microelectrode arrays. Bicuculline (40 ¿M) was utilized to block fast GABAergic transmission, and concentration-dependent effect...

  18. The Neural Association between Tendency to Forgive and Spontaneous Brain Activity in Healthy Young Adults

    OpenAIRE

    Haijiang Li; Jiamei Lu

    2017-01-01

    The tendency to forgive (TTF) refers to one’s global dispositional level of forgiveness across situations and relationships. Previous brain imaging studies examined activation patterns underlying forgiving process, yet the association between individual differences in the TTF and spontaneous brain activity at resting-state remains unknown. In this study, resting-state functional magnetic resonance imaging (fMRI) was used to investigate the correlation between the TTF and spontaneous brain act...

  19. Endosulfan induces changes in spontaneous swimming activity and acetylcholinesterase activity of Jenynsia multidentata (Anablepidae, Cyprinodontiformes)

    Energy Technology Data Exchange (ETDEWEB)

    Ballesteros, M.L. [Facultad de Ciencias Exactas, Fisicas y Naturales, Catedra Diversidad Animal II, Universidad Nacional de Cordoba, Av. Velez Sarsfield 299, 5000 Cordoba (Argentina); Durando, P.E. [Facultad de Ciencias Exactas, Fisicas y Naturales, Departamento de Biologia, Catedra de Fisiologia Animal, Universidad Nacional de San Juan, Complejo ' Islas Malvinas' , Av. Jose I. de la Roza y Meglioli, Rivadavia, San Juan (Argentina); Nores, M.L. [Facultad de Ciencias Medicas, Universidad Nacional de Cordoba-CONICET, Ciudad Universitaria, Cordoba (Argentina); Diaz, M.P. [Facultad de Ciencias Medicas, Catedra de Estadistica y Bioestadistica, Escuela de Nutricion, Universidad Nacional de Cordoba, Pabellon Chile, Ciudad Universitaria, 5000 Cordoba (Argentina); Bistoni, M.A., E-mail: mbistoni@com.uncor.ed [Facultad de Ciencias Exactas, Fisicas y Naturales, Catedra Diversidad Animal II, Universidad Nacional de Cordoba, Av. Velez Sarsfield 299, 5000 Cordoba (Argentina); Wunderlin, D.A. [Facultad de Ciencias Quimicas, Dto. Bioquimica Clinica-CIBICI, Universidad Nacional de Cordoba-CONICET, Haya de la Torre esq. Medina Allende, Ciudad Universitaria, 5000 Cordoba (Argentina)

    2009-05-15

    We assessed changes in spontaneous swimming activity and acetylcholinesterase (AchE) activity of Jenynsia multidentata exposed to Endosulfan (EDS). Females of J. multidentata were exposed to 0.072 and 1.4 mug L{sup -1} EDS. Average speed and movement percentage were recorded during 48 h. We also exposed females to EDS at five concentrations between 0.072 and 1.4 mug L{sup -1} during 24 h, and measured the AchE activity in brain and muscle. At 0.072 mug L{sup -1} EDS swimming motility decreased relative to the control group after 45 h, while at 1.4 mug L{sup -1} EDS swimming motility decreased after 24 h. AchE activity significantly decreased in muscle when J. multidentata were exposed to EDS above 0.072 mug L{sup -1}, while no significant changes were observed in brain. Thus, changes in swimming activity and AchE activity in muscle are good biomarkers of exposure to EDS in J. multidentata. - This work reports changes observed in spontaneous swimming activity and AchE activity of Jenynsia multidentata exposed to sublethal concentrations of Endosulfan.

  20. Endosulfan induces changes in spontaneous swimming activity and acetylcholinesterase activity of Jenynsia multidentata (Anablepidae, Cyprinodontiformes)

    International Nuclear Information System (INIS)

    Ballesteros, M.L.; Durando, P.E.; Nores, M.L.; Diaz, M.P.; Bistoni, M.A.; Wunderlin, D.A.

    2009-01-01

    We assessed changes in spontaneous swimming activity and acetylcholinesterase (AchE) activity of Jenynsia multidentata exposed to Endosulfan (EDS). Females of J. multidentata were exposed to 0.072 and 1.4 μg L -1 EDS. Average speed and movement percentage were recorded during 48 h. We also exposed females to EDS at five concentrations between 0.072 and 1.4 μg L -1 during 24 h, and measured the AchE activity in brain and muscle. At 0.072 μg L -1 EDS swimming motility decreased relative to the control group after 45 h, while at 1.4 μg L -1 EDS swimming motility decreased after 24 h. AchE activity significantly decreased in muscle when J. multidentata were exposed to EDS above 0.072 μg L -1 , while no significant changes were observed in brain. Thus, changes in swimming activity and AchE activity in muscle are good biomarkers of exposure to EDS in J. multidentata. - This work reports changes observed in spontaneous swimming activity and AchE activity of Jenynsia multidentata exposed to sublethal concentrations of Endosulfan.

  1. Recombinant human complement component C2 produced in a human cell line restores the classical complement pathway activity in-vitro: an alternative treatment for C2 deficiency diseases

    Directory of Open Access Journals (Sweden)

    Martini Paolo GV

    2010-08-01

    Full Text Available Abstract Background Complement C2 deficiency is the most common genetically determined complete complement deficiency and is associated with a number of diseases. Most prominent are the associations with recurrent serious infections in young children and the development of systemic lupus erythematosus (SLE in adults. The links with these diseases reflect the important role complement C2 plays in both innate immunity and immune tolerance. Infusions with normal fresh frozen plasma for the treatment of associated disease have demonstrated therapeutic effects but so far protein replacement therapy has not been evaluated. Results Human complement C2 was cloned and expressed in a mammalian cell line. The purity of recombinant human C2 (rhC2 was greater than 95% and it was characterized for stability and activity. It was sensitive to C1s cleavage and restored classical complement pathway activity in C2-deficient serum both in a complement activation ELISA and a hemolytic assay. Furthermore, rhC2 could increase C3 fragment deposition on the human pathogen Streptococcus pneumoniae in C2-deficient serum to levels equal to those with normal serum. Conclusions Taken together these data suggest that recombinant human C2 can restore classical complement pathway activity and may serve as a potential therapeutic for recurring bacterial infections or SLE in C2-deficient patients.

  2. Patchwork-Type Spontaneous Activity in Neonatal Barrel Cortex Layer 4 Transmitted via Thalamocortical Projections

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    Hidenobu Mizuno

    2018-01-01

    Full Text Available Summary: Establishment of precise neuronal connectivity in the neocortex relies on activity-dependent circuit reorganization during postnatal development; however, the nature of cortical activity during this period remains largely unknown. Using two-photon calcium imaging of the barrel cortex in vivo during the first postnatal week, we reveal that layer 4 (L4 neurons within the same barrel fire synchronously in the absence of peripheral stimulation, creating a “patchwork” pattern of spontaneous activity corresponding to the barrel map. By generating transgenic mice expressing GCaMP6s in thalamocortical axons, we show that thalamocortical axons also demonstrate the spontaneous patchwork activity pattern. Patchwork activity is diminished by peripheral anesthesia but is mostly independent of self-generated whisker movements. The patchwork activity pattern largely disappeared during postnatal week 2, as even L4 neurons within the same barrel tended to fire asynchronously. This spontaneous L4 activity pattern has features suitable for thalamocortical (TC circuit refinement in the neonatal barrel cortex. : By two-photon calcium imaging of layer 4 neurons and thalamocortical axon terminals in neonatal mouse barrel cortex, Mizuno et al. find a patchwork-like spontaneous activity pattern corresponding to the barrel map, which may be important for thalamocortical circuit maturation. Keywords: activity-dependent development, spontaneous activity, synchronized activity, barrel cortex, thalamocortical axons, neonates, in vivo calcium imaging, awake, single-cell labeling, whisker monitoring

  3. Peptide inhibitor of complement C1 (PIC1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential

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    Julia A Sharp

    2014-08-01

    Full Text Available The classical pathway of complement plays multiple physiological roles including modulating immunological effectors initiated by adaptive immune responses as well as an essential homeostatic role in the clearance of damaged self-antigens. However, dysregulated classical pathway activation is associated with antibody-initiated, inflammatory diseases processes like cold agglutinin disease (CAD, acute intravascular hemolytic transfusion reaction (AIHTR and acute/hyperacute transplantation rejection. To date, only one putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH, is currently commercially available and its only approved indication is for replacement treatment in hereditary angioedema (HAE, which is predominantly a kinin pathway disease. Given the variety of disease conditions in which the classical pathway is implicated, development of therapeutics that specifically inhibit complement initiation represents a major unmet medical need. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement. In vitro studies have demonstrated that these Peptide Inhibitors of Complement C1 (PIC1 bind to the collagen-like region of the initiator molecule of the classical pathway, C1q. PIC1 binding to C1q blocks activation of the associated serine proteases (C1s-C1r-C1r-C1s and subsequent downstream complement activation. Rational design optimization of PIC1 has resulted in the generation of a highly potent derivative of fifteen amino acids. PIC1 inhibits classical pathway mediated complement activation in ABO incompatibility in vitro as well as inhibiting classical pathway activation in vivo in rats. This review will focus on the pre-clinical development of PIC1 and discuss its potential as a therapeutic in antibody-mediated classical pathway disease, specifically AIHTR.

  4. The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection.

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    Youssif M Ali

    Full Text Available The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan-binding lectin associated serine protease-2 (MASP-2 and shown that this mouse strain is unable to form the lectin pathway specific C3 and C5 convertases. Here we report that MASP-2 deficient mice (which can still activate complement via the classical pathway and the alternative pathway are highly susceptible to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse ficolin A, human L-ficolin, and collectin 11 in both species, but not mannan-binding lectin (MBL, are the pattern recognition molecules that drive lectin pathway activation on the surface of S. pneumoniae. We further show that pneumococcal opsonisation via the lectin pathway can proceed in the absence of C4. This study corroborates the essential function of MASP-2 in the lectin pathway and highlights the importance of MBL-independent lectin pathway activation in the host defense against pneumococci.

  5. Elevated levels of the complement activation product C4d in bronchial fluids for the diagnosis of lung cancer.

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    Daniel Ajona

    Full Text Available Molecular markers in bronchial fluids may contribute to the diagnosis of lung cancer. We previously observed a significant increase of C4d-containing complement degradation fragments in bronchoalveolar lavage (BAL supernatants from lung cancer patients in a cohort of 50 cases and 22 controls (CUN cohort. The present study was designed to determine the diagnostic performance of these complement fragments (hereinafter jointly referred as C4d in bronchial fluids. C4d levels were determined in BAL supernatants from two independent cohorts: the CU cohort (25 cases and 26 controls and the HUVR cohort (60 cases and 98 controls. A series of spontaneous sputum samples from 68 patients with lung cancer and 10 controls was also used (LCCCIO cohort. Total protein content, complement C4, complement C5a, and CYFRA 21-1 were also measured in all cohorts. C4d levels were significantly increased in BAL samples from lung cancer patients. The area under the ROC curve was 0.82 (95%CI = 0.71-0.94 and 0.67 (95%CI = 0.58-0.76 for the CU and HUVR cohorts, respectively. In addition, unlike the other markers, C4d levels in BAL samples were highly consistent across the CUN, CU and HUVR cohorts. Interestingly, C4d test markedly increased the sensitivity of bronchoscopy in the two cohorts in which cytological data were available (CUN and HUVR cohorts. Finally, in the LCCCIO cohort, C4d levels were higher in sputum supernatants from patients with lung cancer (area under the ROC curve: 0.7; 95%CI = 0.56-0.83. In conclusion, C4d is consistently elevated in bronchial fluids from lung cancer patients and may be used to improve the diagnosis of the disease.

  6. Perioperative functional activity of the alternative pathway of complement in patients with colonic cancer

    DEFF Research Database (Denmark)

    Baatrup, G; Zimmermann-Nielsen, E; Qvist, N

    1999-01-01

    OBJECTIVE: To investigate the functional capacity of the alternative pathway of complement in patients with cancer of the colon before, during, and after operation. DESIGN: Prospective study. SETTING: One university and two district hospitals, Denmark. SUBJECTS: 28 patients having elective...... or emergency operations for colonic cancer. INTERVENTIONS: Measurements of C3b fixing capacity of the alternative complement pathway in serum before, during, and after operation. MAIN OUTCOME MEASUREMENTS: The functional capacity of the alternative pathway of complement, and changes during operation. RESULTS......: The functional capacity of the alternative pathway in patients with cancer of the colon was above normal (p

  7. Thrombin activatable fibrinolysis inhibitor (TAFI) - A possible link between coagulation and complement activation in the antiphospholipid syndrome (APS).

    Science.gov (United States)

    Grosso, Giorgia; Vikerfors, Anna; Woodhams, Barry; Adam, Mariette; Bremme, Katarina; Holmström, Margareta; Ågren, Anna; Eelde, Anna; Bruzelius, Maria; Svenungsson, Elisabet; Antovic, Aleksandra

    2017-10-01

    Thrombosis and complement activation are pathogenic features of antiphospholipid syndrome (APS). Their molecular link is Plasma carboxypeptidase-B, also known as thrombin activatable fibrinolysis inhibitor (TAFIa), which plays a dual role: anti-fibrinolytic, by cleaving carboxyl-terminal lysine residues from partially degraded fibrin, and anti-inflammatory, by downregulating complement anaphylatoxins C3a and C5a. To investigate the levels of TAFI (proenzyme) and TAFIa (active enzyme) in relation to complement activation, fibrin clot permeability and fibrinolytic function in clinical and immunological subsets of 52 APS patients and 15 controls. TAFI (pAPS patients compared to controls. Furthermore, TAFIa was increased (pAPS patients affected by arterial thrombosis compared to other APS-phenotypes. Positive associations were found between TAFI and age, fibrinogen and C5a, and between TAFIa and age, fibrinogen and thrombomodulin. TAFI and TAFIa levels were increased in patients with APS as a potential response to complement activation. Interestingly, TAFI activation was associated with arterial thrombotic APS manifestations. Thus, TAFIa may be considered a novel biomarker for arterial thrombosis in APS. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. A serine protease isolated from the bristles of the Amazonic caterpillar, Premolis semirufa, is a potent complement system activator.

    Directory of Open Access Journals (Sweden)

    Isadora Maria Villas Boas

    Full Text Available The caterpillar of the moth Premolis semirufa, commonly named pararama, is found in the Brazilian Amazon region. Accidental contact with the caterpillar bristles causes an intense itching sensation, followed by symptoms of an acute inflammation, which last for three to seven days after the first incident. After multiple accidents a chronic inflammatory reaction, called "Pararamose", characterized by articular synovial membrane thickening with joint deformities common to chronic synovitis, frequently occurs. Although complement mediated inflammation may aid the host defense, inappropriate or excessive activation of the complement system and generation of anaphylatoxins can lead to inflammatory disorder and pathologies. The aim of the present study was to evaluate, in vitro, whether the Premolis semirufa's bristles extract could interfere with the human complement system.The bristles extract was able to inhibit the haemolytic activity of the alternative pathway, as well as the activation of the lectin pathway, but had no effect on the classical pathway, and this inhibition seemed to be caused by activation and consumption of complement components. The extract induced the production of significant amounts of all three anaphylatoxins, C3a, C4a and C5a, promoted direct cleavage of C3, C4 and C5 and induced a significant generation of terminal complement complexes in normal human serum. By using molecular exclusion chromatography, a serine protease of 82 kDa, which activates complement, was isolated from P. semirufa bristles extract. The protease, named here as Ps82, reduced the haemolytic activity of the alternative and classical pathways and inhibited the lectin pathway. In addition, Ps82 induced the cleavage of C3, C4 and C5 and the generation of C3a and C4a in normal human serum and it was capable to cleave human purified C5 and generate C5a. The use of Phenanthroline, metalloprotease inhibitor, in the reactions did not significantly interfere

  9. Ongoing spontaneous activity controls access to consciousness: a neuronal model for inattentional blindness.

    Directory of Open Access Journals (Sweden)

    Stanislas Dehaene

    2005-05-01

    Full Text Available Even in the absence of sensory inputs, cortical and thalamic neurons can show structured patterns of ongoing spontaneous activity, whose origins and functional significance are not well understood. We use computer simulations to explore the conditions under which spontaneous activity emerges from a simplified model of multiple interconnected thalamocortical columns linked by long-range, top-down excitatory axons, and to examine its interactions with stimulus-induced activation. Simulations help characterize two main states of activity. First, spontaneous gamma-band oscillations emerge at a precise threshold controlled by ascending neuromodulator systems. Second, within a spontaneously active network, we observe the sudden "ignition" of one out of many possible coherent states of high-level activity amidst cortical neurons with long-distance projections. During such an ignited state, spontaneous activity can block external sensory processing. We relate those properties to experimental observations on the neural bases of endogenous states of consciousness, and particularly the blocking of access to consciousness that occurs in the psychophysical phenomenon of "inattentional blindness," in which normal subjects intensely engaged in mental activity fail to notice salient but irrelevant sensory stimuli. Although highly simplified, the generic properties of a minimal network may help clarify some of the basic cerebral phenomena underlying the autonomy of consciousness.

  10. Ongoing spontaneous activity controls access to consciousness: a neuronal model for inattentional blindness.

    Science.gov (United States)

    Dehaene, Stanislas; Changeux, Jean-Pierre

    2005-05-01

    Even in the absence of sensory inputs, cortical and thalamic neurons can show structured patterns of ongoing spontaneous activity, whose origins and functional significance are not well understood. We use computer simulations to explore the conditions under which spontaneous activity emerges from a simplified model of multiple interconnected thalamocortical columns linked by long-range, top-down excitatory axons, and to examine its interactions with stimulus-induced activation. Simulations help characterize two main states of activity. First, spontaneous gamma-band oscillations emerge at a precise threshold controlled by ascending neuromodulator systems. Second, within a spontaneously active network, we observe the sudden "ignition" of one out of many possible coherent states of high-level activity amidst cortical neurons with long-distance projections. During such an ignited state, spontaneous activity can block external sensory processing. We relate those properties to experimental observations on the neural bases of endogenous states of consciousness, and particularly the blocking of access to consciousness that occurs in the psychophysical phenomenon of "inattentional blindness," in which normal subjects intensely engaged in mental activity fail to notice salient but irrelevant sensory stimuli. Although highly simplified, the generic properties of a minimal network may help clarify some of the basic cerebral phenomena underlying the autonomy of consciousness.

  11. Effect of b-Propiolactone treatment on the complement activation mediated by equine antisera

    Directory of Open Access Journals (Sweden)

    Rosalvo GUIDOLIN

    1997-03-01

    Full Text Available Reduction of complement activation through an alteration of the Fc fragment of immunoglobulins by b-propiolactone treatment was carried out in equine antisera raised against rabies virus, Bothrops venoms and diphtherial toxin. Results were evaluated by means of an anaphylactic test performed on guinea-pigs, and compared to the ones obtained with the same sera purified by saline precipitation (ammonium sulfate, followed or not by enzymatic digestion with pepsin. Protein purity levels for antibothropic serum were 184.5 mg/g and 488.5 mg/g in b-propiolactone treated and pepsin-digested sera, respectively. The recovery of specific activity was 100% and 62.5% when using antibothropic serum treated by b-propiolactone and pepsin digestion, respectively. The antidiphtherial and anti-rabies sera treated with b-propiolactone and pepsin presented protein purity levels of 5,698 and 7,179 Lf/g, 16,233 and 6,784 IU/g, respectively. The recovery of specific activity for these antisera were 88.8%, 77.7%, 100% and 36,5%, respectively. b-propiolactone treatment induced a reduction in complement activation, tested "in vivo", without significant loss of biological activity. This treatment can be used in the preparation of heterologous immunoglobulins for human use.Efeito do tratamento de antissoros equinos pela b-propiolactona na ativação do complemento. A redução da ativação do complemento através de uma alteração do fragmento Fc das imunoglobulinas pela b-propiolactona foi obtida em soros hiperimunes equinos antivirus rábico, venenos Bothrops e toxina diftérica. Os resultados foram avaliados por teste de anafilaxia em cobaias, e comparados com aqueles obtidos com os mesmos soros purificados por precipitação salina (sulfato de amônio, seguidos ou não por digestão enzimática com pepsina. Os níveis de pureza protéica foram para o soro antibotrópico de 184.5 mg/g e 488.5 mg/g tratado pela b-propiolactona e digeridos pela pepsina, respectivamente

  12. Sex differences in body fluid homeostasis: Sex chromosome complement influences on bradycardic baroreflex response and sodium depletion induced neural activity.

    Science.gov (United States)

    Vivas, L; Dadam, F M; Caeiro, X E

    2015-12-01

    Clinical and basic findings indicate that angiotensin II (ANG II) differentially modulates hydroelectrolyte and cardiovascular responses in male and female. But are only the activational and organizational hormonal effects to blame for such differences? Males and females not only differ in their sex (males are born with testes and females with ovaries) but also carry different sex chromosome complements and are thus influenced throughout life by different genomes. In this review, we discuss our recent studies in order to evaluate whether sex chromosome complement is in part responsible for gender differences previously observed in ANG II bradycardic-baroreflex response and sodium depletion-induced sodium appetite and neural activity. To test the hypothesis that XX or XY contributes to the dimorphic ANG II bradycardic-baroreflex response, we used the four core genotype mouse model, in which the effects of gonadal sex (testes or ovaries) and sex chromosome complement (XX or XY) are dissociated. The results indicate that ANG II bradycardic-baroreflex sexual dimorphic response may be ascribed to differences in sex chromosomes, indicating an XX-sex chromosome complement facilitatory bradycardic-baroreflex control of heart rate. Furthermore, we evaluated whether genetic differences within the sex chromosome complement may differentially modulate the known sexually dimorphic sodium appetite as well as basal or induced brain activity due to physiological stimulation of the renin-angiotensin system by furosemide and low-sodium treatment. Our studies demonstrate an organizational hormonal effect on sexually dimorphic induced sodium intake in mice, while at the brain level (subfornical organ and area postrema) we showed a sex chromosome complement effect in sodium-depleted mice, suggesting a sex chromosome gene participation in the modulation of neural pathways underlying regulatory response to renin-angiotensin stimulation. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Mechanisms of complement activation by dextran-coated superparamagnetic iron oxide (SPIO) nanoworms in mouse versus human serum

    DEFF Research Database (Denmark)

    Banda, Nirmal K; Mehta, Gaurav; Chao, Ying

    2014-01-01

    BACKGROUND: The complement system is a key component of innate immunity implicated in the neutralization and clearance of invading pathogens. Dextran coated superparamagnetic iron oxide (SPIO) nanoparticle is a promising magnetic resonance imaging (MRI) contrast agent. However, dextran SPIO has...... the CP, but that did not affect the total level of C3 deposition on the particles. CONCLUSIONS: There were important differences and similarities in the complement activation by SPIO NW in mouse versus human sera. Understanding the mechanisms of immune recognition of nanoparticles in mouse and human...... systems has important preclinical and clinical implications and could help design more efficient and safe nano-formulations....

  14. (IgA, IgG and IgM) levels and complement fixation activity in HIV

    African Journals Online (AJOL)

    The study was designed to evaluate the immunoglobulin A, G and M levels and complement fixation activity in HIV infected participants, who were not administered antiretroviral therapy (ART). Eighty (80) HIV infected participants, aged between 15 – 55 years (38 ±10 years), were recruited for the study. Forty five (45) of the ...

  15. A systematic analysis of the complement pathways in patients with neuromyelitis optica indicates alteration but no activation during remission

    DEFF Research Database (Denmark)

    Veszeli, Nóra; Füst, György; Csuka, Dorottya

    2014-01-01

    Neuromyelitis optica (NMO) is an autoimmune demyelinating inflammatory disorder, mediated by pathogenic autoantibodies against aquaporin 4 (AQP4), the main water channel of the central nervous system (CNS). NMO is characterized by local IgG deposition and complement activation within the CNS, but...

  16. Immune response to snake envenoming and treatment with antivenom; complement activation, cytokine production and mast cell degranulation.

    Directory of Open Access Journals (Sweden)

    Shelley F Stone

    Full Text Available BACKGROUND: Snake bite is one of the most neglected public health issues in poor rural communities worldwide. In addition to the clinical effects of envenoming, treatment with antivenom frequently causes serious adverse reactions, including hypersensitivity reactions (including anaphylaxis and pyrogenic reactions. We aimed to investigate the immune responses to Sri Lankan snake envenoming (predominantly by Russell's viper and antivenom treatment. METHODOLOGY/PRINCIPAL FINDINGS: Plasma concentrations of Interleukin (IL-6, IL-10, tumor necrosis factor α (TNFα, soluble TNF receptor I (sTNFRI, anaphylatoxins (C3a, C4a, C5a; markers of complement activation, mast cell tryptase (MCT, and histamine were measured in 120 Sri Lankan snakebite victims, both before and after treatment with antivenom. Immune mediator concentrations were correlated with envenoming features and the severity of antivenom-induced reactions including anaphylaxis. Envenoming was associated with complement activation and increased cytokine concentrations prior to antivenom administration, which correlated with non-specific systemic symptoms of envenoming but not with coagulopathy or neurotoxicity. Typical hypersensitivity reactions to antivenom occurred in 77/120 patients (64%, satisfying criteria for a diagnosis of anaphylaxis in 57/120 (48%. Pyrogenic reactions were observed in 32/120 patients (27%. All patients had further elevations in cytokine concentrations, but not complement activation, after the administration of antivenom, whether a reaction was noted to occur or not. Patients with anaphylaxis had significantly elevated concentrations of MCT and histamine. CONCLUSIONS/SIGNIFICANCE: We have demonstrated that Sri Lankan snake envenoming is characterized by significant complement activation and release of inflammatory mediators. Antivenom treatment further enhances the release of inflammatory mediators in all patients, with anaphylactic reactions characterised by high

  17. Complementizer Agreement

    NARCIS (Netherlands)

    van Koppen, J.M.

    2017-01-01

    Complementizers agree in phi-features with the embedded subject in dialects of German and Dutch, in Tense with the embedded clause in Irish and in phi-features with the matrix subject in certain African languages. These complementizer agreement phenomena will be the main empirical focus of this

  18. Mechanisms of evasion of Schistosoma mansoni schistosomula to the lethal activity of complement

    Directory of Open Access Journals (Sweden)

    F. Juarez Ramalho-Pinto

    1992-01-01

    Full Text Available Schistosomula of Schistosoma mansoni became resistant to antibody-dependent complement damage in vitro after pre-incubation with normal human erythrocytes (NHuE whatever the ABO or Rh blood group. Resistant parasites were shown to acquire host decay accelerating factor (DAF , a 70 kDa glycoprotein attached to the membrane of NHue by a GPI anchor. IgG2a mAb anti-human DAF (IA10 immunoprecipitated a 70 kDa molecule from 125I-labeled schistosomula pre-incubated with NHuE and inhibited their resistance to complement-dependent killing in vtro. Incubationof schistosomula with erytrocytes from patients with paroxsimal nocturnal hemoglobinuria (PNHE or SRBC, wich are DAF-deficient, did not protect the parasites from complement lesion. Supernatant of 100,000 x g collected from NHuE incubated for 24 h in defined medium was shown to contain a soluble form of DAF and to protect schistosomula from complement killing. Schistosomula treated with trypsin before incubation with NHuE ghosts did not become resistant to complement damage. On the other hand, pre-treatment with chymotrypsin did not interfere with the acquisition of resistance by the schistosomula. These results indicate that, in vitro, NHuE DAF can be transferred to schistosomula in a soluble form and that the binding of this molecule to the parasite surface is dependent upon trypsin-sensitive chymotrypsin-insensitive polipeptide(s present on the surface of the worm.

  19. Complement and Viral Pathogenesis

    Science.gov (United States)

    Stoermer, Kristina A.; Morrison, Thomas E.

    2011-01-01

    The complement system functions as an immune surveillance system that rapidly responds to infection. Activation of the complement system by specific recognition pathways triggers a protease cascade, generating cleavage products that function to eliminate pathogens, regulate inflammatory responses, and shape adaptive immune responses. However, when dysregulated, these powerful functions can become destructive and the complement system has been implicated as a pathogenic effector in numerous diseases, including infectious diseases. This review highlights recent discoveries that have identified critical roles for the complement system in the pathogenesis of viral infection. PMID:21292294

  20. Spontaneous Neuronal Activity in Developing Neocortical Networks: From Single Cells to Large-Scale Interactions.

    Science.gov (United States)

    Luhmann, Heiko J; Sinning, Anne; Yang, Jenq-Wei; Reyes-Puerta, Vicente; Stüttgen, Maik C; Kirischuk, Sergei; Kilb, Werner

    2016-01-01

    Neuronal activity has been shown to be essential for the proper formation of neuronal circuits, affecting developmental processes like neurogenesis, migration, programmed cell death, cellular differentiation, formation of local and long-range axonal connections, synaptic plasticity or myelination. Accordingly, neocortical areas reveal distinct spontaneous and sensory-driven neuronal activity patterns already at early phases of development. At embryonic stages, when immature neurons start to develop voltage-dependent channels, spontaneous activity is highly synchronized within small neuronal networks and governed by electrical synaptic transmission. Subsequently, spontaneous activity patterns become more complex, involve larger networks and propagate over several neocortical areas. The developmental shift from local to large-scale network activity is accompanied by a gradual shift from electrical to chemical synaptic transmission with an initial excitatory action of chloride-gated channels activated by GABA, glycine and taurine. Transient neuronal populations in the subplate (SP) support temporary circuits that play an important role in tuning early neocortical activity and the formation of mature neuronal networks. Thus, early spontaneous activity patterns control the formation of developing networks in sensory cortices, and disturbances of these activity patterns may lead to long-lasting neuronal deficits.

  1. Effects of Amoxicillin and Clavulanic Acid on the Spontaneous Mechanical Activity of Juvenile Rat Duodenum.

    Science.gov (United States)

    Ciciora, Steven L; Williams, Kent C; Gariepy, Cheryl E

    2015-09-01

    There are a limited number of medications for the treatment of foregut dysmotility. Enteral amoxicillin/clavulanic acid induces phase III duodenal contractions in a fasting pediatric patient. The mechanism by which this occurs is unknown. We examined the individual contributions of amoxicillin and clavulanic acid on the spontaneous mechanical activity of juvenile rat duodenum to better understand this phenomenon. Duodenal segments from juvenile rats were longitudinally attached to force transducers in organ baths. Samples were cumulatively exposed to amoxicillin or clavulanic acid. Separate samples were exposed to carbachol alone to assess response in both the presence and absence of amoxicillin or clavulanic acid. Basal tone, frequency, and amplitude of contractions were digitized and recorded. The amplitude of the spontaneous contractions increased with amoxicillin. Inhibition of neuronal activity prevented this effect. Clavulanic acid did not affect the spontaneous contractions. Basal tone and the rate of contractions did not differ with either drug. Stimulation with carbachol in the presence of amoxicillin caused a statistically significant increase in the contractility compared with carbachol alone. Amoxicillin alters the spontaneous longitudinal mechanical activity of juvenile rat duodenum. Our results suggest that amoxicillin modulates the spontaneous pattern of cyclic mechanical activity of duodenal smooth muscle through noncholinergic, neurally mediated mechanisms. Our work provides an initial physiologic basis for the therapeutic use of amoxicillin in patients with gastrointestinal dysmotility.

  2. The Cytolytically Inactive Terminal Complement Complex Activates Endothelial Cells to Express Adhesion Molecules and Tissue Factor Procoagulant Activity

    Science.gov (United States)

    Tedesco, Francesco; Pausa, Mario; Nardon, Ermanno; Introna, Martino; Mantovani, Alberto; Dobrina, Aldo

    1997-01-01

    The membrane attack complex of complement (C) in sublytic concentrations stimulates endothelial cells (EC) to express adhesion molecules and to release biologically active products. We have examined the ability of a cytolytically inactive form of this complex, which is incapable of inserting into the cell membrane, to upregulate the expression of adhesion molecules and of tissue factor (TF) procoagulant activity. The inactive terminal C complex (iTCC) was prepared by mixing C5b6, C7, C8, and C9 and was purified by fast protein liquid chromatography on a Superose 12 column. Binding of this complex to EC was found to be dose dependent and was inhibited by anti-C9 antibodies, as assessed both by ELISA using an mAb anti-C9 neoantigen and by measuring cell-bound 125I-labeled iTCC. Exposure of EC to iTCC resulted in a dose- and time-dependent expression of endothelial leukocyte adhesion molecule 1, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 accompanied by increased levels of the corresponding mRNA, but not in the rapid expression of P-selectin. Inactive TCC also induced increased TF activity evaluated by a chromogenic assay that measures the formation of factor Xa. These effects were inhibited by anti-C9 antibodies. The data support the conclusion that iTCC may induce proinflammatory and procoagulant activities on EC. PMID:9151899

  3. Aluminum hydroxide adjuvant differentially activates the three complement pathways with major involvement of the alternative pathway

    DEFF Research Database (Denmark)

    Güven, Esin; Duus, Karen; Laursen, Inga

    2013-01-01

    Al(OH)3 is the most common adjuvant in human vaccines, but its mode of action remains poorly understood. Complement involvement in the adjuvant properties of Al(OH)3 has been suggested in several reports together with a depot effect. It is here confirmed that Al(OH)3 treatment of serum depletes c...

  4. Distinct Polymer Architecture Mediates Switching of Complement Activation Pathways at the Nanosphere-Serum Interface: Implications for Stealth Nanoparticle Engineering

    DEFF Research Database (Denmark)

    Hamad, I.; Al-Hanbali, O.; Hunter, A.C.

    2010-01-01

    Nanoparticles with surface projected polyethyleneoxide (PEO) chains in 'mushroom-brush' and "brush" configurations display stealth properties in systemic circulation and have numerous applications in site specific targeting for controlled drug delivery and release as well as diagnostic Imaging. We...... report on the "structure-activity' relationship pertaining to surface immobilized PEO of various configurations on model nanoparticles, and the initiation of complement cascade, which is the most ancient component of innate human immunity, and its activation may induce clinically significant adverse...... reactions in some individuals Conformational states of surface chains, arising from the block copolymer poloxamine 908 adsorption, on polystyrene nanoparticles trigger complement activation differently. Alteration of copolymer architecture on nanospheres from mushroom to brush configuration not only...

  5. Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes

    DEFF Research Database (Denmark)

    Axelgaard, Esben; Østergaard, Jakob Appel; Haxha, Saranda

    2017-01-01

    was injected intravenously in diabetic and nondiabetic mice followed by ex vivo imaging of several organs. We observed that MBL accumulated in the heart, liver, brain, lung, pancreas, and intestines of diabetic mice. We furthermore detected increased systemic complement activation after administration of MBL......Increasing evidence links mannan-binding lectin (MBL) to late vascular complications of diabetes. MBL is a complement-activating pattern recognition molecule of the innate immune system that can mediate an inflammation response through activation of the lectin pathway. In two recent animal studies......, we have shown that autoreactivity of MBL is increased in the kidney in diabetic nephropathy. We hypothesize that long-term exposure to uncontrolled high blood glucose in diabetes may mediate formation of neoepitopes in several tissues and that MBL is able to recognize these structures and thus...

  6. Global Autorecognition and Activation of Complement by Mannan-Binding Lectin in a Mouse Model of Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    Esben Axelgaard

    2017-01-01

    Full Text Available Increasing evidence links mannan-binding lectin (MBL to late vascular complications of diabetes. MBL is a complement-activating pattern recognition molecule of the innate immune system that can mediate an inflammation response through activation of the lectin pathway. In two recent animal studies, we have shown that autoreactivity of MBL is increased in the kidney in diabetic nephropathy. We hypothesize that long-term exposure to uncontrolled high blood glucose in diabetes may mediate formation of neoepitopes in several tissues and that MBL is able to recognize these structures and thus activate the lectin pathway. To test this hypothesis, we induced diabetes by injection of low-dose streptozotocin in MBL double-knockout (MBL/DKO mice. Development of diabetes was followed by measurements of blood glucose and urine albumin-to-creatinine ratio. Fluorophore-labelled recombinant MBL was injected intravenously in diabetic and nondiabetic mice followed by ex vivo imaging of several organs. We observed that MBL accumulated in the heart, liver, brain, lung, pancreas, and intestines of diabetic mice. We furthermore detected increased systemic complement activation after administration of MBL, thus indicating MBL-mediated systemic complement activation in these animals. These new findings indicate a global role of MBL during late diabetes-mediated vascular complications in various tissues.

  7. The effects of tricyclic and 'atypical' antidepressants on spontaneous locomotor activity in rodents.

    Science.gov (United States)

    Tucker, J C; File, S E

    1986-01-01

    With the exception of amineptin, buproprion and nomifensine all tricyclic and 'atypical' antidepressants have been reported to reduce spontaneous motor activity in rodents, after both acute and chronic administration. However, with the diversity of chemical actions of these drugs it is unlikely that a single neurochemical mechanism is underlying this one behavioral effect. These widespread sedative effects have implications for interpreting behavioral changes in other test situations, since sedation generally occurs at doses that fall within the dose-range effective in other tests. We also review the effects on spontaneous motor activity of withdrawal from chronic antidepressant treatment.

  8. Human T cell derived, cell-bound complement iC3b is integrally involved in T cell activation.

    Science.gov (United States)

    Török, Katalin; Kremlitzka, Mariann; Sándor, Noémi; Tóth, Eszter Angéla; Bajtay, Zsuzsa; Erdei, Anna

    2012-03-30

    Although the complement system is thought to be mainly involved in innate immunity and in the humoral arm of adaptive responses, evidence implicating that complement impacts T cell responses are accumulating recently. The role of the various activation products of the major complement component C3 were mainly studied so far in animal systems, and investigations regarding the effect of different C3-fragments on human T cells are sparse. Here we show that anti-CD3 activated human T lymphocytes derived from the blood and tonsil of healthy individuals produce C3, and the major cleavage fragment that appears on the T cell surface is iC3b. Based on studies carried out in allogenic system we demonstrate that the T cell membrane bound iC3b binds to the CR3 and probably to CR4 receptors expressed on monocyte-derived dendritic cells, and this interaction leads to significantly enhanced T-cell proliferation. Since neither C3aR and nor C3a binding could be detected on the membrane of anti-CD3 activated T cells, our findings indicate that in humans – in contrast to mice – the C3a peptide is most probably not involved directly in the T cell activation process.

  9. Changes of spontaneous parthenogenetic activation and development potential of golden hamster oocytes during the aging process.

    Science.gov (United States)

    Jiang, Han; Wang, Ce; Guan, Jiyu; Wang, Lingyan; Li, Ziyi

    2015-01-01

    The golden hamster is an excellent animal experimental model for oocyte research. The hamster oocytes are very useful in clinical examination of human spermatozoan activity. Non-fertile oocytes can lead to time-dependent processes of aging, which will affect the results of human spermatozoa examination. As a consequence there is a need to investigate the aging and anti-aging processes of golden hamster oocytes. In order to study the aging processes and parthenogenetic activation of golden hamster oocytes, in vivo oocytes, oocytes cultured with or without cumulus cells, and oocytes treated with Trichostatin A (TSA) or caffeine were collected and investigated. We found that: (1) spontaneous parthenogenetic activation, developmental potential (cleavage rate), and zona pellucida (ZP) hardening undergo age-dependent changes in in vivo, in vitro, and after TSA or caffeine treatment; (2) in vivo, oocytes became spontaneously parthenogenetic 25 h post-hCG treatment; (3) in vitro, cumulus cells did not significantly increase the parthenogenetic activation rate of cultured hamster oocytes; and (4) TSA or caffeine could delay spontaneous oocyte parthenogenetic activation and the aging processes by at least 5h, but also accelerated the hardening of the ZP. These results define the conditions for the aging and anti-aging processes in golden hamster oocytes. TSA and caffeine play roles in controlling spontaneous activation, which could facilitate the storage and use of golden hamster oocytes for studying processes relevant to human reproduction. Copyright © 2014 Elsevier GmbH. All rights reserved.

  10. Complement activating soluble pattern recognition molecules with collagen-like regions, mannan-binding lectin, ficolins and associated proteins

    DEFF Research Database (Denmark)

    Thiel, Steffen

    2007-01-01

    Mannan-binding lectin (MBL), L-ficolin, M-ficolin and H-ficolin are all complement activating soluble pattern recognition molecules with recognition domains linked to collagen-like regions. All four may form complexes with four structurally related proteins, the three MBL-associated serine...... proteases (MASPs), MASP-1, MASP-2 and MASP-3, and a smaller MBL-associated protein (MAp19). The four recognition molecules recognize patterns of carbohydrate or acetyl-group containing ligands. After binding to the relevant targets all four are able to activate the complement system. We thus have a system...... where four different and/or overlapping patterns of microbial origin or patterns of altered-self may be recognized, but in all cases the signalling molecules, the MASPs, are shared. MASP-1 and MASP-3 are formed from one gene, MASP1/3, by alternative splicing generating two different mRNAs from a single...

  11. Methylation of the phosphate oxygen moiety of phospholipid-methoxy(polyethylene glycol) conjugate prevents PEGylated liposome-mediated complement activation and anaphylatoxin production

    DEFF Research Database (Denmark)

    Moghimi, S.M.; Hamad, I.; Andresen, Thomas Lars

    2006-01-01

    liposome-induced complement activation in normal as well as C1q-deficient human sera, using DPPC vesicles bearing the classical as well as newly synthesized lipid-mPEG conjugates. With PEGylated DPPC vesicles, the net anionic charge on the phosphate moiety of phospholipid-mPEG conjugate played a key role...... anaphylatoxin production through complement activation. Despite the general view that vesicle surface camouflaging with mPEG should dramatically suppress complement activation, here we show that bilayer enrichment of noncomplement activating liposomes [di-palmitoylphosphatidylcholine (DPPC) vesicles......] with phospholipid-mPEG conjugate induces complement activation resulting in vesicle recognition by macrophage complement receptors. The extent of vesicle uptake, however, is dependent on surface mPEG density. We have delineated the likely structural features of phospholipid-mPEG conjugate responsible for PEGylated...

  12. Insight into the intermolecular recognition mechanism involved in complement component 4 activation through serine protease-trypsin.

    Science.gov (United States)

    Sinha, Vikrant Kumar; Sharma, Om Prakash; Kumar, Muthuvel Suresh

    2018-02-01

    Serine protease cleaved-complement component 4 (C4) at sessile loop, which is significant for completion of lectin and classical complement pathways at the time of infections. The co-crystalized structure of C4 with Mannose-binding protein-associated serine protease 2 (MASP2) provided the structural and functional aspects of its interaction and underlined the C4 activation by MASP2. The same study also revealed the significance of complement control protein (CCP) domain through mutational study, where mutated CCP domain led to the inhibition of C4 activation. However, the interaction of trypsin serine domain with C4α sessile loop revealed another aspect of C4 activation. The human C4 cleavage by Trypsin (Tryp) in a control manner was explored but not yet revealed the identification of cleaved fragments. Hence, the present study investigated the Tryp mediated C4 activation using computational approach (protein-protein docking and molecular dynamics simulation) by comparing with the co-crystalized structure of C4-MASP2. Docking result identified the crucial interacting residues Gly219, Gln178, and Asn102 of Tryp catalytic pocket which were interacting with Arg756 and Glu759 (sessile loop) of α-Chain (C4) in a similar manner to C4-MASP2 co-crystallized complex. Moreover, MD simulation results and mutational study underlined the conformational rearrangements in the C4 due to the Tryp interaction. Comparative analysis of C4 alone, C4-Tryp, and C4-MASP2 revealed the impact of Tryp on C4 was similar as MASP2. These studies designate the role of sessile loop in the interaction with serine domain, which could be useful to understand the various interactions of C4 with other complement components.

  13. Recurrently connected and localized neuronal communities initiate coordinated spontaneous activity in neuronal networks.

    Science.gov (United States)

    Lonardoni, Davide; Amin, Hayder; Di Marco, Stefano; Maccione, Alessandro; Berdondini, Luca; Nieus, Thierry

    2017-07-01

    Developing neuronal systems intrinsically generate coordinated spontaneous activity that propagates by involving a large number of synchronously firing neurons. In vivo, waves of spikes transiently characterize the activity of developing brain circuits and are fundamental for activity-dependent circuit formation. In vitro, coordinated spontaneous spiking activity, or network bursts (NBs), interleaved within periods of asynchronous spikes emerge during the development of 2D and 3D neuronal cultures. Several studies have investigated this type of activity and its dynamics, but how a neuronal system generates these coordinated events remains unclear. Here, we investigate at a cellular level the generation of network bursts in spontaneously active neuronal cultures by exploiting high-resolution multielectrode array recordings and computational network modelling. Our analysis reveals that NBs are generated in specialized regions of the network (functional neuronal communities) that feature neuronal links with high cross-correlation peak values, sub-millisecond lags and that share very similar structural connectivity motifs providing recurrent interactions. We show that the particular properties of these local structures enable locally amplifying spontaneous asynchronous spikes and that this mechanism can lead to the initiation of NBs. Through the analysis of simulated and experimental data, we also show that AMPA currents drive the coordinated activity, while NMDA and GABA currents are only involved in shaping the dynamics of NBs. Overall, our results suggest that the presence of functional neuronal communities with recurrent local connections allows a neuronal system to generate spontaneous coordinated spiking activity events. As suggested by the rules used for implementing our computational model, such functional communities might naturally emerge during network development by following simple constraints on distance-based connectivity.

  14. Recurrently connected and localized neuronal communities initiate coordinated spontaneous activity in neuronal networks.

    Directory of Open Access Journals (Sweden)

    Davide Lonardoni

    2017-07-01

    Full Text Available Developing neuronal systems intrinsically generate coordinated spontaneous activity that propagates by involving a large number of synchronously firing neurons. In vivo, waves of spikes transiently characterize the activity of developing brain circuits and are fundamental for activity-dependent circuit formation. In vitro, coordinated spontaneous spiking activity, or network bursts (NBs, interleaved within periods of asynchronous spikes emerge during the development of 2D and 3D neuronal cultures. Several studies have investigated this type of activity and its dynamics, but how a neuronal system generates these coordinated events remains unclear. Here, we investigate at a cellular level the generation of network bursts in spontaneously active neuronal cultures by exploiting high-resolution multielectrode array recordings and computational network modelling. Our analysis reveals that NBs are generated in specialized regions of the network (functional neuronal communities that feature neuronal links with high cross-correlation peak values, sub-millisecond lags and that share very similar structural connectivity motifs providing recurrent interactions. We show that the particular properties of these local structures enable locally amplifying spontaneous asynchronous spikes and that this mechanism can lead to the initiation of NBs. Through the analysis of simulated and experimental data, we also show that AMPA currents drive the coordinated activity, while NMDA and GABA currents are only involved in shaping the dynamics of NBs. Overall, our results suggest that the presence of functional neuronal communities with recurrent local connections allows a neuronal system to generate spontaneous coordinated spiking activity events. As suggested by the rules used for implementing our computational model, such functional communities might naturally emerge during network development by following simple constraints on distance-based connectivity.

  15. Alginate microbeads are coagulation compatible, while alginate microcapsules activate coagulation secondary to complement or directly through FXII.

    Science.gov (United States)

    Gravastrand, Caroline; Hamad, Shamal; Fure, Hilde; Steinkjer, Bjørg; Ryan, Liv; Oberholzer, Josè; Lambris, John D; Lacík, Igor; Mollnes, Tom Eirik; Espevik, Terje; Brekke, Ole-Lars; Rokstad, Anne Mari

    2017-08-01

    Alginate microspheres are presently under evaluation for future cell-based therapy. Their ability to induce harmful host reactions needs to be identified for developing the most suitable devices and efficient prevention strategies. We used a lepirudin based human whole blood model to investigate the coagulation potentials of alginate-based microspheres: alginate microbeads (Ca/Ba Beads), alginate poly-l-lysine microcapsules (APA and AP microcapsules) and sodium alginate-sodium cellulose sulfate-poly(methylene-co-cyanoguanidine) microcapsules (PMCG microcapsules). Coagulation activation measured by prothrombin fragments 1+2 (PTF1.2) was rapidly and markedly induced by the PMCG microcapsules, delayed and lower induced by the APA and AP microcapsules, and not induced by the Ca/Ba Beads. Monocytes tissue factor (TF) expression was similarly activated by the microcapsules, whereas not by the Ca/Ba Beads. PMCG microcapsules-induced PTF1.2 was abolished by FXII inhibition (corn trypsin inhibitor), thus pointing to activation through the contact pathway. PTF1.2 induced by the AP and APA microcapsules was inhibited by anti-TF antibody, pointing to a TF driven coagulation. The TF induced coagulation was inhibited by the complement inhibitors compstatin (C3 inhibition) and eculizumab (C5 inhibition), revealing a complement-coagulation cross-talk. This is the first study on the coagulation potentials of alginate microspheres, and identifies differences in activation potential, pathways and possible intervention points. Alginate microcapsules are prospective candidate materials for cell encapsulation therapy. The material surface must be free of host cell adhesion to ensure free diffusion of nutrition and oxygen to the encapsulated cells. Coagulation activation is one gateway to cellular overgrowth through deposition of fibrin. Herein we used a physiologically relevant whole blood model to investigate the coagulation potential of alginate microcapsules and microbeads. The

  16. A data repository and analysis framework for spontaneous neural activity recordings in developing retina.

    Science.gov (United States)

    Eglen, Stephen John; Weeks, Michael; Jessop, Mark; Simonotto, Jennifer; Jackson, Tom; Sernagor, Evelyne

    2014-03-26

    During early development, neural circuits fire spontaneously, generating activity episodes with complex spatiotemporal patterns. Recordings of spontaneous activity have been made in many parts of the nervous system over the last 25 years, reporting developmental changes in activity patterns and the effects of various genetic perturbations. We present a curated repository of multielectrode array recordings of spontaneous activity in developing mouse and ferret retina. The data have been annotated with minimal metadata and converted into HDF5. This paper describes the structure of the data, along with examples of reproducible research using these data files. We also demonstrate how these data can be analysed in the CARMEN workflow system. This article is written as a literate programming document; all programs and data described here are freely available. 1. We hope this repository will lead to novel analysis of spontaneous activity recorded in different laboratories. 2. We encourage published data to be added to the repository. 3. This repository serves as an example of how multielectrode array recordings can be stored for long-term reuse.

  17. Complement component 4

    Science.gov (United States)

    ... These people are prone to certain infections or autoimmune disorders. There are nine major complement proteins. They are ... may be used to monitor people with an autoimmune disorder . For example, people with active systemic lupus erythematosus ...

  18. The Role of Cellular Coupling in the Spontaneous Generation of Electrical Activity in Uterine Tissue

    Science.gov (United States)

    Xu, Jinshan; Menon, Shakti N.; Singh, Rajeev; Garnier, Nicolas B.; Sinha, Sitabhra; Pumir, Alain

    2015-01-01

    The spontaneous emergence of contraction-inducing electrical activity in the uterus at the beginning of labor remains poorly understood, partly due to the seemingly contradictory observation that isolated uterine cells are not spontaneously active. It is known, however, that the expression of gap junctions increases dramatically in the approach to parturition, by more than one order of magnitude, which results in a significant increase in inter-cellular electrical coupling. In this paper, we build upon previous studies of the activity of electrically excitable smooth muscle cells (myocytes) and investigate the mechanism through which the coupling of these cells to electrically passive cells results in the generation of spontaneous activity in the uterus. Using a recently developed, realistic model of uterine muscle cell dynamics, we investigate a system consisting of a myocyte coupled to passive cells. We then extend our analysis to a simple two-dimensional lattice model of the tissue, with each myocyte being coupled to its neighbors, as well as to a random number of passive cells. We observe that different dynamical regimes can be observed over a range of gap junction conductances: at low coupling strength, corresponding to values measured long before delivery, the activity is confined to cell clusters, while the activity for high coupling, compatible with values measured shortly before delivery, may spread across the entire tissue. Additionally, we find that the system supports the spontaneous generation of spiral wave activity. Our results are both qualitatively and quantitatively consistent with observations from in vitro experiments. In particular, we demonstrate that the increase in inter-cellular electrical coupling observed experimentally strongly facilitates the appearance of spontaneous action potentials that may eventually lead to parturition. PMID:25793276

  19. Putative role of border cells in generating spontaneous morphological activity within Kölliker's organ.

    Science.gov (United States)

    Dayaratne, M W Nishani; Vlajkovic, Srdjan M; Lipski, Janusz; Thorne, Peter R

    2015-12-01

    Kölliker's organ is a transient epithelial structure, comprising a major part of the organ of Corti during pre-hearing stages of development. The auditory system is spontaneously active during development, which serves to retain and refine neural connections. Kölliker's organ is considered a key candidate for generating such spontaneous activity, most likely through purinergic (P2 receptor) signalling and inner hair cell (IHC) activation. Associated with the spontaneous neural activity, ATP released locally by epithelial cells induces rhythmic morphological changes within Kölliker's organ, the purpose of which is not understood. These changes are accompanied by a shift in cellular refractive index, allowing optical detection of this activity in real-time. Using this principle, we investigated the origin of spontaneous morphological activity within Kölliker's organ. Apical turns of Wistar rat cochleae (P9-11) were dissected, and the purinergic involvement was studied following acute tissue exposure to a P2 receptor agonist (ATPγS) and antagonist (suramin). ATPγS induced a sustained darkening throughout Kölliker's organ, reversed by suramin. This effect was most pronounced in the region closest to the inner hair cells, which also displayed the highest frequency of intrinsic morphological events. Additionally, suramin alone induced swelling of this region, suggesting a tight regulation of cell volume by ATP-mediated mechanisms. Histological analysis of cochlear tissues demonstrates the most profound volume changes in the border cell region immediately adjacent to the IHCs. Together, these results underline the role of purinergic signalling in initiating morphological events within Kölliker's organ, and suggest a key involvement of border cells surrounding IHCs in regulating this spontaneous activity. Copyright © 2015. Published by Elsevier B.V.

  20. Activation of Human Complement System by Dextran-Coated Iron Oxide Nanoparticles Is Not Affected by Dextran/Fe Ratio, Hydroxyl Modifications, and Crosslinking

    DEFF Research Database (Denmark)

    Wang, Guankui; Chen, Fangfang; Banda, Nirmal K

    2016-01-01

    activation via calcium-sensitive pathways, but the AP was responsible for the bulk of complement activation and amplification. Activation via the AP required properdin, the positive regulator of the alternative C3bBb convertase. Modification of sugar alcohols of dextran with alkylating, acylating......, or crosslinking agents did not overcome complement activation and C3 opsonization. These data demonstrate that human complement activation is independent of dextran modification of SPIO and suggest a crucial role of the AP in immune recognition of nano-assemblies in human serum....

  1. Effects of language processing on spontaneous muscle activity

    NARCIS (Netherlands)

    Stins, J.F.; Beek, P.J.

    2013-01-01

    There is evidence of the crucial involvement of the motor system in language understanding and production. We tested whether reading verbs that symbolized various actions would lead to an effector-specific modulation in subliminal muscle activity. Participants were lying in a relaxed position, and

  2. Changes of spontaneous oscillatory activity to tonic heat pain.

    Directory of Open Access Journals (Sweden)

    Weiwei Peng

    Full Text Available Transient painful stimuli could induce suppression of alpha oscillatory activities and enhancement of gamma oscillatory activities that also could be greatly modulated by attention. Here, we attempted to characterize changes in cortical activities during tonic heat pain perception and investigated the influence of directed/distracted attention on these responses. We collected 5-minute long continuous Electroencephalography (EEG data from 38 healthy volunteers during four conditions presented in a counterbalanced order: (A resting condition; (B innoxious-distracted condition; (C noxious-distracted condition; (D noxious-attended condition. The effects of tonic heat pain stimulation and selective attention on oscillatory activities were investigated by comparing the EEG power spectra among the four experimental conditions and assessing the relationship between spectral power difference and subjective pain intensity. The change of oscillatory activities in condition D was characterized by stable and persistent decrease of alpha oscillation power over contralateral-central electrodes and widespread increase of gamma oscillation power, which were even significantly correlated with subjective pain intensity. Since EEG responses in the alpha and gamma frequency band were affected by attention in different manners, they are likely related to different aspects of the multidimensional sensory experience of pain. The observed contralateral-central alpha suppression (conditions D vs. B and D vs. C may reflect primarily a top-down cognitive process such as attention, while the widespread gamma enhancement (conditions D vs. A may partly reflect tonic pain processing, representing the summary effects of bottom-up stimulus-related and top-down subject-driven cognitive processes.

  3. Effects of Organophosphorus Flame Retardants on Spontaneous Activity in Neuronal Networks Grown on Microelectrode Arrays

    Science.gov (United States)

    EFFECTS OF ORGANOPHOSPHORUS FLAME RETARDANTS ON SPONTANEOUS ACTIVITY IN NEURONAL NETWORKS GROWN ON MICROELECTRODE ARRAYS TJ Shafer1, K Wallace1, WR Mundy1, M Behl2,. 1Integrated Systems Toxicology Division, NHEERL, USEPA, RTP, NC, USA, 2National Toxicology Program, NIEHS, RTP, NC...

  4. DELTAMETHRIN AND ESFENVALERATE INHIBIT SPONTANEOUS NETWORK ACTIVITY IN RAT CORTICAL NEURONS IN VITRO.

    Science.gov (United States)

    Understanding pyrethroid actions on neuronal networks will help to establish a mode of action for these compounds, which is needed for cumulative risk decisions under the Food Quality Protection Act of 1996. However, pyrethroid effects on spontaneous activity in networks of inter...

  5. Slow-light enhancement of spontaneous emission in active photonic crystal waveguides

    DEFF Research Database (Denmark)

    Ek, Sara; Chen, Yaohui; Semenova, Elizaveta

    2012-01-01

    Photonic crystal defect waveguides with embedded active layers containing single or multiple quantum wells or quantum dots have been fabricated. Spontaneous emission spectra are enhanced close to the bandedge, consistently with the enhancement of gain by slow light effects. These are promising...

  6. Tinnitus perception and distress is related to abnormal spontaneous brain activity as measured by magnetoencephalography.

    Directory of Open Access Journals (Sweden)

    2005-06-01

    Full Text Available BACKGROUND: The neurophysiological mechanisms underlying tinnitus perception are not well understood. Surprisingly, there have been no group studies comparing abnormalities in ongoing, spontaneous neuronal activity in individuals with and without tinnitus perception. METHODS AND FINDINGS: Here, we show that the spontaneous neuronal activity of a group of individuals with tinnitus (n = 17 is characterised by a marked reduction in alpha (8-12 Hz power together with an enhancement in delta (1.5-4 Hz as compared to a normal hearing control group (n = 16. This pattern was especially pronounced for temporal regions. Moreover, correlations with tinnitus-related distress revealed strong associations with this abnormal spontaneous activity pattern, particularly in right temporal and left frontal areas. Overall, effects were stronger for the alpha than for the delta frequency band. A data stream of 5 min, recorded with a whole-head neuromagnetometer under a resting condition, was sufficient to extract the marked differences. CONCLUSIONS: Despite some limitations, there are arguments that the regional pattern of abnormal spontaneous activity we found could reflect a tinnitus-related cortical network. This finding, which suggests that a neurofeedback approach could reduce the adverse effects of this disturbing condition, could have important implications for the treatment of tinnitus.

  7. Altered Spontaneous Activity in Anisometropic Amblyopia Subjects: Revealed by Resting-State fMRI

    Science.gov (United States)

    Lin, Xiaoming; Ding, Kun; Liu, Yong; Yan, Xiaohe; Song, Shaojie; Jiang, Tianzi

    2012-01-01

    Amblyopia, also known as lazy eye, usually occurs during early childhood and results in poor or blurred vision. Recent neuroimaging studies have found cortical structural/functional abnormalities in amblyopia. However, until now, it was still not known whether the spontaneous activity of the brain changes in amblyopia subjects. In the present study, regional homogeneity (ReHo), a measure of the homogeneity of functional magnetic resonance imaging signals, was used for the first time to investigate changes in resting-state local spontaneous brain activity in individuals with anisometropic amblyopia. Compared with age- and gender-matched subjects with normal vision, the anisometropic amblyopia subjects showed decreased ReHo of spontaneous brain activity in the right precuneus, the left medial prefrontal cortex, the left inferior frontal gyrus, and the left cerebellum, and increased ReHo of spontaneous brain activity was found in the bilateral conjunction area of the postcentral and precentral gyri, the left paracentral lobule, the left superior temporal gyrus, the left fusiform gyrus, the conjunction area of the right insula, putamen and the right middle occipital gyrus. The observed decreases in ReHo may reflect decreased visuo-motor processing ability, and the increases in ReHo in the somatosensory cortices, the motor areas and the auditory area may indicate compensatory plasticity in amblyopia. PMID:22937041

  8. General theory for spontaneous emission in active dielectric microstructures: Example of a fiber amplifier

    DEFF Research Database (Denmark)

    Søndergaard, Thomas; Tromborg, Bjarne

    2001-01-01

    A model for spontaneous emission in active dielectric microstructures is given in terms of the classical electric field Green's tensor and the quantum-mechanical operators for the generating currents. A formalism is given for calculating the Green's tensor, which does not rely on the existence...

  9. Early decrease in total hemolytic complement activity (CH100) after fasting or intestinal bypass in the rat.

    Science.gov (United States)

    Montanari, M; Violi, V; Muri, M; Roncoroni, L; Mora, G; Ronzoni, M

    1986-01-01

    An evaluation of total hemolytic complement activity (CH100) after fasting or intestinal bypass was performed in rats. The experiment lasted 6 days. Three groups, of 5 animals each, were studied. On the 1st day, basal values of total complement (TC), albumin and body weight were determined. Group A received normal, ad libitum feeding, group B started on a 'water only' diet, group C underwent intestinal bypass. On the 4th and 6th day the parameters were assessed. TC mean values were significantly lower in groups B and C, as compared to group A, on the 4th as well as on the 6th day (p less than 0.01 by Mann-Whitney's U test). Body weight showed a similar trend. Differences in albumin were never statistically significant. Limitations of the analytical method are discussed. The data show that fasting or bypass-induced malabsorption may determine an early decrease in total hemolytic complement activity, though a development of an immune deficiency is not proved.

  10. Immuno-Detection of C3a, a C3 Complement Activated Product in Mastitis Milk, a Potential Diagnostic Marker.

    Science.gov (United States)

    Jacob, Thanislass; Subramani, Gangasudan; Sivaprakasam, Prathiba; Xavier, Antony P; Mukhopadhyay, Hirak K

    2017-02-23

    The sub-clinical form of mastitis is difficult to detect and causes huge economic loss to the dairy industry. It has become a threat to public health at large, thus there is a need for definite diagnosis of the disease. Therefore, this study was undertaken to identify the novel diagnostic marker for the detection of the sub-clinical form of mastitis. Two-dimensional gel analysis of the whey protein fraction of normal and mastitis milk samples revealed the presence of proteose peptone component 3 precursor, Trypsin precursor, complement component-C3, Ig heavy chain precursors and a C-type lectin domain as differentially expressed protein during the early stage of mastitis. Of these proteins identified, complement component-C3 was tested for its diagnostic potential. Western blot analysis of the milk whey of sub-clinical mastitis cases (M+, M++ & M+++) identified the accumulation of C3a, an activated product of complement component-C3. Further, the hemolytic activity of the above milk whey samples positively correlated with the somatic cell count. As C3a is already reported as an anaphylotoxic agent, it chemo tactically attracts lymphocytes at the site of inflammation, the detection of which in the milk whey can be of diagnostic importance for sub-clinical mastitis.

  11. Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome.

    Science.gov (United States)

    Ståhl, Anne-lie; Sartz, Lisa; Karpman, Diana

    2011-05-19

    Hemolytic uremic syndrome (HUS) is commonly associated with Shiga toxin (Stx)-producing Escherichia coli O157:H7 infection. This study examined patient samples for complement activation on leukocyte-platelet complexes and microparticles, as well as donor samples for Stx and lipopolysaccharide (O157LPS)-induced complement activation on platelet-leukocyte complexes and microparticles. Results, analyzed by flow cytometry, showed that whole blood from a child with HUS had surface-bound C3 on 30% of platelet-monocyte complexes compared with 14% after recovery and 12% in pediatric controls. Plasma samples from 12 HUS patients were analyzed for the presence of microparticles derived from platelets, monocytes, and neutrophils. Acute-phase samples exhibited high levels of platelet microparticles and, to a lesser extent, monocyte microparticles, both bearing C3 and C9. Levels decreased significantly at recovery. Stx or O157LPS incubated with donor whole blood increased the population of platelet-monocyte and platelet-neutrophil complexes with surface-bound C3 and C9, an effect enhanced by costimulation with Stx and O157LPS. Both Stx and O157LPS induced the release of C3- and C9-bearing microparticles from platelets and monocytes. Released microparticles were phagocytosed by neutrophils. The presence of complement on platelet-leukocyte complexes and microparticles derived from these cells suggests a role in the inflammatory and thrombogenic events that occur during HUS.

  12. Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs

    Energy Technology Data Exchange (ETDEWEB)

    Szebeni, Janos, E-mail: jszebeni2@gmail.com [Nanomedicine Research and Education Center, Semmelweis University, Budapest & SeroScience Ltd, Budapest (Hungary); Storm, Gert [Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht (Netherlands)

    2015-12-18

    Liposomes are known to activate the complement (C) system, which can lead in vivo to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA has been getting increasing attention as a safety risk of i.v. therapy with liposomes, whose testing is now recommended in bioequivalence evaluations of generic liposomal drug candidates. This review highlights the adverse consequences of C activation, the unique symptoms of CARPA triggered by essentially all i.v. administered liposomal drugs, and the various features of vesicles influencing this adverse immune effect. For the case of Doxil, we also address the mechanism of C activation and the opsonization vs. long circulation (stealth) paradox. In reviewing the methods of assessing C activation and CARPA, we delineate the most sensitive porcine model and an algorithm for stepwise evaluation of the CARPA risk of i.v. liposomes, which are proposed for standardization for preclinical toxicology evaluation of liposomal and other nanoparticulate drug candidates. - Highlights: • Outlining of difficulties in generic development of liposomal drugs. • New regulatory requirements to evaluate CARPA in preclinical studies. • Review of complement activation by liposomes and its adverse consequences (CARPA). • Assays of C activation in vitro and CARPA in vivo, with the porcine test in focus. • Decision tree how to handle the risk of CARPA assessed by a battery of tests.

  13. Spontaneous Physical Activity Downregulates Pax7 in Cancer Cachexia

    Directory of Open Access Journals (Sweden)

    Dario Coletti

    2016-01-01

    Full Text Available Emerging evidence suggests that the muscle microenvironment plays a prominent role in cancer cachexia. We recently showed that NF-kB-induced Pax7 overexpression impairs the myogenic potential of muscle precursors in cachectic mice, suggesting that lowering Pax7 expression may be beneficial in cancer cachexia. We evaluated the muscle regenerative potential after acute injury in C26 colon carcinoma tumor-bearing mice and healthy controls. Our analyses confirmed that the delayed muscle regeneration observed in muscles form tumor-bearing mice was associated with a persistent local inflammation and Pax7 overexpression. Physical activity is known to exert positive effects on cachectic muscles. However, the mechanism by which a moderate voluntary exercise ameliorates muscle wasting is not fully elucidated. To verify if physical activity affects Pax7 expression, we hosted control and C26-bearing mice in wheel-equipped cages and we found that voluntary wheel running downregulated Pax7 expression in muscles from tumor-bearing mice. As expected, downregulation of Pax7 expression was associated with a rescue of muscle mass and fiber size. Our findings shed light on the molecular basis of the beneficial effect exerted by a moderate physical exercise on muscle stem cells in cancer cachexia. Furthermore, we propose voluntary exercise as a physiological tool to counteract the overexpression of Pax7 observed in cancer cachexia.

  14. Crosstalk between complement and Toll-like receptor activation in relation to donor brain death and renal ischemia-reperfusion injury.

    Science.gov (United States)

    Damman, Jeffrey; Daha, Mohamed R; van Son, Willem J; Leuvenink, Henri G; Ploeg, Rutger J; Seelen, Marc A

    2011-04-01

    Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen activated protein kinases (MAPKs) might be the key molecules linking both the complement and TLR pathways together. Complement and TLRs are important mediators of renal ischemia-reperfusion injury (IRI). Besides IRI, complement C3 can also be upregulated and activated in the kidney before transplantation as a direct result of brain death (BD) in the donor. This local upregulation and activation of complement in the donor kidney has been proven to be detrimental for renal allograft outcome. Also TLR4 and several of its major ligands are upregulated by donor BD compared to living donors. Important and in line with the observations above, kidney transplant recipients have a benefit when receiving a kidney from a TLR4 Asp299Gly/Thr399Ile genotypic donor. The role of complement and TLRs and crosstalk between these two innate immune systems in relation to renal injury during donor BD and ischemia-reperfusion are focus of this review. Future strategies to target complement and TLR activation in kidney transplantation are considered. ©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

  15. Human factor H-related protein 2 (CFHR2 regulates complement activation.

    Directory of Open Access Journals (Sweden)

    Hannes U Eberhardt

    Full Text Available Mutations and deletions within the human CFHR gene cluster on chromosome 1 are associated with diseases, such as dense deposit disease, CFHR nephropathy or age-related macular degeneration. Resulting mutant CFHR proteins can affect complement regulation. Here we identify human CFHR2 as a novel alternative pathway complement regulator that inhibits the C3 alternative pathway convertase and terminal pathway assembly. CFHR2 is composed of four short consensus repeat domains (SCRs. Two CFHR2 molecules form a dimer through their N-terminal SCRs, and each of the two C-terminal ends can bind C3b. C3b bound CFHR2 still allows C3 convertase formation but the CFHR2 bound convertases do not cleave the substrate C3. Interestingly CFHR2 hardly competes off factor H from C3b. Thus CFHR2 likely acts in concert with factor H, as CFHR2 inhibits convertases while simultaneously allowing factor H assisted degradation by factor I.

  16. Effects of imatinib mesylate on the spontaneous activity generated by the guinea-pig prostate.

    Science.gov (United States)

    Lam, Michelle; Dey, Anupa; Lang, Richard J; Exintaris, Betty

    2013-08-01

    What's known on the subject? and what does the study add?: Several studies have examined the functional role of tyrosine kinase receptors in the generation of spontaneous activity in various segments of the gastrointestinal and urogenital tracts through the application of its inhibitor, imatinib mesylate (Glivec®), but results are fairly inconsistent. This is the first study detailing the effects of imatinib mesylate on the spontaneous activity in the young and ageing prostate gland. As spontaneous electrical activity underlies the spontaneous rhythmic prostatic contractions that occur at rest, elucidating the mechanisms involved in the regulation of the spontaneous electrical activity and the resultant phasic contractions could conceivably lead to the identification of better targets and the development of more specific therapeutic agents to treat prostate conditions. To investigate the effect of imatinib mesylate, a tyrosine kinase receptor inhibitor, in the generation of spontaneous electrical and contractile activity in the young and ageing guinea-pig prostate. Standard tension and intracellular recording were used to measure spontaneous contractions and slow waves, respectively from the guinea-pig prostate at varying concentrations of imatinib mesylate (1-50 μm). Imatinib mesylate (1-10 μm), did not significantly affect slow waves recorded in the prostate of both age groups but at 50 μm, the amplitude of slow waves from the ageing guinea-pig prostate was significantly reduced (P imatinib mesylate attenuated the amplitude and slowed the frequency of contractions in ageing guinea-pigs to 5.15% and 3.3% at 1 μm (n = 6); 21.1% and 20.8% at 5 μm (n = 8); 58.4% and 8.8% at 10 μm (n = 11); 72.7% and 60% at 50 μm (n = 5). A significant reduction in contractions but persistence of slow waves suggests imatinib mesylate may affect the smooth muscle contractile mechanism. Imatinib mesylate also significantly reduced contractions in the prostates of younger guinea

  17. Complementation analysis of mutants of 1-aminocyclopropane- 1-carboxylate synthase reveals the enzyme is a dimer with shared active sites.

    Science.gov (United States)

    Tarun, A S; Theologis, A

    1998-05-15

    The pyridoxal phosphate-dependent enzyme 1-aminocyclopropane-1-carboxylate synthase (ACS, EC 4.4.1.14) catalyzes the rate-limiting step in the ethylene biosynthetic pathway. ACS shares the conservation of 11 invariant residues with a family of aminotransferases that includes aspartate aminotransferase. Site-directed mutagenesis on two of these residues, Tyr-92 and Lys-278, in the tomato isoenzyme Le-ACS2 greatly reduces enzymatic activity, indicating their importance in catalysis. These mutants have been used in complementation experiments either in vivo in Escherichia coli or in an in vitro transcription/translation assay to study whether the enzyme functions as a dimer. When the Y92L mutant is coexpressed with the K278A mutant protein, there is partial restoration of enzyme activity, suggesting that the mutant proteins can dimerize and form active heterodimers. Coexpressing a double mutant with the wild-type protein reduces wild-type activity, indicating that inactive heterodimers are formed between the wild-type and the double mutant protein subunits. Furthermore, hybrid complementation shows that another tomato isoenzyme, Le-ACS4, can dimerize and that Le-ACS2 and Le-ACS4 have limited capacity for heterodimerization. The data suggest that ACS functions as a dimer with shared active sites.

  18. Storage of the complement components C4, C3, and C 3-activator in the human liver as PAS-negative globular hyaline bodies.

    Science.gov (United States)

    Storch, W; Riedel, H; Trautmann, B; Justus, J; Hiemann, D

    1982-01-01

    Liver biopsies of a 58-year-old clinically healthy patient with a hepatomegaly and intracisternal PAS-negative globular hyaline bodies were immunofluorescent-optically examined for the content of the complement components C 1 q, C 4, C 9, C 1-inactivator, C 3-activator. Further examinations were performed for fibrinogen, IgG, IgA, IgM, IgD, IgE, L-chain (type chi and lambda), alpha 1-antitrypsin, alpha 1-fetoprotein, alpha 1- and alpha 2-glycoprotein, cholinesterase, ceruloplasmin, myoglobin, hemopexin, HBsAg and HBsAg. Th inclusion bodies reacted with antisera against the complement components C 4, C 3 and C 3-activator, as also identified by double immunofluorescence. Probably this is a disturbance of the protein metabolism of the liver cell with abnormal complement storage in the presence of normal total complement and normal complement components in the serum.

  19. Tumour exosomes display differential mechanical and complement activation properties dependent on malignant state

    DEFF Research Database (Denmark)

    Whitehead, Bradley; Wu, LinPing; Hvam, Michael Lykke

    2015-01-01

    , therefore, increased metastatic spread. Methods : Exosomes isolated from non-malignant immortalized HCV-29 and isogenic malignant non-metastatic T24 and malignant metastatic FL3 bladder cells were characterized by nanoparticle tracking analysis and quantitative nanomechanical mapping atomic force microscopy...... (QNM AFM) to determine size and nanomechanical properties. Effect of HCV-29, T24 and FL3 exosomes on human umbilical vein endothelial cell (HUVEC) monolayer integrity was determined by transendothelial electrical resistance (TEER) measurements and transport was determined by flow cytometry. Complement...... for FL3, 127.6 nm for T24 and 117.9 nm for HCV-29, respectively). T24 and FL3 cell-derived exosomes exhibited a markedly reduced stiffness, 95 MPa and 280 MPa, respectively, compared with 1,527 MPa with non-malignant HCV-29 cell-derived exosomes determined by QNM AFM. FL3 and T24 exosomes induced...

  20. Presbycusis Disrupts Spontaneous Activity Revealed by Resting-State Functional MRI

    Directory of Open Access Journals (Sweden)

    Yu-Chen Chen

    2018-03-01

    Full Text Available Purpose: Presbycusis, age-related hearing loss, is believed to involve neural changes in the central nervous system, which is associated with an increased risk of cognitive impairment. The goal of this study was to determine if presbycusis disrupted spontaneous neural activity in specific brain areas involved in auditory processing, attention and cognitive function using resting-state functional magnetic resonance imaging (fMRI approach.Methods: Hearing and resting-state fMRI measurements were obtained from 22 presbycusis patients and 23 age-, sex- and education-matched healthy controls. To identify changes in spontaneous neural activity associated with age-related hearing loss, we compared the amplitude of low-frequency fluctuations (ALFF and regional homogeneity (ReHo of fMRI signals in presbycusis patients vs. controls and then determined if these changes were linked to clinical measures of presbycusis.Results: Compared with healthy controls, presbycusis patients manifested decreased spontaneous activity mainly in the superior temporal gyrus (STG, parahippocampal gyrus (PHG, precuneus and inferior parietal lobule (IPL as well as increased neural activity in the middle frontal gyrus (MFG, cuneus and postcentral gyrus (PoCG. A significant negative correlation was observed between ALFF/ReHo activity in the STG and average hearing thresholds in presbycusis patients. Increased ALFF/ReHo activity in the MFG was positively correlated with impaired Trail-Making Test B (TMT-B scores, indicative of impaired cognitive function involving the frontal lobe.Conclusions: Presbycusis patients have disrupted spontaneous neural activity reflected by ALFF and ReHo measurements in several brain regions; these changes are associated with specific cognitive performance and speech/language processing. These findings mainly emphasize the crucial role of aberrant resting-state ALFF/ReHo patterns in presbycusis patients and will lead to a better understanding of the

  1. Presbycusis Disrupts Spontaneous Activity Revealed by Resting-State Functional MRI.

    Science.gov (United States)

    Chen, Yu-Chen; Chen, Huiyou; Jiang, Liang; Bo, Fan; Xu, Jin-Jing; Mao, Cun-Nan; Salvi, Richard; Yin, Xindao; Lu, Guangming; Gu, Jian-Ping

    2018-01-01

    Purpose : Presbycusis, age-related hearing loss, is believed to involve neural changes in the central nervous system, which is associated with an increased risk of cognitive impairment. The goal of this study was to determine if presbycusis disrupted spontaneous neural activity in specific brain areas involved in auditory processing, attention and cognitive function using resting-state functional magnetic resonance imaging (fMRI) approach. Methods : Hearing and resting-state fMRI measurements were obtained from 22 presbycusis patients and 23 age-, sex- and education-matched healthy controls. To identify changes in spontaneous neural activity associated with age-related hearing loss, we compared the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) of fMRI signals in presbycusis patients vs. controls and then determined if these changes were linked to clinical measures of presbycusis. Results : Compared with healthy controls, presbycusis patients manifested decreased spontaneous activity mainly in the superior temporal gyrus (STG), parahippocampal gyrus (PHG), precuneus and inferior parietal lobule (IPL) as well as increased neural activity in the middle frontal gyrus (MFG), cuneus and postcentral gyrus (PoCG). A significant negative correlation was observed between ALFF/ReHo activity in the STG and average hearing thresholds in presbycusis patients. Increased ALFF/ReHo activity in the MFG was positively correlated with impaired Trail-Making Test B (TMT-B) scores, indicative of impaired cognitive function involving the frontal lobe. Conclusions : Presbycusis patients have disrupted spontaneous neural activity reflected by ALFF and ReHo measurements in several brain regions; these changes are associated with specific cognitive performance and speech/language processing. These findings mainly emphasize the crucial role of aberrant resting-state ALFF/ReHo patterns in presbycusis patients and will lead to a better understanding of the

  2. A gravimetric method for the measurement of total spontaneous activity in rats.

    Science.gov (United States)

    Biesiadecki, B J; Brand, P H; Koch, L G; Britton, S L

    1999-10-01

    Currently available methods for the measurement of spontaneous activity of laboratory animals require expensive, specialized equipment and may not be suitable for use in low light conditions with nocturnal species. We developed a gravimetric method that uses common laboratory equipment to quantify the total spontaneous activity of rats and is suitable for use in the dark. The rat in its home cage is placed on a top-loading electronic balance interfaced to a computer. Movements are recorded by the balance as changes in weight and transmitted to the computer at 10 Hz. Data are analyzed on-line to derive the absolute value of the difference in weight between consecutive samples, and the one-second average of the absolute values is calculated. The averages are written to file for off-line analysis and summed over the desired observation period to provide a measure of total spontaneous activity. The results of in vitro experiments demonstrated that: 1) recorded weight changes were not influenced by position of the weight on the bottom of the cage, 2) values recorded from a series of weight changes were not significantly different from the calculated values, 3) the constantly decreasing force exerted by a swinging pendulum placed on the balance was accurately recorded, 4) the measurement of activity was not influenced by the evaporation of a fluid such as urine, and 5) the method can detect differences in the activity of sleeping and waking rats over a 10-min period, as well as during 4-hr intervals recorded during active (night-time) and inactive (daytime) periods. These results demonstrate that this method provides an inexpensive, accurate, and noninvasive method to quantitate the spontaneous activity of small animals.

  3. Evaluation of classical complement pathway activation in rheumatoid arthritis: measurement of C1q-C4 complexes as novel activation products

    NARCIS (Netherlands)

    Wouters, Diana; Voskuyl, Alexandre E.; Molenaar, Esmeralda T. H.; Dijkmans, Ben A. C.; Hack, C. Erik

    2006-01-01

    OBJECTIVE: Novel activation products that are stable and minimally susceptible to in vitro artefacts have recently been described in the classical complement pathway. The present study assessed circulating levels of these products, i.e., covalent complexes between the recognition molecule of the

  4. Combined Roles of Human IgG Subclass, Alternative Complement Pathway Activation, and Epitope Density in the Bactericidal Activity of Antibodies to Meningococcal Factor H Binding Protein

    Science.gov (United States)

    Giuntini, Serena; Reason, Donald C.

    2012-01-01

    Meningococcal vaccines containing factor H binding protein (fHbp) are in clinical development. fHbp binds human fH, which enables the meningococcus to resist complement-mediated bacteriolysis. Previously, we found that chimeric human IgG1 mouse anti-fHbp monoclonal antibodies (MAbs) had human complement-mediated bactericidal activity only if the MAb inhibited fH binding. Since IgG subclasses differ in their ability to activate complement, we investigated the role of human IgG subclasses on antibody functional activity. We constructed chimeric MAbs in which three different murine fHbp-specific binding domains were each paired with human IgG1, IgG2, or IgG3. Against a wild-type group B isolate, all three IgG3 MAbs, irrespective of their ability to inhibit fH binding, had bactericidal activity that was >5-fold higher than the respective IgG1 MAbs, while the IgG2 MAbs had the least activity. Against a mutant with increased fHbp expression, the anti-fHbp MAbs elicited greater C4b deposition (classical pathway) and greater bactericidal activity than against the wild-type strain, and the IgG1 MAbs had similar or greater activity than the respective IgG3 MAbs. The bactericidal activity against both wild-type and mutant strains also was dependent, in part, on activation of the alternative complement pathway. Thus, at lower epitope density in the wild-type strain, the IgG3 anti-fHbp MAbs had the greatest bactericidal activity. At a higher epitope density in the mutant, the IgG1 MAbs had similar or greater bactericidal activity than the IgG3 MAbs, and the activity was less dependent on the inhibition of fH binding than at a lower epitope density. PMID:22064712

  5. Human embryonic stem cell-derived neuronal cells form spontaneously active neuronal networks in vitro.

    Science.gov (United States)

    Heikkilä, Teemu J; Ylä-Outinen, Laura; Tanskanen, Jarno M A; Lappalainen, Riikka S; Skottman, Heli; Suuronen, Riitta; Mikkonen, Jarno E; Hyttinen, Jari A K; Narkilahti, Susanna

    2009-07-01

    The production of functional human embryonic stem cell (hESC)-derived neuronal cells is critical for the application of hESCs in treating neurodegenerative disorders. To study the potential functionality of hESC-derived neurons, we cultured and monitored the development of hESC-derived neuronal networks on microelectrode arrays. Immunocytochemical studies revealed that these networks were positive for the neuronal marker proteins beta-tubulin(III) and microtubule-associated protein 2 (MAP-2). The hESC-derived neuronal networks were spontaneously active and exhibited a multitude of electrical impulse firing patterns. Synchronous bursts of electrical activity similar to those reported for hippocampal neurons and rodent embryonic stem cell-derived neuronal networks were recorded from the differentiated cultures until up to 4 months. The dependence of the observed neuronal network activity on sodium ion channels was examined using tetrodotoxin (TTX). Antagonists for the glutamate receptors NMDA [D(-)-2-amino-5-phosphonopentanoic acid] and AMPA/kainate [6-cyano-7-nitroquinoxaline-2,3-dione], and for GABAA receptors [(-)-bicuculline methiodide] modulated the spontaneous electrical activity, indicating that pharmacologically susceptible neuronal networks with functional synapses had been generated. The findings indicate that hESC-derived neuronal cells can generate spontaneously active networks with synchronous communication in vitro, and are therefore suitable for use in developmental and drug screening studies, as well as for regenerative medicine.

  6. Sub-threshold spinal cord stimulation facilitates spontaneous motor activity in spinal rats

    Science.gov (United States)

    2013-01-01

    Background Epidural stimulation of the spinal cord can be used to enable stepping on a treadmill (electrical enabling motor control, eEmc) after a complete mid-thoracic spinal cord transection in adult rats. Herein we have studied the effects of eEmc using a sub-threshold intensity of stimulation combined with spontaneous load-bearing proprioception to facilitate hindlimb stepping and standing during daily cage activity in paralyzed rats. Methods We hypothesized that eEmc combined with spontaneous cage activity would greatly increase the frequency and level of activation of the locomotor circuits in paralyzed rats. Spontaneous cage activity was recorded using a specially designed swivel connector to record EMG signals and an IR based camcorder to record video. Results and conclusion The spinal rats initially were very lethargic in their cages showing little movement. Without eEmc, the rats remained rather inactive with the torso rarely being elevated from the cage floor. When the rats used their forelimbs to move, the hindlimbs were extended and dragged behind with little or no flexion. In contrast, with eEmc the rats were highly active and the hindlimbs showed robust alternating flexion and extension resulting in step-like movements during forelimb-facilitated locomotion and often would stand using the sides of the cages as support. The mean and summed integrated EMG levels in both a hindlimb flexor and extensor muscle were higher with than without eEmc. These data suggest that eEmc, in combination with the associated proprioceptive input, can modulate the spinal networks to significantly amplify the amount and robustness of spontaneous motor activity in paralyzed rats. PMID:24156340

  7. Computational Account of Spontaneous Activity as a Signature of Predictive Coding.

    Directory of Open Access Journals (Sweden)

    Veronika Koren

    2017-01-01

    Full Text Available Spontaneous activity is commonly observed in a variety of cortical states. Experimental evidence suggested that neural assemblies undergo slow oscillations with Up ad Down states even when the network is isolated from the rest of the brain. Here we show that these spontaneous events can be generated by the recurrent connections within the network and understood as signatures of neural circuits that are correcting their internal representation. A noiseless spiking neural network can represent its input signals most accurately when excitatory and inhibitory currents are as strong and as tightly balanced as possible. However, in the presence of realistic neural noise and synaptic delays, this may result in prohibitively large spike counts. An optimal working regime can be found by considering terms that control firing rates in the objective function from which the network is derived and then minimizing simultaneously the coding error and the cost of neural activity. In biological terms, this is equivalent to tuning neural thresholds and after-spike hyperpolarization. In suboptimal working regimes, we observe spontaneous activity even in the absence of feed-forward inputs. In an all-to-all randomly connected network, the entire population is involved in Up states. In spatially organized networks with local connectivity, Up states spread through local connections between neurons of similar selectivity and take the form of a traveling wave. Up states are observed for a wide range of parameters and have similar statistical properties in both active and quiescent state. In the optimal working regime, Up states are vanishing, leaving place to asynchronous activity, suggesting that this working regime is a signature of maximally efficient coding. Although they result in a massive increase in the firing activity, the read-out of spontaneous Up states is in fact orthogonal to the stimulus representation, therefore interfering minimally with the network

  8. The wiring of developing sensory circuits - from patterned spontaneous activity to mechanisms of synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Alexandra Helen Leighton

    2016-09-01

    Full Text Available In order to accurately process incoming sensory stimuli, neurons must be organized into functional networks, with both genetic and environmental factors influencing the precise arrangement of connections between cells. Teasing apart the relative contributions of molecular guidance cues, spontaneous activity and visual experience during this maturation is on-going. During development of the sensory system, the first, rough organization of connections is created by molecular factors. These connections are then modulated by the intrinsically generated activity of neurons, even before the senses have become operational. Spontaneous waves of depolarisations sweep across the nervous system, placing them in a prime position to strengthen correct connections and weaken others, shaping synapses into a useful network. A large body of work now supports the idea that, rather than being a mere side-effect of the system, spontaneous activity actually contains information which readies the nervous system so that, as soon as the senses become active, sensory information can be utilized by the animal. An example is the neonatal mouse. As soon as the eyelids first open, neurons in the cortex respond to visual information without the animal having previously encountered structured sensory input (Cang et al., 2005a; Ko et al., 2013; Rochefort et al., 2011; Zhang et al., 2012. In vivo imaging techniques have advanced considerably, allowing observation of the natural activity in the brain of living animals down to the level of the individual synapse. New (optogenetic methods make it possible to subtly modulate the spatio-temporal properties of activity, aiding our understanding of how these characteristics relate to the function of spontaneous activity. Such experiments have had a huge impact on our knowledge by permitting direct testing of ideas about the plasticity mechanisms at play in the intact system, opening up a provocative range of fresh questions. Here, we

  9. Spontaneous nitroblue-tetrazolium (NBT) reduction related to granulocyte priming and activation.

    Science.gov (United States)

    Wikström, T; Braide, M; Bagge, U; Risberg, B

    1996-06-01

    The aim of the present study was to explore the relationship between the increasing level of spontaneous NBT-reduction and the tendency for PMNs to marginate during experimental hemorrhagic shock in rats. Rat PMNs, isolated on Percoll density gradients or suspended in blood, were examined by chemiluminescence (CL), NBT-test and by their CD-18 expression and F-actin formation. The NBT-test generally produced higher numbers of activated PMNs when the cells were suspended in buffer than in whole blood, probably due to the scavenging properties of blood. The level of spontaneous NBT-reduction of PMNs in blood correlated with the magnitude of the NBT-response to f-MLP stimulation in blood and buffer. On the contrary, there were no significant correlations between spontaneous NBT reduction, CD18 expression and F-actin content. Thus, high levels of spontaneous NBT reduction in blood were associated with priming of the separated PMNs rather than increased rigidity (F-actin) or adhesiveness (CD18).

  10. Interactions of PLGA nanoparticles with blood components: protein adsorption, coagulation, activation of the complement system and hemolysis studies.

    Science.gov (United States)

    Fornaguera, Cristina; Calderó, Gabriela; Mitjans, Montserrat; Vinardell, Maria Pilar; Solans, Conxita; Vauthier, Christine

    2015-04-14

    The intravenous administration of poly(lactic-co-glycolic) acid (PLGA) nanoparticles has been widely reported as a promising alternative for delivery of drugs to specific cells. However, studies on their interaction with diverse blood components using different techniques are still lacking. Therefore, in the present work, the interaction of PLGA nanoparticles with blood components was described using different complementary techniques. The influence of different encapsulated compounds/functionalizing agents on these interactions was also reported. It is worth noting that all these techniques can be simply performed, without the need for highly sophisticated apparatus or skills. Moreover, their transference to industries and application of quality control could be easily performed. Serum albumin was adsorbed onto all types of tested nanoparticles. The saturation concentration was dependent on the nanoparticle size. In contrast, fibrinogen aggregation was dependent on nanoparticle surface charge. The complement activation was also influenced by the nanoparticle functionalization; the presence of a functionalizing agent increased complement activation, while the addition of an encapsulated compound only caused a slight increase. None of the nanoparticles influenced the coagulation cascade at low concentrations. However, at high concentrations, cationized nanoparticles did activate the coagulation cascade. Interactions of nanoparticles with erythrocytes did not reveal any hemolysis. Interactions of PLGA nanoparticles with blood proteins depended both on the nanoparticle properties and the protein studied. Independent of their loading/surface functionalization, PLGA nanoparticles did not influence the coagulation cascade and did not induce hemolysis of erythrocytes; they could be defined as safe concerning induction of embolization and cell lysis.

  11. Spatiotemporal stability of neonatal rat cardiomyocyte monolayers spontaneous activity is dependent on the culture substrate.

    Directory of Open Access Journals (Sweden)

    Jonathan Boudreau-Béland

    Full Text Available In native conditions, cardiac cells must continuously comply with diverse stimuli necessitating a perpetual adaptation. Polydimethylsiloxane (PDMS is commonly used in cell culture to study cellular response to changes in the mechanical environment. The aim of this study was to evaluate the impact of using PDMS substrates on the properties of spontaneous activity of cardiomyocyte monolayer cultures. We compared PDMS to the gold standard normally used in culture: a glass substrate. Although mean frequency of spontaneous activity remained unaltered, incidence of reentrant activity was significantly higher in samples cultured on glass compared to PDMS substrates. Higher spatial and temporal instability of the spontaneous rate activation was found when cardiomyocytes were cultured on PDMS, and correlated with decreased connexin-43 and increased CaV3.1 and HCN2 mRNA levels. Compared to cultures on glass, cultures on PDMS were associated with the strongest response to isoproterenol and acetylcholine. These results reveal the importance of carefully selecting the culture substrate for studies involving mechanical stimulation, especially for tissue engineering or pharmacological high-throughput screening of cardiac tissue analog.

  12. The Neural Association between Tendency to Forgive and Spontaneous Brain Activity in Healthy Young Adults.

    Science.gov (United States)

    Li, Haijiang; Lu, Jiamei

    2017-01-01

    The tendency to forgive (TTF) refers to one's global dispositional level of forgiveness across situations and relationships. Previous brain imaging studies examined activation patterns underlying forgiving process, yet the association between individual differences in the TTF and spontaneous brain activity at resting-state remains unknown. In this study, resting-state functional magnetic resonance imaging (fMRI) was used to investigate the correlation between the TTF and spontaneous brain activity in a young adult sample. Participants were 178 young students (55 men) who completed the TTF scale and underwent a resting-state fMRI scan. Multiple regression analysis was conducted to assess the association between the regional amplitude of low-frequency fluctuations (ALFF) and TTF scores corrected for age and sex. Results showed that the ALFF value in the right dorsomedial prefrontal cortex (dmPFC), precuneus and inferior parietal lobule (IPL) were negatively associated with TTF scores. These findings suggest that the spontaneous brain activity of brain regions like the dmPFC, precuneus and IPL which are implicated in mentalizing and empathic response are associated with individual differences in the TTF.

  13. Dissociable effects of Sry and sex chromosome complement on activity, feeding and anxiety-related behaviours in mice.

    Science.gov (United States)

    Kopsida, Eleni; Lynn, Phoebe M; Humby, Trevor; Wilkinson, Lawrence S; Davies, William

    2013-01-01

    Whilst gonadal hormones can substantially influence sexual differentiation of the brain, recent findings have suggested that sex-linked genes may also directly influence neurodevelopment. Here we used the well-established murine 'four core genotype' (FCG) model on a gonadally-intact, outbred genetic background to characterise the contribution of Sry-dependent effects (i.e. those arising from the expression of the Y-linked Sry gene in the brain, or from hormonal sequelae of gonadal Sry expression) and direct effects of sex-linked genes other than Sry ('sex chromosome complement' effects) to sexually dimorphic mouse behavioural phenotypes. Over a 24 hour period, XX and XY gonadally female mice (lacking Sry) exhibited greater horizontal locomotor activity and reduced food consumption per unit bodyweight than XX and XY gonadally male mice (possessing Sry); in two behavioural tests (the elevated plus and zero mazes) XX and XY gonadally female mice showed evidence for increased anxiety-related behaviours relative to XX and XY gonadally male mice. Exploratory correlational analyses indicated that these Sry-dependent effects could not be simply explained by brain expression of the gene, nor by circulating testosterone levels. We also noted a sex chromosome complement effect on food (but not water) consumption whereby XY mice consumed more over a 24hr period than XX mice, and a sex chromosome complement effect in a third test of anxiety-related behaviour, the light-dark box. The present data suggest that: i) the male-specific factor Sry may influence activity and feeding behaviours in mice, and ii) dissociable feeding and anxiety-related murine phenotypes may be differentially modulated by Sry and by other sex-linked genes. Our results may have relevance for understanding the molecular underpinnings of sexually dimorphic behavioural phenotypes in healthy men and women, and in individuals with abnormal sex chromosome constitutions.

  14. Dissociable effects of Sry and sex chromosome complement on activity, feeding and anxiety-related behaviours in mice.

    Directory of Open Access Journals (Sweden)

    Eleni Kopsida

    Full Text Available Whilst gonadal hormones can substantially influence sexual differentiation of the brain, recent findings have suggested that sex-linked genes may also directly influence neurodevelopment. Here we used the well-established murine 'four core genotype' (FCG model on a gonadally-intact, outbred genetic background to characterise the contribution of Sry-dependent effects (i.e. those arising from the expression of the Y-linked Sry gene in the brain, or from hormonal sequelae of gonadal Sry expression and direct effects of sex-linked genes other than Sry ('sex chromosome complement' effects to sexually dimorphic mouse behavioural phenotypes. Over a 24 hour period, XX and XY gonadally female mice (lacking Sry exhibited greater horizontal locomotor activity and reduced food consumption per unit bodyweight than XX and XY gonadally male mice (possessing Sry; in two behavioural tests (the elevated plus and zero mazes XX and XY gonadally female mice showed evidence for increased anxiety-related behaviours relative to XX and XY gonadally male mice. Exploratory correlational analyses indicated that these Sry-dependent effects could not be simply explained by brain expression of the gene, nor by circulating testosterone levels. We also noted a sex chromosome complement effect on food (but not water consumption whereby XY mice consumed more over a 24hr period than XX mice, and a sex chromosome complement effect in a third test of anxiety-related behaviour, the light-dark box. The present data suggest that: i the male-specific factor Sry may influence activity and feeding behaviours in mice, and ii dissociable feeding and anxiety-related murine phenotypes may be differentially modulated by Sry and by other sex-linked genes. Our results may have relevance for understanding the molecular underpinnings of sexually dimorphic behavioural phenotypes in healthy men and women, and in individuals with abnormal sex chromosome constitutions.

  15. Changes in Mice Brain Spontaneous Electrical Activity during Cortical Spreading Depression due to Mobile Phone Radiation.

    Science.gov (United States)

    Sallam, Samera M; Mohamed, Ehab I; Dawood, Abdel-Fattah B

    2008-06-01

    The objective of the present study was to investigate changes in spontaneous EEG activity during cortical spreading depression (CSD) in mice brain. The cortical region of anaesthetized mice were exposed to the electromagnetic fields (EMFs) emitted from a mobile phone (MP, 935.2-960.2 MHz, 41.8 mW/cm(2)). The effect of EMFs on EEG was investigated before and after exposure to different stimuli (MP, 2% KCl, and MP & 2% KCl). The records of brain spontaneous EEG activity, slow potential changes (SPC), and spindle shaped firings were obtained through an interfaced computer. The results showed increases in the amplitude of evoked spindles by about 87%, 17%, and 226% for MP, 2% KCl, and MP & 2% KCl; respectively, as compared to values for the control group. These results showed that the evoked spindle is a more sensitive indicator of the effect of exposure to EMFs from MP.

  16. Endo- and exocytic rate constants for spontaneous and protein kinase C-activated T cell receptor cycling

    DEFF Research Database (Denmark)

    Menné, Charlotte; Møller Sørensen, Tine; Siersma, Volkert

    2002-01-01

    To determine the rate constants of spontaneous and activated TCR cycling, we examined TCR endo- and exocytosis in the human T cell line Jurkat by three different methods. Using a simple kinetic model for TCR cycling and non-linear regression analyses, we found that the spontaneous endocytic rate...

  17. Spontaneous and Evoked Activity from Murine Ventral Horn Cultures on Microelectrode Arrays

    Directory of Open Access Journals (Sweden)

    Bryan J. Black

    2017-09-01

    Full Text Available Motor neurons are the site of action for several neurological disorders and paralytic toxins, with cell bodies located in the ventral horn (VH of the spinal cord along with interneurons and support cells. Microelectrode arrays (MEAs have emerged as a high content assay platform for mechanistic studies and drug discovery. Here, we explored the spontaneous and evoked electrical activity of VH cultures derived from embryonic mouse spinal cord on multi-well plates of MEAs. Primary VH cultures from embryonic day 15–16 mice were characterized by expression of choline acetyltransferase (ChAT by immunocytochemistry. Well resolved, all-or-nothing spontaneous spikes with profiles consistent with extracellular action potentials were observed after 3 days in vitro, persisting with consistent firing rates until at least day in vitro 19. The majority of the spontaneous activity consisted of tonic firing interspersed with coordinated bursting across the network. After 5 days in vitro, spike activity was readily evoked by voltage pulses where a minimum amplitude and duration required for excitation was 300 mV and 100 μs/phase, respectively. We characterized the sensitivity of spontaneous and evoked activity to a host of pharmacological agents including AP5, CNQX, strychnine, ω-agatoxin IVA, and botulinum neurotoxin serotype A (BoNT/A. These experiments revealed sensitivity of the cultured VH to both agonist and antagonist compounds in a manner consistent with mature tissue derived from slices. In the case of BoNT/A, we also demonstrated intoxication persistence over an 18-day period, followed by partial intoxication recovery induced by N- and P/Q-type calcium channel agonist GV-58. In total, our findings suggest that VH cultures on multi-well MEA plates may represent a moderate throughput, high content assay for performing mechanistic studies and for screening potential therapeutics pertaining to paralytic toxins and neurological disorders.

  18. Myofascial trigger points: spontaneous electrical activity and its consequences for pain induction and propagation

    OpenAIRE

    Ge, Hong-You; Fernández-de-las-Peñas, César; Yue, Shou-Wei

    2011-01-01

    Abstract Active myofascial trigger points are one of the major peripheral pain generators for regional and generalized musculoskeletal pain conditions. Myofascial trigger points are also the targets for acupuncture and/or dry needling therapies. Recent evidence in the understanding of the pathophysiology of myofascial trigger points supports The Integrated Hypothesis for the trigger point formation; however unanswered questions remain. Current evidence shows that spontaneous electrical activi...

  19. Infusion Reactions Associated with the Medical Application of Monoclonal Antibodies: The Role of Complement Activation and Possibility of Inhibition by Factor H

    OpenAIRE

    Tamás Fülöp; Tamás Mészáros; Gergely Tibor Kozma; János Szebeni; Mihály Józsi

    2018-01-01

    Human application of monoclonal antibodies (mAbs), enzymes, as well as contrast media and many other particulate drugs and agents referred to as “nanomedicines”, can initiate pseudoallergic hypersensitivity reactions, also known as infusion reactions. These may in part be mediated by the activation of the complement system, a major humoral defense system of innate immunity. In this review, we provide a brief outline of complement activation-related pseudoallergy (CARPA) in general, and then f...

  20. The effect of low dose gamma irradiation on the activity of blood serum lysozyme and complement in broiler chickens

    International Nuclear Information System (INIS)

    Sotirov, L.; Semerdzhiev, V.; Angelova, A.

    1995-01-01

    Samples from 314 broiler chickens at 2 months age were analyzed for blood serum level of lysozyme and 311 of them were analyzed also for activity of alternative path-way of complement activity (APCA). Chickens were hatched from eggs, irradiated immediately before incubation with different doses of gamma-rays using Rocus M device - group 1 - control (non irradiated), and groups 2, 3 and 4 - irradiated with doses of 0.15, 0.30 and 0.60 Gy, respectively. Lysozyme concentration was highest for the control group, and for the experimental ones it was lower (p<0.001) which is an indication of the strongly negative effect of gamma-rays on this indicator. For APCA the oppsite relationship was observed - increasing of its activity with increasing of irradiation dose (from p<0.05 to p<0.001) which gave reason to suggest that this phenomenon is due to the irradiation. 12 refs., 2 tabs. (author)

  1. Rhythmic Spontaneous Activity Mediates the Age-Related Decline in Somatosensory Function.

    Science.gov (United States)

    Spooner, Rachel K; Wiesman, Alex I; Proskovec, Amy L; Heinrichs-Graham, Elizabeth; Wilson, Tony W

    2018-01-12

    Sensory gating is a neurophysiological process whereby the response to a second stimulus in a pair of identical stimuli is attenuated, and it is thought to reflect the capacity of the CNS to preserve neural resources for behaviorally relevant stimuli. Such gating is observed across multiple sensory modalities and is modulated by age, but the mechanisms involved are not understood. In this study, we examined somatosensory gating in 68 healthy adults using magnetoencephalography (MEG) and advanced oscillatory and time-domain analysis methods. MEG data underwent source reconstruction and peak voxel time series data were extracted to evaluate the dynamics of somatosensory gating, and the impact of spontaneous neural activity immediately preceding the stimulation. We found that gating declined with increasing age and that older adults had significantly reduced gating relative to younger adults, suggesting impaired local inhibitory function. Most importantly, older adults had significantly elevated spontaneous activity preceding the stimulation, and this effect fully mediated the impact of aging on sensory gating. In conclusion, gating in the somatosensory system declines with advancing age and this effect is directly tied to increased spontaneous neural activity in the primary somatosensory cortices, which is likely secondary to age-related declines in local GABA inhibitory function. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  2. Complement activation-related pseudoallergy in dogs following intravenous administration of a liposomal formulation of meglumine antimoniate

    Directory of Open Access Journals (Sweden)

    Raul R. Ribeiro

    2013-08-01

    Full Text Available The increasing use of nanotechnologies in advanced therapies has allowed the observation of specific adverse reactions related to nanostructures. The toxicity of a novel liposome formulation of meglumine antimoniate in dogs with visceral leishmaniasis after single dose has been investigated. Groups of 12 animals received by the intravenous route a single dose of liposomal meglumine antimoniate (group I [GI], 6.5 mg Sb/kg, empty liposomes (GII or isotonic saline (GIII. Evaluation of hematological and biochemical parameters showed no significant changes 4 days after administration. No undesired effects were registered in the GIII. However, adverse reactions were observed in 67.7% of dogs from both groups that received liposomal formulations. The side effects began moments after bolus administration and disappeared during the first 15 minutes after treatment. Prostation, sialorrhea and defecation were the most frequent clinical signs, registered in 33.3% and 41.6 % of animals from the groups GI and GII, respectively. Tachypnea, mydriasis, miosis, vomiting and cyanosis were also registered in both groups. The adverse reactions observed in this study were attributed to the activation of the complement system by lipid vesicles in a phenomenon known as Complement Activation-Related Pseudoallergy (CARPA. The influence of the physical-chemical characteristics of liposomal formulation in the triggering of CARPA is discussed.

  3. Complement activation product C4d in oral and oropharyngeal squamous cell carcinoma.

    Science.gov (United States)

    Ajona, D; Pajares, M J; Chiara, M D; Rodrigo, J P; Jantus-Lewintre, E; Camps, C; Suarez, C; Bagán, J V; Montuenga, L M; Pio, R

    2015-10-01

    Complement C4d-containing fragments have been proposed as diagnostic markers for lung cancer. The purpose of this study was to evaluate the presence of C4d in oropharyngeal (OPSCC) and oral (OSCC) squamous cell carcinomas. C4d staining was analyzed by immunohistochemistry in 244 OPSCC surgical specimens. C4d levels were quantified by ELISA in resting saliva samples from 48 patients with oral leukoplakia and 62 with OSCC. Plasma samples from 21 patients with leukoplakia and 30 with oral carcinoma were also studied. C4d staining in OPSCC specimens was associated with nodal invasion (P = 0.001), histopathologic grade (P = 0.014), disease stage (P = 0.040), and focal-adhesion kinase expression (P Saliva C4d levels were higher in patients with oral cancer than in subjects with leukoplakia (0.07 ± 0.07 vs 0.04 ± 0.03 μg ml(-1) , P = 0.003). The area under the ROC curve was 0.63 (95%CI: 0.55-0.71). Salivary C4d levels in stage IV patients were higher than in patients with earlier stages (P = 0.028) and correlated with tumor size (P = 0.045). Plasma C4d levels also correlated with salivary C4d levels (P = 0.041), but differences between patients with oral cancer and subjects with leukoplakia were not significant (1.26 ± 0.59 vs 1.09 ± 0.39 μg ml(-1) , P = 0.232). C4d-containing fragments are detected in oral primary tumors and are increased in saliva from patients with OSCC. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Regulation of C3 Activation by the Alternative Complement Pathway in the Mouse Retina.

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    Jennifer A E Williams

    Full Text Available The purpose of this study was to examine the retinas of mice carrying hemizygous and null double deletions of Cfb-/- and Cfh-/-, and to compare these with the single knockouts of Cfb, Cfh and Cfd. Retinas were isolated from wild type (WT, Cfb-/-/Cfh-/-, Cfb-/-/Cfh+/-, Cfh-/-/Cfb+/-, Cfb-/-, Cfh-/- Cfd-/-, and Cfd+/- mice. Complement proteins were evaluated by western blotting, ELISA and immunocytochemistry, and retinal morphology was assessed using toluidine blue stained semi-thin sections. WT mice showed staining for C3 and its breakdown products in the retinal vasculature and the basal surface of the retinal pigment epithelium (RPE. Cfb-/- mice exhibited a similar C3 staining pattern to WT in the retinal vessels but a decrease in C3 and its breakdown products at the basal surface of the RPE. Deletion of both Cfb and Cfh restored C3 to levels similar to those observed in WT mice, however this reversal of phenotype was not observed in Cfh-/-/Cfb+/- or Cfb-/-/Cfh+/- mice. Loss of CFD caused an increase in C3 and a decrease in C3 breakdown products along the basal surface of the RPE. Overall the retinal morphology and retinal vasculature did not appear different across the various genotypes. We observed that C3 accumulates at the basal RPE in Cfb-/-, Cfb-/-/Cfh-/-, Cfb-/-/Cfh+/-, Cfd-/- and WT mice, but is absent in Cfh-/- and Cfh-/-/Cfb+/- mice, consistent with its consumption in the serum of mice lacking CFH when CFB is present. C3 breakdown products along the surface of the RPE were either decreased or absent when CFB, CFH or CFD was deleted or partially deleted.

  5. Reproduction of overall spontaneous pain pattern by manual stimulation of active myofascial trigger points in fibromyalgia patients

    DEFF Research Database (Denmark)

    Ge, Hong-You; Wang, Ying; Fernández-de-las-Peñas, César

    2011-01-01

    It has previously been reported that local and referred pain from active myofascial trigger points (MTPs) in the neck and shoulder region contribute to fibromyalgia (FM) pain and that the pain pattern induced from active MTPs can reproduce parts of the spontaneous clinical FM pain pattern....... The current study investigated whether the overall spontaneous FM pain pattern can be reproduced by local and referred pain from active MTPs located in different muscles....

  6. Tsetse GmmSRPN10 has anti-complement activity and is important for successful establishment of trypanosome infections in the fly midgut.

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    Cher-Pheng Ooi

    2015-01-01

    Full Text Available The complement cascade in mammalian blood can damage the alimentary tract of haematophagous arthropods. As such, these animals have evolved their own repertoire of complement-inactivating factors, which are inadvertently exploited by blood-borne pathogens to escape complement lysis. Unlike the bloodstream stages, the procyclic (insect stage of Trypanosoma brucei is highly susceptible to complement killing, which is puzzling considering that a tsetse takes a bloodmeal every 2-4 days. In this study, we identified four tsetse (Glossina morsitans morsitans serine protease inhibitors (serpins from a midgut expressed sequence tag (EST library (GmmSRPN3, GmmSRPN5, GmmSRPN9 and GmmSRPN10 and investigated their role in modulating the establishment of a T. brucei infection in the midgut. Although not having evolved in a common blood-feeding ancestor, all four serpins have an active site sharing remarkable homology with the human complement C1-inhibitor serpin, SerpinG1. RNAi knockdown of individual GmmSRPN9 and GmmSRPN10 genes resulted in a significant decreased rate of infection by procyclic form T. brucei. Furthermore, recombinant GmmSRPN10 was both able to inhibit the activity of human complement-cascade serine proteases, C1s and Factor D, and to protect the in vitro killing of procyclic trypanosomes when incubated with complement-activated human serum. Thus, the secretion of serpins, which may be part of a bloodmeal complement inactivation system in tsetse, is used by procyclic trypanosomes to evade an influx of fresh trypanolytic complement with each bloodmeal. This highlights another facet of the complicated relationship between T. brucei and its tsetse vector, where the parasite takes advantage of tsetse physiology to further its chances of propagation and transmission.

  7. Tsetse GmmSRPN10 has anti-complement activity and is important for successful establishment of trypanosome infections in the fly midgut.

    Science.gov (United States)

    Ooi, Cher-Pheng; Haines, Lee R; Southern, Daniel M; Lehane, Michael J; Acosta-Serrano, Alvaro

    2015-01-01

    The complement cascade in mammalian blood can damage the alimentary tract of haematophagous arthropods. As such, these animals have evolved their own repertoire of complement-inactivating factors, which are inadvertently exploited by blood-borne pathogens to escape complement lysis. Unlike the bloodstream stages, the procyclic (insect) stage of Trypanosoma brucei is highly susceptible to complement killing, which is puzzling considering that a tsetse takes a bloodmeal every 2-4 days. In this study, we identified four tsetse (Glossina morsitans morsitans) serine protease inhibitors (serpins) from a midgut expressed sequence tag (EST) library (GmmSRPN3, GmmSRPN5, GmmSRPN9 and GmmSRPN10) and investigated their role in modulating the establishment of a T. brucei infection in the midgut. Although not having evolved in a common blood-feeding ancestor, all four serpins have an active site sharing remarkable homology with the human complement C1-inhibitor serpin, SerpinG1. RNAi knockdown of individual GmmSRPN9 and GmmSRPN10 genes resulted in a significant decreased rate of infection by procyclic form T. brucei. Furthermore, recombinant GmmSRPN10 was both able to inhibit the activity of human complement-cascade serine proteases, C1s and Factor D, and to protect the in vitro killing of procyclic trypanosomes when incubated with complement-activated human serum. Thus, the secretion of serpins, which may be part of a bloodmeal complement inactivation system in tsetse, is used by procyclic trypanosomes to evade an influx of fresh trypanolytic complement with each bloodmeal. This highlights another facet of the complicated relationship between T. brucei and its tsetse vector, where the parasite takes advantage of tsetse physiology to further its chances of propagation and transmission.

  8. Prophage spontaneous activation promotes DNA release enhancing biofilm formation in Streptococcus pneumoniae.

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    Margarida Carrolo

    Full Text Available Streptococcus pneumoniae (pneumococcus is able to form biofilms in vivo and previous studies propose that pneumococcal biofilms play a relevant role both in colonization and infection. Additionally, pneumococci recovered from human infections are characterized by a high prevalence of lysogenic bacteriophages (phages residing quiescently in their host chromosome. We investigated a possible link between lysogeny and biofilm formation. Considering that extracellular DNA (eDNA is a key factor in the biofilm matrix, we reasoned that prophage spontaneous activation with the consequent bacterial host lysis could provide a source of eDNA, enhancing pneumococcal biofilm development. Monitoring biofilm growth of lysogenic and non-lysogenic pneumococcal strains indicated that phage-infected bacteria are more proficient at forming biofilms, that is their biofilms are characterized by a higher biomass and cell viability. The presence of phage particles throughout the lysogenic strains biofilm development implicated prophage spontaneous induction in this effect. Analysis of lysogens deficient for phage lysin and the bacterial major autolysin revealed that the absence of either lytic activity impaired biofilm development and the addition of DNA restored the ability of mutant strains to form robust biofilms. These findings establish that limited phage-mediated host lysis of a fraction of the bacterial population, due to spontaneous phage induction, constitutes an important source of eDNA for the S. pneumoniae biofilm matrix and that this localized release of eDNA favors biofilm formation by the remaining bacterial population.

  9. Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders

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    Mader Simone

    2011-12-01

    Full Text Available Abstract Background Serum autoantibodies against the water channel aquaporin-4 (AQP4 are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO. However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM and multiple sclerosis (MS patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM remains unresolved. Results We analyzed patients with definite NMO (n = 45, HR-NMO (n = 53, ADEM (n = 33, clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32, MS (n = 71 and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC. AQP4-IgG was found in patients with NMO (n = 43, 96%, HR-NMO (n = 32, 60% and in one CIS patient (3%, but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%, NMO (n = 3, 7%, HR-NMO (n = 7, 13%, 5 rON and 2 LETM, CIS (n = 2, 6%, MS (n = 2, 3% and controls (n = 3, 3%, two SLE and one OND. Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33% AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able

  10. COMPLEMENT REGULATION IN RENAL DISEASE MODELS

    Science.gov (United States)

    Naik, Abhijit; Sharma, Shweta; Quigg, Richard J.

    2014-01-01

    Activation of the complement system is tightly regulated by plasma and cell-associated complement regulatory proteins (CRPs), such as factor H (fH), decay-accelerating factor (DAF), and membrane cofactor protein (MCP). Animal models of disease have provided considerable insights into the important roles for CRPs in the kidney. Mice deficient in fH have excessive fluid phase C3 activation and inactivation leading to deposition of iC3b in glomerular capillary walls (GCW), comparable to dense deposit disease. In contrast, when fH lacks C-terminal surface targeting regions, local activation on the GCW leads to a disease reminiscent of thrombotic microangiopathy. The uniquely rodent protein, CR1-related y (Crry), has features analogous to human MCP. Defective Crry leads to unrestricted alternative pathway activation in the tubulointerstitium (TI) resulting in pathological features ranging from TMA, acute kidney injury and TI nephritis. In the presence of initiators of the classical or lectin pathways, commonly in the form of immune complexes in human glomerular diseases, complement regulation on self is stressed, with the potential for recruitment of the spontaneously active alternative pathway. The threshold for this activation is set by CRPs; pathology is more likely when complement regulation is defective. Within the endocapillary region of the GCW, fH is key, while DAF and Crry are protective on mesangial cells and podocytes. Arguably, acquired alterations in these CRPs is a more common event, extending from pathological states of cellular injury or production of inhibitory antibodies, to physiological fine tuning of the adaptive immune response. PMID:24161042

  11. Complement C5 activation during influenza A infection in mice contributes to neutrophil recruitment and lung injury.

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    Cristiana C Garcia

    Full Text Available Influenza virus A (IAV causes annual epidemics and intermittent pandemics that affect millions of people worldwide. Potent inflammatory responses are commonly associated with severe cases of IAV infection. The complement system, an important mechanism of innate and humoral immune responses to infections, is activated during primary IAV infection and mediates, in association with natural IgM, viral neutralization by virion aggregation and coating of viral hemmagglutinin. Increased levels of the anaphylatoxin C5a were found in patients fatally infected with the most recent H1N1 pandemic virus. In this study, our aim was to evaluate whether targeting C5 activation alters inflammatory lung injury and viral load in a murine model of IAV infection. To address this question C57Bl/6j mice were infected intranasally with 10(4 PFU of the mouse adapted Influenza A virus A/WSN/33 (H1N1 or inoculated with PBS (Mock. We demonstrated that C5a is increased in bronchoalveolar lavage fluid (BALF upon experimental IAV infection. To evaluate the role of C5, we used OmCI, a potent arthropod-derived inhibitor of C5 activation that binds to C5 and prevents release of C5a by complement. OmCI was given daily by intraperitoneal injection from the day of IAV infection until day 5. Treatment with OmCI only partially reduced C5a levels in BALF. However, there was significant inhibition of neutrophil and macrophage infiltration in the airways, Neutrophil Extracellular Traps (NETs formation, death of leukocytes, lung epithelial injury and overall lung damage induced by the infection. There was no effect on viral load. Taken together, these data suggest that targeting C5 activation with OmCI during IAV infection could be a promising approach to reduce excessive inflammatory reactions associated with the severe forms of IAV infections.

  12. ATP enhances spontaneous calcium activity in cultured suburothelial myofibroblasts of the human bladder.

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    Sheng Cheng

    Full Text Available BACKGROUND: Suburothelial myofibroblasts (sMF are located underneath the urothelium in close proximity to afferent nerves. They express purinergic receptors and show calcium transients in response to ATP. Therefore they are supposed to be involved in afferent signaling of the bladder fullness. Since ATP concentration is likely to be very low during the initial filling phase, we hypothesized that sMF Ca(2+ activity is affected even at very low ATP concentrations. We investigated ATP induced modulation of spontaneous activity, intracellular calcium response and purinergic signaling in cultured sMF. METHODOLOGY/PRINCIPAL FINDINGS: Myofibroblast cultures, established from cystectomies, were challenged by exogenous ATP in presence or absence of purinergic antagonist. Fura-2 calcium imaging was used to monitor ATP (10(-16 to 10(-4 mol/l induced alterations of calcium activity. Purinergic receptors (P2X1, P2X2, P2X3 were analysed by confocal immunofluorescence. We found spontaneous calcium activity in 55.18% ± 1.65 of the sMF (N = 48 experiments. ATP significantly increased calcium activity even at 10(-16 mol/l. The calcium transients were partially attenuated by subtype selective antagonist (TNP-ATP, 1 µM; A-317491, 1 µM, and were mimicked by the P2X1, P2X3 selective agonist α,β-methylene ATP. The expression of purinergic receptor subtypes in sMF was confirmed by immunofluorescence. CONCLUSIONS/SIGNIFICANCE: Our experiments demonstrate for the first time that ATP can modulate spontaneous activity and induce intracellular Ca(2+ response in cultured sMF at very low concentrations, most likely involving P2X receptors. These findings support the notion that sMF are able to register bladder fullness very sensitively, which predestines them for the modulation of the afferent bladder signaling in normal and pathological conditions.

  13. SPONTANEOUS IMMUNOGLOBULIN-SYNTHESIZING ACTIVITY OF B LYMPHOCYTES IN INFLAMMATORY RHEUMATIC DISEASES

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    A.T. T. Mamasaidov

    2007-01-01

    Full Text Available Abstract. The aim of present work was to evaluate clinical significance of B-lymphocytes spontaneous antibody-synthesizing activity by B-lymphocytes (LASA in patients with rheumatic inflammatory diseases (RD, i.e., reactive arthritis (ReA, ankylosing spondylitis (AS, rheumatoid arthritis (RA, and systemic lupus erythematosus (SLE. Significantly higher LASA levels were revealed in the patients with ReA, AS, RA, and SLE, as compared with healthy persons and patients with osteoarthrosis. Clinical significance of LASA indexes and their changes may reflect manifestation and degree of immunological activities in ReA, AS, RA, and SLE.

  14. Tumour exosomes display differential mechanical and complement activation properties dependent on malignant state: implications in endothelial leakiness

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    Bradley Whitehead

    2015-12-01

    Full Text Available Background: Exosomes have been implicated in tumour progression and metastatic spread. Little is known of the effect of mechanical and innate immune interactions of malignant cell-derived exosomes on endothelial integrity, which may relate to increased extravasation of circulating tumour cells and, therefore, increased metastatic spread. Methods: Exosomes isolated from non-malignant immortalized HCV-29 and isogenic malignant non-metastatic T24 and malignant metastatic FL3 bladder cells were characterized by nanoparticle tracking analysis and quantitative nanomechanical mapping atomic force microscopy (QNM AFM to determine size and nanomechanical properties. Effect of HCV-29, T24 and FL3 exosomes on human umbilical vein endothelial cell (HUVEC monolayer integrity was determined by transendothelial electrical resistance (TEER measurements and transport was determined by flow cytometry. Complement activation studies in human serum of malignant and non-malignant cell-derived exosomes were performed. Results: FL3, T24 and HCV-29 cells produced exosomes at similar concentration per cell (6.64, 6.61 and 6.46×104 exosomes per cell for FL3, T24 and HCV-29 cells, respectively and of similar size (120.2 nm for FL3, 127.6 nm for T24 and 117.9 nm for HCV-29, respectively. T24 and FL3 cell-derived exosomes exhibited a markedly reduced stiffness, 95 MPa and 280 MPa, respectively, compared with 1,527 MPa with non-malignant HCV-29 cell-derived exosomes determined by QNM AFM. FL3 and T24 exosomes induced endothelial disruption as measured by a decrease in TEER in HUVEC monolayers, whereas no effect was observed for HCV-29 derived exosomes. FL3 and T24 exosomes traffic more readily (11.6 and 21.4% of applied exosomes, respectively across HUVEC monolayers than HCV-29 derived exosomes (7.2% of applied exosomes. Malignant cell-derived exosomes activated complement through calcium-sensitive pathways in a concentration-dependent manner. Conclusions: Malignant

  15. Complement activation in plasma before and after infliximab treatment in Crohn disease

    DEFF Research Database (Denmark)

    Zimmermann-Nielsen, E; Agnholt, J; Thorlacius-Ussing, O

    2003-01-01

    complicated by fistulizing ano-rectal disease was collected before and after three Infliximab infusions (5 mg kg(-1)). RESULTS: Before treatment, the C3-activation capacities (C3-AC) in plasma from patients with Crohn disease were comparable with values obtained from healthy controls. The classical C pathway......-mediated C3-AC, mannan-binding lectin C4-AC, leucocyte count, C-reactive protein concentration and Crohn Disease Activity Index decreased significantly 8 weeks after the first infusion of Infliximab (P ... in plasma from patients with Crohn disease; the decrease observed in the classical pathway-mediated C3-AC after treatment with Infliximab reflects a general down-regulation in immune activation....

  16. Amblyomma americanum tick calreticulin binds C1q but does not inhibit activation of the classical complement cascade.

    Science.gov (United States)

    Kim, Tae Kwon; Ibelli, Adriana Mércia Guaratini; Mulenga, Albert

    2015-02-01

    In this study we characterized Amblyomma americanum (Aam) tick calreticulin (CRT) homolog in tick feeding physiology. In nature, different tick species can be found feeding on the same animal host. This suggests that different tick species found feeding on the same host can modulate the same host anti-tick defense pathways to successfully feed. From this perspective it's plausible that different tick species can utilize universally conserved proteins such as CRT to regulate and facilitate feeding. CRT is a multi-functional protein found in most taxa that is injected into the vertebrate host during tick feeding. Apart from it's current use as a biomarker for human tick bites, role(s) of this protein in tick feeding physiology have not been elucidated. Here we show that annotated functional CRT amino acid motifs are well conserved in tick CRT. However our data show that despite high amino acid identity levels to functionally characterized CRT homologs in other organisms, AamCRT is apparently functionally different. Pichia pastoris expressed recombinant (r) AamCRT bound C1q, the first component of the classical complement system, but it did not inhibit activation of this pathway. This contrast with reports of other parasite CRT that inhibited activation of the classical complement pathway through sequestration of C1q. Furthermore rAamCRT did not bind factor Xa in contrast to reports of parasite CRT binding factor Xa, an important protease in the blood clotting system. Consistent with this observation, rAamCRT did not affect plasma clotting or platelet aggregation. We discuss our findings in the context of tick feeding physiology.

  17. Split-Cre complementation restores combination activity on transgene excision in hair roots of transgenic tobacco.

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    Mengling Wen

    Full Text Available The Cre/loxP system is increasingly exploited for genetic manipulation of DNA in vitro and in vivo. It was previously reported that inactive ''split-Cre'' fragments could restore Cre activity in transgenic mice when overlapping co-expression was controlled by two different promoters. In this study, we analyzed recombination activities of split-Cre proteins, and found that no recombinase activity was detected in the in vitro recombination reaction in which only the N-terminal domain (NCre of split-Cre protein was expressed, whereas recombination activity was obtained when the C-terminal (CCre or both NCre and CCre fragments were supplied. We have also determined the recombination efficiency of split-Cre proteins which were co-expressed in hair roots of transgenic tobacco. No Cre recombination event was observed in hair roots of transgenic tobacco when the NCre or CCre genes were expressed alone. In contrast, an efficient recombination event was found in transgenic hairy roots co-expressing both inactive split-Cre genes. Moreover, the restored recombination efficiency of split-Cre proteins fused with the nuclear localization sequence (NLS was higher than that of intact Cre in transgenic lines. Thus, DNA recombination mediated by split-Cre proteins provides an alternative method for spatial and temporal regulation of gene expression in transgenic plants.

  18. Myofascial trigger points: spontaneous electrical activity and its consequences for pain induction and propagation

    Science.gov (United States)

    2011-01-01

    Active myofascial trigger points are one of the major peripheral pain generators for regional and generalized musculoskeletal pain conditions. Myofascial trigger points are also the targets for acupuncture and/or dry needling therapies. Recent evidence in the understanding of the pathophysiology of myofascial trigger points supports The Integrated Hypothesis for the trigger point formation; however unanswered questions remain. Current evidence shows that spontaneous electrical activity at myofascial trigger point originates from the extrafusal motor endplate. The spontaneous electrical activity represents focal muscle fiber contraction and/or muscle cramp potentials depending on trigger point sensitivity. Local pain and tenderness at myofascial trigger points are largely due to nociceptor sensitization with a lesser contribution from non-nociceptor sensitization. Nociceptor and non-nociceptor sensitization at myofascial trigger points may be part of the process of muscle ischemia associated with sustained focal muscle contraction and/or muscle cramps. Referred pain is dependent on the sensitivity of myofascial trigger points. Active myofascial trigger points may play an important role in the transition from localized pain to generalized pain conditions via the enhanced central sensitization, decreased descending inhibition and dysfunctional motor control strategy. PMID:21439050

  19. Myofascial trigger points: spontaneous electrical activity and its consequences for pain induction and propagation.

    Science.gov (United States)

    Ge, Hong-You; Fernández-de-Las-Peñas, César; Yue, Shou-Wei

    2011-03-25

    Active myofascial trigger points are one of the major peripheral pain generators for regional and generalized musculoskeletal pain conditions. Myofascial trigger points are also the targets for acupuncture and/or dry needling therapies. Recent evidence in the understanding of the pathophysiology of myofascial trigger points supports The Integrated Hypothesis for the trigger point formation; however unanswered questions remain. Current evidence shows that spontaneous electrical activity at myofascial trigger point originates from the extrafusal motor endplate. The spontaneous electrical activity represents focal muscle fiber contraction and/or muscle cramp potentials depending on trigger point sensitivity. Local pain and tenderness at myofascial trigger points are largely due to nociceptor sensitization with a lesser contribution from non-nociceptor sensitization. Nociceptor and non-nociceptor sensitization at myofascial trigger points may be part of the process of muscle ischemia associated with sustained focal muscle contraction and/or muscle cramps. Referred pain is dependent on the sensitivity of myofascial trigger points. Active myofascial trigger points may play an important role in the transition from localized pain to generalized pain conditions via the enhanced central sensitization, decreased descending inhibition and dysfunctional motor control strategy.

  20. Myofascial trigger points: spontaneous electrical activity and its consequences for pain induction and propagation

    Directory of Open Access Journals (Sweden)

    Fernández-de-las-Peñas César

    2011-03-01

    Full Text Available Abstract Active myofascial trigger points are one of the major peripheral pain generators for regional and generalized musculoskeletal pain conditions. Myofascial trigger points are also the targets for acupuncture and/or dry needling therapies. Recent evidence in the understanding of the pathophysiology of myofascial trigger points supports The Integrated Hypothesis for the trigger point formation; however unanswered questions remain. Current evidence shows that spontaneous electrical activity at myofascial trigger point originates from the extrafusal motor endplate. The spontaneous electrical activity represents focal muscle fiber contraction and/or muscle cramp potentials depending on trigger point sensitivity. Local pain and tenderness at myofascial trigger points are largely due to nociceptor sensitization with a lesser contribution from non-nociceptor sensitization. Nociceptor and non-nociceptor sensitization at myofascial trigger points may be part of the process of muscle ischemia associated with sustained focal muscle contraction and/or muscle cramps. Referred pain is dependent on the sensitivity of myofascial trigger points. Active myofascial trigger points may play an important role in the transition from localized pain to generalized pain conditions via the enhanced central sensitization, decreased descending inhibition and dysfunctional motor control strategy.

  1. Fractal analysis reveals subclasses of neurons and suggests an explanation of their spontaneous activity.

    Science.gov (United States)

    Favela, Luis H; Coey, Charles A; Griff, Edwin R; Richardson, Michael J

    2016-07-28

    The present work used fractal time series analysis (detrended fluctuation analysis; DFA) to examine the spontaneous activity of single neurons in an anesthetized animal model, specifically, the mitral cells in the rat main olfactory bulb. DFA bolstered previous research in suggesting two subclasses of mitral cells. Although there was no difference in the fractal scaling of the interspike interval series at the shorter timescales, there was a significant difference at longer timescales. Neurons in Group B exhibited fractal, power-law scaled interspike intervals, whereas neurons in Group A exhibited random variation. These results raise questions about the role of these different cells within the olfactory bulb and potential explanations of their dynamics. Specifically, self-organized criticality has been proposed as an explanation of fractal scaling in many natural systems, including neural systems. However, this theory is based on certain assumptions that do not clearly hold in the case of spontaneous neural activity, which likely reflects intrinsic cell dynamics rather than activity driven by external stimulation. Moreover, it is unclear how self-organized criticality might account for the random dynamics observed in Group A, and how these random dynamics might serve some functional role when embedded in the typical activity of the olfactory bulb. These theoretical considerations provide direction for additional experimental work. Published by Elsevier Ireland Ltd.

  2. P-I snake venom metalloproteinase is able to activate the complement system by direct cleavage of central components of the cascade.

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    Giselle Pidde-Queiroz

    Full Text Available BACKGROUND: Snake Venom Metalloproteinases (SVMPs are amongst the key enzymes that contribute to the high toxicity of snake venom. We have recently shown that snake venoms from the Bothrops genus activate the Complement system (C by promoting direct cleavage of C-components and generating anaphylatoxins, thereby contributing to the pathology and spread of the venom. The aim of the present study was to isolate and characterize the C-activating protease from Bothrops pirajai venom. RESULTS: Using two gel-filtration chromatography steps, a metalloproteinase of 23 kDa that activates Complement was isolated from Bothrops pirajai venom. The mass spectrometric identification of this protein, named here as C-SVMP, revealed peptides that matched sequences from the P-I class of SVMPs. C-SVMP activated the alternative, classical and lectin C-pathways by cleaving the α-chain of C3, C4 and C5, thereby generating anaphylatoxins C3a, C4a and C5a. In vivo, C-SVMP induced consumption of murine complement components, most likely by activation of the pathways and/or by direct cleavage of C3, leading to a reduction of serum lytic activity. CONCLUSION: We show here that a P-I metalloproteinase from Bothrops pirajai snake venom activated the Complement system by direct cleavage of the central C-components, i.e., C3, C4 and C5, thereby generating biologically active fragments, such as anaphylatoxins, and by cleaving the C1-Inhibitor, which may affect Complement activation control. These results suggest that direct complement activation by SVMPs may play a role in the progression of symptoms that follow envenomation.

  3. P-I Snake Venom Metalloproteinase Is Able to Activate the Complement System by Direct Cleavage of Central Components of the Cascade

    Science.gov (United States)

    Pidde-Queiroz, Giselle; Magnoli, Fábio Carlos; Portaro, Fernanda C. V.; Serrano, Solange M. T.; Lopes, Aline Soriano; Paes Leme, Adriana Franco; van den Berg, Carmen W.; Tambourgi, Denise V.

    2013-01-01

    Background Snake Venom Metalloproteinases (SVMPs) are amongst the key enzymes that contribute to the high toxicity of snake venom. We have recently shown that snake venoms from the Bothrops genus activate the Complement system (C) by promoting direct cleavage of C-components and generating anaphylatoxins, thereby contributing to the pathology and spread of the venom. The aim of the present study was to isolate and characterize the C-activating protease from Bothrops pirajai venom. Results Using two gel-filtration chromatography steps, a metalloproteinase of 23 kDa that activates Complement was isolated from Bothrops pirajai venom. The mass spectrometric identification of this protein, named here as C-SVMP, revealed peptides that matched sequences from the P-I class of SVMPs. C-SVMP activated the alternative, classical and lectin C-pathways by cleaving the α-chain of C3, C4 and C5, thereby generating anaphylatoxins C3a, C4a and C5a. In vivo, C-SVMP induced consumption of murine complement components, most likely by activation of the pathways and/or by direct cleavage of C3, leading to a reduction of serum lytic activity. Conclusion We show here that a P-I metalloproteinase from Bothrops pirajai snake venom activated the Complement system by direct cleavage of the central C-components, i.e., C3, C4 and C5, thereby generating biologically active fragments, such as anaphylatoxins, and by cleaving the C1-Inhibitor, which may affect Complement activation control. These results suggest that direct complement activation by SVMPs may play a role in the progression of symptoms that follow envenomation. PMID:24205428

  4. Analysis of the complement sensitivity of oral treponemes and the potential influence of FH binding, FH cleavage and dentilisin activity on the pathogenesis of periodontal disease.

    Science.gov (United States)

    Miller, D P; McDowell, J V; Bell, J K; Goetting-Minesky, M P; Fenno, J C; Marconi, R T

    2014-10-01

    Treponema denticola, a periopathogen, evades complement-mediated killing by binding the negative complement regulatory protein factor H (FH) to its surface via the FhbB protein. Paradoxically, bound FH is cleaved by T. denticola's dentilisin protease, a process hypothesized to trigger localized dysregulation of complement activation in periodontal pockets. The ability of other oral treponemes to evade complement-mediated killing and bind and cleave FH has not been assessed. In this report, we demonstrate that representative isolates of Treponema socranskii, Treponema medium, Treponema pectinovorum and Treponema maltophilum are also serum resistant, whereas Treponema vincentii and Treponema amylovorum are serum sensitive. Although T. denticola's ability to evade complement-mediated killing is strictly dependent on FH binding, other serum-resistant treponemal species lack FhbB and do not bind FH, indicating an FH-independent mechanism of complement evasion. To assess the influence of FhbB sequence variation on FH binding and cleavage by T. denticola, fhbB sequences were determined for 30 isolates. Three distinct phyletic types were identified. All T. denticola strains bound FH and were serum resistant, but differences in binding kinetics, dentilisin activity and FH cleavage ability were observed. Based on these analyses, we hypothesize that the composition of the T. denticola population is a determining factor that influences the progression and severity of periodontal disease. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Complement-Mediated Bactericidal Activity of Anti-Factor H Binding Protein Monoclonal Antibodies against the Meningococcus Relies upon Blocking Factor H Binding ▿

    Science.gov (United States)

    Giuntini, Serena; Reason, Donald C.; Granoff, Dan M.

    2011-01-01

    Binding of the complement-downregulating protein factor H (fH) to the surface of the meningococcus is important for survival of the organism in human serum. The meningococcal vaccine candidate factor H binding protein (fHbp) is an important ligand for human fH. While some fHbp-specific monoclonal antibodies (MAbs) block binding of fH to fHbp, the stoichiometry of blocking in the presence of high serum concentrations of fH and its effect on complement-mediated bactericidal activity are unknown. To investigate this question, we constructed chimeric antibodies in which the human IgG1 constant region was paired with three murine fHbp-specific binding domains designated JAR 3, JAR 5, and MAb502. By surface plasmon resonance, the association rates for binding of all three MAbs to immobilized fHbp were >50-fold higher than that for binding of fH to fHbp, and the MAb dissociation rates were >500-fold lower than that for fH. While all three MAbs elicited similar C1q-dependent C4b deposition on live bacteria (classical complement pathway), only those antibodies that inhibited binding of fH to fHbp (JAR 3 and JAR 5) had bactericidal activity with human complement. MAb502, which did not inhibit fH binding, had complement-mediated bactericidal activity only when tested with fH-depleted human complement. When an IgG1 anti-fHbp MAb binds to sparsely exposed fHbp on the bacterial surface, there appears to be insufficient complement activation for bacteriolysis unless fH binding also is inhibited. The ability of fHbp vaccines to elicit protective antibodies, therefore, is likely to be enhanced if the antibody repertoire is of high avidity and includes fH-blocking activity. PMID:21708990

  6. Accuracy of rate coding: When shorter time window and higher spontaneous activity help

    Czech Academy of Sciences Publication Activity Database

    Leváková, Marie; Tamborrino, M.; Košťál, Lubomír; Lánský, Petr

    2017-01-01

    Roč. 95, č. 2 (2017), č. článku 022310. ISSN 2470-0045 R&D Projects: GA ČR(CZ) GA15-08066S; GA MŠk(CZ) 7AMB17AT048 Institutional support: RVO:67985823 Keywords : rate coding * observation window * spontaneous activity * Fisher information * perfect integrate- and -fire model * Wiener process Subject RIV: BB - Applied Statistics, Operational Research OBOR OECD: Biology (theoretical, mathematical, thermal, cryobiology, biological rhythm), Evolutionary biology Impact factor: 2.366, year: 2016

  7. Complement binding to erythrocytes is associated with macrophage activation and reduced haemoglobin in Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Goka, B Q; Kwarko, H; Kurtzhals, J A

    2001-01-01

    patients and were able to confirm the results in a total of 49 DAT-positive and 183 DAT-negative patients. This second study (in 1998) was designed to look at the importance of erythrophagocytosis through measurement of plasma neopterin levels and total nitrite and nitrate as markers of NO-release. Both...... parameters were significantly higher in DAT-positive than in DAT-negative patients (P macrophage activation. Plasma levels of haptoglobin, interleukin-10 and tumour necrosis factor-alpha did not vary between the groups...

  8. Spontaneous membrane formation and self-encapsulation of active rods in an inhomogeneous motility field

    Science.gov (United States)

    Grauer, Jens; Löwen, Hartmut; Janssen, Liesbeth M. C.

    2018-02-01

    We study the collective dynamics of self-propelled rods in an inhomogeneous motility field. At the interface between two regions of constant but different motility, a smectic rod layer is spontaneously created through aligning interactions between the active rods, reminiscent of an artificial, semipermeable membrane. This "active membrane" engulfes rods which are locally trapped in low-motility regions and thereby further enhances the trapping efficiency by self-organization, an effect which we call "self-encapsulation." Our results are gained by computer simulations of self-propelled rod models confined on a two-dimensional planar or spherical surface with a stepwise constant motility field, but the phenomenon should be observable in any geometry with sufficiently large spatial inhomogeneity. We also discuss possibilities to verify our predictions of active-membrane formation in experiments of self-propelled colloidal rods and vibrated granular matter.

  9. Alpha-Band Activity Reveals Spontaneous Representations of Spatial Position in Visual Working Memory.

    Science.gov (United States)

    Foster, Joshua J; Bsales, Emma M; Jaffe, Russell J; Awh, Edward

    2017-10-23

    An emerging view suggests that spatial position is an integral component of working memory (WM), such that non-spatial features are bound to locations regardless of whether space is relevant [1, 2]. For instance, past work has shown that stimulus position is spontaneously remembered when non-spatial features are stored. Item recognition is enhanced when memoranda appear at the same location where they were encoded [3-5], and accessing non-spatial information elicits shifts of spatial attention to the original position of the stimulus [6, 7]. However, these findings do not establish that a persistent, active representation of stimulus position is maintained in WM because similar effects have also been documented following storage in long-term memory [8, 9]. Here we show that the spatial position of the memorandum is actively coded by persistent neural activity during a non-spatial WM task. We used a spatial encoding model in conjunction with electroencephalogram (EEG) measurements of oscillatory alpha-band (8-12 Hz) activity to track active representations of spatial position. The position of the stimulus varied trial to trial but was wholly irrelevant to the tasks. We nevertheless observed active neural representations of the original stimulus position that persisted throughout the retention interval. Further experiments established that these spatial representations are dependent on the volitional storage of non-spatial features rather than being a lingering effect of sensory energy or initial encoding demands. These findings provide strong evidence that online spatial representations are spontaneously maintained in WM-regardless of task relevance-during the storage of non-spatial features. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. MRI-constrained spectral imaging of benzodiazepine modulation of spontaneous neuromagnetic activity in human cortex.

    Science.gov (United States)

    Ahveninen, Jyrki; Lin, Fa-Hsuan; Kivisaari, Reetta; Autti, Taina; Hämäläinen, Matti; Stufflebeam, Steven; Belliveau, John W; Kähkönen, Seppo

    2007-04-01

    Spontaneous electromagnetic brain rhythms have been widely used in human neuropharmacology, but their applicability is complicated by the difficulties to localize their origins in the human cortex. Here, we used a novel multi-modal non-invasive imaging approach to localize lorazepam (30 microg/kg i.v.) modulation of cortical generators of spontaneous brain rhythms. Eight healthy subjects were measured with 306-channel magnetoencephalography (MEG) in a double-blind, randomized, placebo-controlled (saline), crossover design. For anatomically realistic source modeling, wavelet-transformed MEG data were combined with high-resolution MRI to constrain the current locations to the cortical mantle, after which individual data were co-registered to surface-based coordinate system for the calculation of group statistical parametric maps of drug effects. The distributed MRI-constrained MEG source estimates demonstrated decreased alpha (10 Hz) activity in and around the parieto-occipital sulcus and in the calcarine sulcus of the occipital lobe, following from increased GABA(A)-inhibition by lorazepam. Anatomically constrained spectral imaging displays the cortical loci of drug effects on oscillatory brain activity, providing a novel tool for human pharmacological neuroimaging.

  11. Triclosan causes spontaneous abortion accompanied by decline of estrogen sulfotransferase activity in humans and mice.

    Science.gov (United States)

    Wang, Xiaoli; Chen, Xiaojiao; Feng, Xuejiao; Chang, Fei; Chen, Minjian; Xia, Yankai; Chen, Ling

    2015-12-15

    Triclosan (TCS), an antibacterial agent, is identified in serum and urine of humans. Here, we show that the level of urinary TCS in 28.3% patients who had spontaneous abortion in mid-gestation were increased by 11.3-fold (high-TCS) compared with normal pregnancies. Oral administration of TCS (10 mg/kg/day) in mice (TCS mice) caused an equivalent urinary TCS level as those in the high-TCS abortion patients. The TCS-exposure from gestation day (GD) 5.5 caused dose-dependently fetal death during GD12.5-16.5 with decline of live fetal weight. GD15.5 TCS mice appeared placental thrombus and tissue necrosis with enhancement of platelet aggregation. The levels of placenta and plasma estrogen sulfotransferase (EST) mRNA and protein in TCS mice or high-TCS abortion patients were not altered, but their EST activities were significantly reduced compared to controls. Although the levels of serum estrogen (E2) in TCS mice and high-TCS abortion patients had no difference from controls, their ratio of sulfo-conjugated E2 and unconjugated E2 was reduced. The estrogen receptor antagonist ICI-182,780 prevented the enhanced platelet aggregation and placental thrombosis and attenuated the fetal death in TCS mice. The findings indicate that TCS-exposure might cause spontaneous abortion probably through inhibition of EST activity to produce placental thrombosis.

  12. Dopamine Attenuates Ketamine-Induced Neuronal Apoptosis in the Developing Rat Retina Independent of Early Synchronized Spontaneous Network Activity.

    Science.gov (United States)

    Dong, Jing; Gao, Lingqi; Han, Junde; Zhang, Junjie; Zheng, Jijian

    2017-07-01

    Deprivation of spontaneous rhythmic electrical activity in early development by anesthesia administration, among other interventions, induces neuronal apoptosis. However, it is unclear whether enhancement of neuronal electrical activity attenuates neuronal apoptosis in either normal development or after anesthesia exposure. The present study investigated the effects of dopamine, an enhancer of spontaneous rhythmic electrical activity, on ketamine-induced neuronal apoptosis in the developing rat retina. TUNEL and immunohistochemical assays indicated that ketamine time- and dose-dependently aggravated physiological and ketamine-induced apoptosis and inhibited early-synchronized spontaneous network activity. Dopamine administration reversed ketamine-induced neuronal apoptosis, but did not reverse the inhibitory effects of ketamine on early synchronized spontaneous network activity despite enhancing it in controls. Blockade of D1, D2, and A2A receptors and inhibition of cAMP/PKA signaling partially antagonized the protective effect of dopamine against ketamine-induced apoptosis. Together, these data indicate that dopamine attenuates ketamine-induced neuronal apoptosis in the developing rat retina by activating the D1, D2, and A2A receptors, and upregulating cAMP/PKA signaling, rather than through modulation of early synchronized spontaneous network activity.

  13. Nanomedicine and the complement paradigm.

    Science.gov (United States)

    Moghimi, S Moein; Farhangrazi, Z Shadi

    2013-05-01

    The role of complement in idiosyncratic reactions to nanopharmaceutical infusion is receiving increasing attention. We discuss this in relation to nanopharmaceutical development and the possible use of complement inhibitors to prevent related adverse reactions. We further call on initiation of genetic association studies to unravel the genetic basis of nanomedicine infusion-related adverse responses, since most of the polymorphic genes in the genome belong to the immune system. In this paper, idiosyncratic reactions based on complement activation are discussed in the context of newly available complement inhibitors. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Distinct Temporal Coordination of Spontaneous Population Activity between Basal Forebrain and Auditory Cortex

    Directory of Open Access Journals (Sweden)

    Josue G. Yague

    2017-09-01

    Full Text Available The basal forebrain (BF has long been implicated in attention, learning and memory, and recent studies have established a causal relationship between artificial BF activation and arousal. However, neural ensemble dynamics in the BF still remains unclear. Here, recording neural population activity in the BF and comparing it with simultaneously recorded cortical population under both anesthetized and unanesthetized conditions, we investigate the difference in the structure of spontaneous population activity between the BF and the auditory cortex (AC in mice. The AC neuronal population show a skewed spike rate distribution, a higher proportion of short (≤80 ms inter-spike intervals (ISIs and a rich repertoire of rhythmic firing across frequencies. Although the distribution of spontaneous firing rate in the BF is also skewed, a proportion of short ISIs can be explained by a Poisson model at short time scales (≤20 ms and spike count correlations are lower compared to AC cells, with optogenetically identified cholinergic cell pairs showing exceptionally higher correlations. Furthermore, a smaller fraction of BF neurons shows spike-field entrainment across frequencies: a subset of BF neurons fire rhythmically at slow (≤6 Hz frequencies, with varied phase preferences to ongoing field potentials, in contrast to a consistent phase preference of AC populations. Firing of these slow rhythmic BF cells is correlated to a greater degree than other rhythmic BF cell pairs. Overall, the fundamental difference in the structure of population activity between the AC and BF is their temporal coordination, in particular their operational timescales. These results suggest that BF neurons slowly modulate downstream populations whereas cortical circuits transmit signals on multiple timescales. Thus, the characterization of the neural ensemble dynamics in the BF provides further insight into the neural mechanisms, by which brain states are regulated.

  15. Sex differences in endogenous cortical network activity: spontaneously recurring Up/Down states.

    Science.gov (United States)

    Sigalas, Charalambos; Konsolaki, Eleni; Skaliora, Irini

    2017-01-01

    Several molecular and cellular processes in the vertebrate brain exhibit differences between males and females, leading to sexual dimorphism in the formation of neural circuits and brain organization. While studies on large-scale brain networks provide ample evidence for both structural and functional sex differences, smaller-scale local networks have remained largely unexplored. In the current study, we investigate sexual dimorphism in cortical dynamics by means of spontaneous Up/Down states, a type of network activity that is exhibited during slow-wave sleep, quiet wakefulness, and anesthesia and is thought to represent the default activity of the cortex. Up state activity was monitored by local field potential recordings in coronal brain slices of male and female mice across three ages with distinct secretion profiles of sex hormones: (i) pre-puberty (17-21 days old), (ii) 3-9 adult (months old), and (iii) old (19-24 months old). Female mice of all ages exhibited longer and more frequent Up states compared to aged-matched male mice. Power spectrum analysis revealed sex differences in the relative power of Up state events, with female mice showing reduced power in the delta range (1-4 Hz) and increased power in the theta range (4-8 Hz) compared to male mice. No sex differences were found in the characteristics of Up state peak voltage and latency. The present study revealed for the first time sex differences in intracortical network activity, using an ex vivo paradigm of spontaneously occurring Up/Down states. We report significant sex differences in Up state properties that are already present in pre-puberty animals and are maintained through adulthood and old age.

  16. Research on spontaneous activity in adult anisometropic amblyopia with regional homogeneity

    Science.gov (United States)

    Huang, Yufeng; Zhou, Yifeng

    2017-06-01

    Amblyopia usually occurs in early childhood and results in monocular visual impairment. The functional magnetic resonance imaging (fMRI) studies have reflected functional anomaly in amblyopia. In resting-state fMRI study, spontaneous activity changes abnormally in anisometropic amblyopia could be revealed by the regional homogeneity (ReHo). Twenty two adult anisometropic amblyopes and Twenty one normal controls participated in this fMRI study. Two sample T test was carried out to analysis ReHo within the whole brain for the inter groups. Compare with normal group, our study found that the amblyopia’s ReHo mainly increased in the left frontal lobe, while decreased in the left cerebellum, the temporal lobe (left and right), and the left parietal lobe. And the ReHo values in middle and inferior temporal lobe, the prefrontal lobe, frontal lobe (positive) and parietal lobe and medial frontal gyrus (negative) could be correlated with the acuity deficit of amblyopia. The results increased in ReHo may indicate compensatory plasticity in higher vision information process, while the decreased in ReHo may reflect decreased ability in eye movement, spatial sense and visuo-motor coordination. The correlation revealed that the vision deficit may correspond to the spontaneous in certain brain area.

  17. Outcomes of Nulliparous Women with Spontaneous Labor Onset Admitted to Hospitals in Pre-active versus Active Labor

    Science.gov (United States)

    NEAL, Jeremy L.; LAMP, Jane M.; BUCK, Jacalyn S.; LOWE, Nancy K.; GILLESPIE, Shannon L.; RYAN, Sharon L.

    2014-01-01

    Introduction The timing of when a woman is admitted to the hospital for labor care following spontaneous contraction onset may be among the most important decisions that labor attendants make as it can influence care patterns and birth outcomes. The aims of this study were to estimate the percentage of low-risk, nulliparous women at term who are admitted to labor units prior to active labor and to evaluate the effects of the timing of admission (i.e., pre-active versus active labor) on labor interventions and mode of birth. Methods Obstetrics data from low-risk, nulliparous women with spontaneous labor onset at term gestation (N = 216) were merged from two prospective studies conducted at three large, Midwestern hospitals. Baseline characteristics, labor interventions, and outcomes were compared between groups using Fisher’s exact and Mann-Whitney U tests, as appropriate. Likelihoods for oxytocin augmentation, amniotomy, and cesarean delivery were assessed by logistic regression. Results Of the sample of 216 low-risk nulliparous women, 114 (52.8%) were admitted in pre-active labor and 102 (47.2%) were admitted in active labor. Women admitted in pre-active labor were more likely to undergo oxytocin augmentation (84.2% and 45.1%, respectively; odds ratio (OR) 6.5, 95% confidence interval (CI) 3.43–12.27) but not amniotomy (55.3% and 61.8%, respectively; OR 0.8, 95% CI 0.44–1.32) when compared to women admitted in active labor. The likelihood of cesarean delivery was higher for women admitted before active labor onset (15.8% and 6.9%, respectively; OR 2.6, 95% CI 1.02–6.37). Discussion Many low-risk nulliparous women with regular, spontaneous uterine contractions are admitted to labor units before active labor onset, which increases their likelihood of receiving oxytocin and being delivered via cesarean section. An evidence-based, standardized approach for labor admission decision-making is recommended to decrease inadvertent admissions of women in pre-active

  18. Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion.

    Science.gov (United States)

    Yamamoto, Tsunehisa; Tamaki, Kayoko; Shirakawa, Kohsuke; Ito, Kentaro; Yan, Xiaoxiang; Katsumata, Yoshinori; Anzai, Atsushi; Matsuhashi, Tomohiro; Endo, Jin; Inaba, Takaaki; Tsubota, Kazuo; Sano, Motoaki; Fukuda, Keiichi; Shinmura, Ken

    2016-04-15

    Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol 308: H894-H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM-Sirt1(-/-)) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM-Sirt1(-/-)mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM-Sirt1(-/-)mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout (C3(-/-)) mice treated with CR was similar to that in the ad libitum-fed C3(-/-)mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting

  19. Xeroderma pigmentosum complementation group C cells remove pyrimidine dimers selectively from the transcribed strand of active genes

    International Nuclear Information System (INIS)

    Venema, J.; van Hoffen, A.; Karcagi, V.; Natarajan, A.T.; van Zeeland, A.A.; Mullenders, L.H.

    1991-01-01

    The authors have measured the removal of UV-induced pyrimidine dimers from DNA fragments of the adenosine deaminase (ADA) and dihydrofolate reductase (DHFR) genes in primary normal human and xeroderma pigmentosum complementation group C (XP-C) cells. Using strand-specific probes, we show that in normal cells, preferential repair of the 5' part of the ADA gene is due to the rapid and efficient repair of the transcribed strand. Within 8 h after irradiation with UV at 10 J m-2, 70% of the pyrimidine dimers in this strand are removed. The nontranscribed strand is repaired at a much slower rate, with 30% dimers removed after 8 h. Repair of the transcribed strand in XP-C cells occurs at a rate indistinguishable from that in normal cells, but the nontranscribed strand is not repaired significantly in these cells. Similar results were obtained for the DHFR gene. In the 3' part of the ADA gene, however, both normal and XP-C cells perform fast and efficient repair of either strand, which is likely to be caused by the presence of transcription units on both strands. The factor defective in XP-C cells is apparently involved in the processing of DNA damage in inactive parts of the genome, including nontranscribed strands of active genes. These findings have important implications for the understanding of the mechanism of UV-induced excision repair and mutagenesis in mammalian cells

  20. Reproduction of overall spontaneous pain pattern by manual stimulation of active myofascial trigger points in fibromyalgia patients

    DEFF Research Database (Denmark)

    Ge, Hong-You; Wang, Ying; Fernández-de-las-Peñas, César

    2011-01-01

    It has previously been reported that local and referred pain from active myofascial trigger points (MTPs) in the neck and shoulder region contribute to fibromyalgia (FM) pain and that the pain pattern induced from active MTPs can reproduce parts of the spontaneous clinical FM pain pattern...

  1. Reproduction of overall spontaneous pain pattern by manual stimulation of active myofascial trigger points in fibromyalgia patients

    DEFF Research Database (Denmark)

    Ge, Hong-You; Wang, Ying; Fernandez-de-las-Penas, Cesar

    2011-01-01

    It has previously been reported that local and referred pain from active myofascial trigger points (MTPs) in the neck and shoulder region contribute to fibromyalgia (FM) pain and that the pain pattern induced from active MTPs can reproduce parts of the spontaneous clinical FM pain pattern. The cu...

  2. C-reactive protein and natural IgM antibodies are activators of complement in a rat model of intestinal ischemia and reperfusion

    NARCIS (Netherlands)

    Padilla, Niubel Diaz; van Vliet, Arlene K.; Schoots, Ivo G.; Seron, Mercedes Valls; Maas, M. Adrie; Peltenburg, Esther E. Posno; de Vries, Annebeth; Niessen, Hans W. M.; Hack, C. Erik; van Gulik, Thomas M.

    2007-01-01

    Background. The role of C-reactive protein (CRP), natural immunoglobulin M (IgM), and natural IgM against phosphorylcholine (anti-Pc IgM) was investigated in relation with complement activation in a rat model of intestinal ischemia and reperfusion (II/R). The effect of Cl-esterase inhibitor (C1-Inh)

  3. ANTIMICROBIAL ACTIVITY OF EXTRACTS OF WILD GARLIC (Allium ursinum FROM ROMANIAN SPONTANEOUS FLORA

    Directory of Open Access Journals (Sweden)

    MARIANA LUPOAE

    2014-05-01

    Full Text Available Wild Romanian spontaneous garlic’s (Allium ursinum antimicrobial activity was tested in order to establish the inhibition potential of growth of some microorganisms. As test microorganisms were used pure cultures of fungs (Aspergillus glaucus, Geotrichum candidum, Mucor mucedo, Saccharomyces cerevisiae and bacteria (Bacillus subtilis isolated from food microbiota. There were also, used microbial strains isolated from different pathological products: wound secretions (Staphylococcus aureus, throat swab (Streptococcus pyogenes, urine (Escherichia coli and oral mucosa (Candida albicans. The antimicrobial potential of used extracts is highlighted depending on the type of the vegetal tissue (leaves, roots, bulbs and the nature of the solvent used for extraction. Extracts used in these experiments are recommended to use in food industry to preserve the stability and to improve the organoleptic quality of products.

  4. Impact of corticosterone treatment on spontaneous seizure frequency and epileptiform activity in mice with chronic epilepsy.

    Directory of Open Access Journals (Sweden)

    Olagide W Castro

    Full Text Available Stress is the most commonly reported precipitating factor for seizures in patients with epilepsy. Despite compelling anecdotal evidence for stress-induced seizures, animal models of the phenomena are sparse and possible mechanisms are unclear. Here, we tested the hypothesis that increased levels of the stress-associated hormone corticosterone (CORT would increase epileptiform activity and spontaneous seizure frequency in mice rendered epileptic following pilocarpine-induced status epilepticus. We monitored video-EEG activity in pilocarpine-treated mice 24/7 for a period of four or more weeks, during which animals were serially treated with CORT or vehicle. CORT increased the frequency and duration of epileptiform events within the first 24 hours of treatment, and this effect persisted for up to two weeks following termination of CORT injections. Interestingly, vehicle injection produced a transient spike in CORT levels - presumably due to the stress of injection - and a modest but significant increase in epileptiform activity. Neither CORT nor vehicle treatment significantly altered seizure frequency; although a small subset of animals did appear responsive. Taken together, our findings indicate that treatment of epileptic animals with exogenous CORT designed to mimic chronic stress can induce a persistent increase in interictal epileptiform activity.

  5. Spontaneous Activity Patterns in Primary Visual Cortex Predispose to Visual Hallucinations.

    Science.gov (United States)

    Pajani, Auréliane; Kok, Peter; Kouider, Sid; de Lange, Floris P

    2015-09-16

    According to theoretical frameworks casting perception as inference, vision results from the integration of bottom-up visual input with top-down expectations. Under conditions of strongly degraded sensory input, this may occasionally result in false perceptions in the absence of a sensory signal, also termed "hallucinations." Here, we investigated whether spontaneous prestimulus activity patterns in sensory circuits, which may embody a participant's prior expectations, predispose the observer toward false perceptions. Specifically, we used fMRI to investigate whether the representational content of prestimulus activity in early visual cortex is linked to subsequent perception during a challenging detection task. Human participants were asked to detect oriented gratings of a particular orientation that were embedded in noise. We found two characteristics of prestimulus activity that predisposed participants to hallucinations: overall lower prestimulus activity and a bias in the prestimulus activity patterns toward the to-be-detected (expected) grating. These results suggest that perceptual hallucinations may be due to an imprecise and biased state of sensory circuits preceding sensory evidence collection. When sensory stimulation is strongly degraded, we occasionally misperceive a stimulus when only noise is present: a perceptual hallucination. Using fMRI in healthy participants, we investigated whether the state of early visual cortex preceding stimulus onset predisposes an observer to hallucinations. We found two characteristics of prestimulus activity that predisposed participants to hallucinations: overall lower prestimulus activity and a bias in the prestimulus activity patterns toward the expected grating. These results suggest that perceptual hallucinations are due to an imprecise and biased state of sensory circuits preceding sensation. Copyright © 2015 the authors 0270-6474/15/3512947-07$15.00/0.

  6. The Complement System and Adverse Pregnancy Outcomes

    Science.gov (United States)

    Regal, Jean F.; Gilbert, Jeffrey S.; Burwick, Richard M.

    2015-01-01

    Adverse pregnancy outcomes significantly contribute to morbidity and mortality for mother and child, with lifelong health consequences for both. The innate and adaptive immune system must be regulated to insure survival of the feta allograft, and the complement system is no exception. An intact complement system optimizes placental development and function and is essential to maintain host defense and fetal survival. Complement regulation is apparent at the placental interface from early pregnancy with some degree of complement activation occurring normally throughout gestation. However, a number of pregnancy complications including early pregnancy loss, fetal growth restriction, hypertensive disorders of pregnancy and preterm birth are associated with excessive or misdirected complement activation, and are more frequent in women with inherited or acquired complement system disorders or complement gene mutations. Clinical studies employing complement biomarkers in plasma and urine implicate dysregulated complement activation in components of each of the adverse pregnancy outcomes. In addition, mechanistic studies in rat and mouse models of adverse pregnancy outcomes address the complement pathways or activation products of importance and allow critical analysis of the pathophysiology. Targeted complement therapeutics are already in use to control adverse pregnancy outcomes in select situations. A clearer understanding of the role of the complement system in both normal pregnancy and complicated or failed pregnancy will allow a rational approach to future therapeutic strategies for manipulating complement with the goal of mitigating adverse pregnancy outcomes, preserving host defense, and improving long term outcomes for both mother and child. PMID:25802092

  7. The epileptic human hippocampal cornu ammonis 2 region generates spontaneous interictal-like activity in vitro.

    Science.gov (United States)

    Wittner, Lucia; Huberfeld, Gilles; Clémenceau, Stéphane; Eross, Loránd; Dezamis, Edouard; Entz, László; Ulbert, István; Baulac, Michel; Freund, Tamás F; Maglóczky, Zsófia; Miles, Richard

    2009-11-01

    The dentate gyrus, the cornu ammonis 2 region and the subiculum of the human hippocampal formation are resistant to the cell loss associated with temporal lobe epilepsy. The subiculum, but not the dentate gyrus, generates interictal-like activity in tissue slices from epileptic patients. In this study, we asked whether a similar population activity is generated in the cornu ammonis 2 region and examined the electrophysiological and neuroanatomical characteristics of human epileptic cornu ammonis 2 neurons that may be involved. Hippocampal slices were prepared from postoperative temporal lobe tissue derived from epileptic patients. Field potentials and multi-unit activity were recorded in vitro using multiple extracellular microelectrodes. Pyramidal cells were characterized in intra-cellular records and were filled with biocytin for subsequent anatomy. Fluorescent immunostaining was made on fixed tissue against the chloride-cation cotransporters sodium-potassium-chloride cotransporter-1 and potassium-chloride cotransporter-2. Light and electron microscopy were used to examine the parvalbumin-positive perisomatic inhibitory network. In 15 of 20 slices, the hippocampal cornu ammonis 2 region generated a spontaneous interictal-like activity, independently of population events in the subiculum. Most cornu ammonis 2 pyramidal cells fired spontaneously. All cells fired single action potentials and burst firing was evoked in three cells. Spontaneous excitatory postsynaptic potentials were recorded in all cells, but hyperpolarizing inhibitory postsynaptic potentials were detected in only 27% of the cells. Two-thirds of cornu ammonis 2 neurons showed depolarizing responses during interictal-like events, while the others were inhibited, according to the current sink in the cell body layer. Two biocytin-filled cells both showed a pyramidal-like morphology with axons projecting to the cornu ammonis 2 and cornu ammonis 3 regions. Expression of sodium

  8. Drug-induced modification of the system properties associated with spontaneous human electroencephalographic activity

    Science.gov (United States)

    Liley, David T.; Cadusch, Peter J.; Gray, Marcus; Nathan, Pradeep J.

    2003-11-01

    The benzodiazepine (BZ) class of minor tranquilizers are important modulators of the γ-amino butyric acid (GABAA)/BZ receptor complex that are well known to affect the spectral properties of spontaneous electroencephalographic activity. While it is experimentally well established that the BZs reduce total alpha band (8 13 Hz) power and increase total beta band (13 30 Hz) power, it is unclear what the physiological basis for this effect is. Based on a detailed theory of cortical electrorhythmogenesis it is conjectured that such an effect is explicable in terms of the modulation of GABAergic neurotransmission within locally connected populations of excitatory and inhibitory cortical neurons. Motivated by this theory, fixed order autoregressive moving average (ARMA) models were fitted to spontaneous eyes-closed electroencephalograms recorded from subjects before and approximately 2 h after the oral administration of a single 1 mg dose of the BZ alprazolam. Subsequent pole-zero analysis revealed that BZs significantly transform the dominant system pole such that its frequency and damping increase. Comparisons of ARMA derived power spectra with fast Fourier transform derived spectra indicate an enhanced ability to identify benzodiazepine induced electroencephalographic changes. This experimental result is in accord with the theoretical predictions implying that alprazolam enhances inhibition acting on inhibitory neurons more than inhibition acting on excitatory neurons. Further such a result is consistent with reported cortical neuronal distributions of the various GABAA receptor pharmacological subtypes. Therefore physiologically specified fixed order ARMA modeling is expected to become an important tool for the systematic investigation and modeling of a wide range of cortically acting compounds.

  9. The Lectin Pathway of Complement and Biocompatibility

    DEFF Research Database (Denmark)

    Hein, Estrid; Garred, Peter

    2015-01-01

    activation, the coagulation system and the complement system. The complement system is an important part of the initial immune response and consists of fluid phase molecules in the blood stream. Three different activation pathways can initiate the complement system, the lectin, the classical...... and the alternative pathway, all converging in an amplification loop of the cascade system and downstream reactions. Thus, when exposed to foreign substances complement components will be activated and lead to a powerful inflammatory response. Biosurface induced complement activation is a recognised issue that has...

  10. Complement Evasion by Pathogenic Leptospira.

    Science.gov (United States)

    Fraga, Tatiana Rodrigues; Isaac, Lourdes; Barbosa, Angela Silva

    2016-01-01

    Leptospirosis is a neglected infectious disease caused by spirochetes from the genus Leptospira . Pathogenic microorganisms, notably those which reach the blood circulation such as Leptospira , have evolved multiple strategies to escape the host complement system, which is important for innate and acquired immunity. Leptospira avoid complement-mediated killing through: (i) recruitment of host complement regulators; (ii) acquisition of host proteases that cleave complement proteins on the bacterial surface; and, (iii) secretion of proteases that inactivate complement proteins in the Leptospira surroundings. The recruitment of host soluble complement regulatory proteins includes the acquisition of Factor H (FH) and FH-like-1 (alternative pathway), C4b-binding protein (C4BP) (classical and lectin pathways), and vitronectin (Vn) (terminal pathway). Once bound to the leptospiral surface, FH and C4BP retain cofactor activity of Factor I in the cleavage of C3b and C4b, respectively. Vn acquisition by leptospires may result in terminal pathway inhibition by blocking C9 polymerization. The second evasion mechanism lies in plasminogen (PLG) binding to the leptospiral surface. In the presence of host activators, PLG is converted to enzymatically active plasmin, which is able to degrade C3b, C4b, and C5 at the surface of the pathogen. A third strategy used by leptospires to escape from complement system is the active secretion of proteases. Pathogenic, but not saprophytic leptospires, are able to secrete metalloproteases that cleave C3 (central complement molecule), Factor B (alternative pathway), and C4 and C2 (classical and lectin pathways). The purpose of this review is to fully explore these complement evasion mechanisms, which act together to favor Leptospira survival and multiplication in the host.

  11. Cellular Origin of Spontaneous Ganglion Cell Spike Activity in Animal Models of Retinitis Pigmentosa

    Directory of Open Access Journals (Sweden)

    David J. Margolis

    2011-01-01

    Full Text Available Here we review evidence that loss of photoreceptors due to degenerative retinal disease causes an increase in the rate of spontaneous ganglion spike discharge. Information about persistent spike activity is important since it is expected to add noise to the communication between the eye and the brain and thus impact the design and effective use of retinal prosthetics for restoring visual function in patients blinded by disease. Patch-clamp recordings from identified types of ON and OFF retinal ganglion cells in the adult (36–210 d old rd1 mouse show that the ongoing oscillatory spike activity in both cell types is driven by strong rhythmic synaptic input from presynaptic neurons that is blocked by CNQX. The recurrent synaptic activity may arise in a negative feedback loop between a bipolar cell and an amacrine cell that exhibits resonant behavior and oscillations in membrane potential when the normal balance between excitation and inhibition is disrupted by the absence of photoreceptor input.

  12. Electrophysiological study in the infraorbital nerve of the rat: Spontaneous and evoked activity

    Energy Technology Data Exchange (ETDEWEB)

    AlbarracIn, A L [Catedra de Neurociencias, Facultad de Medicina, Universidad Nacional de Tucuman, Av. Roca 2200, PC 4000 (Argentina); Farfan, F D [Departamento de BioingenierIa, FACET, Universidad Nacional de Tucuman, INSIBIO - CONICET, CC 327, PC 4000 (Argentina); Felice, C J [Departamento de BioingenierIa, FACET, Universidad Nacional de Tucuman, INSIBIO - CONICET, CC 327, PC 4000 (Argentina)

    2007-11-15

    In this work we present some studies in the afferent nerve of the rat vibrissae. Studies on spontaneous activity (SA) in this sensorial system are of long data. Nevertheless, SA recordings in the nerve of a single vibrissa have not been made until present. In this work, we use an algorithm based on signal decomposition with Continuous Wavelet Transform (CWT) to analyse the discharges of two nerves. The action potentials of both nerves were detected and the firing rates were calculated. These results suggest that the firing rate of one vibrissa innervation is low considering that this nerve contains hundred of fibers. In addition, we present preliminary studies suggesting important effects of the hair shaft length in the afferent discharge during the vibrissae movements. The experiments consisted in recording the nerve activity after the vibrissae were sectioned at two different levels. The results showed important differences in the signal energy contents. It suggests that the hair shaft length would produce a differential activation of the mechanoreceptors located in the vibrissae follicle.

  13. Hypotensive and Angiotensin-Converting Enzyme Inhibitory Activities of Eisenia fetida Extract in Spontaneously Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Shumei Mao

    2015-01-01

    Full Text Available Objectives. This study aimed to investigate the antihypertensive effects of an Eisenia fetida extract (EFE and its possible mechanisms in spontaneously hypertensive rats (SHR rats. Methods. Sixteen-week-old SHR rats and Wistar-Kyoto rats (WKY rats were used in this study. Rats were, respectively, given EFE (EFE group, captopril (captopril group, or phosphate-buffered saline (PBS (normal control group and SHR group for 4 weeks. ACE inhibitory activity of EFE in vitro was determined. The systolic blood pressure (SBP and diastolic blood pressure (DBP were measured using a Rat Tail-Cuff Blood Pressure System. Levels of angiotensin II (Ang II, aldosterone (Ald, and 6-keto-prostaglandin F1 alpha (6-keto-PGF1α in plasma were determined by radioimmunoassay, and serum nitric oxide (NO concentration was measured by Griess reagent systems. Results. EFE had marked ACE inhibitory activity in vitro (IC50 = 2.5 mg/mL. After the 4-week drug management, SHR rats in EFE group and in captopril group had lower SBP and DBP, lower levels of Ang II and Ald, and higher levels of 6-keto-PGF1α and NO than the SHR rats in SHR group. Conclusion. These results indicate that EFE has hypotensive effects in SHR rats and its effects might be associated with its ACE inhibitory activity.

  14. Expression and activity of matrix metalloproteinases in the uterus of bitches after spontaneous and induced abortion.

    Science.gov (United States)

    Kanca, H; Walter, I; Miller, I; Schäfer-Somi, S; Izgur, H; Aslan, S

    2011-04-01

    Aim of this study was to determine the intrauterine activity of matrix metalloproteinases (MMP)-2 and -9 after cessation of the local effect of progesterone. For this purpose, pregnancy was terminated in 10 bitches at mid-gestation with the progesterone receptor antagonist aglepristone (10 mg/kg body weight, sc, Alizine®; Virbac, France) at two subsequent days (group IRA = induced resorption/abortion). The IRA group was divided into two subgroups (Group I, n = 5, days 25-35 of pregnancy; group II, n = 5, days 36-45). Five further bitches were introduced with beginning abortion (group SRA = spontaneous resorption/abortion). Seven healthy bitches between day 25 and 45 of gestation served as controls. After ovariohysterectomy at the end of abortion and between days 25 and 45 of gestation, respectively, the distribution and activity of collagenases were investigated by immunohistochemistry and gelatin zymography. At placental sites, MMP-2 activity in the endometrium was significantly lower in IRA groups than in the SRA group (33.7 ± 11.8% and 39.3 ± 5.4% vs 52.2 ± 10.2%, p < 0.05); however, MMP-2 expression was lowest in the control group (control: 21.4 ± 6.3%; p < 0.01) and similarly in the myometrium (controls: 13.1 ± 2.5%; p < 0.05). MMP-9 activity was also lower in the endometrium and myometrium of the control group in comparison to SRA and IRA groups (11.8 ± 3.2%; p < 0.01 and 28.4 ± 32.8%; p < 0.05). At interplacental sites, the amount of active collagenases in the myometrium was significantly lower in the control group. It is concluded that the blockade of the biological progesterone effect was associated with an increase in activity of both collagenases. © 2010 Blackwell Verlag GmbH.

  15. Human stem cell-derived retinal epithelial cells activate complement via collectin 11 in response to stress

    DEFF Research Database (Denmark)

    Fanelli, Giorgia; Gonzalez-Cordero, Anai; Gardner, Peter J

    2017-01-01

    Age-related macular degeneration (AMD) is a major cause of blindness and is associated with complement dysregulation. The disease is a potential target for stem cell therapy but success is likely to be limited by the inflammatory response. We investigated the innate immune properties of human ind...

  16. Antibody-mediated activation of the classical pathway of complement may compensate for mannose-binding lectin deficiency

    NARCIS (Netherlands)

    Roos, Anja; Garred, Peter; Wildenberg, Manon E.; Lynch, Nicholas J.; Munoz, Jeric R.; Zuiverloon, Tahlita C. M.; Bouwman, Lee H.; Schlagwein, Nicole; Fallaux van den Houten, Francien C.; Faber-Krol, Maria C.; Madsen, Hans O.; Schwaeble, Wilhelm J.; Matsushita, Misao; Fujita, Teizo; Daha, Mohamed R.

    2004-01-01

    Deficiency of mannose-binding lectin (MBL), a recognition molecule of the lectin pathway of complement, is associated with increased susceptibility to infections. The high frequency of MBL deficiency suggests that defective MBL-mediated innate immunity can be compensated by alternative defense

  17. Endogenous cholinergic tone modulates spontaneous network level neuronal activity in primary cortical cultures grown on multi-electrode arrays

    OpenAIRE

    Hammond, Mark W; Xydas, Dimitris; Downes, Julia H; Bucci, Giovanna; Becerra, Victor; Warwick, Kevin; Constanti, Andrew; Nasuto, Slawomir J; Whalley, Benjamin J

    2013-01-01

    Background\\ud Cortical cultures grown long-term on multi-electrode arrays (MEAs) are frequently and extensively used as models of cortical networks in studies of neuronal firing activity, neuropharmacology, toxicology and mechanisms underlying synaptic plasticity. However, in contrast to the predominantly asynchronous neuronal firing activity exhibited by intact cortex, electrophysiological activity of mature cortical cultures is dominated by spontaneous epileptiform-like global burst events ...

  18. Abnormal Spontaneous Brain Activity in Patients With Anisometropic Amblyopia Using Resting-State Functional Magnetic Resonance Imaging.

    Science.gov (United States)

    Tang, Angcang; Chen, Taolin; Zhang, Junran; Gong, Qiyong; Liu, Longqian

    2017-09-01

    To explore the abnormality of spontaneous activity in patients with anisometropic amblyopia under resting-state functional magnetic resonance imaging (Rs-fMRI). Twenty-four participants were split into two groups. The anisometropic amblyopia group had 10 patients, all of whom had anisometropic amblyopia of the right eye, and the control group had 14 healthy subjects. All participants underwent Rs-fMRI scanning. Measurement of amplitude of low frequency fluctuations of the brain, which is a measure of the amplitudes of spontaneous brain activity, was used to investigate brain changes between the anisometropic amblyopia and control groups. Compared with an age- and gender-matched control group, the anisometropic amblyopia group showed increased amplitude of low frequency fluctuations of spontaneous brain activity in the left superior temporal gyrus, the left inferior parietal lobe, the left pons, and the right inferior semi-lunar lobe. The anisometropic amblyopia group also showed decreased amplitude of low frequency fluctuations in the bilateral medial frontal gyrus. This study demonstrated abnormal spontaneous brain activities in patients with anisometropic amblyopia under Rs-fMRI, and these abnormalities might contribute to the neuropathological mechanisms of anisometropic amblyopia. [J Pediatr Ophthalmol Strabismus. 2017;54(5):303-310.]. Copyright 2017, SLACK Incorporated.

  19. Altered spontaneous brain activity in patients with acute spinal cord injury revealed by resting-state functional MRI.

    Directory of Open Access Journals (Sweden)

    Ling Zhu

    Full Text Available Previous neuroimaging studies have provided evidence of structural and functional reorganization of brain in patients with chronic spinal cord injury (SCI. However, it remains unknown whether the spontaneous brain activity changes in acute SCI. In this study, we investigated intrinsic brain activity in acute SCI patients using a regional homogeneity (ReHo analysis based on resting-state functional magnetic resonance imaging.A total of 15 patients with acute SCI and 16 healthy controls participated in the study. The ReHo value was used to evaluate spontaneous brain activity, and voxel-wise comparisons of ReHo were performed to identify brain regions with altered spontaneous brain activity between groups. We also assessed the associations between ReHo and the clinical scores in brain regions showing changed spontaneous brain activity.Compared with the controls, the acute SCI patients showed decreased ReHo in the bilateral primary motor cortex/primary somatosensory cortex, bilateral supplementary motor area/dorsal lateral prefrontal cortex, right inferior frontal gyrus, bilateral dorsal anterior cingulate cortex and bilateral caudate; and increased ReHo in bilateral precuneus, the left inferior parietal lobe, the left brainstem/hippocampus, the left cingulate motor area, bilateral insula, bilateral thalamus and bilateral cerebellum. The average ReHo values of the left thalamus and right insula were negatively correlated with the international standards for the neurological classification of spinal cord injury motor scores.Our findings indicate that acute distant neuronal damage has an immediate impact on spontaneous brain activity. In acute SCI patients, the ReHo was prominently altered in brain regions involved in motor execution and cognitive control, default mode network, and which are associated with sensorimotor compensatory reorganization. Abnormal ReHo values in the left thalamus and right insula could serve as potential biomarkers for

  20. Pharmacological evidence of hypotensive activity of Marrubium vulgare and Foeniculum vulgare in spontaneously hypertensive rat.

    Science.gov (United States)

    El Bardai, S; Lyoussi, B; Wibo, M; Morel, N

    2001-05-01

    The hypotensive effects of the water extract of Marrubium vulgare L. and Foeniculum vulgare L. were investigated in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto rats (WKY). Oral administration of Marrubium or Foeniculum extract lowered the systolic blood pressure of SHR but not of WKY. In SHR, Foeniculum but not Marrubium treatment increased water, sodium and potassium excretion. Ex vivo as well as in vitro, Marrubium extract inhibited the contractile responses of rat aorta to noradrenaline and to KCl (100 mM). Inhibition was greater in aorta from SHR compared to WKY and was not affected by the NO synthase inhibitor N-nitro-L-arginine. Vascular effects of Foeniculum extract were less pronounced than those of Marrubium and were blocked by N-nitro-L-arginine. These results indicate that hypotensive activity of Marrubium and Foeniculum extracts seems to be mediated through different pathways: Foeniculum appeared to act mainly as a diuretic and a natriuretic while Marrubium displayed vascular relaxant activity.

  1. Beyond blow-up in excitatory integrate and fire neuronal networks: Refractory period and spontaneous activity.

    Science.gov (United States)

    Cáceres, María J; Perthame, Benoît

    2014-06-07

    The Network Noisy Leaky Integrate and Fire equation is among the simplest model allowing for a self-consistent description of neural networks and gives a rule to determine the probability to find a neuron at the potential v. However, its mathematical structure is still poorly understood and, concerning its solutions, very few results are available. In the midst of them, a recent result shows blow-up in finite time for fully excitatory networks. The intuitive explanation is that each firing neuron induces a discharge of the others; thus increases the activity and consequently the discharge rate of the full network. In order to better understand the details of the phenomena and show that the equation is more complex and fruitful than expected, we analyze further the model. We extend the finite time blow-up result to the case when neurons, after firing, enter a refractory state for a given period of time. We also show that spontaneous activity may occur when, additionally, randomness is included on the firing potential VF in regimes where blow-up occurs for a fixed value of VF. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Complement defects in patients with chronic rhinosinusitis

    DEFF Research Database (Denmark)

    Gaunsbaek, Maria Quisgaard; Lange, Bibi; Kjeldsen, Anette D

    2012-01-01

    The complement system is an important part of our immune system, and complement defects lead generally to increased susceptibility to infections and autoimmune diseases. We have studied the role of complement activity in relation with chronic rhinosinusitis (CRS), and more specifically studied wh...

  3. Physiological reactivity to spontaneously occurring seizure activity in dogs with epilepsy and their carers.

    Science.gov (United States)

    Packer, R M A; Volk, H A; Fowkes, R C

    2017-08-01

    There is a complex bidirectional relationship between stress and epilepsy. Stressful stimuli and subsequent cortisol release act as a trigger for seizure activity in some individuals with epilepsy, and seizure activity itself may act as a stressor to the affected individual. Epilepsy is the most common chronic neurological condition in domestic dogs and requires chronic management by their human carers, impacting upon the quality of life of both dog and carer. Seizures occur unpredictably and may be stressful for carers to witness and manage. In the present study we investigated the role of seizure activity as a stressor, measuring the effect of spontaneously occurring seizure activity in dogs with epilepsy upon their own cortisol levels and that of their carers. Furthermore, we tested whether individual differences in HPA reactivity were associated with owner personality characteristics and the quality of the dog-carer relationship. Saliva samples were obtained from sixteen dog-carer dyads in the home setting 20 and 40minute post-seizure, and at time-matched points on the following (non-seizure) day. Significant differences in cortisol levels were found in dogs at 40minute post-seizure (265.1% increase), and at 20minute post-seizure in their carers (40.5% increase). No associations were found between cortisol reactivity and the strength of the dog-carer bond. Carers with higher neuroticism scores exhibited higher cortisol levels at both post-seizure sampling points. As there was a gender bias in the carer sample (15/16 were female), and there are known sex differences in cortisol reactivity in response to psychological stress, the conclusions of this study may be limited to female carers. These findings are the first to objectively demonstrate the acutely stressful effects of seizures in dogs with epilepsy and their carers. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. The Complement System: A Prey of Trypanosoma cruzi

    Science.gov (United States)

    Lidani, Kárita C. F.; Bavia, Lorena; Ambrosio, Altair R.; de Messias-Reason, Iara J.

    2017-01-01

    Trypanosoma cruzi is a protozoan parasite known to cause Chagas disease (CD), a neglected sickness that affects around 6–8 million people worldwide. Originally, CD was mainly found in Latin America but more recently, it has been spread to countries in North America, Asia, and Europe due the international migration from endemic areas. Thus, at present CD represents an important concern of global public health. Most of individuals that are infected by T. cruzi may remain in asymptomatic form all lifelong, but up to 40% of them will develop cardiomyopathy, digestive mega syndromes, or both. The interaction between the T. cruzi infective forms and host-related immune factors represents a key point for a better understanding of the physiopathology of CD. In this context, the complement, as one of the first line of host defense against infection was shown to play an important role in recognizing T. cruzi metacyclic trypomastigotes and in controlling parasite invasion. The complement consists of at least 35 or more plasma proteins and cell surface receptors/regulators, which can be activated by three pathways: classical (CP), lectin (LP), and alternative (AP). The CP and LP are mainly initiated by immune complexes or pathogen-associated molecular patterns (PAMPs), respectively, whereas AP is spontaneously activated by hydrolysis of C3. Once activated, several relevant complement functions are generated which include opsonization and phagocytosis of particles or microorganisms and cell lysis. An important step during T. cruzi infection is when intracellular trypomastigotes are release to bloodstream where they may be target by complement. Nevertheless, the parasite uses a sequence of events in order to escape from complement-mediated lysis. In fact, several T. cruzi molecules are known to interfere in the initiation of all three pathways and in the assembly of C3 convertase, a key step in the activation of complement. Moreover, T. cruzi promotes secretion of plasma

  5. The Complement System: A Prey of Trypanosoma cruzi

    Directory of Open Access Journals (Sweden)

    Kárita C. F. Lidani

    2017-04-01

    Full Text Available Trypanosoma cruzi is a protozoan parasite known to cause Chagas disease (CD, a neglected sickness that affects around 6–8 million people worldwide. Originally, CD was mainly found in Latin America but more recently, it has been spread to countries in North America, Asia, and Europe due the international migration from endemic areas. Thus, at present CD represents an important concern of global public health. Most of individuals that are infected by T. cruzi may remain in asymptomatic form all lifelong, but up to 40% of them will develop cardiomyopathy, digestive mega syndromes, or both. The interaction between the T. cruzi infective forms and host-related immune factors represents a key point for a better understanding of the physiopathology of CD. In this context, the complement, as one of the first line of host defense against infection was shown to play an important role in recognizing T. cruzi metacyclic trypomastigotes and in controlling parasite invasion. The complement consists of at least 35 or more plasma proteins and cell surface receptors/regulators, which can be activated by three pathways: classical (CP, lectin (LP, and alternative (AP. The CP and LP are mainly initiated by immune complexes or pathogen-associated molecular patterns (PAMPs, respectively, whereas AP is spontaneously activated by hydrolysis of C3. Once activated, several relevant complement functions are generated which include opsonization and phagocytosis of particles or microorganisms and cell lysis. An important step during T. cruzi infection is when intracellular trypomastigotes are release to bloodstream where they may be target by complement. Nevertheless, the parasite uses a sequence of events in order to escape from complement-mediated lysis. In fact, several T. cruzi molecules are known to interfere in the initiation of all three pathways and in the assembly of C3 convertase, a key step in the activation of complement. Moreover, T. cruzi promotes secretion

  6. The Complement System: A Prey ofTrypanosoma cruzi.

    Science.gov (United States)

    Lidani, Kárita C F; Bavia, Lorena; Ambrosio, Altair R; de Messias-Reason, Iara J

    2017-01-01

    Trypanosoma cruzi is a protozoan parasite known to cause Chagas disease (CD), a neglected sickness that affects around 6-8 million people worldwide. Originally, CD was mainly found in Latin America but more recently, it has been spread to countries in North America, Asia, and Europe due the international migration from endemic areas. Thus, at present CD represents an important concern of global public health. Most of individuals that are infected by T. cruzi may remain in asymptomatic form all lifelong, but up to 40% of them will develop cardiomyopathy, digestive mega syndromes, or both. The interaction between the T. cruzi infective forms and host-related immune factors represents a key point for a better understanding of the physiopathology of CD. In this context, the complement, as one of the first line of host defense against infection was shown to play an important role in recognizing T. cruzi metacyclic trypomastigotes and in controlling parasite invasion. The complement consists of at least 35 or more plasma proteins and cell surface receptors/regulators, which can be activated by three pathways: classical (CP), lectin (LP), and alternative (AP). The CP and LP are mainly initiated by immune complexes or pathogen-associated molecular patterns (PAMPs), respectively, whereas AP is spontaneously activated by hydrolysis of C3. Once activated, several relevant complement functions are generated which include opsonization and phagocytosis of particles or microorganisms and cell lysis. An important step during T. cruzi infection is when intracellular trypomastigotes are release to bloodstream where they may be target by complement. Nevertheless, the parasite uses a sequence of events in order to escape from complement-mediated lysis. In fact, several T. cruzi molecules are known to interfere in the initiation of all three pathways and in the assembly of C3 convertase, a key step in the activation of complement. Moreover, T. cruzi promotes secretion of plasma

  7. The Wiring of Developing Sensory Circuits-From Patterned Spontaneous Activity to Synaptic Plasticity Mechanisms

    NARCIS (Netherlands)

    Leighton, Alexandra H; Lohmann, C.

    2016-01-01

    In order to accurately process incoming sensory stimuli, neurons must be organized into functional networks, with both genetic and environmental factors influencing the precise arrangement of connections between cells. Teasing apart the relative contributions of molecular guidance cues, spontaneous

  8. EXERCISE TRAINING IMPROVES CARDIOVASCULAR AUTONOMIC ACTIVITY AND ATTENUATES RENAL DAMAGE IN SPONTANEOUSLY HYPERTENSIVE RATS

    Directory of Open Access Journals (Sweden)

    Octávio Barbosa Neto

    2013-03-01

    Full Text Available Experiments were performed to determine the influence of exercise training by swimming on cardiovascular autonomic control and renal morphology in spontaneously hypertensive rats (SHR and Wystar-Kyoto (WKY rats. Sedentary normotensive (SN, trained normotensive (TN, sedentary hypertensive (SH, and trained hypertensive (TH rats were included in this study. Arterial pressure (AP, heart rate (HR, means of power spectral analysis of HR (HRV and systolic AP variability (SAPV were recorded in baseline conditions. Following, the HR baroreflex and autonomic tonus control were assessed. At the end, all animals were euthanized and their kidneys were excised to evaluate renal damage. Resting bradycardia was observed in TH and TN rats compared with their respective sedentary animals (p < 0.05. Exercise training attenuated AP in TH vs. SH (p < 0.001. The LF component of HRV and SAPV were lower in TH than SH (p < 0.05. The LF/HF relation was lower in TH than SH and SN (p < 0.05. TN and TH rats showed a sympathetic tonus reduction in comparison to SN and SH rats (p < 0.001. The TH presented an increased vagal tonus compared to SH (p < 0.05. Exercise training improved baroreflex control of HR in TH group versus SH (p < 0.05. The TH showed a lower number of sclerotic glomeruli compared to SH (p < 0.005. The exercise training decrease the glomerular indexes in TN and TH (p < 0.05. Further analysis showed a significant correlation between sympathetic nervous activity and AP levels (p < 0.05. A positive association was also found between sympathetic nervous activity and glomerular index (p < 0.05. Therefore, the exercise training reduces AP and attenuates renal damage. In addition, the attenuation of renal injury was associated with lower sympathetic activity. These findings strongly suggest that exercise training may be a therapeutic tool for improving structure and renal function in hypertensive individuals.

  9. Effects of taurine on resting-state fMRI activity in spontaneously hypertensive rats.

    Directory of Open Access Journals (Sweden)

    Vincent Chin-Hung Chen

    Full Text Available Attention deficit hyperactivity disorder (ADHD is a global behavior illness among children and adults. To investigate the effects of taurine on resting-state fMRI activity in ADHD, a spontaneously hypertensive rat (SHR animal model was adopted. Significantly decreased serum C-reactive protein (CRP was detected in rats of Wistar Kyoto (WKY high-taurine group and significantly decreased interleukin (IL-1β and CRP were detected in rats of SHR low-taurine and high-taurine groups. Moreover, significantly higher horizontal locomotion was detected in rats of WKY low-taurine and SHR low-taurine groups than in those of controls. In contrast, significantly lower horizontal locomotion was detected in rats of the SHR high-taurine group than in those of the SHR control group. Additionally, significantly lower functional connectivity (FC and mean amplitude of low-frequency fluctuation (mALFF in the bilateral hippocampus in rats of WKY high-taurine and SHR high-taurine groups was detected. Notably, the mALFF in rats of the SHR low-taurine and high-taurine groups was significantly lower than in those of the SHR control group. These findings suggest that the administration of a high-dose taurine probably improves hyperactive behavior in SHR rats by ameliorating the inflammatory cytokines and modulating brain functional signals in SHR rats.

  10. Electroacupuncture Delays Hypertension Development through Enhancing NO/NOS Activity in Spontaneously Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Hye Suk Hwang

    2011-01-01

    Full Text Available Using spontaneously hypertensive rats (SHR, this study investigated whether electroacupuncture (EA could reduce early stage hypertension by examining nitric oxide (NO levels in plasma and nitric oxide synthase (NOS levels in the mesenteric resistance artery. EA was applied to the acupuncture point Governor Vessel 20 (GV20 or to a non-acupuncture point in the tail twice weekly for 3 weeks under anesthesia. In conscious SHR and normotensive Wistar Kyoto (WKY rats, blood pressure was determined the day after EA treatment by the tail-cuff method. We measured plasma NO concentration, and evaluated endothelial NO syntheses (eNOS and neuronal NOS (nNOS protein expression in the mesenteric artery. Systolic blood pressure (SBP and diastolic blood pressure (DBP were lower after 3 weeks of GV20 treatment than EA at non-acupuncture point and no treatment control in SHR. nNOS expression by EA was significantly different between both WKY and no treatment SHR control, and EA at GV20 in SHR. eNOS expression was significantly high in EA at GV 20 compared with no treatment control. In conclusion, EA could attenuate the blood pressure elevation of SHR, along with enhancing NO/NOS activity in the mesenteric artery in SHR.

  11. Brain activity dynamics in human parietal regions during spontaneous switches in bistable perception.

    Science.gov (United States)

    Megumi, Fukuda; Bahrami, Bahador; Kanai, Ryota; Rees, Geraint

    2015-02-15

    The neural mechanisms underlying conscious visual perception have been extensively investigated using bistable perception paradigms. Previous functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) studies suggest that the right anterior superior parietal (r-aSPL) and the right posterior superior parietal lobule (r-pSPL) have opposite roles in triggering perceptual reversals. It has been proposed that these two areas are part of a hierarchical network whose dynamics determine perceptual switches. However, how these two parietal regions interact with each other and with the rest of the brain during bistable perception is not known. Here, we investigated such a model by recording brain activity using fMRI while participants viewed a bistable structure-from-motion stimulus. Using dynamic causal modeling (DCM), we found that resolving such perceptual ambiguity was specifically associated with reciprocal interactions between these parietal regions and V5/MT. Strikingly, the strength of bottom-up coupling between V5/MT to r-pSPL and from r-pSPL to r-aSPL predicted individual mean dominance duration. Our findings are consistent with a hierarchical predictive coding model of parietal involvement in bistable perception and suggest that visual information processing underlying spontaneous perceptual switches can be described as changes in connectivity strength between parietal and visual cortical regions. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Effects of taurine on resting-state fMRI activity in spontaneously hypertensive rats

    Science.gov (United States)

    Chen, Vincent Chin-Hung; Hsu, Tsai-Ching; Chen, Li-Jeng; Chou, Hong-Chun

    2017-01-01

    Attention deficit hyperactivity disorder (ADHD) is a global behavior illness among children and adults. To investigate the effects of taurine on resting-state fMRI activity in ADHD, a spontaneously hypertensive rat (SHR) animal model was adopted. Significantly decreased serum C-reactive protein (CRP) was detected in rats of Wistar Kyoto (WKY) high-taurine group and significantly decreased interleukin (IL)-1β and CRP were detected in rats of SHR low-taurine and high-taurine groups. Moreover, significantly higher horizontal locomotion was detected in rats of WKY low-taurine and SHR low-taurine groups than in those of controls. In contrast, significantly lower horizontal locomotion was detected in rats of the SHR high-taurine group than in those of the SHR control group. Additionally, significantly lower functional connectivity (FC) and mean amplitude of low-frequency fluctuation (mALFF) in the bilateral hippocampus in rats of WKY high-taurine and SHR high-taurine groups was detected. Notably, the mALFF in rats of the SHR low-taurine and high-taurine groups was significantly lower than in those of the SHR control group. These findings suggest that the administration of a high-dose taurine probably improves hyperactive behavior in SHR rats by ameliorating the inflammatory cytokines and modulating brain functional signals in SHR rats. PMID:28700674

  13. Effects of taurine on resting-state fMRI activity in spontaneously hypertensive rats.

    Science.gov (United States)

    Chen, Vincent Chin-Hung; Hsu, Tsai-Ching; Chen, Li-Jeng; Chou, Hong-Chun; Weng, Jun-Cheng; Tzang, Bor-Show

    2017-01-01

    Attention deficit hyperactivity disorder (ADHD) is a global behavior illness among children and adults. To investigate the effects of taurine on resting-state fMRI activity in ADHD, a spontaneously hypertensive rat (SHR) animal model was adopted. Significantly decreased serum C-reactive protein (CRP) was detected in rats of Wistar Kyoto (WKY) high-taurine group and significantly decreased interleukin (IL)-1β and CRP were detected in rats of SHR low-taurine and high-taurine groups. Moreover, significantly higher horizontal locomotion was detected in rats of WKY low-taurine and SHR low-taurine groups than in those of controls. In contrast, significantly lower horizontal locomotion was detected in rats of the SHR high-taurine group than in those of the SHR control group. Additionally, significantly lower functional connectivity (FC) and mean amplitude of low-frequency fluctuation (mALFF) in the bilateral hippocampus in rats of WKY high-taurine and SHR high-taurine groups was detected. Notably, the mALFF in rats of the SHR low-taurine and high-taurine groups was significantly lower than in those of the SHR control group. These findings suggest that the administration of a high-dose taurine probably improves hyperactive behavior in SHR rats by ameliorating the inflammatory cytokines and modulating brain functional signals in SHR rats.

  14. Observation of new spontaneous fission activities from elements 100 to 105

    International Nuclear Information System (INIS)

    Somerville, L.P.

    1982-03-01

    Several new Spontaneous Fission (SF) activities have been found. No definite identification could be made for any of the new SF activities; however, half-lives and possible assignments to element-104 isotopes consistent with several cross bombardments include 257 Rf(3.8 s, 14% SF), 258 Rf(13 ms), 259 Rf(approx. 3 s, 8% SF), 260 Rf(approx. 20 ms), and 262 Rf(approx. 50 ms). The 80-ms SF activity claimed by the Dubna group for the discovery of element 104 ( 260 104) was not observed. A difficulty exists in the interpretation that 260 Rf is a approx. 20-ms SF activity: in order to be correct, for example, the SF activities with half-lives between 14 and 24 ms produced in the reactions 109- to 119-MeV 18 O + 248 Cm, 88- to 100-MeV 15 N + 249 Bk, and 96-MeV 18 O + 249 Cf must be other nuclides due to their large production cross sections, or the cross sections for production of 260 Rf must be enhanced by unknown mechanisms. Based on calculated total production cross sections a possible approx. 1% electron-capture branch in 258 Lr(4.5 s) to the SF emitter 258 No(1.2 ms) and an upper limit of 0.05% for SF branching in 254 No(55 s) were determined. Other measured half-lives from unknown nuclides produced in respective reactions include approx. 1.6 s ( 18 O + 248 CM), indications of a approx. 47-s SF activity (75-MeV 12 C + 249 Cf), and two or more SF activities with 3 s less than or equal to T/sub 1/2/ less than or equal to 60 s ( 18 O + 249 Bk). The most exciting conclusion of this work is that if the tentative assignments to even-even element 104 isotopes are correct, there would be a sudden change in the SF half-life systematics at element 104 which has been predicted theoretically and attributed to the disappearance of the second hump of the double-humped fission barrier

  15. Influence of O(2)-carrying plasma hemoprotein "albumin-heme" on complement system and platelet activation in vitro and physiological responses to exchange transfusion.

    Science.gov (United States)

    Komatsu, Teruyuki; Huang, Yubin; Wakamoto, Shinobu; Abe, Hideki; Fujihara, Mitsuhiro; Azuma, Hiroshi; Ikeda, Hisami; Yamamoto, Hisashi; Horinouchi, Hirohisa; Kobayashi, Koichi; Tsuchida, Eishun

    2007-06-15

    Recombinant human serum albumin (HSA) including the synthetic iron(II)-porphyrin (FeP), albumin-heme (HSA-FeP), is a unique O(2)-carrying plasma hemoprotein as a red blood cell substitute. We have investigated the possible influence of HSA-FeP on the complement system and platelet activation in vitro. The amounts of the serum complement titer CH(50) and terminal complement complex SC5b-9 of human blood serum, incubated with HSA-FeP (10, 20, and 40 vol %), were almost the same as those of the corresponding samples with HSA. The effect of HSA-FeP on the platelet reactivity has been demonstrated by conformational changes in the membrane glycoprotein IIb/IIIa and surface expression of an alpha-granule membrane protein P-selectin. Platelet activation in response to the ADP-stimulation was not influenced by the presence of HSA-FeP. It can be concluded that the albumin-heme solution does not facilitate the immunological reaction and platelet activation. Moreover, a 20% exchange transfusion with HSA-FeP into anesthetized rats has been performed to evaluate the circulation and blood parameters for 6 h. Time course changes in all parameters showed features identical to the control group (without infusion) and HSA group. (c) 2007 Wiley Periodicals, Inc.

  16. Interactions between procedural learning and cocaine exposure alter spontaneous and cortically-evoked spike activity in the dorsal striatum

    Directory of Open Access Journals (Sweden)

    Janie eOndracek

    2010-12-01

    Full Text Available We have previously shown that cocaine enhances gene regulation in the sensorimotor striatum associated with procedural learning in a running-wheel paradigm. Here we assessed whether cocaine produces enduring modifications of learning-related changes in striatal neuron activity, using single-unit recordings in anesthetized rats 1 day after the wheel training. Spontaneous and cortically-evoked spike activity was compared between groups treated with cocaine or vehicle immediately prior to the running-wheel training or placement in a locked wheel (control conditions. We found that wheel training in vehicle-treated rats increased the average firing rate of spontaneously active neurons without changing the relative proportion of active to quiescent cells. In contrast, in rats trained under the influence of cocaine, the proportion of spontaneously firing to quiescent cells was significantly greater than in vehicle-treated, trained rats. However, this effect was associated with a lower average firing rate in these spontaneously active cells, suggesting that training under the influence of cocaine recruited additional low-firing cells. Measures of cortically-evoked activity revealed a second interaction between cocaine treatment and wheel training, namely, a cocaine-induced decrease in spike onset latency in control rats (locked wheel. This facilitatory effect of cocaine was abolished when rats trained in the running wheel during cocaine action. These findings highlight important interactions between cocaine and procedural learning, which act to modify population firing activity and the responsiveness of striatal neurons to excitatory inputs. Moreover, these effects were found 24 hours after the training and last drug exposure indicating that cocaine exposure during the learning phase triggers long-lasting changes in synaptic plasticity in the dorsal striatum. Such changes may contribute to the transition from recreational to habitual or compulsive drug

  17. Learning to modulate one's own brain activity: The effect of spontaneous mental strategies

    Directory of Open Access Journals (Sweden)

    Silvia Erika Kober

    2013-10-01

    Full Text Available Using neurofeedback (NF, individuals can learn to modulate their own brain activity, in most cases electroencephalographic (EEG rhythms. Although a large body of literature reports positive effects of NF training on behavior and cognitive functions, there are hardly any reports on how participants can successfully learn to gain control over their own brain activity. About one third of people fail to gain significant control over their brain signals even after repeated training sessions. The reasons for this failure are still largely unknown. In this context, we investigated the effects of spontaneous mental strategies on NF performance. Twenty healthy participants performed either a SMR (sensorimotor rhythm, 12-15 Hz based or a Gamma (40-43 Hz based NF training over ten sessions. After the first and the last training session, they were asked to write down which mental strategy they have used for self-regulating their EEG. After the first session, all participants reported the use of various types of mental strategies such as visual strategies, concentration, or relaxation. After the last NF training session, four participants of the SMR group reported to employ no specific strategy. These four participants showed linear improvements in NF performance over the ten training sessions. In contrast, participants still reporting the use of specific mental strategies in the last NF session showed no changes in SMR based NF performance over the ten sessions. This effect could not be observed in the Gamma group. The Gamma group showed no prominent changes in Gamma power over the NF training sessions, regardless of the mental strategies used. These results indicate that successful SMR based NF performance is associated with implicit learning mechanisms. Participants stating vivid reports on strategies to control their SMR probably overload cognitive resources, which might be counterproductive in terms of increasing SMR power.

  18. Natural IgM antibodies that bind neoepitopes exposed as a result of spinal cord injury , drive secondary injury by activating complement.

    Science.gov (United States)

    Narang, Aarti; Qiao, Fei; Atkinson, Carl; Zhu, Hong; Yang, Xiaofeng; Kulik, Liudmila; Holers, V Michael; Tomlinson, Stephen

    2017-06-19

    Natural IgM antibodies (Abs) function as innate immune sensors of injury via recognition of neoepitopes expressed on damaged cells, although how this recognition systems function following spinal cord injury (SCI) exposes various neoepitopes and their precise nature remains largely unknown. Here, we investigated the role of two natural IgM monoclonal Abs (mAbs), B4 and C2, that recognize post-ischemic neoepitopes following ischemia and reperfusion in other tissues. Identification of post-SCI expressed neoepitopes was examined using previously characterized monoclonal Abs (B4 and C2 mAbs). The role of post-SCI neoepitopes and their recognition by natural IgM Abs in propagating secondary injury was examined in Ab-deficient Rag1-/- or wild type C57BL/6 mice using Ab reconstitution experiments and neoepitope-targeted therapeutic studies, respectively. Administration of B4 or C2 mAb following murine SCI increased lesion size and worsened functional outcome in otherwise protected Ab-deficient Rag1-/- mice. Injury correlated with colocalized deposition of IgM and C3d in injured spinal cords from both mAb reconstituted Rag1-/- mice and untreated wild-type mice. Depletion of peritoneal B1 B cells, a source of natural Abs, reduced circulating levels of IgM with B4 (annexin-IV) and C2 (subset of phospholipids) reactivity, reduced IgM and complement deposition in the spinal cord, and protected against SCI. We therefore investigated whether the B4 neoepitope represents a therapeutic target for complement inhibition. B4-Crry, a fusion protein consisting of a single-chain Ab derived from B4 mAb, linked to the complement inhibitor Crry, significantly protected against SCI. B4-Crry exhibited a dual function in that it inhibited both the binding of pathogenic IgM and blocked complement activation in the spinal cord. This study identifies important neoepitopes expressed within the spinal cord after injury. These neoepitopes are recognized by clonally specific natural IgM Abs that

  19. Altered local spontaneous activity in frontal lobe epilepsy: a resting-state functional magnetic resonance imaging study.

    Science.gov (United States)

    Dong, Li; Li, Hechun; He, Zhongqiong; Jiang, Sisi; Klugah-Brown, Benjamin; Chen, Lin; Wang, Pu; Tan, Song; Luo, Cheng; Yao, Dezhong

    2016-11-01

    The purpose of this study was to investigate the local spatiotemporal consistency of spontaneous brain activity in patients with frontal lobe epilepsy (FLE). Eyes closed resting-state functional magnetic resonance imaging (fMRI) data were collected from 19 FLE patients and 19 age- and gender-matched healthy controls. A novel measure, named FOur-dimensional (spatiotemporal) Consistency of local neural Activities (FOCA) was used to assess the spatiotemporal consistency of local spontaneous activity (emphasizing both local temporal homogeneity and regional stability of brain activity states). Then, two-sample t test was performed to detect the FOCA differences between two groups. Partial correlations between the FOCA values and durations of epilepsy were further analyzed. Compared with controls, FLE patients demonstrated increased FOCA in distant brain regions including the frontal and parietal cortices, as well as the basal ganglia. The decreased FOCA was located in the temporal cortex, posterior default model regions, and cerebellum. In addition, the FOCA measure was linked to the duration of epilepsy in basal ganglia. Our study suggested that alterations of local spontaneous activity in frontoparietal cortex and basal ganglia was associated with the pathophysiology of FLE; and the abnormality in frontal and default model regions might account for the potential cognitive impairment in FLE. We also presumed that the FOCA measure had potential to provide important insights into understanding epilepsy such as FLE.

  20. GABA-A receptor antagonists increase firing, bursting and synchrony of spontaneous activity in neuronal networks grown on microelectrode arrays: a step towards chemical "fingerprinting"

    Science.gov (United States)

    Assessment of effects on spontaneous network activity in neurons grown on MEAs is a proposed method to screen chemicals for potential neurotoxicity. In addition, differential effects on network activity (chemical "fingerprints") could be used to classify chemical modes of action....

  1. The Role of Complement in Tumor Growth

    Science.gov (United States)

    Pio, Ruben; Corrales, Leticia; Lambris, John D.

    2015-01-01

    Complement is a central part of the immune system that has developed as a first defense against non-self cells. Neoplastic transformation is accompanied by an increased capacity of the malignant cells to activate complement. In fact, clinical data demonstrate complement activation in cancer patients. On the basis of the use of protective mechanisms by malignant cells, complement activation has traditionally been considered part of the body's immunosurveillance against cancer. Inhibitory mechanisms of complement activation allow cancer cells to escape from complement-mediated elimination and hamper the clinical efficacy of monoclonal antibody–based cancer immunotherapies. To overcome this limitation, many strategies have been developed with the goal of improving complement-mediated effector mechanisms. However, significant work in recent years has identified new and surprising roles for complement activation within the tumor microenvironment. Recent reports suggest that complement elements can promote tumor growth in the context of chronic inflammation. This chapter reviews the data describing the role of complement activation in cancer immunity, which offers insights that may aid the development of more effective therapeutic approaches to control cancer. PMID:24272362

  2. AN INFLUENCE OF SPONTANEOUS MICROFLORA OF FERMENTED HORSEMEAT PRODUCTS ON THE FORMATION OF BIOLOGICALLY ACTIVE PEPTIDES

    Directory of Open Access Journals (Sweden)

    I. M. Chernukha

    2017-01-01

    Full Text Available At present, different methods are used to accumulate functional peptides in meat raw materials, including the use of spontaneous microflora during autolysis, the use of the microbial enzymes (the application of starter cultures and the use of the non-microbial enzymes (enzymes of animals and plant origin. Each method has its own specific characteristics of an impact on raw materials, which requires their detail study. This paper examines an effect of spontaneous microflora of fermented meat products from horsemeat on formation of biologically active peptides. Using the T-RFLP analysis, it was established that in air dried and uncooked smoked sausages produced with the use of the muscle tissue of horsemeat as a raw material, a significant proportion of microflora was presented by lactic acid microorganisms. The highest content of lactic acid microflora was observed in sample 1 (52.45 %, and the least in sample 3 (29.62 %. Sample 2 had the medium percent content of microflora compared to samples 1 and 3 — 38.82 %. It is necessary to note that about 25 % of microflora was unculturable; i.e., it had metabolic processes but did not grow on culture media. In the samples, the representatives of Actinobacteria and Pseudomonadales were found. Pathogenic and conditionally pathogenic microflora was not detected. Not only quantitative but also qualitative changes were observed in the studied samples. For example, in samples 1 and 2, the fractions of amilo-1,6-glucosidase, fast-type muscle myosin-binding-protein C; glucose-6-phosphate isomerase; fast skeletal muscle troponin I, phosphoglycerate kinase, pyruvate kinase and skeletal muscle actin were found, which were absent or reduced in sample 3. Therefore, in the studied product, good preservation of the main spectra of muscle proteins was observed, and the identified fractions, apparently, can be sources of new functional peptides. Not only quantitative but also qualitative changes were observed in the

  3. Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2

    DEFF Research Database (Denmark)

    Yaseen, Sadam; Demopulos, Gregory; Dudler, Thomas

    2017-01-01

    All 3 activation pathways of complement-the classic pathway (CP), the alternative pathway, and the lectin pathway (LP)- converge into a common central event: the cleavage and activation of the abundant third complement component, C3,viaformation of C3-activating enzymes (C3 convertases). The four......., Sacks, S., Garred, P., Andrew, P., Sim, R. B., Lachmann, P. J., Wallis, R., Lynch, N., Schwaeble, W. J. Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2....

  4. Population calcium imaging of spontaneous respiratory and novel motor activity in the facial nucleus and ventral brainstem in newborn mice

    DEFF Research Database (Denmark)

    Persson, Karin; Rekling, Jens C

    2011-01-01

    The brainstem contains rhythm and pattern forming circuits, which drive cranial and spinal motor pools to produce respiratory and other motor patterns. Here we used calcium imaging combined with nerve recordings in newborn mice to reveal spontaneous population activity in the ventral brainstem...... in lateral and medial subnuclei. Whole-cell recordings from facial motoneurons showed weak respiratory drives, and electrical field potential recordings confirmed respiratory drive to particularly the dorsal and lateral subnuclei. Putative facial premotoneurons showed respiratory-related calcium signals...

  5. Complement receptor type 1 (CR1/CD35) expressed on activated human CD4+ T cells contributes to generation of regulatory T cells.

    Science.gov (United States)

    Török, Katalin; Dezső, Balázs; Bencsik, András; Uzonyi, Barbara; Erdei, Anna

    2015-04-01

    The role of complement in the regulation of T cell immunity has been highlighted recently by several groups. We were prompted to reinvestigate the role of complement receptor type 1 (CR1, CD35) [corrected] in human T cells based on our earlier data showing that activated human T cells produce C3 (Torok et al. (2012) [48]) and also by results demonstrating that engagement of Membrane Cofactor Protein (MCP, CD46) induces a switch of anti-CD35-activated [corrected] helper T cells into regulatory T cells (Kemper et al. (2003) [17]). We demonstrate here that co-ligation of CD46 and CD35, [corrected] the two C3b-binding structures present on activated CD4+ human T cells significantly enhances CD25 expression, elevates granzyme B production and synergistically augments cell proliferation. The role of CR1 in the development of the Treg phenotype was further confirmed by demonstrating that its engagement enhances IL-10 production and reduces IFNγ release by the activated CD4+ T cells in the presence of excess IL-2. The functional in vivo relevance of our findings was highlighted by the immunohistochemical staining of tonsils, revealing the presence of CD4/CD35 [corrected] double positive lymphocytes mainly in the inter-follicular regions where direct contact between CD4+ T cells and B lymphocytes occurs. Regarding the in vivo relevance of the complement-dependent generation of regulatory T cells in secondary lymphoid organs we propose a scenario shown in the figure. The depicted process involves the sequential binding of locally produced C3 fragments to CD46 and CD35 [corrected] expressed on activated T cells, which - in the presence of excess IL-2 - leads to the development of Treg cells. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  6. The secreted Candida albicans protein Pra1 disrupts host defense by broadly targeting and blocking complement C3 and C3 activation fragments.

    Science.gov (United States)

    Luo, Shanshan; Dasari, Prasad; Reiher, Nadine; Hartmann, Andrea; Jacksch, Susanne; Wende, Elisabeth; Barz, Dagmar; Niemiec, Maria Joanna; Jacobsen, Ilse; Beyersdorf, Niklas; Hünig, Thomas; Klos, Andreas; Skerka, Christine; Zipfel, Peter F

    2018-01-01

    Candida albicans the most frequently isolated clinical fungal pathogen can cause local as well as systemic and life-threatening infections particularly in immune-compromised individuals. A better and more detailed understanding how C. albicans evades human immune attack is therefore needed for identifying fungal immune-evasive proteins and develop new therapies. Here, we identified Pra1, the pH-regulated C. albicans antigen as a hierarchical complement inhibitor that targets C3, the central human complement component. Pra1 cleaved C3 at a unique site and further inhibited effector function of the activation fragments. The newly formed C3a-like peptide lacked the C-terminal arginine residue needed for C3a-receptor binding and activation. Moreover, Pra1 also blocked C3a-like antifungal activity as shown in survival assays, and the C3b-like molecule formed by Pra1 was degraded by the host protease Factor I. Pra1 also bound to C3a and C3b generated by human convertases and blocked their effector functions, like C3a antifungal activity shown by fungal survival, blocked C3a binding to human C3a receptor-expressing HEK cells, activation of Fura2-AM loaded cells, intracellular Ca 2+ signaling, IL-8 release, C3b deposition, as well as opsonophagocytosis and killing by human neutrophils. Thus, upon infection C. albicans uses Pra1 to destroy C3 and to disrupt host complement attack. In conclusion, candida Pra1 represents the first fungal C3-cleaving protease identified and functions as a fungal master regulator of innate immunity and as a central fungal immune-escape protein. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Activation and binding of opsonic fragments of C3 on encapsulated Cryptococcus neoformans by using an alternative complement pathway reconstituted from six isolated proteins.

    Science.gov (United States)

    Kozel, T R; Wilson, M A; Pfrommer, G S; Schlageter, A M

    1989-07-01

    Encapsulated Cryptococcus neoformans yeast cells are potent activators of the complement system. We examined the interaction of the yeast cells with an alternative complement pathway reconstituted from isolated factor D, factor B, factor H, factor I, C3, and properdin. Incubation of encapsulated cryptococci with the reconstituted pathway led to activation and binding of C3 fragments to the yeast cells that was quantitatively and qualitatively identical to that observed with normal human serum. Incubation with either normal serum or a mixture of isolated proteins led to binding of 4 x 10(7) to 5 x 10(7) C3 molecules to the yeast cells. The kinetics for activation and binding of C3 were identical, with maximum binding observed after a 20-min incubation. Immunoglobulin G was not needed for optimal activation kinetics. C3 fragments eluted from the yeast cells by treatment with hydroxylamine and subsequent analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated the presence primarily of iC3b on yeast cells incubated with either normal serum or the reconstituted pathway. Ultrastructural examination of the opsonized yeast cells showed that the cryptococcal capsule was the site for binding of C3 activated from normal serum or the reconstituted pathway, with a dense accumulation of C3 at the periphery of the capsule. Thus, incubation of encapsulated cryptococci in the reconstituted pathway led to deposition of opsonic complement fragments at a site that was appropriate for interaction with phagocyte receptors. Cryptococci opsonized with the reconstituted pathway showed a markedly enhanced interaction with cultured human monocytes compared with unopsonized yeast cells, indicating that the alternative pathway alone is opsonic for yeast cells. However, the results indicate that additional serum factors are needed for optimal opsonization of yeast cells because a 35% reduction in the number of cryptococci bound to macrophages was observed with

  8. Complement pathways and meningococcal disease : diagnostic aspects

    DEFF Research Database (Denmark)

    Sjöholm, A G; Truedsson, L; Jensenius, Jens Christian

    2001-01-01

    Complement is an immunological effector system that bridges innate and acquired immunity in several ways. There is a striking association between susceptibility to meningococcal disease and various forms of complement deficiency (1,2). In defense against bacterial infection, the most important...... activation on the bacterial surface (6,7). The newly discovered mannan-binding lectin (MBL) pathway of complement activation appears to be protective against many types of infection (8) and adds previously unsuspected aspects of innate immunity to complement-mediated defense. Interestingly, immune responses...... function of complement is probably to serve as a mediator of antibody-dependent immunity. Specific antibodies can trigger activation of the classical and the alternative pathways of complement activation (3-5). It is well known that antibody-independent mechanisms interfere with alternative pathway...

  9. Does low protein concentration of tissue-type plasminogen activator predict a low risk of spontaneous deep vein thrombosis?

    DEFF Research Database (Denmark)

    Gram, J; Sidelmann, Johannes Jakobsen; Jespersen, J

    1995-01-01

    Many reports have demonstrated an abnormal fibrinolysis in a subset of patients with deep vein thrombosis. We have studied systemic global fibrinolytic activity and protein concentrations of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) in plasma of 25...... young patients with a previous instance of spontaneous deep vein thrombosis documented by phlebography and in 50 healthy controls. The two populations were comparable with respect to a number of base-line variables (age, height, weight, etc.), while the patients had significantly lower fibrinolytic...

  10. Binding of complement factor H to PorB3 and NspA enhances resistance of Neisseria meningitidis to anti-factor H binding protein bactericidal activity.

    Science.gov (United States)

    Giuntini, Serena; Pajon, Rolando; Ram, Sanjay; Granoff, Dan M

    2015-04-01

    Among 25 serogroup B Neisseria meningitidis clinical isolates, we identified four (16%) with high factor H binding protein (FHbp) expression that were resistant to complement-mediated bactericidal activity of sera from mice immunized with recombinant FHbp vaccines. Two of the four isolates had evidence of human FH-dependent complement downregulation independent of FHbp. Since alternative complement pathway recruitment is critical for anti-FHbp bactericidal activity, we hypothesized that in these two isolates binding of FH to ligands other than FHbp contributes to anti-FHbp bactericidal resistance. Knocking out NspA, a known meningococcal FH ligand, converted both resistant isolates to anti-FHbp susceptible isolates. The addition of a nonbactericidal anti-NspA monoclonal antibody to the bactericidal reaction also increased anti-FHbp bactericidal activity. To identify a role for FH ligands other than NspA or FHbp in resistance, we created double NspA/FHbp knockout mutants. Mutants from both resistant isolates bound 10-fold more recombinant human FH domains 6 and 7 fused to Fc than double knockout mutants prepared from two sensitive meningococcal isolates. In light of recent studies showing functional FH-PorB2 interactions, we hypothesized that PorB3 from the resistant isolates recruited FH. Allelic exchange of porB3 from a resistant isolate to a sensitive isolate increased resistance of the sensitive isolate to anti-FHbp bactericidal activity (and vice versa). Thus, some PorB3 variants functionally bind human FH, which in the presence of NspA enhances anti-FHbp resistance. Combining anti-NspA antibodies with anti-FHbp antibodies can overcome resistance. Meningococcal vaccines that target both NspA and FHbp are likely to confer greater protection than either antigen alone. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  11. Peptide Inhibitor of Complement C1 (PIC1) demonstrates antioxidant activity via single electron transport (SET) and hydrogen atom transfer (HAT).

    Science.gov (United States)

    Gregory Rivera, Magdielis; Hair, Pamela S; Cunnion, Kenji M; Krishna, Neel K

    2018-01-01

    Reactive oxygen species (ROS) are natural byproducts of oxidative respiration that are toxic to organs and tissues. To mitigate ROS damage, organisms have evolved a variety of antioxidant systems to counteract these harmful molecules, however in certain pathological conditions these protective mechanisms can be overwhelmed. We have recently demonstrated that Peptide Inhibitor of Complement C1 (PIC1) mitigates peroxidase activity of the heme bearing proteins myeloperoxidase, hemoglobin, and myoglobin through a reversible process. To determine if this property of PIC1 was antioxidant in nature, we tested PIC1 in a number of well-established antioxidant assays. PIC1 showed dose-dependent antioxidant activity in a total antioxidant (TAC) assay, hydroxyl radical antioxidant capacity (HORAC) assay, oxygen radical antioxidant capacity (ORAC) assay as well as the thiobarbituric acid reactive substances (TBARS) assay to screen for PIC1 antioxidant activity in human plasma. The antioxidant activity of PIC1 in the TAC assay, as well as the HORAC/ORAC assay demonstrated that this peptide acts via the single electron transport (SET) and hydrogen atom transfer (HAT) mechanisms, respectively. Consistent with this mechanism of action, PIC1 did not show activity in a metal chelating activity (MCA) assay. PIC1 contains two vicinal cysteine residues and displayed similar antioxidant activity to the well characterized cysteine-containing tripeptide antioxidant molecule glutathione (GSH). Consistent with the role of the cysteine residues in the antioxidant activity of PIC1, oxidation of these residues significantly abrogated antioxidant activity. These results demonstrate that in addition to its described complement inhibiting activity, PIC1 displays in vitro antioxidant activity.

  12. Activity-dependent plasticity in the isolated embryonic avian brainstem following manipulations of rhythmic spontaneous neural activity.

    Science.gov (United States)

    Vincen-Brown, Michael A; Revill, Ann L; Pilarski, Jason Q

    2016-07-15

    When rhythmic spontaneous neural activity (rSNA) first appears in the embryonic chick brainstem and cranial nerve motor axons it is principally driven by nicotinic neurotransmission (NT). At this early age, the nicotinic acetylcholine receptor (nAChR) agonist nicotine is known to critically disrupt rSNA at low concentrations (0.1-0.5μM), which are levels that mimic the blood plasma levels of a fetus following maternal cigarette smoking. Thus, we quantified the effect of persistent exposure to exogenous nicotine on rSNA using an in vitro developmental model. We found that rSNA was eliminated by continuous bath application of exogenous nicotine, but rSNA recovered activity within 6-12h despite the persistent activation and desensitization of nAChRs. During the recovery period rSNA was critically driven by chloride-mediated membrane depolarization instead of nicotinic NT. To test whether this observed compensation was unique to the antagonism of nicotinic NT or whether the loss of spiking behavior also played a role, we eliminated rSNA by lowering overall excitatory drive with a low [K(+)]o superfusate. In this context, rSNA again recovered, although the recovery time was much quicker, and exhibited a lower frequency, higher duration, and an increase in the number of bursts per episode when compared to control embryos. Importantly, we show that the main compensatory response to lower overall excitatory drive, similar to nicotinergic block, is a result of potentiated chloride mediated membrane depolarization. These results support increasing evidence that early neural circuits sense spiking behavior to maintain primordial bioelectric rhythms. Understanding the nature of developmental plasticity in the nervous system, especially versions that preserve rhythmic behaviors following clinically meaningful environmental stimuli, both normal and pathological, will require similar studies to determine the consequences of feedback compensation at more mature chronological ages

  13. Central command does not suppress baroreflex control of cardiac sympathetic nerve activity at the onset of spontaneous motor activity in the decerebrate cat.

    Science.gov (United States)

    Matsukawa, Kanji; Ishii, Kei; Asahara, Ryota; Idesako, Mitsuhiro

    2016-10-01

    Our laboratory has reported that central command blunts the sensitivity of the aortic baroreceptor-heart rate (HR) reflex at the onset of voluntary static exercise in animals. We have examined whether baroreflex control of cardiac sympathetic nerve activity (CSNA) and/or cardiovagal baroreflex sensitivity are altered at the onset of spontaneously occurring motor behavior, which was monitored with tibial nerve activity in paralyzed, decerebrate cats. CSNA exhibited a peak increase (126 ± 17%) immediately after exercise onset, followed by increases in HR and mean arterial pressure (MAP). With development of the pressor response, CSNA and HR decreased near baseline, although spontaneous motor activity was not terminated. Atropine methyl nitrate (0.1-0.2 mg/kg iv) with little central influence delayed the initial increase in HR but did not alter the response magnitudes of HR and CSNA, while atropine augmented the pressor response. The baroreflex-induced decreases in CSNA and HR elicited by brief occlusion of the abdominal aorta were challenged at the onset of spontaneous motor activity. Spontaneous motor activity blunted the baroreflex reduction in HR by aortic occlusion but did not alter the baroreflex inhibition of CSNA. Similarly, atropine abolished the baroreflex reduction in HR but did not influence the baroreflex inhibition of CSNA. Thus it is likely that central command increases CSNA and decreases cardiac vagal outflow at the onset of spontaneous motor activity while preserving baroreflex control of CSNA. Accordingly, central command must attenuate cardiovagal baroreflex sensitivity against an excess rise in MAP as estimated from the effect of muscarinic blockade. Copyright © 2016 the American Physiological Society.

  14. Combining task-evoked and spontaneous activity to improve pre-operative brain mapping with fMRI

    Science.gov (United States)

    Fox, Michael D.; Qian, Tianyi; Madsen, Joseph R.; Wang, Danhong; Li, Meiling; Ge, Manling; Zuo, Huan-cong; Groppe, David M.; Mehta, Ashesh D.; Hong, Bo; Liu, Hesheng

    2016-01-01

    Noninvasive localization of brain function is used to understand and treat neurological disease, exemplified by pre-operative fMRI mapping prior to neurosurgical intervention. The principal approach for generating these maps relies on brain responses evoked by a task and, despite known limitations, has dominated clinical practice for over 20 years. Recently, pre-operative fMRI mapping based on correlations in spontaneous brain activity has been demonstrated, however this approach has its own limitations and has not seen widespread clinical use. Here we show that spontaneous and task-based mapping can be performed together using the same pre-operative fMRI data, provide complimentary information relevant for functional localization, and can be combined to improve identification of eloquent motor cortex. Accuracy, sensitivity, and specificity of our approach are quantified through comparison with electrical cortical stimulation mapping in eight patients with intractable epilepsy. Broad applicability and reproducibility of our approach is demonstrated through prospective replication in an independent dataset of six patients from a different center. In both cohorts and every individual patient, we see a significant improvement in signal to noise and mapping accuracy independent of threshold, quantified using receiver operating characteristic curves. Collectively, our results suggest that modifying the processing of fMRI data to incorporate both task-based and spontaneous activity significantly improves functional localization in pre-operative patients. Because this method requires no additional scan time or modification to conventional pre-operative data acquisition protocols it could have widespread utility. PMID:26408860

  15. Complementing the patient: a complement component deficiency in a patient with recurrent infections and glomerulonephritis.

    Science.gov (United States)

    Sinclair, David; Wilde, Graeme; Bex, Samantha; Peters, Sheila

    2005-01-01

    We present a case showing the investigation of a 7-year-old girl with empyema and glomerulonephritis whose "immunological" defect was a single complement component (C2) deficiency which prevented her from activating her classical complement pathway. A defect in complement function should be suspected in any patient with severe or recurring pyogenic infections. Investigations of "? immune deficiency" should always include tests to assess the patency of the patient's complement system.

  16. Urokinase vs Tissue-Type Plasminogen Activator for Thrombolytic Evacuation of Spontaneous Intracerebral Hemorrhage in Basal Ganglia

    Directory of Open Access Journals (Sweden)

    Yuqian Li

    2017-08-01

    Full Text Available Spontaneous intracerebral hemorrhage (ICH is a devastating form of stroke, which leads to a high rate of mortality and poor neurological outcomes worldwide. Thrombolytic evacuation with urokinase-type plasminogen activator (uPA or tissue-type plasminogen activator (tPA has been showed to be a hopeful treatment for ICH. However, to the best of our knowledge, no clinical trials were reported to compare the efficacy and safety of these two fibrinolytics administrated following minimally invasive stereotactic puncture (MISP in patients with spontaneous basal ganglia ICH. Therefore, the authors intended here to evaluate the differential impact of uPA and tPA in a retrospective study. In the present study, a total of 86 patients with spontaneous ICH in basal ganglia using MISP received either uPA (uPA group, n = 45 or tPA (tPA group, n = 41, respectively. The clinical baseline characteristics prior to the operation were collected. In addition, therapeutic responses were assessed by the short-term outcomes within 30 days postoperation, as well as long-term outcomes at 1 year postoperation. Our findings showed that, in comparison with tPA, uPA was able to better promote hematoma evacuation and ameliorate perihematomal edema, but the differences were not statistically significant. Moreover, the long-term functional outcomes of both groups were similar, with no statistical difference. In conclusion, these results provide evidence supporting that uPA and tPA are similar in the efficacy and safety for thrombolytic evacuation in combination with MISP in patients with spontaneous basal ganglia ICH.

  17. An integrated assessment of morphology, size, and complement activation of the PEGylated liposomal doxorubicin products Doxil®, Caelyx®, DOXOrubicin, and SinaDoxosome

    DEFF Research Database (Denmark)

    Wibroe, Peter P; Ahmadvand, Davoud; Oghabian, Mohammad Ali

    2016-01-01

    In order to improve patient's benefit and safety, comprehensive regulatory guidelines on specificities of Non-Biological Complex Drugs (NBCDs), such as doxorubicin-encapsulated liposomes, and their follow-on versions are needed. Here, we compare Doxil® and its European analog Caelyx® with the two...... follow-on products DOXOrubicin (approved by the US Food and Drug Administration) and SinaDoxosome (produced in Iran) by cryogenic transmission electron microscopy, dynamic light scattering and Nanoparticle Tracking Analysis, and assess their potential in activating the complement system in human sera. We...

  18. Characterization of vanadate-dependent NADH oxidation activity and isolation of yeast DNA which complements a class 1 vanadate resistance mutation

    International Nuclear Information System (INIS)

    Minasi, L.E.

    1989-01-01

    A vanadate-dependent NADH oxidation activity has been characterized in plasma membranes from the yeast S cerevisiae. NADH oxidation activity was maximally stimulated at pH 5.0 in phosphate buffer. NADH oxidation was not dependent on the concentration of plasma membranes. The vanadate-dependent NADH oxidation activity was abolished under anaerobic conditions and the concomitant uptake of oxygen occurred during NADH oxidation. The activity was inhibited by superoxide dismutase and stimulated by the presence of paraquat. These results indicate that the vanadate stimulation of NADH oxidation in yeast plasma membranes occurs as a result of the vanadate-dependent oxidation of NADH by superoxide, generated by a plasma membrane NADH oxidase. 51 V-NMR results indicated that a phosphate-vanadate anhydride was the stimulatory species in pH 5.0 and pH 7.0 phosphate buffer. Yeast DNA has been isolated which complements a class 1 vanadate resistance mutation

  19. Complement activation capacity in plasma before and during high-dose prednisolone treatment and tapering in exacerbations of Crohn's disease and ulcerative colitis

    Directory of Open Access Journals (Sweden)

    Baatrup Gunnar

    2005-09-01

    Full Text Available Abstract Background Ulcerative colitis (UC and Crohn's disease (CD are characterized by intestinal inflammation mainly caused by a disturbance in the balance between cytokines and increased complement (C activation. Our aim was to evaluate possible associations between C activation capacity and prednisolone treatment. Methods Plasma from patients with exacerbations of UC (n = 18 or CD (n = 18 were collected before and during high dose prednisolone treatment (1 mg/kg body weight and tapering. Friedman's two way analysis of variance, Mann-Whitney U test and Wilcoxon signed-rank sum test were used Results Before treatment, plasma from CD patients showed significant elevations in all C-mediated analyses compared to the values obtained from 38 healthy controls (p Conclusion Our findings indicate that C activation capacity is up-regulated significantly in plasma from CD patients. The decreases observed after prednisolone treatment reflect a general down-regulation in immune activation.

  20. High-Tc superconducting quantum interference device recordings of spontaneous brain activity: Towards high-Tc magnetoencephalography

    Science.gov (United States)

    Öisjöen, F.; Schneiderman, J. F.; Figueras, G. A.; Chukharkin, M. L.; Kalabukhov, A.; Hedström, A.; Elam, M.; Winkler, D.

    2012-03-01

    We have performed single- and two-channel high transition temperature (high-Tc) superconducting quantum interference device (SQUID) magnetoencephalography (MEG) recordings of spontaneous brain activity in two healthy human subjects. We demonstrate modulation of two well-known brain rhythms: the occipital alpha rhythm and the mu rhythm found in the motor cortex. We further show that despite higher noise-levels compared to their low-Tc counterparts, high-Tc SQUIDs can be used to detect and record physiologically relevant brain rhythms with comparable signal-to-noise ratios. These results indicate the utility of high-Tc technology in MEG recordings of a broader range of brain activity.

  1. Anti-nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery-induced pain.

    Science.gov (United States)

    Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T; Ossipov, Michael H; Mantyh, Patrick W

    2017-04-01

    Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are 2 of the most common and successful surgical interventions to relieve osteoarthritis pain. Control of postoperative pain is critical for patients to fully participate in the required physical therapy which is the most influential factor in effective postoperative knee rehabilitation. Currently, opiates are a mainstay for managing postoperative orthopedic surgery pain including TKA or THA pain. Recently, issues including efficacy, dependence, overdose, and death from opiates have made clinicians and researchers more critical of use of opioids for treating nonmalignant skeletal pain. In the present report, a nonopiate therapy using a monoclonal antibody raised against nerve growth factor (anti-NGF) was assessed for its ability to increase the spontaneous activity of the operated knee joint in a mouse model of orthopedic surgery pain-induced by drilling and coring the trochlear groove of the mouse femur. Horizontal activity and velocity and vertical rearing were continually assessed over a 20 hours day/night period using automated activity boxes in an effort to reduce observer bias and capture night activity when the mice are most active. At days 1 and 3, after orthopedic surgery, there was a marked reduction in spontaneous activity and vertical rearing; anti-NGF significantly attenuated this decline. The present data suggest that anti-NGF improves limb use in a rodent model of joint/orthopedic surgery and as such anti-NGF may be useful in controlling pain after orthopedic surgeries such as TKA or THA.

  2. Effects of the antitumor agents from various natural sources on drug-metabolizing system, phagocytic activity and complement system in sarcoma 180-bearing mice.

    Science.gov (United States)

    Ito, H

    1986-03-01

    Correlation between antitumor activity and effects on some biological properties, such as phagocytic activity of the reticuloendothelial system, the third component of complement (C3) activation, hepatic drug-metabolizing activities and pentobarbital-induced narcosis, of antitumor agents from various natural sources such as B B (Broncasma Berna), GU-P (Grifora umbellata polysaccharide), OK-432, PS-K (Polysaccharide Kureha), and RA-P (Rumex acetosa polysaccharide) were studied with female ICR mice implanted with Sarcoma 180 solid tumor. All of these agents depressed aniline hydroxylase and aminopyrine demethylase activities, prolonged the duration of pentobarbital-induced narcosis, and significantly enhanced the phagocytic activity and C3 activity. Especially, RA-P which has the strongest antitumor activity was the most effective in changing these activities. The biological activities of GU-P at a dose of 10 mg/kg reached the same level as that found with PS-K at a dose of 100 mg/kg. a possible mechanism of inhibition of Sarcoma 180 solid tumor growth by the treatment with the antitumor agents could be interpreted as due to the C3 activation, the stimulation of phagocytic activity and depression of the hepatic microsomal drug-metabolizing system in tumor-bearing mice.

  3. Effect of age and severity of cognitive dysfunction on spontaneous activity in pet dogs - part 1: locomotor and exploratory behaviour.

    Science.gov (United States)

    Rosado, B; González-Martínez, A; Pesini, P; García-Belenguer, S; Palacio, J; Villegas, A; Suárez, M-L; Santamarina, G; Sarasa, M

    2012-11-01

    Age-related cognitive dysfunction syndrome (CDS) has been reported in dogs and it is considered a natural model for Alzheimer's disease in humans. Changes in spontaneous activity (including locomotor and exploratory behaviour) and social responsiveness have been related to the age and cognitive status of kennel-reared Beagle dogs. The aim of this study was to assess the influence of age and severity of CDS on locomotor and exploratory behaviour of privately owned dogs. This is the first part of a two-part report on spontaneous activity in pet dogs. An open-field (OF) test and a curiosity test were administered at baseline and 6 months later to young (1-4 years, n=9), middle-aged (5-8 years, n=9), cognitively unimpaired aged (≥ 9 years, n=31), and cognitively impaired aged ( ≥ 9 years, n=36) animals. Classification of cognitive status was carried out using an owner-based observational questionnaire, and in the cognitively impaired group, the dogs were categorised as having either mild or severe cognitive impairment. Dogs were recorded during sessions in the testing room and the video-recordings were subsequently analysed. The severity of CDS (but not age) influenced locomotion and exploratory behaviour so that the more severe the impairment, the higher the locomotor activity and frequency of corner-directed (aimless) behaviours, and the lower the frequency of door-aimed activities. Curiosity directed toward novel stimuli exhibited an age-dependent decline although severely affected animals displayed more sniffing episodes directed towards the objects. OF activity did not change after 6 months. Testing aged pet dogs for spontaneous behaviour might help to better characterise cognitively affected individuals. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Neuronal functional connection graphs among multiple areas of the rat somatosensory system during spontaneous and evoked activities.

    Science.gov (United States)

    Zippo, Antonio G; Storchi, Riccardo; Nencini, Sara; Caramenti, Gian Carlo; Valente, Maurizio; Biella, Gabriele Eliseo M

    2013-01-01

    Small-World Networks (SWNs) represent a fundamental model for the comprehension of many complex man-made and biological networks. In the central nervous system, SWN models have been shown to fit well both anatomical and functional maps at the macroscopic level. However, the functional microscopic level, where the nodes of a network are represented by single neurons, is still poorly understood. At this level, although recent evidences suggest that functional connection graphs exhibit small-world organization, it is not known whether and how these maps, potentially distributed in multiple brain regions, change across different conditions, such as spontaneous and stimulus-evoked activities. We addressed these questions by analyzing the data from simultaneous multi-array extracellular recordings in three brain regions of rats, diversely involved in somatosensory information processing: the ventropostero-lateral thalamic nuclei, the primary somatosensory cortex and the centro-median thalamic nuclei. From both spike and Local Field Potential (LFP) recordings, we estimated the functional connection graphs by using the Normalized Compression Similarity for spikes and the Phase Synchrony for LFPs. Then, by using graph-theoretical statistics, we characterized the functional topology both during spontaneous activity and sensory stimulation. Our main results show that: (i) spikes and LFPs show SWN organization during spontaneous activity; (ii) after stimulation onset, while substantial functional graph reconfigurations occur both in spike and LFPs, small-worldness is nonetheless preserved; (iii) the stimulus triggers a significant increase of inter-area LFP connections without modifying the topology of intra-area functional connections. Finally, investigating computationally the functional substrate that supports the observed phenomena, we found that (iv) the fundamental concept of cell assemblies, transient groups of activating neurons, can be described by small

  5. Sources of variation and genetic profile of spontaneous, out-of-season ovulatory activity in the Chios sheep

    Directory of Open Access Journals (Sweden)

    Kouttos Athanasios

    2003-01-01

    Full Text Available Abstract Organising the breeding plan of a seasonally breeding species, such as sheep, presents a challenge to farmers and the industry as a whole, since both economical and biological considerations need to be carefully balanced. Understanding the breeding activity of individual animals becomes a prerequisite for a successful breeding program. This study set out to investigate the sources of variation and the genetic profile of the spontaneous, out-of-season ovulatory activity of ewes of the Chios dairy sheep breed in Greece. The definition of the trait was based on blood progesterone levels, measured before exposing the ewes to rams, which marks the onset of the usual breeding season. Data were 707 records, taken over two consecutive years, of 435 ewes kept at the Agricultural Research Station of Chalkidiki in northern Greece. When all available pedigree was included, the total number of animals involved was 1068. On average, 29% of all ewes exhibited spontaneous, out-of-season ovulatory activity, with no substantial variation between the years. Significant sources of systematic variation were the ewe age and live weight, and the month of previous lambing. Older, heavier ewes, that had lambed early the previous autumn, exhibited more frequent activity. Heritability estimates were 0.216 (± 0.084 with a linear and 0.291 with a threshold model. The latter better accounts for the categorical nature of the trait. The linear model repeatability was 0.230 (± 0.095. The results obtained in this study support the notion that spontaneous out-of-season ovulatory activity can be considered in the development of a breeding plan for the Chios sheep breed.

  6. Complement: Alive and Kicking Nanomedicines

    DEFF Research Database (Denmark)

    Andersen, Alina Joukainen; Hashemi, S.H.; Andresen, Thomas Lars

    2009-01-01

    Administration of liposome- and polymer-based clinical nanomedicines, as well as many other proposed multifunctional nanoparticles, often triggers hypersensitivity reactions without the involvement of IgE. These anaphylactic reactions are believed to be secondary to activation of the complement s...

  7. Spontaneous food allergy in Was-/-mice occurs independent of FcεRI-mediated mast cell activation.

    Science.gov (United States)

    Lexmond, W S; Goettel, J A; Sallis, B F; McCann, K; Rings, E H H M; Jensen-Jarolim, E; Nurko, S; Snapper, S B; Fiebiger, E

    2017-12-01

    Food allergies are a growing health problem, and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome (WAS) and defined whether spontaneous disease in Was -/- mice recapitulates the pathology of a conventional disease model and/or human food allergy. Comparative ImmunoCAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was -/- mice was compared to an adjuvant-based model in wild-type mice (WT-OVA/alum). Intestinal and systemic anaphylaxis was assessed, and the role of the high-affinity IgE Fc receptor (FcεRI) in allergic sensitization was evaluated using Was -/- Fcer1a -/- mice. Polysensitization to food was detected in both WAS and food-allergic patients which was recapitulated in the Was -/- model. Oral administration of ovalbumin (OVA) in Was -/- mice induced low titers of OVA-specific IgE compared to the WT-OVA/alum model. Irrespectively, 79% of Was -/- mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was -/- mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of FcεRI expression on mast cells (MCs) and basophils. Was -/- mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/FcεRI activation cascade will not affect sensitization to food. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

  8. Spontaneous Brain Activity Did Not Show the Effect of Violent Video Games on Aggression: A Resting-State fMRI Study

    OpenAIRE

    Wei Pan; Wei Pan; Wei Pan; Xuemei Gao; Shuo Shi; Fuqu Liu; Chao Li

    2018-01-01

    A great many of empirical researches have proved that longtime exposure to violent video game can lead to a series of negative effects. Although research has focused on the neural basis of the correlation between violent video game and aggression, little is known whether the spontaneous brain activity is associated with violent video game exposure. To address this question, we measured the spontaneous brain activity using resting-state functional magnetic resonance imaging (fMRI). We used the...

  9. A high-fat diet rich in corn oil reduces spontaneous locomotor activity and induces insulin resistance in mice.

    Science.gov (United States)

    Wong, Chi Kin; Botta, Amy; Pither, Jason; Dai, Chuanbin; Gibson, William T; Ghosh, Sanjoy

    2015-04-01

    Over the last few decades, polyunsaturated fatty acid (PUFA), especially n-6 PUFA, and monounsaturated fatty acid content in 'Western diets' has increased manyfold. Such a dietary shift also parallels rising sedentary behavior and diabetes in the Western world. We queried if a shift in dietary fats could be linked to physical inactivity and insulin insensitivity in mice. Eight-week old female C57/Bl6 mice were fed either high-fat (HF) diets [40% energy corn oil (CO) or isocaloric olive oil (OO) diets] or chow (n=10/group) for 6 weeks, followed by estimation of spontaneous locomotor activity, body composition and in vivo metabolic outcomes. Although lean mass and resting energy expenditure stayed similar in both OO- and CO-fed mice, only CO-fed mice demonstrated reduced spontaneous locomotor activity. Such depressed activity in CO-fed mice was accompanied by a lower respiratory ratio, hyperinsulinemia and impaired glucose disposal following intraperitoneal glucose tolerance and insulin tolerance tests compared to OO-fed mice. Unlike the liver, where both HF diets increased expression of fat oxidation genes like PPARs, the skeletal muscle of CO-fed mice failed to up-regulate such genes, thereby supporting the metabolic insufficiencies observed in these mice. In summary, this study demonstrates a specific contribution of n-6 PUFA-rich oils like CO to the loss of spontaneous physical activity and insulin sensitivity in mice. If these data hold true for humans, this study could provide a novel link between recent increases in dietary n-6 PUFA to sedentary behavior and the development of insulin resistance in the Western world. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Protection of host cells by complement regulators

    Science.gov (United States)

    Schmidt, Christoph Q.; Lambris, John D.; Ricklin, Daniel

    2017-01-01

    Summary The complement cascade is an ancient immune-surveillance system that not only provides protection from pathogen invasion but has also evolved to participate in physiological processes to maintain tissue homeostasis. The alternative pathway (AP) of complement activation is the evolutionarily oldest part of this innate immune cascade. It is unique in that it is continuously activated at a low level and arbitrarily probes foreign, modified-self, and also unaltered self-structures. This indiscriminate activation necessitates the presence of preformed regulators on autologous surfaces to spare self-cells from the undirected nature of AP activation. Although the other two canonical complement activation routes, the classical and lectin pathways, initiate the cascade more specifically through pattern recognition, their activity still needs to be tightly controlled to avoid excessive reactivity. It is the perpetual duty of complement regulators to protect the self from damage inflicted by inadequate complement activation. Here, we review the role of complement regulators as preformed mediators of defense, explain their common and specialized functions, and discuss selected cases in which alterations in complement regulators lead to disease. Finally, rational engineering approaches using natural complement inhibitors as potential therapeutics are highlighted. PMID:27782321

  11. N-terminal prodomain of Pfs230 synthesized using a cell-free system is sufficient to induce complement-dependent malaria transmission-blocking activity.

    Science.gov (United States)

    Tachibana, Mayumi; Wu, Yimin; Iriko, Hideyuki; Muratova, Olga; MacDonald, Nicholas J; Sattabongkot, Jetsumon; Takeo, Satoru; Otsuki, Hitoshi; Torii, Motomi; Tsuboi, Takafumi

    2011-08-01

    The aim of a malaria transmission-blocking vaccine is to block the development of malaria parasites in the mosquito and thus prevent subsequent infection of the human host. Previous studies have demonstrated that the gametocyte/gamete surface protein Pfs230 can induce transmission-blocking immunity and have evaluated Escherichia coli-produced Pfs230 as a transmission-blocking vaccine candidate. In this study, we used the wheat germ cell-free expression system to produce N-terminal fragments of Pfs230 and evaluated the transmission-blocking activity of antisera raised against the recombinant Pfs230 protein. The rabbit antisera reacted to the surface of cultured gametocytes and gametes of the Plasmodium falciparum NF54 line, recognized the 360-kDa form of parasite-produced Pfs230 by Western blot assay, and reduced the infectivity of NF54 parasites to Anopheles stefensi mosquitoes in the presence of complement in a standard membrane feeding assay. Thus, our data demonstrate that the N-terminal pro domain of Pfs230 is sufficient to induce complement-dependent transmission-blocking activity against P. falciparum.

  12. Comparative Analysis of Human and Rodent Brain Primary Neuronal Culture Spontaneous Activity Using Micro-Electrode Array Technology.

    Science.gov (United States)

    Napoli, Alessandro; Obeid, Iyad

    2016-03-01

    Electrical activity in embryonic brain tissue has typically been studied using Micro Electrode Array (MEA) technology to make dozens of simultaneous recordings from dissociated neuronal cultures, brain stem cell progenitors, or brain slices from fetal rodents. Although these rodent neuronal primary culture electrical properties are mostly investigated, it has not been yet established to what extent the electrical characteristics of rodent brain neuronal cultures can be generalized to those of humans. A direct comparison of spontaneous spiking activity between rodent and human primary neurons grown under the same in vitro conditions using MEA technology has never been carried out before and will be described in the present study. Human and rodent dissociated fetal brain neuronal cultures were established in-vitro by culturing on a glass grid of 60 planar microelectrodes neurons under identical conditions. Three different cultures of human neurons were produced from tissue sourced from a single aborted fetus (at 16-18 gestational weeks) and these were compared with seven different cultures of embryonic rat neurons (at 18 gestational days) originally isolated from a single rat. The results show that the human and rodent cultures behaved significantly differently. Whereas the rodent cultures demonstrated robust spontaneous activation and network activity after only 10 days, the human cultures required nearly 40 days to achieve a substantially weaker level of electrical function. These results suggest that rat neuron preparations may yield inferences that do not necessarily transfer to humans. © 2015 Wiley Periodicals, Inc.

  13. Relaxant effect of a novel calcium-activated potassium channel modulator on human myometrial spontaneous contractility in vitro

    DEFF Research Database (Denmark)

    Rosenbaum, S.T.; Larsen, T.; Joergensen, J.C.

    2012-01-01

    Aim: To investigate the effect of 4,5-dichloro-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (NS4591), a novel SK/IK channels positive modulator, on human myometrial activity. Methods: Organ bath studies were performed on myometrial preparations obtained from women undergoing elective caesarean....... Simultaneous vehicle controls were performed for all experiments. The effects of drugs were studied on spontaneous contractions. Results: NS4591 exerted an inhibitory effect on myometrial contractions in muscle strips from non-pregnant and pregnant women. The contractility in non-pregnant and pregnant...

  14. Normal patterns of spontaneous activity are required for correct motor axon guidance and the expression of specific guidance molecules.

    Science.gov (United States)

    Hanson, M Gartz; Landmesser, Lynn T

    2004-09-02

    Rhythmic spontaneous electrical activity occurs in many parts of the developing nervous system, where it plays essential roles in the refinement of neural connections. By blocking or slowing this bursting activity, via in ovo drug applications at precise developmental periods, we show that such activity is also required at much earlier stages for spinal motoneurons to accurately execute their first major dorsal-ventral pathfinding decision. Blockade or slowing of rhythmic bursting activity also prevents the normal expression patterns of EphA4 and polysialic acid on NCAM, which may contribute to the pathfinding errors observed. More prolonged (E2-5) blockade resulted in a downregulation of LIM homeodomain transcription factors, but since this occurred only after the pathfinding errors and alterations in guidance molecules, it cannot have contributed to them.

  15. Complement activation capacity in plasma before and during high-dose prednisolone treatment and tapering in exacerbations of Crohn's disease and ulcerative colitis

    DEFF Research Database (Denmark)

    Zimmermann-Nielsen, Erik; Grønbaek, Henning; Dahlerup, Jens Frederik

    2005-01-01

    BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are characterized by intestinal inflammation mainly caused by a disturbance in the balance between cytokines and increased complement (C) activation. Our aim was to evaluate possible associations between C activation capacity...... and prednisolone treatment. METHODS: Plasma from patients with exacerbations of UC (n = 18) or CD (n = 18) were collected before and during high dose prednisolone treatment (1 mg/kg body weight) and tapering. Friedman's two way analysis of variance, Mann-Whitney U test and Wilcoxon signed-rank sum test were used...... RESULTS: Before treatment, plasma from CD patients showed significant elevations in all C-mediated analyses compared to the values obtained from 38 healthy controls (p UC patients (p

  16. Role of complement in graft rejection after organ transplantation

    NARCIS (Netherlands)

    Bos, Ineke G. A.; ten Berge, Ineke J. M.; Hack, C. Erik

    2002-01-01

    Activation of the complement system may significantly contribute to the inflammatory reaction after solid organ transplantation. In allotransplantation, the complement system may be activated by ischemia/reperfusion and, possibly, by antibodies directed against the graft. In xenotransplantation from

  17. Spontaneous pneumothorax

    Directory of Open Access Journals (Sweden)

    Davari R

    1996-07-01

    Full Text Available A case with bilateral spontaneous pneumothorax was presented. Etiology, mechanism, and treatment were discussed on the review of literature. Spontaneous Pneumothorax is a clinical entity resulting from a sudden non traumatic rupture of the lung. Biach reported in 1880 that 78% of 916 patients with spontaneous pneumothorax had tuberculosis. Kjergaard emphasized 1932 the primary importance of subpleural bleb disease. Currently the clinical spectrum of spontaneous pneumothorax seems to have entered a third era with the recognition of the interstitial lung disease and AIDS as a significant etiology. Standard treatment is including: observation, thoracocentesis, tube thoracostomy. Chemical pleurodesis, bullectomy or wedge resection of lung with pleural abrasion and occasionally pleurectomy. Little information has been reported regarding the efficacy of such treatment in spontaneous pneumothorax secondary to non bleb disease

  18. Self-monitoring of spontaneous physical activity and sedentary behavior to prevent weight regain in older adults

    Science.gov (United States)

    Nicklas, Barbara J.; Gaukstern, Jill E.; Beavers, Kristen M.; Newman, Jill C.; Leng, Xiaoyan; Rejeski, W. Jack

    2014-01-01

    Objective This study determined whether adding a self-regulatory intervention (SRI) focused on self-monitoring of spontaneous physical activity and sedentary behavior to a standard weight loss intervention improved maintenance of lost weight. Design and Methods Older (65–79 yrs), obese (BMI=30–40 kg/m2) adults (n=48) were randomized to a five-month weight loss intervention involving a hypocaloric diet (DIET) and aerobic exercise (EX) with or without the SRI to promote spontaneous physical activity and decrease sedentary behavior (SRI+DIET+EX compared to DIET+EX). Following the weight loss phase, both groups transitioned to self-selected diet and exercise behavior during a 5-month follow-up. Throughout the 10-months, the SRI+DIET+EX group utilized real-time accelerometer feedback for self-monitoring. Results There was an overall group by time effect of the SRI (P physical activity and decrease sedentary behavior, to a standard weight loss intervention enhances successful maintenance of lost weight. PMID:24585701

  19. Growth, serum biochemistry, complement activity, and liver gene expression responses of Pekin ducklings to graded levels of cultured aflatoxin B1.

    Science.gov (United States)

    Chen, X; Horn, N; Cotter, P F; Applegate, T J

    2014-08-01

    A 14-d study was conducted to evaluate the effects of cultured aflatoxin B1 (AFB1) on performance, serum biochemistry, serum natural antibody and complement activity, and hepatic gene expression parameters in Pekin ducklings. A total of 144 male Pekin ducklings were weighed, tagged, and randomly allotted to 4 dietary treatments containing 4 concentrations of AFB1 (0, 0.11, 0.14, and 0.21 mg/kg) from 0 to 14 d of age (6 cages per diet; 6 ducklings per cage). Compared with the control group, there was a 10.9, 31.7, and 47.4% (P feed efficiency was not affected. Increasing concentrations of AFB1 reduced cumulative BW gain and feed intake both linearly and quadratically, and regression equations were developed with r(2) ≥0.73. Feeding 0.11 to 0.21 mg of AFB1/kg reduced serum glucose, creatinine, albumin, total protein, globulin, Ca, P, and creatine phosphokinase linearly, whereas serum urea N, Cl, alkaline phosphatase, and aspartate amino transferase concentrations increased linearly with increasing AFB1 (P complement pathways in the duckling serum when tested by lysis of rabbit, human type O, and horse erythrocytes, and decreased rabbit and horse agglutinins (P feed intake and BW gain decrease approximately 230 and 169 g per duckling from hatch to 14 d; and that AFB1 at very low concentrations can significantly impair liver function and gene expression, and innate immune dynamics in Pekin ducklings. © Poultry Science Association Inc.

  20. Combining task-evoked and spontaneous activity to improve pre-operative brain mapping with fMRI.

    Science.gov (United States)

    Fox, Michael D; Qian, Tianyi; Madsen, Joseph R; Wang, Danhong; Li, Meiling; Ge, Manling; Zuo, Huan-Cong; Groppe, David M; Mehta, Ashesh D; Hong, Bo; Liu, Hesheng

    2016-01-01

    Noninvasive localization of brain function is used to understand and treat neurological disease, exemplified by pre-operative fMRI mapping prior to neurosurgical intervention. The principal approach for generating these maps relies on brain responses evoked by a task and, despite known limitations, has dominated clinical practice for over 20years. Recently, pre-operative fMRI mapping based on correlations in spontaneous brain activity has been demonstrated, however this approach has its own limitations and has not seen widespread clinical use. Here we show that spontaneous and task-based mapping can be performed together using the same pre-operative fMRI data, provide complimentary information relevant for functional localization, and can be combined to improve identification of eloquent motor cortex. Accuracy, sensitivity, and specificity of our approach are quantified through comparison with electrical cortical stimulation mapping in eight patients with intractable epilepsy. Broad applicability and reproducibility of our approach are demonstrated through prospective replication in an independent dataset of six patients from a different center. In both cohorts and every individual patient, we see a significant improvement in signal to noise and mapping accuracy independent of threshold, quantified using receiver operating characteristic curves. Collectively, our results suggest that modifying the processing of fMRI data to incorporate both task-based and spontaneous activity significantly improves functional localization in pre-operative patients. Because this method requires no additional scan time or modification to conventional pre-operative data acquisition protocols it could have widespread utility. Copyright © 2015. Published by Elsevier Inc.

  1. The dynamics of cortical neuronal activity in the first minutes after spontaneous awakening in rats and mice.

    Science.gov (United States)

    Vyazovskiy, Vladyslav V; Cui, Nanyi; Rodriguez, Alexander V; Funk, Chadd; Cirelli, Chiara; Tononi, Giulio

    2014-08-01

    Upon awakening from sleep, a fully awake brain state is not reestablished immediately, but the origin and physiological properties of the distinct brain state during the first min after awakening are unclear. To investigate whether neuronal firing immediately upon arousal is different from the remaining part of the waking episode, we recorded and analyzed the dynamics of cortical neuronal activity in the first 15 min after spontaneous awakenings in freely moving rats and mice. Intracortical recordings of the local field potential and neuronal activity in freely-moving mice and rats. Basic sleep research laboratory. WKY adult male rats, C57BL/6 adult male mice. N/A. In both species the average population spiking activity upon arousal was initially low, though substantial variability in the dynamics of firing activity was apparent between individual neurons. A distinct population of neurons was found that was virtually silent in the first min upon awakening. The overall lower population spiking initially after awakening was associated with the occurrence of brief periods of generalized neuronal silence (OFF periods), whose frequency peaked immediately after awakening and then progressively declined. OFF periods incidence upon awakening was independent of ongoing locomotor activity but was sensitive to immediate preceding sleep/wake history. Notably, in both rats and mice if sleep before a waking episode was enriched in rapid eye movement sleep, the incidence of OFF periods was initially higher as compared to those waking episodes preceded mainly by nonrapid eye movement sleep. We speculate that an intrusion of sleep-like patterns of cortical neuronal activity into the wake state immediately after awakening may account for some of the changes in the behavior and cognitive function typical of what is referred to as sleep inertia. Vyazovskiy VV, Cui N, Rodriguez AV, Funk C, Cirelli C, Tononi G. The dynamics of cortical neuronal activity in the first minutes after

  2. Complement elevation in spinal cord injury.

    Science.gov (United States)

    Rebhun, J; Botvin, J

    1980-05-01

    Laboratory studies revealed an elevated complement in 66% of patients with spinal cord injury. It is postulated that the activated complement may be a component of self-feeding immunological mechanism responsible for the failure of regeneration of a mature mammalian spinal cord. There was no evidence that such an injury had any effect on pre-existing atopy.

  3. Viral mimicry of the complement system

    Indian Academy of Sciences (India)

    Unknown

    et al 2002), hepatitis C virus (Ishii et al 2001) and HIV. (Ezekowitz et al 1989; Saifuddin et al 2000). Activation of the complement system in the absence of proper regulation can lead to virus neutralization. The various mechanisms which are known to inactivate viruses are: (i) neutralization by complement dependant ...

  4. Viral mimicry of the complement system

    Indian Academy of Sciences (India)

    The complement system is a potent innate immune mechanism consisting of cascades of proteins which are designed to fight against and annul intrusion of all the foreign pathogens. Although viruses are smaller in size and have relatively simple structure, they are not immune to complement attack. Thus, activation of the ...

  5. Translational Science: How experimental research has contributed to the understanding of spontaneous Physical Activity and Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Izabelle D Benfato

    2017-05-01

    Full Text Available Abstract Spontaneous physical activity (SPA consists of all daily living activities other than volitional exercise (e.g. sports and fitness-related activities. SPA is an important component of energy expenditure and may protect from overweight and obesity. Little is known about the biological regulation of SPA, but animal researchhas contributedsignificantly to expand our knowledge in this field. Studies in rodents have shown that SPA is influenced by nutrients and volitional exercise. High-fat diet seems to decrease SPA, which contributes to weigh gain. Volitional exercisemayalso reduce SPA, helping to explain the commonly reported low efficiency of exercise to cause weight loss, and highlighting the need to finda volume/intensity of exercise to maximize total daily energy expenditure. Animal studieshave also allowed for the identification of some brain areas and chemical mediatorsinvolved in SPA regulation. These discoveries could enable the development of new therapeutics aiming to enhance SPA.

  6. Spontaneous activity in electromyography may differentiate certain benign lower motor neuron disease forms from amyotrophic lateral sclerosis.

    Science.gov (United States)

    Jokela, Manu E; Jääskeläinen, Satu K; Sandell, Satu; Palmio, Johanna; Penttilä, Sini; Saukkonen, Annamaija; Soikkeli, Raija; Udd, Bjarne

    2015-08-15

    There is limited data on electromyography (EMG) findings in other motor neuron disorders than amyotrophic lateral sclerosis (ALS). We assessed whether the distribution of active denervation detected by EMG, i.e. fibrillations and fasciculations, differs between ALS and slowly progressive motor neuron disorders. We compared the initial EMG findings of 43 clinically confirmed, consecutive ALS patients with those of 41 genetically confirmed Late-onset Spinal Motor Neuronopathy and 14 Spinal and Bulbar Muscular Atrophy patients. Spontaneous activity was more frequently detected in the first dorsal interosseus and deltoid muscles of ALS patients than in patients with the slowly progressive motor neuron diseases. The most important observation was that absent fibrillations in the first dorsal interosseus muscle identified the benign forms with sensitivities of 66%-77% and a specificity of 93%. The distribution of active denervation may help to separate ALS from mimicking disorders at an early stage. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Modulation by endothelin-1 of spontaneous activity and membrane currents of atrioventricular node myocytes from the rabbit heart.

    Directory of Open Access Journals (Sweden)

    Stéphanie C Choisy

    Full Text Available The atrioventricular node (AVN is a key component of the cardiac pacemaker-conduction system. Although it is known that receptors for the peptide hormone endothelin-1 (ET-1 are expressed in the AVN, there is very little information available on the modulatory effects of ET-1 on AVN electrophysiology. This study characterises for the first time acute modulatory effects of ET-1 on AVN cellular electrophysiology.Electrophysiological experiments were conducted in which recordings were made from rabbit isolated AVN cells at 35-37°C using the whole-cell patch clamp recording technique.Application of ET-1 (10 nM to spontaneously active AVN cells led rapidly (within ~13 s to membrane potential hyperpolarisation and cessation of spontaneous action potentials (APs. This effect was prevented by pre-application of the ET(A receptor inhibitor BQ-123 (1 µM and was not mimicked by the ET(B receptor agonist IRL-1620 (300 nM. In whole-cell voltage-clamp experiments, ET-1 partially inhibited L-type calcium current (I(Ca,L and rapid delayed rectifier K(+ current (I(Kr, whilst it transiently activated the hyperpolarisation-activated current (I(f at voltages negative to the pacemaking range, and activated an inwardly rectifying current that was inhibited by both tertiapin-Q (300 nM and Ba(2+ ions (2 mM; each of these effects was sensitive to ET(A receptor inhibition. In cells exposed to tertiapin-Q, ET-1 application did not produce membrane potential hyperpolarisation or immediate cessation of spontaneous activity; instead, there was a progressive decline in AP amplitude and depolarisation of maximum diastolic potential.Acutely applied ET-1 exerts a direct modulatory effect on AVN cell electrophysiology. The dominant effect of ET-1 in this study was activation of a tertiapin-Q sensitive inwardly rectifying K(+ current via ET(A receptors, which led rapidly to cell quiescence.

  8. CSF coccidioides complement fixation

    Science.gov (United States)

    Skip navigation U.S. National Library of Medicine The navigation menu has been collapsed. ... of this page: //medlineplus.gov/ency/article/003526.htm CSF coccidioides complement fixation test To use the sharing features ...

  9. Histoplasma complement fixation

    Science.gov (United States)

    Skip navigation U.S. National Library of Medicine The navigation menu has been collapsed. ... this page: //medlineplus.gov/ency/article/003527.htm Histoplasma complement fixation To use the sharing features on this page, ...

  10. The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification

    DEFF Research Database (Denmark)

    Harboe, Morten; Garred, Peter; Karlstrøm, Ellen

    2009-01-01

    was not observed even at high mannan concentrations since addition of the inhibiting anti-MBL mAb 3F8 completely abolished generation of the terminal C5b-9 complex (TCC). However, selective blockade of AP by anti-factor D inhibited more than 80% of TCC release into the fluid phase after LP activation showing...... that AP amplification is quantitatively responsible for the final effect of initial specific LP activation. TCC generation on the solid phase was distinctly but less inhibited by anti-fD. C2 bypass of the LP pathway could be demonstrated, and AP amplification was also essential during C2 bypass in LP...... as shown by complete inhibition of TCC generation in C2-deficient serum by anti-fD and anti-properdin antibodies. In conclusion, the down-stream effect of LP activation depends strongly on AP amplification in normal human serum and in the C2 bypass pathway....

  11. Effects of experimentally increased in ovo lysozyme on egg hatchability, chicks complement activity, and phenotype in a precocial bird

    Czech Academy of Sciences Publication Activity Database

    Javůrková, Veronika; Krkavcová, E.; Kreisinger, J.; Hyršl, P.; Hyánková, L.

    2015-01-01

    Roč. 323, č. 8 (2015), s. 497-505 ISSN 1932-5223 R&D Projects: GA ČR(CZ) GAP506/12/2472; GA MŠk EE2.3.20.0303 Institutional support: RVO:68081766 Keywords : gram-negative bacteria * barn swallow nestlings * white proteins * embryonic development * divergent selection * albumin removal * japanese-quail * avian egg * antimicrobial proteins * antibacterial activity Subject RIV: EG - Zoology Impact factor: 1.226, year: 2015

  12. Kinematic analysis of preterm newborns' spontaneous movements for postural activity assessment.

    Science.gov (United States)

    Halek, Jan; Muckova, Anita; Svoboda, Zdenek; Janura, Miroslav; Marikova, Jana; Horakova, Katerina; Kantor, Lumir; Nemcova, Nina

    2015-12-01

    The objectives of this pilot study were to assess the potential use of 3D videography for analyzing the motion of the body center of mass (COM) in newborns and to determine differences in spontaneous movements between preterm and full-term infants. The group comprised 10 preterm newborns (gestational age at birth between 26 and 37 weeks; birth weight 800 to 2960 g; gestational age at the time of examination 34 to 39 weeks) and 10 full-term infants (gestational week 38 to 41; birth weight 2810 to 4360 g). To determine the range of motion of the COM, 3D videography was used (2 cameras, 25 Hz). When recording their movements, the infants were in the supine position, calm and awake. The recordings were processed using the APAS software. Selected points on the body were marked to obtain data for calculating the basic parameters of COM trajectories. The range of motion of the COM in both craniocaudal and anteroposterior directions was significantly greater in premature infants (P preterm babies. This was also valid for the velocity of motion of the COM in the craniocaudal direction (P preterm infants. Basic kinematic characteristics of the motion of the COM (range, variability, velocity) are greater in preterm infants.

  13. Etiology of spontaneous pneumothorax in 105 HIV-infected patients without highly active antiretroviral therapy

    International Nuclear Information System (INIS)

    Rivero, Antonio; Perez-Camacho, Ines; Lozano, Fernando; Santos, Jesus; Camacho, Angela; Serrano, Ascencion; Cordero, Elisa; Jimenez, Francisco; Torres-Tortosa, Manuel; Torre-Cisneros, Julian

    2009-01-01

    Introduction: Spontaneous pneumothorax (SP) is a frequent complication in non-treated HIV-infected patients as a complication of opportunistic infections and tumours. Objective: To analyse the aetiology of SP in non-treated HIV patients. Patients and methods: Observational study of SP cases observed in a cohort of 9831 of non-treated HIV-infected patients attended in seven Spanish hospitals. Results: 105 patients (1.06%) developed SP. The aetiological cause was identified in 89 patients. The major causes identified were: bacterial pneumonia (36 subjects, 34.3%); Pneumocystis jiroveci pneumonia (PJP) (31 patients, 29.5%); and pulmonary tuberculosis (17 cases, 15.2%). The most common cause of SP in drugs users was bacterial pneumonia (40%), whereas PJP was more common (65%) in sexual transmitted HIV-patients. The most common cause of bilateral SP was PJP (62.5%) whereas unilateral SP was most commonly associated with bacterial pneumonia (40.2%). The most common cause of SP in patients with a CD4+ lymphocyte count >200 cells/ml and in patients without AIDS criteria was bacterial pneumonia. PJP was the more common cause in patients with a CD4+ lymphocyte count <200 cells/ml or with AIDS. Conclusion: The incidence of SP in non-treated HIV-infected patients was 1.06%. The aetiology was related to the patients risk practices and to their degree of immunosuppression. Bacterial pneumonia was the most common cause of SP.

  14. Synaptotagmin I regulates patterned spontaneous activity in the developing rat retina via calcium binding to the C2AB domains.

    Directory of Open Access Journals (Sweden)

    Chung-Wei Chiang

    Full Text Available BACKGROUND: In neonatal binocular animals, the developing retina displays patterned spontaneous activity termed retinal waves, which are initiated by a single class of interneurons (starburst amacrine cells, SACs that release neurotransmitters. Although SACs are shown to regulate wave dynamics, little is known regarding how altering the proteins involved in neurotransmitter release may affect wave dynamics. Synaptotagmin (Syt family harbors two Ca(2+-binding domains (C2A and C2B which serve as Ca(2+ sensors in neurotransmitter release. However, it remains unclear whether SACs express any specific Syt isoform mediating retinal waves. Moreover, it is unknown how Ca(2+ binding to C2A and C2B of Syt affects wave dynamics. Here, we investigated the expression of Syt I in the neonatal rat retina and examined the roles of C2A and C2B in regulating wave dynamics. METHODOLOGY/PRINCIPAL FINDINGS: Immunostaining and confocal microscopy showed that Syt I was expressed in neonatal rat SACs and cholinergic synapses, consistent with its potential role as a Ca(2+ sensor mediating retinal waves. By combining a horizontal electroporation strategy with the SAC-specific promoter, we specifically expressed Syt I mutants with weakened Ca(2+-binding ability in C2A or C2B in SACs. Subsequent live Ca(2+ imaging was used to monitor the effects of these molecular perturbations on wave-associated spontaneous Ca(2+ transients. We found that targeted expression of Syt I C2A or C2B mutants in SACs significantly reduced the frequency, duration, and amplitude of wave-associated Ca(2+ transients, suggesting that both C2 domains regulate wave temporal properties. In contrast, these C2 mutants had relatively minor effects on pairwise correlations over distance for wave-associated Ca(2+ transients. CONCLUSIONS/SIGNIFICANCE: Through Ca(2+ binding to C2A or C2B, the Ca(2+ sensor Syt I in SACs may regulate patterned spontaneous activity to shape network activity during development

  15. GLUCOCORTICOSTEROIDS' EFFECT UPON THE COMPLEMENT LEVEL

    Directory of Open Access Journals (Sweden)

    Voja Pavlovic

    2001-03-01

    Full Text Available The effect of high doses of cortisol upon the level of the overall complements'hemolytic activity and particular complements' components is studies. The experimentsinvolved guinea pigs of male sex of the body mass from 300 to 400 g, namelythose that have not been treated by anything so far. The doses of hydrocortisone(Hemofarm DD were also used for the experiment. The overall complements'activity was determined by testing the capabilities of a series of various solutions ofthe guinea pigs' serum to separate sheep erythrocytes that were made sensitive byrabbit anti-erythrocyte antibodies. The determination of the C1, C2, C3 and C4complements' components was done by the method of the quantitative diffusion ofthe radial type by using the Partigen blocks Behringwerke AG. The series comprised25 guinea pigs of male sex. The low cortisol level rapidly increase the overallhemolytic activity of the complements of the C1 est erase concentration. Along withthe cortisol dose increase the overall hemolytic complements' activity is dropping aswell as that of the C1, C2, C3 and C4 complements' components.

  16. Crosstalk between Complement and Toll-like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia-Reperfusion Injury

    NARCIS (Netherlands)

    Damman, Jeffrey; Daha, Mohamed R.; van Son, Willem J.; Leuvenink, Henri G.; Ploeg, Rutger J.; Seelen, Marc A.

    Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen

  17. Depletion of the Third Complement Component Ameliorates Age-Dependent Oxidative Stress and Positively Modulates Autophagic Activity in Aged Retinas in a Mouse Model.

    Science.gov (United States)

    Rogińska, Dorota; Kawa, Miłosz P; Pius-Sadowska, Ewa; Lejkowska, Renata; Łuczkowska, Karolina; Wiszniewska, Barbara; Kaarniranta, Kai; Paterno, Jussi J; Schmidt, Christian A; Machaliński, Bogusław; Machalińska, Anna

    2017-01-01

    The aim of the study was to investigate the influence of complement component C3 global depletion on the biological structure and function of the aged retina. In vivo morphology (OCT), electrophysiological function (ERG), and the expression of selected oxidative stress-, apoptosis-, and autophagy-related proteins were assessed in retinas of 12-month-old C3-deficient and WT mice. Moreover, global gene expression in retinas was analyzed by RNA arrays. We found that the absence of active C3 was associated with (1) alleviation of the age-dependent decrease in retinal thickness and gradual deterioration of retinal bioelectrical function, (2) significantly higher levels of antioxidant enzymes (catalase and glutathione reductase) and the antiapoptotic survivin and Mcl-1/Bak dimer, (3) lower expression of the cellular oxidative stress marker-4HNE-and decreased activity of proapoptotic caspase-3, (4) ameliorated retinal autophagic activity with localization of ubiquitinated protein conjugates commonly along the retinal pigment epithelium (RPE) layer, and (5) significantly increased expression of several gene sets associated with maintenance of the physiological functions of the neural retina. Our findings shed light on mechanisms of age-related retinal alterations by identifying C3 as a potential therapeutic target for retinal aging.

  18. Depletion of the Third Complement Component Ameliorates Age-Dependent Oxidative Stress and Positively Modulates Autophagic Activity in Aged Retinas in a Mouse Model

    Directory of Open Access Journals (Sweden)

    Dorota Rogińska

    2017-01-01

    Full Text Available The aim of the study was to investigate the influence of complement component C3 global depletion on the biological structure and function of the aged retina. In vivo morphology (OCT, electrophysiological function (ERG, and the expression of selected oxidative stress-, apoptosis-, and autophagy-related proteins were assessed in retinas of 12-month-old C3-deficient and WT mice. Moreover, global gene expression in retinas was analyzed by RNA arrays. We found that the absence of active C3 was associated with (1 alleviation of the age-dependent decrease in retinal thickness and gradual deterioration of retinal bioelectrical function, (2 significantly higher levels of antioxidant enzymes (catalase and glutathione reductase and the antiapoptotic survivin and Mcl-1/Bak dimer, (3 lower expression of the cellular oxidative stress marker—4HNE—and decreased activity of proapoptotic caspase-3, (4 ameliorated retinal autophagic activity with localization of ubiquitinated protein conjugates commonly along the retinal pigment epithelium (RPE layer, and (5 significantly increased expression of several gene sets associated with maintenance of the physiological functions of the neural retina. Our findings shed light on mechanisms of age-related retinal alterations by identifying C3 as a potential therapeutic target for retinal aging.

  19. Surface-bound capsular polysaccharide of type Ia group B Streptococcus mediates C1 binding and activation of the classic complement pathway

    International Nuclear Information System (INIS)

    Levy, N.J.; Kasper, D.L.

    1986-01-01

    The role of surface-bound type Ia group B Streptococcus (GBS) capsular polysaccharide in anti-body-independent binding of C1 and activation of the classic component pathway was investigated. In a radiolabeled bacterial-polymorphonuclear leukocyte (PMN) association assay, a measure of bacterial opsonization, preincubation of 3 H-type Ia GBS with purified F(ab') 2 to the organism blocked the association of the bacteria with PMN', and the inhibitory effect was dose dependent. The specificity of F(ab') 2 blocking was shown after adsorption of F(ab') 2 with type Ia polysaccharide-sensitized erythrocytes. Polysaccharide-adsorbed F(ab') 2 had a 70% decrease in ability to block the association of bacteria with PMN. Neuraminidase digestion removed 80% of the terminal sialic acid residues from the native polysaccharide. These neuraminidase-digested organisms had a 72% decrease in binding and transfer of purified C1 compared with non-enzyme-treated organisms. Type Ia capsular polysaccharide bound to sheep erythrocytes promoted classic complement pathway-mediated hemolysis of the cells. The role of C1 inhibitor (INH) in modulation of C1 activation by the organisms was investigated. The possibility existed that the C1 INH could be bound by the bacteria, allowing C1 activation to occur in the fluid phase. The inhibitor was purified from human serum, and its activity was measured before and after incubation with type Ia GBS. The organisms had no effect on C1 INH activity. Thus surface-bound capsular polysacchardie of type Ia GBS mediates C1 binding and classic pathway activation, and this does not involve the C1 INH

  20. Study of spontaneous deposition of 210Po on various metals and application for activity assessment in cigarette smoke

    International Nuclear Information System (INIS)

    Karali, T.; Oelmez, S.; Yener, G.

    1996-01-01

    210 Po in environmental samples has been accumulated on various metals using the chemical electrodeposition technique. The 210 Po was deposited spontaneously on metal discs after decomposition of the sample in HCl acid and then measured using a ZnS(Ag)α-particle detector. Silver was observed to have the highest deposition efficiency when 210 Po deposition on different metals was studied. Copper discs were used in the application of activity assessment in cigarette smoke as this is more available and more economical although silver has a higher efficiency than that of other materials examined. The technique is applied for the analysis of 210 Po in tobacco, ash and butt for several brands of imported and domestic cigarettes smoked in Turkey. (Author)

  1. Regional homogeneity of spontaneous brain activity in adult patients with obsessive-compulsive disorder before and after cognitive behavioural therapy.

    Science.gov (United States)

    Yang, Xiang-Yun; Sun, Jing; Luo, Jia; Zhong, Zhao-Xi; Li, Ping; Yao, Shu-Min; Xiong, Hong-Fang; Huang, Fang-Fang; Li, Zhan-Jiang

    2015-12-01

    Cognitive behavioural therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD). Several neuroimaging studies have explored alterations of brain function in OCD patients as they performed tasks after CBT. However, the effects of CBT on the neural activityin OCD during rest remain unknown. Therefore, we investigated changes in regional homogeneity (ReHo) in OCD patients before and after CBT. Twenty-two OCD patients and 22 well-matched healthy controls participated in the resting-state functional magnetic resonance imaging scans. We compared differences in ReHo between the OCD and control groups before treatment and investigated the changes of ReHo in 17 OCD patients who responded to CBT. Compared to healthy controls, OCD patients exhibited higher ReHo in the right orbitofrontal cortex (OFC), bilateral middle frontal cortex, right precuneus, left cerebellum, and vermis, as well as lower ReHo in the bilateral caudate, right calcarine, right posterior cingulate cortex, and right middle temporal cortex. Along with the clinical improvement in OCD patients after CBT, we found decreased ReHo in the right OFC, bilateral middle frontal cortex, left cerebellum and vermis, and increased ReHo in the left caudate. Improvement of OCD symptoms was significantly correlated with the changed ReHo in the right OFC and left cerebellum. Although these findings are preliminary and need to be replicated in larger samples, they indicate the presence of abnormal spontaneous brain activity of the prefrontal-striatal-cerebellar circuit in OCD patients, and provide evidence that CBT can selectively modulate the spontaneous brain activity of this circuit in OCD patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Spontaneous flow in polar active fluids: the effect of a phenomenological self propulsion-like term.

    Science.gov (United States)

    Bonelli, Francesco; Gonnella, Giuseppe; Tiribocchi, Adriano; Marenduzzo, Davide

    2016-01-01

    We present hybrid lattice Boltzmann simulations of extensile and contractile active fluids where we incorporate phenomenologically the tendency of active particles such as cell and bacteria, to move, or swim, along the local orientation. Quite surprisingly, we show that the interplay between alignment and activity can lead to completely different results, according to geometry (periodic boundary conditions or confinement between flat walls) and nature of the activity (extensile or contractile). An interesting generic outcome is that the alignment interaction can transform stationary active patterns into continuously moving ones: the dynamics of these evolving patterns can be oscillatory or chaotic according to the strength of the alignment term. Our results suggest that flow-polarisation alignment can have important consequences on the collective dynamics of active fluids and active gel.

  3. Population calcium imaging of spontaneous respiratory and novel motor activity in the facial nucleus and ventral brainstem in newborn mice.

    Science.gov (United States)

    Persson, Karin; Rekling, Jens C

    2011-05-15

    The brainstem contains rhythm and pattern forming circuits, which drive cranial and spinal motor pools to produce respiratory and other motor patterns. Here we used calcium imaging combined with nerve recordings in newborn mice to reveal spontaneous population activity in the ventral brainstem and in the facial nucleus. In Fluo-8AM loaded brainstem-spinal cord preparations, respiratory activity on cervical nerves was synchronized with calcium signals at the ventrolateral brainstem surface. Individual ventrolateral neurons at the level of the parafacial respiratory group showed perfect or partial synchrony with respiratory nerve bursts. In brainstem-spinal cord preparations, cut at the level of the mid-facial nucleus, calcium signals were recorded in the dorsal, lateral and medial facial subnuclei during respiratory activity. Strong activity initiated in the dorsal subnucleus, followed by activity in lateral and medial subnuclei. Whole-cell recordings from facial motoneurons showed weak respiratory drives, and electrical field potential recordings confirmed respiratory drive to particularly the dorsal and lateral subnuclei. Putative facial premotoneurons showed respiratory-related calcium signals, and were predominantly located dorsomedial to the facial nucleus. A novel motor activity on facial, cervical and thoracic nerves was synchronized with calcium signals at the ventromedial brainstem extending from the level of the facial nucleus to the medulla–spinal cord border. Cervical dorsal root stimulation induced similar ventromedial activity. The medial facial subnucleus showed calcium signals synchronized with this novel motor activity on cervical nerves, and cervical dorsal root stimulation induced similar medial facial subnucleus activity. In conclusion, the dorsal and lateral facial subnuclei are strongly respiratory-modulated, and the brainstem contains a novel pattern forming circuit that drives the medial facial subnucleus and cervical motor pools.

  4. Complement in immune and inflammatory disorders: pathophysiological mechanisms

    Science.gov (United States)

    Ricklin, Daniel; Lambris, John D.

    2013-01-01

    While acute or chronic inflammation is a common component of many clinical disorders, the underlying processes can be highly distinct. In recent years, the complement system has been associated with a growing number of immunological and inflammatory conditions that include degenerative diseases, cancer and transplant rejection. It becomes evident that excessive activation or insufficient control of complement activation on host cells can cause an immune imbalance that may fuel a vicious cycle between complement, inflammatory cells and tissue damage that exacerbates clinical complications. Although the exact involvement of complement needs to be carefully investigated for each disease, therapeutic modulation of complement activity emerges as attractive target for upstream inhibition of inflammatory processes. This review provides an update about the functional and collaborative capabilities of complement, highlights major disease areas with known complement contribution, and indicates the potential for complement as focal point in immunomodulatory strategies for treating inflammatory diseases. PMID:23564577

  5. Antiglycopeptide Mouse Monoclonal Antibody LpMab-21 Exerts Antitumor Activity Against Human Podoplanin Through Antibody-Dependent Cellular Cytotoxicity and Complement-Dependent Cytotoxicity.

    Science.gov (United States)

    Kato, Yukinari; Kunita, Akiko; Fukayama, Masashi; Abe, Shinji; Nishioka, Yasuhiko; Uchida, Hiroaki; Tahara, Hideaki; Yamada, Shinji; Yanaka, Miyuki; Nakamura, Takuro; Saidoh, Noriko; Yoshida, Kanae; Fujii, Yuki; Honma, Ryusuke; Takagi, Michiaki; Ogasawara, Satoshi; Murata, Takeshi; Kaneko, Mika K

    2017-02-01

    The interaction between podoplanin (PDPN) and C-type lectin-like receptor 2 (CLEC-2) is involved in tumor malignancy. We have established many monoclonal antibodies (mAbs) against human podoplanin using the cancer-specific mAb (CasMab) technology. LpMab-21, one of the mouse antipodoplanin mAbs, is of the IgG 2a subclass, and its minimum epitope was determined to be Thr76-Arg79 of the human podoplanin. Importantly, sialic acid is linked to Thr76; therefore, LpMab-21 is an antiglycopeptide mAb (GpMab). In this study, we investigated whether LpMab-21 shows antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against human podoplanin-expressing cancer cell lines in vitro and also studied its antitumor activities using a xenograft model. LpMab-21 showed high ADCC and CDC activities against not only podoplanin-expressing Chinese hamster ovary cells but also LN319 glioblastoma cells and PC-10 lung cancer cells, both of which endogenously express podoplanin. Furthermore, LpMab-21 decreased tumor growth in vivo, indicating that LpMab-21 could be useful for antibody therapy against human podoplanin-expressing cancers.

  6. Complement and thrombosis in the antiphospholipid syndrome.

    Science.gov (United States)

    Oku, Kenji; Nakamura, Hiroyuki; Kono, Michihiro; Ohmura, Kazumasa; Kato, Masaru; Bohgaki, Toshiyuki; Horita, Tetsuya; Yasuda, Shinsuke; Amengual, Olga; Atsumi, Tatsuya

    2016-10-01

    The involvement of complement activation in the pathophysiology of antiphospholipid syndrome (APS) was first reported in murine models of antiphospholipid antibody (aPL)-related pregnancy morbidities. We previously reported that complement activation is prevalent and may function as a source of procoagulant cell activation in the sera of APS patients. Recently, autoantibodies against C1q, a component of complement 1, were reported to be correlated with complement activation in systemic lupus erythematosus. These antibodies target neoepitopes of deformed C1q bound to various molecules (i.e., anionic phospholipids) and induce accelerated complement activation. We found that anti-C1q antibodies are more frequently detected in primary APS patients than in control patients and in refractory APS patients with repeated thrombotic events. The titer of anti-C1q antibodies was significantly higher in refractory APS patients than in APS patients without flare. The binding of C1q to anionic phospholipids may be associated with the surge in complement activation in patients with anti-C1q antibodies when triggered by 'second-hit' biological stressors such as infection. Such stressors will induce overexpression of anionic phospholipids, with subsequent increases in deformed C1q that is targeted by anti-C1q antibodies. Copyright © 2016. Published by Elsevier B.V.

  7. Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension.

    Science.gov (United States)

    Iliescu, Radu; Tudorancea, Ionut; Irwin, Eric D; Lohmeier, Thomas E

    2013-10-01

    The sensitivity of baroreflex control of heart rate is depressed in subjects with obesity hypertension, which increases the risk for cardiac arrhythmias. The mechanisms are not fully known, and there are no therapies to improve this dysfunction. To determine the cardiovascular dynamic effects of progressive increases in body weight leading to obesity and hypertension in dogs fed a high-fat diet, 24-h continuous recordings of spontaneous fluctuations in blood pressure and heart rate were analyzed in the time and frequency domains. Furthermore, we investigated whether autonomic mechanisms stimulated by chronic baroreflex activation and renal denervation-current therapies in patients with resistant hypertension, who are commonly obese-restore cardiovascular dynamic control. Increases in body weight to ∼150% of control led to a gradual increase in mean arterial pressure to 17 ± 3 mmHg above control (100 ± 2 mmHg) after 4 wk on the high-fat diet. In contrast to the gradual increase in arterial pressure, tachycardia, attenuated chronotropic baroreflex responses, and reduced heart rate variability were manifest within 1-4 days on high-fat intake, reaching 130 ± 4 beats per minute (bpm) (control = 86 ± 3 bpm) and ∼45% and baroreflex activation and renal denervation abolished the hypertension. However, only baroreflex activation effectively attenuated the tachycardia and restored cardiac baroreflex sensitivity and heart rate variability. These findings suggest that baroreflex activation therapy may reduce the risk factors for cardiac arrhythmias as well as lower arterial pressure.

  8. To Take the Stairs or Not to Take the Stairs? Employing the Reflective–Impulsive Model to Predict Spontaneous Physical Activity

    Directory of Open Access Journals (Sweden)

    Marcos Daou

    2017-09-01

    Full Text Available The reflective–impulsive model (RIM has been employed to explain various health behaviors. The present study used RIM to predict a spontaneous physical activity behavior. Specifically, 107 participants (75 females; Mage = 20.6 years, SD = 1.92 years completed measures of (1 reflections about spontaneous physical activity, as indexed by self-report questionnaire; (2 impulse toward physical activity, as indexed by the manikin task; and (3 (state self-control, as indexed by the Stroop task. The dependent variable was whether participants took the stairs or the elevator to the study laboratory. Results revealed reflections toward spontaneous physical activity positively predicted stair-taking. Further, a significant impulse toward physical activity × self-control interaction was observed. This interaction revealed that participants with high self-control who had a high impulse toward PA were more likely to take the stairs than their counterparts with a low impulse toward PA, whereas the opposite was the case for participants with low self-control. However, the impulse × self-control interaction was not significant when employing a self-report measure of trait self-control. Thus, RIM may be a good framework with which to consider spontaneous physical activity, but careful consideration must be given when examining variables within RIM (e.g., the boundary condition of self-control.

  9. Spontaneous and cytokine induced expression and activity of matrix metalloproteinases in human colonic epithelium

    DEFF Research Database (Denmark)

    Pedersen, G; Saermark, T; Kirkegaard, T

    2009-01-01

    levels in cells from inflamed IBD mucosa. MMP-2 and -8 mRNA were expressed inconsistently and MMP-11, -13 and -14 mRNA undetectable. Proteolytic MMP activity was detected in CEC supernatants and the level was increased significantly in inflamed IBD epithelium. The enzyme activity was inhibited strongly...

  10. Spontaneous cluster activity in the inferior olivary nucleus in brainstem slices from postnatal mice

    DEFF Research Database (Denmark)

    Rekling, Jens C; Reveles Jensen, Kristian; Jahnsen, Henrik

    2012-01-01

    A distinctive property of the cerebellar system is olivocerebellar modules, where synchronized electrical activity in neurons in the inferior olivary nucleus (IO) evokes organized activity in the cerebellar cortex. However, the exact function of these modules, and how they are developed, is still...

  11. Expression, purification, cocrystallization and preliminary crystallographic analysis of sucrose octasulfate/human complement regulator factor H SCRs 6–8

    Energy Technology Data Exchange (ETDEWEB)

    Prosser, Beverly E.; Johnson, Steven; Roversi, Pietro [The Sir William Dunn School of Pathology, The University of Oxford, South Parks Road, Oxford OX1 3RE (United Kingdom); Clark, Simon J. [Faculty of Life Sciences, Manchester University, Michael Smith Building, Oxford Road, Manchester M13 9PT (United Kingdom); Tarelli, Edward [Medical Biomics Centre, St George’s, University of London, Cranmer Terrace, London SW17 0RE (United Kingdom); Sim, Robert B. [The MRC Immunochemistry Unit, The University of Oxford, South Parks Road, Oxford OX1 3RE (United Kingdom); Day, Antony J. [Faculty of Life Sciences, Manchester University, Michael Smith Building, Oxford Road, Manchester M13 9PT (United Kingdom); Lea, Susan M., E-mail: susan.lea@bnc.ox.ac.uk [The Sir William Dunn School of Pathology, The University of Oxford, South Parks Road, Oxford OX1 3RE (United Kingdom)

    2007-06-01

    The crystallization of human complement regulator FH-678{sub 402H} with a glycosaminoglycan analogue is described. Human plasma protein complement factor H (FH) is an inhibitor of the spontaneously activated alternative complement pathway. An allotypic variant of FH, 402His, has been associated with age-related macular degeneration, the leading cause of blindness in the elderly. Crystals of FH domains 6–8 (FH678) containing 402His have been grown in the presence of a polyanionic sucrose octasulfate ligand (an analogue of the natural glycosaminoglycan ligands of FH) using both native and selenomethionine-derivatized protein. Native data sets diffracting to 2.3 Å and SeMet data sets of up to 2.8 Å resolution have been collected. An anomalous difference Patterson map reveals self- and cross-peaks from two incorporated Se atoms. The corresponding selenium substructure has been solved.

  12. Effect of distance vision and refractive error on the spontaneous eye blink activity in human subjects in primary eye gaze.

    Science.gov (United States)

    Doughty, Michael J

    2018-04-04

    To evaluate whether visual target character and visibility affects spontaneous eye blink rate (SEBR) in primary eye gaze and silence. Video recordings were made of young healthy adults who were either emmetropic (n=32) or who wore spectacles for refractive error (range -4.75D and +4.50D (n=31). Emmetropes had 5min recordings made whilst seated and looking towards a distant whiteboard. For spectacle wearers, recordings were made whilst looking towards the whiteboard with a 35mm sized cross, and repeated after spectacle removal. The average number of eye blinks over 5min was assessed, and its intra-subject variability as the coefficient of variation (COV). Over 5min without a distance target, an average SEBR of 10.4blinks/min was observed in emmetropes with a of COV=38.1%, and a significant increase in SEBR over the 5th minute to 13.6blinks/min. Hyperopes being asked to look towards a distant target showed the essentially same blinking rate of 11.1/min with or without spectacle wear with the intra-subject variability (COV) being 21.3%. Myopic subjects showed a slightly higher SEBR if looking towards a target without their spectacles (12.4 vs. 11.0blinks/min), with the COV being 18.8%. The studies indicate that some form of visual target could be useful to promote constancy of spontaneous eye blink activity over time, but that a distance visual target (when provided) does not need to be seen clearly. Crown Copyright © 2018. Published by Elsevier España, S.L.U. All rights reserved.

  13. MHC class I-restricted determinants on the glutamic acid decarboxylase 65 molecule induce spontaneous CTL activity.

    Science.gov (United States)

    Quinn, A; McInerney, M F; Sercarz, E E

    2001-08-01

    CD4(+) T cell responses to glutamic acid decarboxylase (GAD65) spontaneously arise in nonobese diabetic (NOD) mice before the onset of insulin-dependent diabetes mellitus (IDDM) and may be critical to the pathogenic process. However, since both CD4(+) and CD8(+) T cells are involved in autoimmune diabetes, we sought to determine whether GAD65-specific CD8(+) T cells were also present in prediabetic NOD mice and contribute to IDDM. To refine the analysis, putative K(d)-binding determinants that were proximal to previously described dominant Th determinants (206-220 and 524-543) were examined for their ability to elicit cytolytic activity in young NOD mice. Naive NOD spleen cells stimulated with GAD65 peptides 206-214 (p206) and 546-554 (p546) produced IFN-gamma and showed Ag-specific CTL responses against targets pulsed with homologous peptide. Conversely, several GAD peptides distal to the Th determinants, and control K(d)-binding peptides did not induce similar responses. Spontaneous CTL responses to p206 and p546 were mediated by CD8(+) T cells that are capable of lysing GAD65-expressing target cells, and p546-specific T cells transferred insulitis to NOD.scid mice. Young NOD mice pretreated with p206 and p546 showed reduced CTL responses to homologous peptides and a delay in the onset of IDDM. Thus, MHC class I-restricted responses to GAD65 may provide an inflammatory focus for the generation of islet-specific pathogenesis and beta cell destruction. This report reveals a potential therapeutic role for MHC class I-restricted peptides in treating autoimmune disease and revisits the notion that the CD4- and CD8-inducing determinants on some molecules may benefit from a proximal relationship.

  14. Correlation properties of spontaneous motor activity in healthy infants: a new computer-assisted method to evaluate neurological maturation.

    Science.gov (United States)

    Waldmeier, Sandra; Grunt, Sebastian; Delgado-Eckert, Edgar; Latzin, Philipp; Steinlin, Maja; Fuhrer, Katharina; Frey, Urs

    2013-06-01

    Qualitative assessment of spontaneous motor activity in early infancy is widely used in clinical practice. It enables the description of maturational changes of motor behavior in both healthy infants and infants who are at risk for later neurological impairment. These assessments are, however, time-consuming and are dependent upon professional experience. Therefore, a simple physiological method that describes the complex behavior of spontaneous movements (SMs) in infants would be helpful. In this methodological study, we aimed to determine whether time series of motor acceleration measurements at 40-44 weeks and 50-55 weeks gestational age in healthy infants exhibit fractal-like properties and if this self-affinity of the acceleration signal is sensitive to maturation. Healthy motor state was ensured by General Movement assessment. We assessed statistical persistence in the acceleration time series by calculating the scaling exponent α via detrended fluctuation analysis of the time series. In hand trajectories of SMs in infants we found a mean α value of 1.198 (95 % CI 1.167-1.230) at 40-44 weeks. Alpha changed significantly (p = 0.001) at 50-55 weeks to a mean of 1.102 (1.055-1.149). Complementary multilevel regression analysis confirmed a decreasing trend of α with increasing age. Statistical persistence of fluctuation in hand trajectories of SMs is sensitive to neurological maturation and can be characterized by a simple parameter α in an automated and observer-independent fashion. Future studies including children at risk for neurological impairment should evaluate whether this method could be used as an early clinical screening tool for later neurological compromise.

  15. Spontaneous deregulation

    NARCIS (Netherlands)

    Edelman, Benjamin; Geradin, Damien

    Platform businesses such as Airbnb and Uber have risen to success partly by sidestepping laws and regulations that encumber their traditional competitors. Such rule flouting is what the authors call “spontaneous private deregulation,” and it’s happening in a growing number of industries. The authors

  16. Spontaneous and cytokine induced expression and activity of matrix metalloproteinases in human colonic epithelium

    DEFF Research Database (Denmark)

    Pedersen, G; Saermark, T; Kirkegaard, T

    2009-01-01

    levels in cells from inflamed IBD mucosa. MMP-2 and -8 mRNA were expressed inconsistently and MMP-11, -13 and -14 mRNA undetectable. Proteolytic MMP activity was detected in CEC supernatants and the level was increased significantly in inflamed IBD epithelium. The enzyme activity was inhibited strongly......Matrix metalloproteinases (MMPs) have been implicated in tissue damage associated with inflammatory bowel disease (IBD).As the role of the intestinal epithelium in this process is unknown, we determined MMP expression and enzyme activity in human colonic epithelial cells (CEC). MMP mRNA expression...... was assessed by reverse transcription-polymerase chain reaction in HT-29 and DLD-1 cells and in CEC isolated from biopsies from IBD and control patients. Total MMP activity in the cells was measured by a functional assay, based on degradation of a fluorescent synthetic peptide containing the specific bond...

  17. High-efficiency electroluminescence and amplified spontaneous emission from a thermally activated delayed fluorescent near-infrared emitter

    Science.gov (United States)

    Kim, Dae-Hyeon; D'Aléo, Anthony; Chen, Xian-Kai; Sandanayaka, Atula D. S.; Yao, Dandan; Zhao, Li; Komino, Takeshi; Zaborova, Elena; Canard, Gabriel; Tsuchiya, Youichi; Choi, Eunyoung; Wu, Jeong Weon; Fages, Frédéric; Brédas, Jean-Luc; Ribierre, Jean-Charles; Adachi, Chihaya

    2018-02-01

    Near-infrared organic light-emitting diodes and semiconductor lasers could benefit a variety of applications including night-vision displays, sensors and information-secured displays. Organic dyes can generate electroluminescence efficiently at visible wavelengths, but organic light-emitting diodes are still underperforming in the near-infrared region. Here, we report thermally activated delayed fluorescent organic light-emitting diodes that operate at near-infrared wavelengths with a maximum external quantum efficiency of nearly 10% using a boron difluoride curcuminoid derivative. As well as an effective upconversion from triplet to singlet excited states due to the non-adiabatic coupling effect, this donor-acceptor-donor compound also exhibits efficient amplified spontaneous emission. By controlling the polarity of the active medium, the maximum emission wavelength of the electroluminescence spectrum can be tuned from 700 to 780 nm. This study represents an important advance in near-infrared organic light-emitting diodes and the design of alternative molecular architectures for photonic applications based on thermally activated delayed fluorescence.

  18. Urinary and serum soluble CD25 complements urinary soluble CD163 to detect active renal anti-neutrophil cytoplasmic autoantibody-associated vasculitis: a cohort study.

    Science.gov (United States)

    Dekkema, Gerjan J; Abdulahad, Wayel H; Bijma, Theo; Moran, Sarah M; Ryan, Louise; Little, Mark A; Stegeman, Coen A; Heeringa, Peter; Sanders, Jan-Stephan F

    2018-03-01

    Early detection of renal involvement in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is of major clinical importance to allow prompt initiation of treatment and limit renal damage. Urinary soluble cluster of differentiation 163 (usCD163) has recently been identified as a potential biomarker for active renal vasculitis. However, a significant number of patients with active renal vasculitis test negative using usCD163. We therefore studied whether soluble CD25 (sCD25), a T cell activation marker, could improve the detection of renal flares in AAV. sCD25 and sCD163 levels in serum and urine were measured by enzyme-linked immunosorbent assay in 72 patients with active renal AAV, 20 with active extrarenal disease, 62 patients in remission and 18 healthy controls. Urinary and blood CD4+ T and CD4+ T effector memory (TEM) cell counts were measured in 22 patients with active renal vasculitis. Receiver operating characteristics (ROC) curves were generated and recursive partitioning was used to calculate whether usCD25 and serum soluble CD25 (ssCD25) add utility to usCD163. usCD25, ssCD25 and usCD163 levels were significantly higher during active renal disease and significantly decreased after induction of remission. A combination of usCD25, usCD163 and ssCD25 outperformed all individual markers (sensitivity 84.7%, specificity 95.1%). Patients positive for sCD25 but negative for usCD163 (n = 10) had significantly higher C-reactive protein levels and significantly lower serum creatinine and proteinuria levels compared with the usCD163-positive patients. usCD25 correlated positively with urinary CD4+ T and CD4+ TEM cell numbers, whereas ssCD25 correlated negatively with circulating CD4+ T and CD4+ TEM cells. Measurement of usCD25 and ssCD25 complements usCD163 in the detection of active renal vasculitis.

  19. Preictal activity of subicular, CA1, and dentate gyrus principal neurons in the dorsal hippocampus before spontaneous seizures in a rat model of temporal lobe epilepsy.

    Science.gov (United States)

    Fujita, Satoshi; Toyoda, Izumi; Thamattoor, Ajoy K; Buckmaster, Paul S

    2014-12-10

    Previous studies suggest that spontaneous seizures in patients with temporal lobe epilepsy might be preceded by increased action potential firing of hippocampal neurons. Preictal activity is potentially important because it might provide new opportunities for predicting when a seizure is about to occur and insight into how spontaneous seizures are generated. We evaluated local field potentials and unit activity of single, putative excitatory neurons in the subiculum, CA1, CA3, and dentate gyrus of the dorsal hippocampus in epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Average action potential firing rates of neurons in the subiculum, CA1, and dentate gyrus, but not CA3, increased significantly and progressively beginning 2-4 min before locally recorded spontaneous seizures. In the subiculum, CA1, and dentate gyrus, but not CA3, 41-57% of neurons displayed increased preictal activity with significant consistency across multiple seizures. Much of the increased preictal firing of neurons in the subiculum and CA1 correlated with preictal theta activity, whereas preictal firing of neurons in the dentate gyrus was independent of theta. In addition, some CA1 and dentate gyrus neurons displayed reduced firing rates preictally. These results reveal that different hippocampal subregions exhibit differences in the extent and potential underlying mechanisms of preictal activity. The finding of robust and significantly consistent preictal activity of subicular, CA1, and dentate neurons in the dorsal hippocampus, despite the likelihood that many seizures initiated in other brain regions, suggests the existence of a broader neuronal network whose activity changes minutes before spontaneous seizures initiate. Copyright © 2014 the authors 0270-6474/14/3416671-17$15.00/0.

  20. Vibroacustic microvibrations enhance kidney blood supply, glomerular filtration and glutathione peroxidase activity in spontaneously hypertensive rats.

    Science.gov (United States)

    Miloradović, Zoran; Mihailović-Stanojević, Nevena; Jovović, Đurđica; Ivanov, Milan; Vajić, Una J; Karanović, Danijela; Grujić Milanović, Jelica

    2015-01-01

    Limited numbers of studies include research of microvibration therapy in experimental models. We examined effects of chronic vibroacustic-microvibration treatment on haemodynamics and anti-oxidative defense in experimental hypertension. Study was performed on chronically treated hypertensive and normotensive Wistar rats. Mean arterial pressure (MAP), cardiac output (CO), renal blood flow (RBF), glomerular filtration and activity of anti-oxidative enzymes were determined after three weeks treatment. Vibroacustic treatment had no influence on MAP and CO, but RBF was increased in both groups of treated rats. Additionally, vibroacustic treatment enhanced diuresis and increased glomerular filtration in hypertensive rats. Glutathione peroxidase (GSH-Px) activity was elevated in both treated rat strains, but activity of superoxide dismutase was unchanged. We conclude that microvibration treatment doesn't ameliorate hypertension but improves renal blood supply (trough diminished renal vascular resistance), glomerular filtration, diuresis, and enhances glutathione dependent anti-oxidant defense with more important beneficials in hypertensive animals.

  1. Autocrine Effects of Tumor-Derived Complement

    Directory of Open Access Journals (Sweden)

    Min Soon Cho

    2014-03-01

    Full Text Available We describe a role for the complement system in enhancing cancer growth. Cancer cells secrete complement proteins that stimulate tumor growth upon activation. Complement promotes tumor growth via a direct autocrine effect that is partially independent of tumor-infiltrating cytotoxic T cells. Activated C5aR and C3aR signal through the PI3K/AKT pathway in cancer cells, and silencing the PI3K or AKT gene in cancer cells eliminates the progrowth effects of C5aR and C3aR stimulation. In patients with ovarian or lung cancer, higher tumoral C3 or C5aR mRNA levels were associated with decreased overall survival. These data identify a role for tumor-derived complement proteins in promoting tumor growth, and they therefore have substantial clinical and therapeutic implications.

  2. Effect of Imperatorin on the Spontaneous Motor Activity of Rat Isolated Jejunum Strips

    Directory of Open Access Journals (Sweden)

    Marta Mendel

    2015-01-01

    Full Text Available Imperatorin, a psoralen-type furanocoumarin, is a potent myorelaxant agent acting as a calcium antagonist on vascular smooth muscle. Its effects on other types of smooth muscle remain unknown. Therefore, the aim of this study was to investigate the hypothesized myorelaxant effect of imperatorin on gut motor activity and, possibly, to define the underlying mechanism of action. Imperatorin was made available for pharmacological studies from the fruits of the widely available Angelica officinalis through the application of high-performance countercurrent chromatography (HPCCC. Imperatorin generated reversible relaxation of jejunum strips dose-dependently (1–100 μM. At 25 and 50 μM, imperatorin caused relaxation comparable to the strength of the reaction induced by isoproterenol (Isop at 0.1 μM. The observed response resulted neither from the activation of soluble guanylate cyclase, nor from β-adrenoreceptor involvement, nor from Ca2+-activated potassium channels. Imperatorin relaxed intestine strips precontracted with high potassium concentration, attenuated the force and duration of K+-induced contractions, and modulated the response of jejunum strips to acetylcholine. The results suggest that imperatorin probably interacts with various Ca2+ influx pathways in intestine smooth muscle. The types of some calcium channels involved in the activity of imperatorin will be examined in a subsequent study.

  3. Spontaneous Brain Activity Did Not Show the Effect of Violent Video Games on Aggression: A Resting-State fMRI Study

    Directory of Open Access Journals (Sweden)

    Wei Pan

    2018-01-01

    Full Text Available A great many of empirical researches have proved that longtime exposure to violent video game can lead to a series of negative effects. Although research has focused on the neural basis of the correlation between violent video game and aggression, little is known whether the spontaneous brain activity is associated with violent video game exposure. To address this question, we measured the spontaneous brain activity using resting-state functional magnetic resonance imaging (fMRI. We used the amplitude of low-frequency fluctuations (ALFF and fractional ALFF (fALFF to quantify spontaneous brain activity. The results showed there is no significant difference in ALFF, or fALFF, between violent video game group and the control part, indicating that long time exposure to violent video games won’t significantly influence spontaneous brain activity, especially the core brain regions such as execution control, moral judgment and short-term memory. This implies the adverse impact of violent video games is exaggerated.

  4. Spontaneous Brain Activity Did Not Show the Effect of Violent Video Games on Aggression: A Resting-State fMRI Study.

    Science.gov (United States)

    Pan, Wei; Gao, Xuemei; Shi, Shuo; Liu, Fuqu; Li, Chao

    2017-01-01

    A great many of empirical researches have proved that longtime exposure to violent video game can lead to a series of negative effects. Although research has focused on the neural basis of the correlation between violent video game and aggression, little is known whether the spontaneous brain activity is associated with violent video game exposure. To address this question, we measured the spontaneous brain activity using resting-state functional magnetic resonance imaging (fMRI). We used the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) to quantify spontaneous brain activity. The results showed there is no significant difference in ALFF, or fALFF, between violent video game group and the control part, indicating that long time exposure to violent video games won't significantly influence spontaneous brain activity, especially the core brain regions such as execution control, moral judgment and short-term memory. This implies the adverse impact of violent video games is exaggerated.

  5. THE EFFECT OF SOME ALPHA-ADRENOCEPTOR ANTAGONISTS ON SPONTANEOUS MYOGENIC ACTIVITY IN THE RAT PORTAL-VEIN AND THE PUTATIVE INVOLVEMENT OF ATP-SENSITIVE K+ CHANNELS

    NARCIS (Netherlands)

    SCHWIETERT, R; WILHELM, D; WILFFERT, B; VANZWIETEN, PA

    1992-01-01

    In the present study we showed that the alpha-adrenoceptor antagonists phentolamine, yohimbine, prazosin, corynanthine and idazoxan, when cumulatively applied in high concentrations (1-100-mu-mol/l), can increase spontaneous myogenic activity in the rat portal vein. 5-Methyl-urapidil and rauwolscine

  6. The effect of some α-adrenoceptor antagonists on spontaneous myogenic activity in the rat portal vein and the putative involvement of ATP-sensitive K+channels

    NARCIS (Netherlands)

    Schwietert, R.; Wilhelm, D.; Wilffert, B.; Van Zwieten, P.A.

    1992-01-01

    In the present study we showed that the α-adrenoceptor antagonists phentolamine, yohimbine, prazosin, corynanthine and idazoxan, when cumulatively applied in high concentrations (1-100 μmol/l), can increase spontaneous myogenic activity in the rat portal vein. 5-Methyl-urapidil and rauwolscine were

  7. Altered spontaneous activity of posterior cingulate cortex and superior temporal gyrus are associated with a smoking cessation treatment outcome using varenicline revealed by regional homogeneity.

    Science.gov (United States)

    Wang, Chao; Shen, Zhujing; Huang, Peiyu; Qian, Wei; Yu, Xinfeng; Sun, Jianzhong; Yu, Hualiang; Yang, Yihong; Zhang, Minming

    2017-06-01

    Compared to nonsmokers, smokers exhibit a number of potentially important differences in regional brain function. However, little is known about the associations between the local spontaneous brain activity and smoking cessation treatment outcomes. In the present analysis, we aimed to evaluate whether the local features of spontaneous brain activity prior to the target quit date was associated with the smoking cessation outcomes. All the participants underwent magnetic resonance imaging scans and smoking-related behavioral assessments. After a 12-week treatment with varenicline, 23 smokers succeeded in quitting smoking and 32 failed. Smokers underwent functional magnetic resonance imaging (fMRI) scanning prior to an open label smoking cessation treatment trial. Regional homogeneity (ReHo) was used to measure spontaneous brain activity, and whole-brain voxel-wise comparisons of ReHo were performed to detect brain regions with altered spontaneous brain activity between relapser and quitter groups. After controlling for potentially confounding factors including years of education, years smoked, cigarettes smoked per day and FTND score as covariates, compared to quitters, relapsers displayed significantly decreased ReHo in bilateral posterior cingulate cortex (PCC), as well as increased ReHo in left superior temporal gyrus (STG). These preliminary results suggest that regional brain function variables may be promising predictors of smoking relapse. This study provided novel insights into the neurobiological mechanisms underlying smoking relapse. A deeper understanding of the neurobiological mechanisms associated with relapse may result in novel pharmacological and behavioral interventions.

  8. The activity of spontaneous action potentials in developing hair cells is regulated by Ca(2+-dependence of a transient K+ current.

    Directory of Open Access Journals (Sweden)

    Snezana Levic

    Full Text Available Spontaneous action potentials have been described in developing sensory systems. These rhythmic activities may have instructional roles for the functional development of synaptic connections. The importance of spontaneous action potentials in the developing auditory system is underpinned by the stark correlation between the time of auditory system functional maturity, and the cessation of spontaneous action potentials. A prominent K(+ current that regulates patterning of action potentials is I(A. This current undergoes marked changes in expression during chicken hair cell development. Although the properties of I(A are not normally classified as Ca(2+-dependent, we demonstrate that throughout the development of chicken hair cells, I(A is greatly reduced by acute alterations of intracellular Ca(2+. As determinants of spike timing and firing frequency, intracellular Ca(2+ buffers shift the activation and inactivation properties of the current to more positive potentials. Our findings provide evidence to demonstrate that the kinetics and functional expression of I(A are tightly regulated by intracellular Ca(2+. Such feedback mechanism between the functional expression of I(A and intracellular Ca(2+ may shape the activity of spontaneous action potentials, thus potentially sculpting synaptic connections in an activity-dependent manner in the developing cochlea.

  9. Spontaneous Activity Associated with Delusions of Schizophrenia in the Left Medial Superior Frontal Gyrus: A Resting-State fMRI Study.

    Directory of Open Access Journals (Sweden)

    Bin Gao

    Full Text Available Delusions of schizophrenia have been found to be associated with alterations of some brain regions in structure and task-induced activation. However, the relationship between spontaneously occurring symptoms and spontaneous brain activity remains unclear. In the current study, 14 schizophrenic patients with delusions and 14 healthy controls underwent a resting-state functional magnetic resonance imaging (RS-fMRI scan. Patients with delusions of schizophrenia patients were rated with Positive and Negative Syndrome Scale (PANSS and Characteristics of Delusional Rating Scale (CDRS. Regional homogeneity (ReHo was calculated to measure the local synchronization of the spontaneous activity in a voxel-wise way. A two-sample t-test showed that ReHo of the right anterior cingulate gyrus and left medial superior frontal gyrus were higher in patients, and ReHo of the left superior occipital gyrus was lower, compared to healthy controls. Further, among patients, correlation analysis showed a significant difference between delusion scores of CRDS and ReHo of brain regions. ReHo of the left medial superior frontal gyrus was negatively correlated with patients' CDRS scores but not with delusional PANSS scores. These results suggested that altered local synchronization of spontaneous brain activity may be related to the pathophysiology of delusion in schizophrenia.

  10. Spontaneous Brain Activity Did Not Show the Effect of Violent Video Games on Aggression: A Resting-State fMRI Study

    Science.gov (United States)

    Pan, Wei; Gao, Xuemei; Shi, Shuo; Liu, Fuqu; Li, Chao

    2018-01-01

    A great many of empirical researches have proved that longtime exposure to violent video game can lead to a series of negative effects. Although research has focused on the neural basis of the correlation between violent video game and aggression, little is known whether the spontaneous brain activity is associated with violent video game exposure. To address this question, we measured the spontaneous brain activity using resting-state functional magnetic resonance imaging (fMRI). We used the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) to quantify spontaneous brain activity. The results showed there is no significant difference in ALFF, or fALFF, between violent video game group and the control part, indicating that long time exposure to violent video games won’t significantly influence spontaneous brain activity, especially the core brain regions such as execution control, moral judgment and short-term memory. This implies the adverse impact of violent video games is exaggerated. PMID:29375416

  11. Reduction of circulating annexin A5 levels and resistance to annexin A5 anticoagulant activity in women with recurrent spontaneous pregnancy losses.

    NARCIS (Netherlands)

    Rand, J.H.; Arslan, A.A.; Wu, X.X.; Wein, R.; Mulholland, J.; Shah, M.; Heerde, W.L. van; Reutelingsperger, C.P.M.; Lockwood, C.J.; Kuczynski, E.

    2006-01-01

    OBJECTIVE: We investigated whether levels of annexin A5, evidence for resistance to annexin A5 activity, and levels anti-annexin A5 antibodies might be altered in women with a history of recurrent spontaneous pregnancy losses. STUDY DESIGN: These annexin A5 parameters were assayed in 70 nonpregnant

  12. Use of scripts and script-fading procedures and activity schedules to develop spontaneous social interaction in a three-year-old girl with autism

    Directory of Open Access Journals (Sweden)

    Anna Budzińska

    2014-05-01

    Full Text Available Autism entails serious deficiencies in communication and social behaviors. Individuals with autism, even those who have received intensive language intervention, are often viewed as lacking spontaneous language. In addition, some children with autism lack the ability of spontaneously seeking to share enjoyment, interests, or achievements with other people (e.g., a lack of showing, bringing, or pointing out objects of interest to other people. The aim of the study was to use ABA teaching techniques such as script and script fading procedure and activity schedule to teach three-year-old girl with autism spontaneous social interaction and shape joint attention skills. The result shows that ABA techniques were very effective in teaching many verbal skills such as answering questions, making requests, initiating conversation and asking question. Comparison made after implemented teaching procedure shows her initiating of joint attention skill (IJA is at the appropriate level for her age.

  13. Novel Target for Ameliorating Pain and Other Problems after SCI: Spontaneous Activity in Nociceptors

    Science.gov (United States)

    2016-06-01

    neurons within pain pathways and thus their electrical activity leads to the conscious sensation of pain as well associated reflex responses. These...promote pain sensations , and so it was not surprising to find that this chronic nociceptor SA was closely correlated with behavioral measures of pain...similar to those underlying long-term memory in the brain, such as late-phase long-term synaptic potentiation (LTP) (Asiedu et al., 2011; Laferriere et

  14. Bioactive compounds and antioxidant activity of Rosa canina L. biotypes from spontaneous flora of Transylvania.

    Science.gov (United States)

    Roman, Ioana; Stănilă, Andreea; Stănilă, Sorin

    2013-04-23

    The theoretical, but especially the practical values of identifying the biochemical compounds from the Rosa canina L. fruits are of present interest, this aspect being illustrated by the numerous researches. It was reported that the Rosa canina L. fruit, with its high ascorbic acid, phenolics and flavonoids contents, have antioxidant, antimutagenic and anticarcinogenic effects.This study was performed on order to evaluate the amount of the main phytochemicals (vitamin C, total polyphenols, and total flavonoids) content and their antioxidant activity. The results obtained revealed that the average amounts of vitamin C within the studied genotypes were: 360.22 mg/100 g frozen pulp (var. transitoria f. ramosissima, altitude 1250 m) and 112.20 mg/100 g frozen pulp (var. assiensis, altitude 440 m), giving a good correlation between the vitamin C content of the rosehip and the altitude. The total polyphenols content varied from 575 mg/100 g frozen pulp (var. transitoria f. ramosissima) to 326 mg/100 g frozen pulp (var. lutetiana f. fallens). The total flavonoids content showed the highest value for var. assiensis variant 163.3 mg/100 g frozen pulp and the lowest value attributed to var. transitoria f. montivaga 101.3 mg/100 g frozen pulp. The antioxidant activity of eight rose hip extracts from wild Transylvania populations was investigated through DPPH method. The antioxidant activity revealed a good correlation only with vitamin C content and total polyphenols. Eight Rose hip fruit species were compared taking into consideration the ascorbic acid, total polyphenols, total flavonoids contents and their antioxidant activity. Based on these results, two of the rosehip genotypes that were analysed could be of perspective for these species' amelioration, due to their content of phytochemicals mentioned above. These varieties are var. transitoria f. ramosissima (Bistrita-Nasaud, Agiesel) and var. transitoria f. montivaga (Bistrita-Nasaud, Salva) which can be used as a

  15. Are spontaneous conformational interconversions a molecular basis for long-period oscillations in enzyme activity?

    Science.gov (United States)

    Queiroz-Claret, C; Valon, C; Queiroz, O

    1988-01-01

    An unconventional hypothesis to the molecular basis of enzyme rhythms is that the intrinsic physical instability of the protein molecules which, in an aqueous medium, tend to move continuously from one conformational state to another could lead, in the population of enzyme molecules, to sizeable long-period oscillations in affinity for substrate and sensitivity to ligands and regulatory effects. To investigate this hypothesis, malate dehydrogenase was extracted and purified from leaves of the plant Kalanchoe blossfeldiana. The enzyme solutions were maintained under constant conditions and sampled at regular intervals for up to 40 or 70 h for measurements of activity as a function of substrate concentration, Km for oxaloacetic acid and sensitivity to the action of 2,3-butanedione, a modifier of active site arginyl residues. The results show that continuous slow oscillations in the catalytic capacity of the enzyme occur in all the extracts checked, together with fluctuations in Km. Apparent circadian periodicities were observed in accordance with previous data established during long run (100 h) experiments. The saturation curves for substrate showed multiple kinetic functions, with various pronounced intermediary plateaus and "bumps" depending on the time of sampling. Variation in the response to the effect of butanedione indicated fluctuation in the accessibility to the active site. Taken together, the results suggest that, under constant conditions, the enzyme in solution shifts continuously and reversibly between different configurations. This was confirmed by parallel studies on the proton-NMR spectrum of water aggregates in the enzyme solution and proton exchange rates.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Differential effect of central command on aortic and carotid sinus baroreceptor-heart rate reflexes at the onset of spontaneous, fictive motor activity.

    Science.gov (United States)

    Matsukawa, Kanji; Ishii, Kei; Kadowaki, Akito; Liang, Nan; Ishida, Tomoko

    2012-08-15

    Our laboratory has reported that central command blunts the sensitivity of the aortic baroreceptor-heart rate (HR) reflex at the onset of voluntary static exercise in conscious cats and spontaneous contraction in decerebrate cats. The purpose of this study was to examine whether central command attenuates the sensitivity of the carotid sinus baroreceptor-HR reflex at the onset of spontaneous, fictive motor activity in paralyzed, decerebrate cats. We confirmed that aortic nerve (AN)-stimulation-induced bradycardia was markedly blunted to 26 ± 4.4% of the control (21 ± 1.3 beats/min) at the onset of spontaneous motor activity. Although the baroreflex bradycardia by electrical stimulation of the carotid sinus nerve (CSN) was suppressed (P activity was much weaker (P abdominal aorta was blunted to 36% of the control (36 ± 1.6 beats/min) during spontaneous motor activity, suggesting that central command is able to inhibit the cardiomotor sensitivity of arterial baroreflexes as the net effect. Mechanical stretch of the triceps surae muscle never affected the baroreflex bradycardia elicited by AN or CSN stimulation and by aortic occlusion, suggesting that muscle mechanoreflex did not modify the cardiomotor sensitivity of aortic and carotid sinus baroreflex. Since the inhibitory effect of central command on the carotid baroreflex pathway, associated with spontaneous motor activity, was much weaker compared with the aortic baroreflex pathway, it is concluded that central command does not force a generalized modulation on the whole pathways of arterial baroreflexes but provides selective inhibition for the cardiomotor component of the aortic baroreflex.

  17. Spontaneous brain activity and EEG microstates. A novel EEG/fMRI analysis approach to explore resting-state networks.

    Science.gov (United States)

    Musso, F; Brinkmeyer, J; Mobascher, A; Warbrick, T; Winterer, G

    2010-10-01

    The brain is active even in the absence of explicit input or output as demonstrated from electrophysiological as well as imaging studies. Using a combined approach we measured spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal along with electroencephalography (EEG) in eleven healthy subjects during relaxed wakefulness (eyes closed). In contrast to other studies which used the EEG frequency information to guide the functional MRI (fMRI) analysis, we opted for transient EEG events, which identify and quantify brain electric microstates as time epochs with quasi-stable field topography. We then used this microstate information as regressors for the BOLD fluctuations. Single trial EEGs were segmented with a specific module of the LORETA (low resolution electromagnetic tomography) software package in which microstates are represented as normalized vectors constituted by scalp electric potentials, i.e., the related 3-dimensional distribution of cortical current density in the brain. Using the occurrence and the duration of each microstate, we modeled the hemodynamic response function (HRF) which revealed BOLD activation in all subjects. The BOLD activation patterns resembled well known resting-state networks (RSNs) such as the default mode network. Furthermore we "cross validated" the data performing a BOLD independent component analysis (ICA) and computing the correlation between each ICs and the EEG microstates across all subjects. This study shows for the first time that the information contained within EEG microstates on a millisecond timescale is able to elicit BOLD activation patterns consistent with well known RSNs, opening new avenues for multimodal imaging data processing. Copyright 2010. Published by Elsevier Inc.

  18. Effects of voluntary exercise on spontaneous physical activity and food consumption in mice: Results from an artificial selection experiment.

    Science.gov (United States)

    Copes, Lynn E; Schutz, Heidi; Dlugosz, Elizabeth M; Acosta, Wendy; Chappell, Mark A; Garland, Theodore

    2015-10-01

    We evaluated the effect of voluntary exercise on spontaneous physical activity (SPA) and food consumption in mice from 4 replicate lines bred for 57 generations for high voluntary wheel running (HR) and from 4 non-selected control (C) lines. Beginning at ~24 days of age, mice were housed in standard cages or in cages with attached wheels. Wheel activity and SPA were monitored in 1-min intervals. Data from the 8th week of the experiment were analyzed because mice were sexually mature and had plateaued in body mass, weekly wheel running distance, SPA, and food consumption. Body mass, length, and masses of the retroperitoneal fat pad, liver, and heart were recorded after the 13th week. SPA of both HR and C mice decreased with wheel access, due to reductions in both duration and average intensity of SPA. However, total activity duration (SPA+wheel running; min/day) was ~1/3 greater when mice were housed with wheels, and food consumption was significantly increased. Overall, food consumption in both HR and C mice was more strongly affected by wheel running than by SPA. Duration of wheel running had a stronger effect than average speed, but the opposite was true for SPA. With body mass as a covariate, chronic wheel access significantly reduced fat pad mass and increased heart mass in both HR and C mice. Given that both HR and C mice housed with wheels had increased food consumption, the energetic cost of wheel running was not fully compensated by concomitant reductions in SPA. The experiment demonstrates that both duration and intensity of both wheel running and SPA were significant predictors of food consumption. This sort of detailed analysis of the effects of different aspects of physical activity on food consumption has not previously been reported for a non-human animal, and it sets the stage for longitudinal examination of energy balance and its components in rodent models. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Essential Oil Composition, Antioxidant, Cytotoxic and Antiviral Activities of Teucrium pseudochamaepitys Growing Spontaneously in Tunisia

    Directory of Open Access Journals (Sweden)

    Saoussen Hammami

    2015-11-01

    Full Text Available The chemical composition, antioxidant, cytotoxic and antiviral activities of the essential oil obtained by hydrodistillation from the aerial parts of Teucrium pseudochamaepitys (Lamiaceae collected from Zaghouan province of Tunisia are reported. The essential oil was analyzed by gas chromatography equipped with a flame ionization detector (GC-FID and gas chromatography coupled with mass spectrometry (GC/MS. Thirty-one compounds were identified representing 88.6% of the total essential oil. Hexadecanoic acid was found to be the most abundant component (26.1% followed by caryophyllene oxide (6.3%, myristicin (4.9% and α-cubebene (3.9%. The antioxidant capacity of the oil was measured on the basis of the scavenging activity to the stable 2,2-diphenyl-1-picrylhydrazyl (DPPH. The IC50 value of the oil was evaluated as 0.77 mg·mL−1. In addition, the essential oil was found to possess moderate cytotoxic effects on the HEp-2 cell line (50% cytotoxic concentration (CC50 = 653.6 µg·mL−1. The potential antiviral effect was tested against Coxsackievirus B (CV-B, a significant human and mouse pathogen that causes pediatric central nervous system disease, commonly with acute syndromes. The reduction of viral infectivity by the essential oil was measured using a cytopathic (CPE reduction assay.

  20. Brain activation for spontaneous and explicit false belief tasks overlaps: new fMRI evidence on belief processing and violation of expectation.

    Science.gov (United States)

    Bardi, Lara; Desmet, Charlotte; Nijhof, Annabel; Wiersema, Jan R; Brass, Marcel

    2017-03-01

    There is extensive discussion on whether spontaneous and explicit forms of ToM are based on the same cognitive/neural mechanisms or rather reflect qualitatively different processes. For the first time, we analyzed the BOLD signal for false belief processing by directly comparing spontaneous and explicit ToM task versions. In both versions, participants watched videos of a scene including an agent who acquires a true or false belief about the location of an object (belief formation phase). At the end of the movies (outcome phase), participants had to react to the presence of the object. During the belief formation phase, greater activity was found for false vs true belief trials in the right posterior parietal cortex. The ROI analysis of the right temporo-parietal junction (TPJ), confirmed this observation. Moreover, the anterior medial prefrontal cortex (aMPFC) was active during the outcome phase, being sensitive to violation of both the participant's and agent's expectations about the location of the object. Activity in the TPJ and aMPFC was not modulated by the spontaneous/explicit task. Overall, these data show that neural mechanisms for spontaneous and explicit ToM overlap. Interestingly, a dissociation between TPJ and aMPFC for belief tracking and outcome evaluation, respectively, was also found. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  1. Renal C3 complement component: feed forward to diabetic kidney disease.

    Science.gov (United States)

    Kelly, Katherine J; Liu, Yunlong; Zhang, Jizhong; Dominguez, Jesus H

    2015-01-01

    Diabetic nephropathy is the main cause of end-stage renal disease and has reached epidemic proportions. Comprehensive genomic profiling (RNAseq) was employed in the ZS (F1 hybrids of Zucker and spontaneously hypertensive heart failure) model of diabetic nephropathy. Controls were lean littermates. Diabetic nephropathy in obese, diabetic ZS was accelerated by a single episode of renal ischemia (DI). This rapid renal decline was accompanied by the activation of the renal complement system in DI, and to a lesser extent in sham-operated diabetic rats (DS). In DI there were significant increases in renal mRNA encoding C3, C4, C5, C6, C8, and C9 over sham-operated lean normal controls (LS). Moreover, mRNAs encoding the receptors for the anaphylatoxins C3a and C5a were also significantly increased in DI compared to LS. The classic complement pathway was activated in diabetic kidneys with significant increases of C1qa, C1qb, and C1qc mRNAs in DI over LS. In addition, critical regulators of complement activation were significantly attenuated in DI and DS. These included mRNAs encoding CD55, decay accelerating factor, and CD59, which inhibit the membrane attack complex. C3, C4, and C9 proteins were demonstrated in renal tubules and glomeruli. The complement RNAseq data were incorporated into a gene network showing interactions among C3-generating renal tubular cells and other immune competent migratory cells. We conclude that local activation of the complement system mediates renal injury in diabetic nephropathy. © 2015 S. Karger AG, Basel.

  2. Predicting stroop effect from spontaneous neuronal activity: a study of regional homogeneity.

    Science.gov (United States)

    Liu, Congcong; Chen, Zhencai; Wang, Ting; Tang, Dandan; Hitchman, Glenn; Sun, Jiangzhou; Zhao, Xiaoyue; Wang, Lijun; Chen, Antao

    2015-01-01

    The Stroop effect is one of the most robust and well-studied phenomena in cognitive psychology and cognitive neuroscience. However, little is known about the relationship between intrinsic brain activity and the individual differences of this effect. In the present study, we explored this issue by examining whether resting-state functional magnetic resonance imaging (rs-fMRI) signals could predict individual differences in the Stroop effect of healthy individuals. A partial correlation analysis was calculated to examine the relationship between regional homogeneity (ReHo) and Stroop effect size, while controlling for age, sex, and framewise displacement (FD). The results showed positive correlations in the left inferior frontal gyrus (LIFG), the left insula, the ventral anterior cingulate cortex (vACC), and the medial frontal gyrus (MFG), and negative correlation in the left precentral gyrus (LPG). These results indicate the possible influences of the LIFG, the left insula, and the LPG on the efficiency of cognitive control, and demonstrate that the key nodes of default mode network (DMN) may be important in goal-directed behavior and/or mental effort during cognitive control tasks.

  3. Neural activations during visual sequence learning leave a trace in post-training spontaneous EEG.

    Directory of Open Access Journals (Sweden)

    Clara Moisello

    Full Text Available Recent EEG studies have shown that implicit learning involving specific cortical circuits results in an enduring local trace manifested as local changes in spectral power. Here we used a well characterized visual sequence learning task and high density-(hd-EEG recording to determine whether also declarative learning leaves a post-task, local change in the resting state oscillatory activity in the areas involved in the learning process. Thus, we recorded hd-EEG in normal subjects before, during and after the acquisition of the order of a fixed spatial target sequence (VSEQ and during the presentation of targets in random order (VRAN. We first determined the temporal evolution of spectral changes during VSEQ and compared it to VRAN. We found significant differences in the alpha and theta bands in three main scalp regions, a right occipito-parietal (ROP, an anterior-frontal (AFr, and a right frontal (RFr area. The changes in frontal theta power during VSEQ were positively correlated with the learning rate. Further, post-learning EEG recordings during resting state revealed a significant increase in alpha power in ROP relative to a pre-learning baseline. We conclude that declarative learning is associated with alpha and theta changes in frontal and posterior regions that occur during the task, and with an increase of alpha power in the occipito-parietal region after the task. These post-task changes may represent a trace of learning and a hallmark of use-dependent plasticity.

  4. Spontaneous pre-stimulus fluctuations in the activity of right fronto-parietal areas influence inhibitory control performance

    Directory of Open Access Journals (Sweden)

    Camille F. Chavan

    2013-06-01

    Full Text Available Inhibitory control refers to the ability to suppress planned or ongoing cognitive or motor processes. Electrophysiological indices of inhibitory control failure have been found to manifest even before the presentation of the stimuli triggering the inhibition, suggesting that pre-stimulus brain-states modulate inhibition performance. However, previous electrophysiological investigations on the state-dependency of inhibitory control were based on averaged event-related potentials, a method eliminating the variability in the ongoing brain activity not time-locked to the event of interest. These studies thus left unresolved whether spontaneous variations in the brain-state immediately preceding unpredictable inhibition-triggering stimuli also influence inhibitory control performance.To address this question, we applied single-trial EEG topographic analyses on the time interval immediately preceding NoGo stimuli in conditions where the responses to NoGo trials were correctly inhibited (correct rejection vs. committed (false alarms during an auditory spatial Go/NoGo task.We found a specific configuration of the EEG voltage field manifesting more frequently before correctly inhibited responses to NoGo stimuli than before false alarms. There was no evidence for an EEG topography occurring more frequently before false alarms than before correct rejections. The visualization of distributed electrical source estimations of the EEG topography preceding successful response inhibition suggested that it resulted from the activity of a right fronto-parietal brain network.Our results suggest that the fluctuations in the ongoing brain activity immediately preceding stimulus presentation contribute to the behavioral outcomes during an inhibitory control task. Our results further suggest that the state-dependency of sensory-cognitive processing might not only concern perceptual processes, but also high-order, top-down inhibitory control mechanisms.

  5. Decreased Spontaneous Electrical Activity and Acetylcholine at Myofascial Trigger Spots after Dry Needling Treatment: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Qing-Guang Liu

    2017-01-01

    Full Text Available Objective. The aims of this study are to investigate the changes in spontaneous electrical activities (SEAs and in acetylcholine (ACh, acetylcholine receptor (AChR, and acetylcholine esterase (AChE levels after dry needling at myofascial trigger spots in model rats. Materials and Methods. Forty-eight male Sprague-Dawley rats were divided into four groups. Thirty-six rats were assigned to three model groups, which underwent MTrSs modeling intervention. Twelve rats were assigned to the blank control (BC group. After model construction, the 36 model rats were randomly subdivided into three groups according to treatment: MTrSs model control (MC and two dry needling groups. One dry needling group received puncturing at MTrSs (DN-M, whereas the other underwent puncturing at non-MTrSs (DN-nM. Dry needling treatment will last for two weeks, once a week. SEAs and ACh, AChR, and AChE levels were measured after one-week rest of dry needling treatment. Results. The amplitudes and frequencies of endplate noise (EPN and endplate spike (EPS significantly decreased after dry needling treatment in the DN-M group. Moreover, ACh and AChR levels significantly decreased, whereas AChE significantly increased after dry needling treatment in the DN-M group. Conclusion. Dry needling at the exact MTrSs is more effective than dry needling at non-MTrSs.

  6. Self-monitoring of spontaneous physical activity and sedentary behavior to prevent weight regain in older adults.

    Science.gov (United States)

    Nicklas, Barbara J; Gaukstern, Jill E; Beavers, Kristen M; Newman, Jill C; Leng, Xiaoyan; Rejeski, W Jack

    2014-06-01

    The objective was to determine whether adding a self-regulatory intervention (SRI) focused on self-monitoring of spontaneous physical activity (SPA) and sedentary behavior to a standard weight loss intervention improved maintenance of lost weight. Older (65-79 years), obese (BMI = 30-40 kg/m(2) ) adults (n = 48) were randomized to a 5-month weight loss intervention involving a hypocaloric diet (DIET) and aerobic exercise (EX) with or without the SRI to promote SPA and decrease sedentary behavior (SRI + DIET + EX compared with DIET + EX). Following the weight loss phase, both groups transitioned to self-selected diet and exercise behavior during a 5-month follow-up. Throughout the 10-months, the SRI + DIET + EX group utilized real-time accelerometer feedback for self-monitoring. There was an overall group by time effect of the SRI (P weight and regained more weight than SRI + DIET + EX. The average weight regain during follow-up was 1.3 kg less in the SRI + DIET + EX group. Individuals in this group maintained approximately 10% lower weight than baseline compared with those in the DIET + EX group whom maintained approximately 5% lower weight than baseline. Addition of a SRI, designed to increase SPA and decrease sedentary behavior, to a standard weight loss intervention enhanced successful maintenance of lost weight. Copyright © 2014 The Obesity Society.

  7. Relative antibacterial functions of complement and NETs: NETs trap and complement effectively kills bacteria.

    Science.gov (United States)

    Azzouz, Louiza; Cherry, Ahmed; Riedl, Magdalena; Khan, Meraj; Pluthero, Fred G; Kahr, Walter H A; Palaniyar, Nades; Licht, Christoph

    2018-03-20

    Neutrophil extracellular traps (NETs) are web-like DNA structures released by activated neutrophils. These structures are decorated with antimicrobial proteins, and considered to trap and kill bacteria extracellularly. However, the exact functions of NETs remain elusive, and contradictory observations have been made with NETs functioning as an antimicrobial or a pathogentrapping mechanism. There is a disconnect in the interpretation of the involvement of other major immune mechanisms, such as the complement system, as effectors of the function of NETs. We have recently shown that NETs activate complement. In this study, we aimed to elucidate the relative antimicrobial roles of NETs in the absence and presence of complement. Using primary human neutrophils, human serum (normal, heat inactivated, and C5-depleted), P. aeruginosa (at multiplicity of infection, MOI, of 1 or 10), S. aureus (MOI of 1), colony-counting assays and confocal microscopy, we demonstrate that most bacteria trapped by NETs remain viable, indicating that NETs have limited bactericidal properties. By contrast, complement effectively killed bacteria, but NETs decreased the bactericidal ability of complement and degrading NETs by DNases restored complement-mediated killing. Experiments with conditions allowing for specific pathway activation showed that the complement classical and lectin, but not the alternative, pathway lead to bacterial killing. NETs under static conditions showed limited killing of bacteria while NETs under dynamic conditions showed enhanced bacteria trapping and reduced killing. Furthermore, NETs incubated with normal human serum depleted complement and reduced the hemolytic capacity of the serum. This report, for the first time, clarifies the relative bactericidal contributions of NETs and complement. We propose that - while NETs can ensnare bacteria such as P. aeruginosa - complement is necessary for efficient bacterial killing. Copyright © 2018 Elsevier Ltd. All rights

  8. Effect of a non lethal whole-body gamma irradiation on the spontaneous and evoked electroencephalographic activities of the adult rabbit

    International Nuclear Information System (INIS)

    Court, L.

    1969-01-01

    The whole of the experimental methods described (animal preparation, achievement of a precise physiological technique, dosimetry, biological information processing) allowed us to follow the changes for 15 days in the spontaneous and evoked electroencephalogram activities of rabbits submitted to a non-lethal 400 rads whole-body gamma-irradiation. Behavioural troubles, changes in the arousal state and the spontaneous electrical activity of the neo-cortex and hippocampus were noticed constantly together with an enhanced cortical excitability, and the appearance of elements of the paroxystic series sometimes in contrast with a general decrease in amplitude. After a visual stimulus the general morphology of evoked activities at the level of the primary visual areas and hippocampus was unchanged, but enhanced latencies and delays, less systematic modifications in amplitudes seemed to show out a direct effect of radiations on the nervous system and sensorial activities; these troubles seemed to occur independently from the basic electrical activity. As a whole, the changes observed were usually transitory and varied with each individual. Finally an assumption is made to explain the mechanism of arousal troubles and the general evolution of spontaneous electrical activity in the brain. (author) [fr

  9. Associations of lifetime active and passive smoking with spontaneous abortion, stillbirth and tubal ectopic pregnancy: a cross-sectional analysis of historical data from the Women's Health Initiative.

    Science.gov (United States)

    Hyland, Andrew; Piazza, Kenneth M; Hovey, Kathleen M; Ockene, Judith K; Andrews, Christopher A; Rivard, Cheryl; Wactawski-Wende, Jean

    2015-07-01

    To examine the associations between tobacco exposure and adverse pregnancy outcomes using quantitative measures of lifetime active smoking and secondhand smoke (SHS) exposure. Historical reproductive data on 80 762 women who participated in the Women's Health Initiative Observational Study were examined with a cross-sectional analysis. We assessed self-reported lifetime active and passive tobacco smoke exposure, self-reported spontaneous abortions, stillbirths and ectopic pregnancies. When compared with never-smoking women, participants who were ever active smokers during their reproductive years had ORs (OR) of 1.16 (95% CI 1.08 to 1.26) for 1 or more spontaneous abortions, 1.44 (95% CI 1.20 to 1.73) for 1 or more stillbirths, and 1.43 (95% CI 1.10 to 1.86) for 1 or more ectopic pregnancies. Never-smoking women participants with the highest levels of lifetime SHS exposure, including childhood >10 years, adult home >20 years and adult work exposure >10 years, when compared with never-smoking women with no SHS exposure had adjusted ORs of 1.17 (95% CI 1.05 to 1.30) for spontaneous abortion, 1.55 (95% CI 1.21 to 1.97) for stillbirth, and 1.61 (95% CI 1.16 to 2.24) for ectopic pregnancy. Women who were ever-smokers during their reproductive years had significantly greater estimates of risk for spontaneous abortion, stillbirth and tubal ectopic pregnancy. Never-smoking women with the highest levels of lifetime exposure to SHS had significantly increased estimates of risk for spontaneous abortion, stillbirth and tubal ectopic pregnancy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  10. Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion.

    Science.gov (United States)

    Hovingh, Elise S; van den Broek, Bryan; Jongerius, Ilse

    2016-01-01

    The human complement system plays an important role in the defense against invading pathogens, inflammation and homeostasis. Invading microbes, such as bacteria, directly activate the complement system resulting in the formation of chemoattractants and in effective labeling of the bacteria for phagocytosis. In addition, formation of the membrane attack complex is responsible for direct killing of Gram-negative bacteria. In turn, bacteria have evolved several ways to evade complement activation on their surface in order to be able to colonize and invade the human host. One important mechanism of bacterial escape is attraction of complement regulatory proteins to the microbial surface. These molecules are present in the human body for tight regulation of the complement system to prevent damage to host self-surfaces. Therefore, recruitment of complement regulatory proteins to the bacterial surface results in decreased complement activation on the microbial surface which favors bacterial survival. This review will discuss recent advances in understanding the binding of complement regulatory proteins to the bacterial surface at the molecular level. This includes, new insights that have become available concerning specific conserved motives on complement regulatory proteins that are favorable for microbial binding. Finally, complement evasion molecules are of high importance for vaccine development due to their dominant role in bacterial survival, high immunogenicity and homology as well as their presence on the bacterial surface. Here, the use of complement evasion molecules for vaccine development will be discussed.

  11. Intervening on spontaneous physical activity to prevent weight regain in older adults: design of a randomized, clinical trial.

    Science.gov (United States)

    Nicklas, Barbara J; Gaukstern, Jill E; Legault, Claudine; Leng, Iris; Rejeski, W Jack

    2012-03-01

    There is a need to identify evidenced-based obesity treatments that are effective in maintaining lost weight. Weight loss results in reductions in energy expenditure, including spontaneous physical activity (SPA) which is defined as energy expenditure resulting primarily from unstructured mobility-related activities that occur during daily life. To date, there is little research, especially randomized, controlled trials, testing strategies that can be adopted and sustained to prevent declines in SPA that occur with weight loss. Self-monitoring is a successful behavioral strategy to facilitate behavior change, so a provocative question is whether monitoring SPA-related energy expenditure would override these reductions in SPA, and slow weight regain. This study is a randomized trial in older, obese men and women designed to test the hypothesis that adding a self-regulatory intervention (SRI), focused around self-monitoring of SPA, to a weight loss intervention will result in less weight and fat mass regain following weight loss than a comparable intervention that lacks this self-regulatory behavioral strategy. Participants (n=72) are randomized to a 5-month weight loss intervention with or without the addition of a behavioral component that includes an innovative approach to promoting increased SPA. Both groups then transition to self-selected diet and exercise behavior for a 5-month follow-up. Throughout the 10-month period, the SRI group is provided with an intervention designed to promote a SPA level that is equal to or greater than each individual's baseline SPA level, allowing us to isolate the effects of the SPA self-regulatory intervention component on weight and fat mass regain. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Antibody-dependent NK cell activation is associated with late kidney allograft dysfunction and the complement-independent alloreactive potential of donor-specific antibodies

    Directory of Open Access Journals (Sweden)

    Tristan Legris

    2016-08-01

    Full Text Available Although kidney transplantation remains the best treatment for end-stage renal failure, it is limited by chronic humoral aggression of the graft vasculature by donor-specific antibodies (DSAs. The complement-independent mechanisms that lead to the antibody-mediated rejection (ABMR of kidney allografts remain poorly understood. Increasing lines of evidence have revealed the relevance of natural killer (NK cells as innate immune effectors of antibody-dependent cellular cytotoxicity, but few studies have investigated their alloreactive potential in the context of solid organ transplantation. Our study aimed to investigate the potential contribution of the antibody-dependent alloreactive function of NK cells to kidney graft dysfunction. We first conducted an observational study to investigate whether the cytotoxic function of NK cells is associated with chronic allograft dysfunction. The NK-Cellular Humoral Activation Test (NK-CHAT was designed to evaluate the recipient and antibody-dependent reactivity of NK cells against allogeneic target cells. The release of CD107a/Lamp1+ cytotoxic granules, resulting from the recognition of rituximab-coated B cells by NK cells, was analyzed in 148 kidney transplant recipients (KTRs, mean graft duration: 6.2 years. Enhanced ADCC responsiveness was associated with reduced graft function and identified as an independent risk factor predicting a decline in the estimated glomerular filtration rate (eGFR over a 1-year period (hazard ratio: 2.83. In a second approach, we used the NK-CHAT to reveal the cytotoxic potential of circulating alloantibodies in vitro. The level of CD16 engagement resulting from the in vitro recognition of serum-coated allogeneic B cells or splenic cells was further identified as a specific marker of DSA-induced ADCC. The NK-CHAT scoring of sera obtained from 40 patients at the time of transplant biopsy was associated with ABMR diagnosis. Our findings indicate that despite the administration

  13. Human IgG is produced in a pro-form that requires clipping of C-terminal lysines for maximal complement activation

    DEFF Research Database (Denmark)

    van den Bremer, E. T. J.; Beurskens, F. J.; Voorhorst, M.

    2015-01-01

    Human IgG is produced with C-terminal lysines that are cleaved off in circulation. The function of this modification was unknown and generally thought not to affect antibody function. We recently reported that efficient C1q binding and complement-dependent cytotoxicity (CDC) requires IgG hexameri...

  14. Complement inhibition: a promising concept for cancer treatment

    Science.gov (United States)

    Pio, Ruben; Ajona, Daniel; Lambris, John D.

    2013-01-01

    For decades, complement has been recognized as an effector arm of the immune system that contributes to the destruction of tumor cells. In fact, many therapeutic strategies have been proposed that are based on the intensification of complement-mediated responses against tumors. However, recent studies have challenged this paradigm by demonstrating a tumor-promoting role for complement. Cancer cells seem to be able to establish a convenient balance between complement activation and inhibition, taking advantage of complement initiation without suffering its deleterious effects. Complement activation may support chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and activate cancer-related signaling pathways. In this context, inhibition of complement activation would be a therapeutic option for treating cancer. This concept is relatively novel and deserves closer attention. In this paper, we will summarize the mechanisms of complement activation on cancer cells, the cancer-promoting effect of complement initiation, and the rationale behind the use of complement inhibition as a therapeutic strategy against cancer. PMID:23706991

  15. Soluble complement receptor 1 protects the peripheral nerve from early axon loss after injury

    NARCIS (Netherlands)

    Ramaglia, Valeria; Wolterman, Ruud; de Kok, Maryla; Vigar, Miriam Ann; Wagenaar-Bos, Ineke; King, Rosalind Helen Mary; Morgan, Brian Paul; Baas, Frank

    2008-01-01

    Complement activation is a crucial early event in Wallerian degeneration. In this study we show that treatment of rats with soluble complement receptor 1 (sCR1), an inhibitor of all complement pathways, blocked both systemic and local complement activation after crush injury of the sciatic nerve.

  16. Unaltered Network Activity and Interneuronal Firing During Spontaneous Cortical Dynamics In Vivo in a Mouse Model of Severe Myoclonic Epilepsy of Infancy.

    Science.gov (United States)

    De Stasi, Angela Michela; Farisello, Pasqualina; Marcon, Iacopo; Cavallari, Stefano; Forli, Angelo; Vecchia, Dania; Losi, Gabriele; Mantegazza, Massimo; Panzeri, Stefano; Carmignoto, Giorgio; Bacci, Alberto; Fellin, Tommaso

    2016-04-01

    Severe myoclonic epilepsy of infancy (SMEI) is associated with loss of function of the SCN1A gene encoding the NaV1.1 sodium channel isoform. Previous studies in Scn1a(-/+) mice during the pre-epileptic period reported selective reduction in interneuron excitability and proposed this as the main pathological mechanism underlying SMEI. Yet, the functional consequences of this interneuronal dysfunction at the circuit level in vivo are unknown. Here, we investigated whether Scn1a(-/+) mice showed alterations in cortical network function. We found that various forms of spontaneous network activity were similar in Scn1a(-/+) during the pre-epileptic period compared with wild-type (WT) in vivo. Importantly, in brain slices from Scn1a(-/+) mice, the excitability of parvalbumin (PV) and somatostatin (SST) interneurons was reduced, epileptiform activity propagated more rapidly, and complex synaptic changes were observed. However, in vivo, optogenetic reduction of firing in PV or SST cells in WT mice modified ongoing network activities, and juxtasomal recordings from identified PV and SST interneurons showed unaffected interneuronal firing during spontaneous cortical dynamics in Scn1a(-/+) compared with WT. These results demonstrate that interneuronal hypoexcitability is not observed in Scn1a(-/+) mice during spontaneous activities in vivo and suggest that additional mechanisms may contribute to homeostatic rearrangements and the pathogenesis of SMEI. © The Author 2016. Published by Oxford University Press.

  17. Complementing Gender Analysis Methods.

    Science.gov (United States)

    Kumar, Anant

    2016-01-01

    The existing gender analysis frameworks start with a premise that men and women are equal and should be treated equally. These frameworks give emphasis on equal distribution of resources between men and women and believe that this will bring equality which is not always true. Despite equal distribution of resources, women tend to suffer and experience discrimination in many areas of their lives such as the power to control resources within social relationships, and the need for emotional security and reproductive rights within interpersonal relationships. These frameworks believe that patriarchy as an institution plays an important role in women's oppression, exploitation, and it is a barrier in their empowerment and rights. Thus, some think that by ensuring equal distribution of resources and empowering women economically, institutions like patriarchy can be challenged. These frameworks are based on proposed equality principle which puts men and women in competing roles. Thus, the real equality will never be achieved. Contrary to the existing gender analysis frameworks, the Complementing Gender Analysis framework proposed by the author provides a new approach toward gender analysis which not only recognizes the role of economic empowerment and equal distribution of resources but suggests to incorporate the concept and role of social capital, equity, and doing gender in gender analysis which is based on perceived equity principle, putting men and women in complementing roles that may lead to equality. In this article the author reviews the mainstream gender theories in development from the viewpoint of the complementary roles of gender. This alternative view is argued based on existing literature and an anecdote of observations made by the author. While criticizing the equality theory, the author offers equity theory in resolving the gender conflict by using the concept of social and psychological capital.

  18. Effect of calorie restriction on spontaneous physical activity and body mass in mice divergently selected for basal metabolic rate (BMR).

    Science.gov (United States)

    Brzęk, Paweł; Gębczyński, Andrzej K; Książek, Aneta; Konarzewski, Marek

    2016-07-01

    Spontaneous physical activity (SPA) represents an important component of daily energy expenditures in animals and humans. Intra-specific variation in SPA may be related to the susceptibility to metabolic disease or obesity. In particular, reduced SPA under conditions of limited food availability may conserve energy and prevent loss of body and fat mass ('thrifty genotype hypothesis'). However, both SPA and its changes during food restriction show wide inter-individual variations. We studied the effect of 30% caloric restriction (CR) on SPA in laboratory mice divergently selected for high (H-BMR) and low (L-BMR) basal metabolic rate. Selection increased SPA in the H-BMR line but did not change it in the L-BMR mice. This effect reflected changes in SPA intensity but not SPA duration. CR increased SPA intensity more strongly in the L-BMR line than in the H-BMR line and significantly modified the temporal variation of SPA. However, the initial between-line differences in SPA were not affected by CR. Loss of body mass during CR did not differ between both lines. Our results show that the H-BMR mice can maintain their genetically determined high SPA under conditions of reduced food intake without sacrificing their body mass. We hypothesize that this pattern may reflect the higher flexibility in the energy budget in the H-BMR line, as we showed previously that mice from this line reduced their BMR during CR. These energy savings may allow for the maintenance of elevated SPA in spite of reduced food intake. We conclude that the effect of CR on SPA is in large part determined by the initial level of BMR, whose variation may account for the lack of universal pattern of behavioural responses to CR. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Association of exercise training and angiotensin-converting enzyme 2 activator improves baroreflex sensitivity of spontaneously hypertensive rats.

    Science.gov (United States)

    Lopes, P R; Moreira, M C S; Marques, S M; Pinto, I S J; Macedo, L M; Silva, C C; Freiria-Oliveira, A H; Rebelo, A C S; Reis, A A S; Rosa, D A; Ferreira-Neto, M L; Castro, C H; Pedrino, G R

    2016-08-01

    The present study sought to determine cardiovascular effects of aerobic training associated with diminazene aceturate (DIZE), an activator of the angiotensin converting enzyme 2, in spontaneously hypertensive rats (SHRs). Male SHRs (280-350 g) were either subjected to exercise training or not (sedentary group). The trained group was subjected to 8 weeks of aerobic training on a treadmill (five times a week, lasting 60 min at an intensity of 50-60% of maximum aerobic speed). In the last 15 days of the experimental protocol, these groups were redistributed into four groups: i) sedentary SHRs with daily treatment of 1 mg/kg DIZE (S+D1); ii) trained SHRs with daily treatment of 1 mg/kg DIZE (T+D1); iii) sedentary SHRs with daily treatment of vehicle (S+V); and iv) trained SHRs with daily treatment of vehicle (T+V). After treatment, SHRs were anesthetized and subjected to artery and femoral vein cannulation prior to the implantation of ECG electrode. After 24 h, mean arterial pressure (MAP) and heart rate (HR) were recorded; the baroreflex sensitivity and the effect of double autonomic blockade (DAB) were evaluated in non-anesthetized SHRs. DIZE treatment improved baroreflex sensitivity in the T+D1 group as compared with the T+V and S+D1 groups. The intrinsic heart rate (IHR) and MAP were reduced in T+D1 group as compared with T+V and S+D1 groups. Hence, we conclude that the association of exercise training with DIZE treatment improved baroreflex function and cardiovascular regulation.

  20. Functional Architecture of Noise Correlations in Human Early Visual Cortex and its Relationship with Coherent Spontaneous Activity

    Directory of Open Access Journals (Sweden)

    Jungwon Ryu

    2012-10-01

    Full Text Available Responses of single sensory neurons to stimuli are ‘noisy’, varying substantially across repeated trials of identical stimulation. Intriguingly, these individual ‘noise responses’ (NR—deviations from their means—are not isolated; rather they are highly correlated, referred to as ‘noise correlation’ (NC. From a computational viewpoint, the presence and nature of NC exert great impacts on the information processing capacity of neurons as they encode sensory events as a population, decode those encoded neural responses, and contribute to perceptual choices for action. Regarding the origin of NR, on the other hand, there has been growing evidence pointing to its tight linkage with ‘spontaneous responses’ (SR—fluctuations of neural activity in the absence of external input or tasks. To investigate the functional structure of NC and its relationship with ‘correlations in SR’ (SC, we defined population receptive fields (pRFs of unit volumes of gray matter (UV in human early visual cortex and computed NRs and SRs using fMRI. NC increased with an increasing degree of similarity in pRF tuning properties such as orientation, spatial frequency, and visuotopic position, particularly between UV pairs close in cortical distance. This ‘like-to-like’ structure of NC remained unaltered across scan runs with different stimuli, even among between-area UV pairs. SC was higher than NC, and its functional and temporal structures were quite similar to those of NC. Furthermore, the partial correlation analysis revealed that NC between a given pair of UVs was best predicted by their SC than by any other factors examined in the current study.

  1. Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future.

    Science.gov (United States)

    Risitano, Antonio M; Marotta, Serena

    2016-06-01

    The introduction in the clinic of anti-complement agents represented a major achievement which gave to physicians a novel etiologic treatment for different human diseases. Indeed, the first anti-complement agent eculizumab has changed the treatment paradigm of paroxysmal nocturnal hemoglobinuria (PNH), dramatically impacting its severe clinical course. In addition, eculizumab is the first agent approved for atypical Hemolytic Uremic Syndrome (aHUS), a life-threatening inherited thrombotic microangiopathy. Nevertheless, such remarkable milestone in medicine has brought to the fore additional challenges for the scientific community. Indeed, the list of complement-mediated anemias is not limited to PNH and aHUS, and other human diseases can be considered for anti-complement treatment. They include other thrombotic microangiopathies, as well as some antibody-mediated hemolytic anemias. Furthermore, more than ten years of experience with eculizumab led to a better understanding of the individual steps of the complement cascade involved in the pathophysiology of different human diseases. Based on this, new unmet clinical needs are emerging; a number of different strategies are currently under development to improve current anti-complement treatment, trying to address these specific clinical needs. They include: (i) alternative anti-C5 agents, which may improve the heaviness of eculizumab treatment; (ii) broad-spectrum anti-C3 agents, which may improve the efficacy of anti-C5 treatment by intercepting the complement cascade upstream (i.e., preventing C3-mediated extravascular hemolysis in PNH); (iii) targeted inhibitors of selective complement activating pathways, which may prevent early pathogenic events of specific human diseases (e.g., anti-classical pathway for antibody-mediated anemias, or anti-alternative pathway for PNH and aHUS). Here we briefly summarize the status of art of current and future complement inhibition for different complement-mediated anemias

  2. Pectoral fin beat frequency predicts oxygen consumption during spontaneous activity in a labriform swimming fish (Embiotoca lateralis)

    DEFF Research Database (Denmark)

    Tudorache, Christian; Jordan, Anders D.; Svendsen, Jon Christian

    2009-01-01

    The objective of this study was to identify kinematic variables correlated with oxygen consumption during spontaneous labriform swimming. Kinematic variables (swimming speed, change of speed, turning angle, turning rate, turning radius and pectoral fin beat frequency) and oxygen consumption (MO2......) of spontaneous swimming in Embiotoca lateralis were measured in a circular arena using video tracking and respirometry, respectively. The main variable influencing MO2 was pectoral fin beat frequency (r (2) = 0.71). No significant relationship was found between swimming speed and pectoral fin beat frequency...

  3. Spontaneous mechanical and electrical activities of human calf musculature at rest assessed by repetitive single-shot diffusion-weighted MRI and simultaneous surface electromyography.

    Science.gov (United States)

    Schwartz, Martin; Steidle, Günter; Martirosian, Petros; Ramos-Murguialday, Ander; Preißl, Hubert; Stemmer, Alto; Yang, Bin; Schick, Fritz

    2018-05-01

    Assessment of temporal and spatial relations between spontaneous mechanical activities in musculature (SMAM) at rest as revealed by diffusion-weighted imaging (DWI) and electrical muscular activities in surface EMG (sEMG). Potential influences of static and radiofrequency magnetic fields on muscular activity on sEMG measurements at rest were examined systematically. Series of diffusion-weighted stimulated echo planar imaging were recorded with concurrent sEMG measurements. Electrical activities in sEMG were analyzed by non-parametric Friedman and two-sample Kolmogorov-Smirnov test. Direct correlation of both modalities was investigated by temporal mapping of electrical activity in sEMG to DWI repetition interval. Electrical activities in sEMG and number of visible SMAMs in DWI showed a strong correlation (ρ = 0.9718). High accordance between sEMG activities and visible SMAMs in DWI in a near-surface region around sEMG electrodes was achieved. Characteristics of sEMG activities were almost similar under varying magnetic field conditions. Visible SMAMs in DWI have shown a close and direct relation to concurrent signals recorded by sEMG. MR-related magnetic fields had no significant effects on findings in sEMG. Hence, appearance of SMAMs in DWI should not be considered as imaging artifact or as effects originating from the special conditions of MR examinations. Spatial and temporal distributions of SMAMs indicate characteristics of spontaneous (microscopic) mechanical muscular action at rest. Therefore, DWI techniques should be considered as non-invasive tools for studying physiology and pathophysiology of spontaneous activities in resting muscle. Magn Reson Med 79:2784-2794, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

  4. Role of hindbrain melanocortin-4 receptor activity in controlling cardiovascular and metabolic functions in spontaneously hypertensive rats.

    Science.gov (United States)

    do Carmo, Jussara M; da Silva, Alexandre A; Hall, John E

    2015-06-01

    Although we previously demonstrated that activation of central nervous system (CNS) melanocortin3/4 receptors (MC3/4R) play a key role in blood pressure (BP) regulation, especially in spontaneously hypertensive rats (SHRs), the importance of hindbrain MC4R is still unclear. In the present study, we examined the cardiovascular and metabolic effects of chronic inhibition of MC3/4R in the hindbrain of SHRs and normotensive Wistar-Kyoto (WKY) rats. Male WKY rats (n = 6) and SHRs (n = 7) were implanted with telemetry probes to measure BP and heart rate (HR) 24 h/day, and an intracerebroventricular cannula was placed into the fourth ventricle. After 10 days of recovery and 5 days of control measurements, the MC3/4R antagonist (SHU-9119) was infused into the fourth ventricle (1 nmol/h) to antagonize hindbrain MC4R for 10 days, followed by a 5-day recovery period. Chronic hindbrain MC3/4R antagonism significantly increased food intake and body weight in WKY rats (17 ± 1 to 35 ± 2 g/day and 280 ± 8 to 353 ± 8 g) and SHRs (19 ± 2 to 35 ± 2 g/day and 323 ± 7 to 371 ± 11 g), and markedly increased fasting insulin and leptin levels while causing no changes in blood glucose levels (99 ± 4 to 87 ± 4 and 89 ± 5 to 89 ± 4 mg/dl, respectively, for WKY rats and SHRs). Chronic SHU-9119 infusion reduced mean arterial pressure and HR similarly in WKY rats (-8 ± 1 mmHg and -47 ± 3 b.p.m.) and SHRs (-11 ± 3 mmHg and -44 ± 3 b.p.m.). These results suggest that although hindbrain MC4R activity contributes to appetite and HR regulation, it does not play a major role in mediating the elevated BP in SHRs.

  5. Age-related weakening of baroreflex-mediated sympathetic activity in spontaneously hypertensive rats in response to blood pressure reduction.

    Science.gov (United States)

    Prados, P; Santa, T; Fukushima, T; Homma, H; Kasai, C; Martin, M A; del Castillo, B; Imai, K

    1998-09-01

    Nicardipine, a dihydropyridine type calcium channel blocker, was infused into 4-, 6-, and 23-wk-old spontaneously hypertensive (SH) and age-matched normotensive Wistar-Kyoto (WKY) rats (under sodium thiobutabarbital anesthesia and ventilation, n = 4) through the left femoral vein, resulting in the reduction of blood pressure. In each rat, mean arterial blood pressure, heart rate, and the concentration of plasma catecholamines (CAs), norepinephrine (NE), and epinephrine (E) were concomitantly determined, and the correlations between these three variables were studied. During the infusion of nicardipine, the plasma concentration of CAs was measured with an automatic detection system in blood samples collected from the right femoral artery of each rat. The reduction in blood pressure induced by nicardipine brought about an increase in plasma CA levels. The blood pressure correlated well with the logarithm of plasma NE or E concentration according to the formula Y= -alpha log (X) + m (Y, blood pressure; X, concentration of plasma NE or E; a, slope; and m, intercept). The slopes (as) of 6-wk-old and 23-wk-old SH rats were significantly greater than those of aged-matched WKY rats, meaning that the increment in plasma CAs in response to a decrease in blood pressure was smaller in SH than in WKY rats of similar ages. However, no significant differences were found between the as of 4-wk-old SH and WKY rats. We conclude that the increment in the baroreflex-mediated sympathetic activity in response to a drop in blood pressure induced by nicardipine is similar or greater in prehypertensive SH than in normotensive WKY 4-wk-old rats, while the increment becomes smaller in SH rats with the onset of hypertension (6-wk-old rats), and is much less in fully hypertensive adult (23-wk-old) SH rats than in age-matched WKY rats. On the basis of these findings and previous data obtained by neurography, we conclude that plasma CAs can be used to evaluate baroreflex-mediated sympathetic

  6. Primary angle-closure glaucomas disturb regional spontaneous brain activity in the visual pathway: an fMRI study

    Directory of Open Access Journals (Sweden)

    Chen W

    2017-05-01

    Full Text Available Wei Chen, Li Zhang, Yong-gen Xu, Kai Zhu, Man Luo Department of Ophthalmology, Shaoxing People’s Hospital, Shaoxing, Zhejiang, People’s Republic of China Objective: To explore the underlying regional brain activity deficits in the visual cortex in patients with primary angle-closure glaucoma (PACG relative to normal controls (NCs using regional homogeneity (ReHo method, and its relationship with behavioral performances. Patients: Twenty PACG patients (10 females, 10 males; mean age ± standard deviation [SD]: 54.42±9.46 years and 20 age-, and sex status-matched NCs (10 females, 10 males; mean age ± SD: 53.75±9.16 years were included in this study. Measurements and results: Compared with NCs, patients with PACG showed significant atrophic peripapillary retinal nerve fiber layer (pRNFL and neuroretinal rim area, increased optic disk cup-to-disc ratio (CDR and optic disk volume (P<0.05, higher ReHo value in the left fusiform gyrus, left cerebellum anterior lobe, right frontal-temporal space, and right insula, and lower ReHo value in the bilateral middle occipital gyrus, left claustrum, and right paracentral lobule lobe. The receiver operating characteristic analysis revealed these different areas with high value of area under curve, and high degree of sensitivity and specificity. The mean beta values of these different areas were extracted. In PACG, the duration of disease showed a negative correlation with the mean beta value of left cerebellum anterior lobe (r=-0.453, P=0.045 and a positive correlation with right middle occipital gyrus (r=0.586, P=0.007; left middle occipital gyrus showed positive correlations with duration of disease (r=0.562, P=0.01 and left pRNFL (r=0.49, P=0.028; left claustrum had a positive correlation with left CDR (r=0.515, P=0.02; and right paracentral lobule lobe demonstrated a positive correlation with left pRNFL (r=0.623, P=0.003. Conclusion: PACG is involved in abnormal spontaneous brain activity in multiple

  7. The ancestral complement system in sea urchins.

    Science.gov (United States)

    Smith, L C; Clow, L A; Terwilliger, D P

    2001-04-01

    The origin of adaptive immunity in the vertebrates can be traced to the appearance of the ancestral RAG genes in the ancestral jawed vertebrate; however, the innate immune system is more ancient. A central subsystem within innate immunity is the complement system, which has been identified throughout and seems to be restricted to the deuterostomes. The evolutionary history of complement can be traced from the sea urchins (members of the echinoderm phylum), which have a simplified system homologous to the alternative pathway, through the agnathans (hagfish and lamprey) and the elasmobranchs (sharks and rays) to the teleosts (bony fish) and tetrapods, with increases in the numbers of complement components and duplications in complement pathways. Increasing complexity in the complement system parallels increasing complexity in the deuterostome animals. This review focuses on the simplest of the complement systems that is present in the sea urchin. Two components have been identified that show significant homology to vertebrate C3 and factor B (Bf), called SpC3 and SpBf, respectively. Sequence analysis from both molecules reveals their ancestral characteristics. Immune challenge of sea urchins indicates that SpC3 is inducible and is present in coelomic fluid (the body fluids) in relatively high concentrations, while SpBf expression is constitutive and is present in much lower concentrations. Opsonization of foreign cells and particles followed by augmented uptake by phagocytic coelomocytes appears to be a central function for this simpler complement system and important for host defense in the sea urchin. These activities are similar to some of the functions of the homologous proteins in the vertebrate complement system. The selective advantage for the ancestral deuterostome may have been the amplification feedback loop that is still of central importance in the alternative pathway of complement in higher vertebrates. Feedback loop functions would quickly coat

  8. Conditional firing probabilities in cultured neuronal networks: a stable underlying structure in widely varying spontaneous activity patterns

    NARCIS (Netherlands)

    le Feber, Jakob; Rutten, Wim; Stegenga, J.; Wolters, P.S.; Ramakers, G.J.A.; van Pelt, J.

    2007-01-01

    To properly observe induced connectivity changes after training sessions, one needs a network model that describes individual relationships in sufficient detail to enable observation of induced changes and yet reveals some kind of stability in these relationships. We analyzed spontaneous firing

  9. Immune complex detection and complement activity in rheumatoid arthritis: a comparative study of a radioimmunoassay using monoclonal rheumatoid factor, gel diffusion techniques and C4 activity

    International Nuclear Information System (INIS)

    Halla, J.T.; Volanakis, J.E.; Hardin, J.G.; Schrohenloher, R.E.

    1978-01-01

    Paired sera and synovial fluids from 49 patients with rheumatoid arthritis and 25 with other forms of arthritis were tested for immune complexes by a radioimmunoa