Science.gov

Sample records for d3-modified regulatory dendritic

  1. Regulatory Dendritic Cells for Immunotherapy in Immunologic Diseases

    PubMed Central

    Gordon, John R.; Ma, Yanna; Churchman, Laura; Gordon, Sara A.; Dawicki, Wojciech

    2013-01-01

    We recognize well the abilities of dendritic cells to activate effector T cell (Teff cell) responses to an array of antigens and think of these cells in this context as pre-eminent antigen-presenting cells, but dendritic cells are also critical to the induction of immunologic tolerance. Herein, we review our knowledge on the different kinds of tolerogenic or regulatory dendritic cells that are present or can be induced in experimental settings and humans, how they operate, and the diseases in which they are effective, from allergic to autoimmune diseases and transplant tolerance. The primary conclusions that arise from these cumulative studies clearly indicate that the agent(s) used to induce the tolerogenic phenotype and the status of the dendritic cell at the time of induction influence not only the phenotype of the dendritic cell, but also that of the regulatory T cell responses that they in turn mobilize. For example, while many, if not most, types of induced regulatory dendritic cells lead CD4+ naïve or Teff cells to adopt a CD25+Foxp3+ Treg phenotype, exposure of Langerhans cells or dermal dendritic cells to vitamin D leads in one case to the downstream induction of CD25+Foxp3+ regulatory T cell responses, while in the other to Foxp3− type 1 regulatory T cells (Tr1) responses. Similarly, exposure of human immature versus semi-mature dendritic cells to IL-10 leads to distinct regulatory T cell outcomes. Thus, it should be possible to shape our dendritic cell immunotherapy approaches for selective induction of different types of T cell tolerance or to simultaneously induce multiple types of regulatory T cell responses. This may prove to be an important option as we target diseases in different anatomic compartments or with divergent pathologies in the clinic. Finally, we provide an overview of the use and potential use of these cells clinically, highlighting their potential as tools in an array of settings. PMID:24550907

  2. Prospective Clinical Testing of Regulatory Dendritic Cells in Organ Transplantation

    PubMed Central

    Thomson, Angus W.; Zahorchak, Alan F.; Ezzelarab, Mohamed B.; Butterfield, Lisa H.; Lakkis, Fadi G.; Metes, Diana M.

    2016-01-01

    Dendritic cells (DC) are rare, professional antigen-presenting cells with ability to induce or regulate alloimmune responses. Regulatory DC (DCreg) with potential to down-modulate acute and chronic inflammatory conditions that occur in organ transplantation can be generated in vitro under a variety of conditions. Here, we provide a rationale for evaluation of DCreg therapy in clinical organ transplantation with the goal of promoting sustained, donor-specific hyporesponsiveness, while lowering the incidence and severity of rejection and reducing patients’ dependence on anti-rejection drugs. Generation of donor- or recipient-derived DCreg that suppress T cell responses and prolong transplant survival in rodents or non-human primates has been well-described. Recently, good manufacturing practice (GMP)-grade DCreg have been produced at our Institution for prospective use in human organ transplantation. We briefly review experience of regulatory immune therapy in organ transplantation and describe our experience generating and characterizing human monocyte-derived DCreg. We propose a phase I/II safety study in which the influence of donor-derived DCreg combined with conventional immunosuppression on subclinical and clinical rejection and host alloimmune responses will be examined in detail. PMID:26858719

  3. How tolerogenic dendritic cells induce regulatory T cells

    PubMed Central

    Maldonado, Roberto A.; von Andrian, Ulrich H.

    2010-01-01

    Since their discovery by Steinman and Cohn in 1973, dendritic cells (DCs) have become increasingly recognized for their crucial role as regulators of innate and adaptive immunity. DCs are exquisitely adept at acquiring, processing and presenting antigens to T cells. They also adjust the context (and hence the outcome) of antigen presentation in response to a plethora of environmental inputs that signal the occurence of pathogens or tissue damage. Such signals generally boost DC maturation, which promotes their migration from peripheral tissues into and within secondary lymphoid organs and their capacity to induce and regulate effector T cell responses. Conversely, more recent observations indicate that DCs are also crucial to ensure immunological peace. Indeed, DCs constantly present innocuous self and non-self antigens in a fashion that promotes tolerance, at least in part, through the control of regulatory T cells (Tregs). Tregs are specialized T cells that exert their immuno-suppressive function through a variety of mechanisms affecting both DCs and effector cells. Here, we review recent advances in our understanding of the relationship between tolerogenic DCs and Tregs. PMID:21056730

  4. Tolerogenic Dendritic Cells for Regulatory T Cell Induction in Man

    PubMed Central

    Raker, Verena K.; Domogalla, Matthias P.; Steinbrink, Kerstin

    2015-01-01

    Dendritic cells (DCs) are highly specialized professional antigen-presenting cells that regulate immune responses, maintaining the balance between tolerance and immunity. Mechanisms via which they can promote central and peripheral tolerance include clonal deletion, the inhibition of memory T cell responses, T cell anergy, and induction of regulatory T cells (Tregs). These properties have led to the analysis of human tolerogenic DCs as a therapeutic strategy for the induction or re-establishment of tolerance. In recent years, numerous protocols for the generation of human tolerogenic DCs have been developed and their tolerogenic mechanisms, including induction of Tregs, are relatively well understood. Phase I trials have been conducted in autoimmune disease, with results that emphasize the feasibility and safety of treatments with tolerogenic DCs. Therefore, the scientific rationale for the use of tolerogenic DCs therapy in the fields of transplantation medicine and allergic and autoimmune diseases is strong. This review will give an overview on efforts and protocols to generate human tolerogenic DCs with focus on IL-10-modulated DCs as inducers of Tregs and discuss their clinical applications and challenges faced in further developing this form of immunotherapy. PMID:26617604

  5. Orchestration of transplantation tolerance by regulatory dendritic cell therapy or in situ targeting of dendritic cells

    PubMed Central

    Morelli, Adrian E.; Thomson, Angus W.

    2014-01-01

    Purpose of review Extensive research in murine transplant models over the past two decades has convincingly demonstrated the ability of regulatory dendritic cells (DCreg) to promote long-term allograft survival. We review important considerations regarding the source of therapeutic DCreg (donor or recipient) and their mode of action, in situ targeting of DCreg, and optimal therapeutic regimens to promote DCreg function. Recent findings Recent studies have defined protocols and mechanisms whereby ex vivo-generated DCreg of donor or recipient origin subvert allogeneic T cell responses and promote long-term organ transplant survival. Particular interest has focused on how donor antigen (Ag) is acquired, processed and presented by autologous DCs, on the stability of DCreg, and on in situ targeting of DC to promote their tolerogenic function. New evidence of the therapeutic efficacy of DCreg in a clinically-relevant non-human primate organ transplant model and production of clinical grade DCreg support early evaluation of DCreg therapy in human graft recipients. Summary We discuss strategies currently used to promote DC tolerogenicity, including DCreg therapy and in situ targeting of DC, with a view to improved understanding of underlying mechanisms and identification of the most promising strategies for therapeutic application. PMID:24926700

  6. Trypanosoma cruzi Induces Regulatory Dendritic Cells In Vitro▿

    PubMed Central

    Poncini, Carolina Verónica; Soto, Catalina Dirney Alba; Batalla, Estela; Solana, Maria Elisa; González Cappa, Stella Maris

    2008-01-01

    A main feature of acute infection with Trypanosoma cruzi is the presence of immunological disorders. A previous study demonstrated that acute infection with the virulent RA strain downregulates the expression of major histocompatibility complex class II (MHC-II) on antigen-presenting cells and impairs the T-cell stimulatory capacity of splenic dendritic cells (DC). In the present work, we assessed the ability of trypomastigotes (Tp) to modulate the differentiation stage and functionality of bone marrow-derived DC in vitro. We observed that the Tp stage of T. cruzi failed to activate DC, which preserved their low expression of MHC-II and costimulatory molecules, as well as their endocytic activity. We also show that Tp induced transforming growth factor β (TGF-β) secretion by DC and enhanced the gap between interleukin-10 (IL-10) and IL-12p70 production, showing a higher IL-10/IL-12p70 ratio upon lipopolysaccharide (LPS) treatment. In addition, we observed that Tp prevented DC full activation induced by LPS, thereby downregulating their MHC-II surface expression and inhibiting their capacity to stimulate lymphocyte proliferation. In vitro IL-10 neutralization during the differentiation process of DC with Tp+LPS showed a reversion of their inhibitory effect during mixed lymphocyte reaction. In contrast, only simultaneous neutralization of IL-10 and TGF-β, after DC differentiation, was involved in the partial restitution of lymphocyte proliferation. Since both TGF-β and IL-10 are immunosuppressive cytokines essential in the modulation of the immune response and important in the induction of tolerance, our results suggest for the first time that Tp are responsible for the generation of regulatory DC in vitro. PMID:18347042

  7. Regulatory dendritic cells: there is more than just immune activation

    PubMed Central

    Schmidt, Susanne V.; Nino-Castro, Andrea C.; Schultze, Joachim L.

    2012-01-01

    The immune system exists in a delicate equilibrium between inflammatory responses and tolerance. This unique feature allows the immune system to recognize and respond to potential threats in a controlled but normally limited fashion thereby preventing a destructive overreaction against healthy tissues. While the adaptive immune system was the major research focus concerning activation vs. tolerance in the immune system more recent findings suggest that cells of the innate immune system are important players in the decision between effective immunity and induction of tolerance or immune inhibition. Among immune cells of the innate immune system dendritic cells (DCs) have a special function linking innate immune functions with the induction of adaptive immunity. DCs are the primary professional antigen presenting cells (APCs) initiating adaptive immune responses. They belong to the hematopoietic system and arise from CD34+ stem cells in the bone marrow. Particularly in the murine system two major subgroups of DCs, namely myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) can be distinguished. DCs are important mediators of innate and adaptive immunity mostly due to their remarkable capacity to present processed antigens via major histocompatibility complexes (MHC) to T cells and B cells in secondary lymphoid organs. A large body of literature has been accumulated during the last two decades describing which role DCs play during activation of T cell responses but also during the establishment and maintenance of central tolerance (Steinman et al., 2003). While the concept of peripheral tolerance has been clearly established during the last years, the role of different sets of DCs and their particular molecular mechanisms of immune deviation has not yet fully been appreciated. In this review we summarize accumulating evidence about the role of regulatory DCs in situations where the balance between tolerance and immunogenicity has been altered leading to pathologic

  8. The Effect of Traditional Chinese Formula Danchaiheji on the Differentiation of Regulatory Dendritic Cells

    PubMed Central

    Wang, Xiaodong; Tong, Jingzhi; Li, Keqiu; Jing, Yaqing

    2016-01-01

    Recently, regulatory dendritic cells (DCregs), a newly described dendritic cell subset with potent immunomodulatory function, have attracted increased attention for their utility in treating immune response-related diseases, such as graft-versus-host disease, hypersensitivity, and autoimmune diseases. Danchaiheji (DCHJ) is a traditional Chinese formula that has been used for many years in the clinic. However, whether DCHJ can program dendritic cells towards a regulatory phenotype and the underlying mechanism behind this process remain unknown. Herein, we investigate the effects of traditional Chinese DCHJ on DCregs differentiation and a mouse model of skin transplantation. The current study demonstrates that DCHJ can induce dendritic cells to differentiate into DCregs, which are represented by high CD11b and low CD86 and HLA-DR expression as well as the secretion of IL-10 and TGF-β. In addition, DCHJ inhibited DC migration and T cell proliferation, which correlated with increased IDO expression. Furthermore, DCHJ significantly prolonged skin graft survival time in a mouse model of skin transplantation without any liver or kidney toxicity. The traditional Chinese formula DCHJ has the potential to be a potent immunosuppressive agent with high efficiency and nontoxicity. PMID:27525028

  9. Expression of regulatory dendritic cell-related cytokines in cattle experimentally infected with Trypanosoma evansi

    PubMed Central

    MEKATA, Hirohisa; MURATA, Shiro; MINGALA, Claro Niegos; OHASHI, Kazuhiko; KONNAI, Satoru

    2015-01-01

    Trypanosoma evansi causes wasting disease in many livestock. T. evansi infection gives rise to inflammatory immune responses, which contribute to the development of inflammation-associated tissue injury. We previously reported that regulatory dendritic cells (DCs), which act as potential regulators of inflammation, were activated in infected mice and transfer of regulatory DCs to infected mice prolonged their survival. However, the kinetics of regulatory DCs in cattle, which are natural hosts of T. evansi, remained unclear. In this study, we report that the expressions of CCL8 and IL-10, which promote the development of regulatory DCs, were up-regulated in cattle experimentally infected with T. evansi. This finding is potentially useful for studying the control strategy of T. evansi infection in cattle. PMID:25819543

  10. Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms.

    PubMed

    Cobbold, Stephen P; Nolan, Kathleen F; Graca, Luis; Castejon, Raquel; Le Moine, Alain; Frewin, Mark; Humm, Susan; Adams, Elizabeth; Thompson, Sara; Zelenika, Diana; Paterson, Alison; Yates, Stephen; Fairchild, Paul J; Waldmann, Herman

    2003-12-01

    Transplantation tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two well-characterized populations of T cells, demonstrating regulatory capacity: the "natural" CD4+CD25+ T cells and the interleukin (IL)-10-producing Tr1 cells. Although both types of regulatory T cells can induce transplantation tolerance under appropriate conditions, it is not clear whether either one plays any role in drug-induced dominant tolerance, primarily due to a lack of clear-cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T-cell and antigen-presenting cell libraries to identify gene-expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1-like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4+CD25+ regulatory T cells from the spleen. DCs that were treated with the tolerance-enhancing agents IL-10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells. PMID:14617201

  11. A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus

    PubMed Central

    Menon, Madhvi; Blair, Paul A.; Isenberg, David A.; Mauri, Claudia

    2016-01-01

    Summary Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an “auto”-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24+CD38hi Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24+CD38hi Breg cells conversely restrained IFN-α production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α. Defective pDC-mediated expansion of CD24+CD38hi Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24+CD38hi Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24+CD38hi Breg cell interaction contributes to the pathogenesis of SLE. PMID:26968426

  12. Antibody Targeting of “Steady-State” Dendritic Cells Induces Tolerance Mediated by Regulatory T Cells

    PubMed Central

    Mahnke, Karsten; Ring, Sabine; Enk, Alexander H.

    2016-01-01

    Dendritic cells (DCs) are often defined as pivotal inducers of immunity, but these proinflammatory properties only develop after stimulation or ex vivo manipulation of DCs. Under non-inflammatory conditions in vivo, DCs are embedded into a tissue environment and encounter a plethora of self-antigens derived from apoptotic material. This material is transported to secondary lymphoid organs. As DCs maintain their non-activated phenotype in a sterile tissue environment, interaction with T cells will induce rather regulatory T cells than effector T cells. Thus, DCs are not only inducers of immunity but are also critical for maintenance of peripheral tolerance. Therapeutically, intervention for the induction of long-lasting tolerance in several autoimmune conditions may therefore be possible by manipulating DC activation and/or targeting of DCs in their “natural” tissue environment. PMID:26941742

  13. Drosophila Valosin-Containing Protein is required for dendrite pruning through a regulatory role in mRNA metabolism

    PubMed Central

    Rumpf, Sebastian; Bagley, Joshua A.; Thompson-Peer, Katherine L.; Zhu, Sijun; Gorczyca, David; Beckstead, Robert B.; Jan, Lily Yeh; Jan, Yuh Nung

    2014-01-01

    The dendritic arbors of the larval Drosophila peripheral class IV dendritic arborization neurons degenerate during metamorphosis in an ecdysone-dependent manner. This process—also known as dendrite pruning—depends on the ubiquitin–proteasome system (UPS), but the specific processes regulated by the UPS during pruning have been largely elusive. Here, we show that mutation or inhibition of Valosin-Containing Protein (VCP), a ubiquitin-dependent ATPase whose human homolog is linked to neurodegenerative disease, leads to specific defects in mRNA metabolism and that this role of VCP is linked to dendrite pruning. Specifically, we find that VCP inhibition causes an altered splicing pattern of the large pruning gene molecule interacting with CasL and mislocalization of the Drosophila homolog of the human RNA-binding protein TAR–DNA-binding protein of 43 kilo-Dalton (TDP-43). Our data suggest that VCP inactivation might lead to specific gain-of-function of TDP-43 and other RNA-binding proteins. A similar combination of defects is also seen in a mutant in the ubiquitin-conjugating enzyme ubcD1 and a mutant in the 19S regulatory particle of the proteasome, but not in a 20S proteasome mutant. Thus, our results highlight a proteolysis-independent function of the UPS during class IV dendritic arborization neuron dendrite pruning and link the UPS to the control of mRNA metabolism. PMID:24799714

  14. Targeted genomic sequencing of follicular dendritic cell sarcoma reveals recurrent alterations in NF-κB regulatory genes.

    PubMed

    Griffin, Gabriel K; Sholl, Lynette M; Lindeman, Neal I; Fletcher, Christopher D M; Hornick, Jason L

    2016-01-01

    Follicular dendritic cell sarcoma is a rare mesenchymal neoplasm with a variable and unpredictable clinical course. The genetic alterations that drive tumorigenesis in follicular dendritic cell sarcoma are largely unknown. One recent study performed BRAF sequencing and found V600E mutations in 5 of 27 (19%) cases. No other recurrent genetic alterations have been reported. The aim of the present study was to identify somatic alterations in follicular dendritic cell sarcoma by targeted sequencing of a panel of 309 known cancer-associated genes. DNA was isolated from formalin-fixed paraffin-embedded tissue from 13 cases of follicular dendritic cell sarcoma and submitted for hybrid capture-based enrichment and massively parallel sequencing with the Illumina HiSeq 2500 platform. Recurrent loss-of-function alterations were observed in tumor suppressor genes involved in the negative regulation of NF-κB activation (5 of 13 cases, 38%) and cell cycle progression (4 of 13 cases, 31%). Loss-of-function alterations in the NF-κB regulatory pathway included three cases with frameshift mutations in NFKBIA and two cases with bi-allelic loss of CYLD. Both cases with CYLD loss were metastases and carried concurrent alterations in at least one cell cycle regulatory gene. Alterations in cell cycle regulatory genes included two cases with bi-allelic loss of CDKN2A, one case with bi-allelic loss of RB1, and one case with a nonsense mutation in RB1. Last, focal copy-number gain of chromosome 9p24 including the genes CD274 (PD-L1) and PDCD1LG2 (PD-L2) was noted in three cases, which represents a well-described mechanism of immune evasion in cancer. These findings provide the first insight into the unique genomic landscape of follicular dendritic cell sarcoma and suggest shared mechanisms of tumorigenesis with a subset of other tumor types, notably B-cell lymphomas.

  15. Induction of CD4+ Regulatory and Polarized Effector/helper T Cells by Dendritic Cells

    PubMed Central

    2016-01-01

    Dendritic cells (DCs) are considered to play major roles during the induction of T cell immune responses as well as the maintenance of T cell tolerance. Naive CD4+ T cells have been shown to respond with high plasticity to signals inducing their polarization into effector/helper or regulatory T cells. Data obtained from in vitro generated bone-marrow (BM)-derived DCs as well as genetic mouse models revealed an important but not exclusive role of DCs in shaping CD4+ T cell responses. Besides the specialization of some conventional DC subsets for the induction of polarized immunity, also the maturation stage, activation of specialized transcription factors and the cytokine production of DCs have major impact on CD4+ T cells. Since in vitro generated BM-DCs show a high diversity to shape CD4+ T cells and their high similarity to monocyte-derived DCs in vivo, this review reports data mainly on BM-DCs in this process and only touches the roles of transcription factors or of DC subsets, which have been discussed elsewhere. Here, recent findings on 1) the conversion of naive into anergic and further into Foxp3− regulatory T cells (Treg) by immature DCs, 2) the role of RelB in steady state migratory DCs (ssmDCs) for conversion of naive T cells into Foxp3+ Treg, 3) the DC maturation signature for polarized Th2 cell induction and 4) the DC source of IL-12 for Th1 induction are discussed. PMID:26937228

  16. Dendritic Cells Coordinate the Development and Homeostasis of Organ-Specific Regulatory T Cells.

    PubMed

    Leventhal, Daniel S; Gilmore, Dana C; Berger, Julian M; Nishi, Saki; Lee, Victoria; Malchow, Sven; Kline, Douglas E; Kline, Justin; Vander Griend, Donald J; Huang, Haochu; Socci, Nicholas D; Savage, Peter A

    2016-04-19

    Although antigen recognition mediated by the T cell receptor (TCR) influences many facets of Foxp3(+) regulatory T (Treg) cell biology, including development and function, the cell types that present antigen to Treg cells in vivo remain largely undefined. By tracking a clonal population of Aire-dependent, prostate-specific Treg cells in mice, we demonstrated an essential role for dendritic cells (DCs) in regulating organ-specific Treg cell biology. We have shown that the thymic development of prostate-specific Treg cells required antigen presentation by DCs. Moreover, Batf3-dependent CD8α(+) DCs were dispensable for the development of this clonotype and had negligible impact on the polyclonal Treg cell repertoire. In the periphery, CCR7-dependent migratory DCs coordinated the activation of organ-specific Treg cells in the prostate-draining lymph nodes. Our results demonstrate that the development and peripheral regulation of organ-specific Treg cells are dependent on antigen presentation by DCs, implicating DCs as key mediators of organ-specific immune tolerance.

  17. Interleukin 10 and dendritic cells are the main suppression mediators of regulatory T cells in human neurocysticercosis.

    PubMed

    Arce-Sillas, A; Álvarez-Luquín, D D; Cárdenas, G; Casanova-Hernández, D; Fragoso, G; Hernández, M; Proaño Narváez, J V; García-Vázquez, F; Fleury, A; Sciutto, E; Adalid-Peralta, L

    2016-02-01

    Neurocysticercosis is caused by the establishment of Taenia solium cysticerci in the central nervous system. It is considered that, during co-evolution, the parasite developed strategies to modulate the host's immune response. The action mechanisms of regulatory T cells in controlling the immune response in neurocysticercosis are studied in this work. Higher blood levels of regulatory T cells with CD4(+) CD45RO(+) forkhead box protein 3 (FoxP3)(high) and CD4(+) CD25(high) FoxP3(+) CD95(high) phenotype and of non-regulatory CD4(+) CD45RO(+) FoxP3(med) T cells were found in neurocysticercosis patients with respect to controls. Interestingly, regulatory T cells express higher levels of cytotoxic T lymphocyte antigen 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1) and glucocorticoid-induced tumour necrosis factor receptor (GITR), suggesting a cell-to-cell contact mechanism with dendritic cells. Furthermore, higher IL-10 and regulatory T cell type 1 (Tr1) levels were found in neurocysticercosis patients' peripheral blood, suggesting that the action mechanism of regulatory T cells involves the release of immunomodulatory cytokines. No evidence was found of the regulatory T cell role in inhibiting the proliferative response. Suppressive regulatory T cells from neurocysticercosis patients correlated negatively with late activated lymphocytes (CD4(+) CD38(+) ). Our results suggest that, during neurocysticercosis, regulatory T cells could control the immune response, probably by a cell-to-cell contact with dendritic cells and interleukin (IL)-10 release by Tr1, to create an immunomodulatory environment that may favour the development of T. solium cysticerci and their permanence in the central nervous system.

  18. Dendritic Cells in the Periphery Control Antigen-Specific Natural and Induced Regulatory T Cells

    PubMed Central

    Yamazaki, Sayuri; Morita, Akimichi

    2013-01-01

    Dendritic cells (DCs) are specialized antigen-presenting cells that regulate both immunity and tolerance. DCs in the periphery play a key role in expanding naturally occurring Foxp3+ CD25+ CD4+ regulatory T cells (Natural T-regs) and inducing Foxp3 expression (Induced T-regs) in Foxp3− CD4+ T cells. DCs are phenotypically and functionally heterogeneous, and further classified into several subsets depending on distinct marker expression and their location. Recent findings indicate the presence of specialized DC subsets that act to expand Natural T-regs or induce Foxp3+ T-regs from Foxp3− CD4+ T cells. For example, two major subsets of DCs in lymphoid organs act differentially in inducing Foxp3+ T-regs from Foxp3− cells or expanding Natural T-regs with model-antigen delivery by anti-DC subset monoclonal antibodies in vivo. Furthermore, DCs expressing CD103 in the intestine induce Foxp3+ T-regs from Foxp3− CD4+ T cells with endogenous TGF-β and retinoic acid. In addition, antigen-presenting DCs have a capacity to generate Foxp3+ T-regs in the oral cavity where many antigens and commensals exist, similar to intestine and skin. In skin and skin-draining lymph nodes, at least six DC subsets have been identified, suggesting a complex DC-T-reg network. Here, we will review the specific activity of DCs in expanding Natural T-regs and inducing Foxp3+ T-regs from Foxp3− precursors, and further discuss the critical function of DCs in maintaining tolerance at various locations including skin and oral cavity. PMID:23801989

  19. Characterization of regulatory dendritic cells differentiated from the bone marrow of UV-irradiated mice.

    PubMed

    Ng, Royce L X; Scott, Naomi M; Bisley, Jackie L; Lambert, Misty J; Gorman, Shelley; Norval, Mary; Hart, Prue H

    2013-12-01

    When antigen-loaded dendritic cells (DCs) differentiated from the bone marrow (BM) of UV-irradiated mice (UV-BMDCs) were adoptively transferred into naive mice or mice pre-sensitized with that antigen, the recipients exhibited a reduced immune response following antigen challenge. Hence, UV-BMDCs are poorly immunogenic and can suppress pre-existing immunity. The UV-induced effect on BM-derived DCs was rapid (observed 1 day after UV radiation), long-lasting (observed 10 days after UV radiation) and UV dose-dependent. The mechanism by which UV-BMDCs could regulate immunity was investigated. The CD11c(+) cells, differentiated using granulocyte-macrophage colony-stimulating factor + interleukin-4, were confirmed to be DCs because they did not express the myeloid-derived suppressor cell marker, Gr1. UV-BMDCs did not display altered antigen uptake, processing or ability to activate T cells in vitro. When gene expression in UV-BMDCs and DCs differentiated from the BM of non-irradiated mice (control-BMDCs) was examined, Ccl7, Ccl8 and CSF1R (CD115) mRNA transcripts were up-regulated in UV-BMDCs compared with control-BMDCs. However, neutralizing antibodies for Ccl7 and Ccl8 did not abrogate the reduced immunogenicity of UV-BMDCs in vivo. Moreover, the up-regulation of CSF1R transcript did not correspond with increased receptor expression on UV-BMDCs. The phenotypes of UV-BMDCs and control-BMDCs were similar, with no difference in the expression of CD4, CD8α, CD103, B220 or F4/80, or the regulatory molecules CCR7 (CD197), FasL (CD95L), B7H3 (CD276) and B7H4. However, PDL1 (CD274) expression was reduced in UV-BMDCs compared with control-BMDCs following lipopolysaccharide stimulation. In summary, UV-BMDCs do not express the classical phenotypic or gene expression properties of DCs reported by others as 'regulatory' or 'tolerogenic'. PMID:23826713

  20. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation.

    PubMed

    Cheng, J-T; Deng, Y-N; Yi, H-M; Wang, G-Y; Fu, B-S; Chen, W-J; Liu, W; Tai, Y; Peng, Y-W; Zhang, Q

    2016-02-22

    Although carcinoma-associated fibroblasts (CAFs) in tumor microenvironments have a critical role in immune cell modulation, their effects on the generation of regulatory dendritic cells (DCs) are still unclear. In this study, we initially show that CAFs derived from hepatocellular carcinoma (HCC) tumors facilitate the generation of regulatory DCs, which are characterized by low expression of costimulatory molecules, high suppressive cytokines production and enhanced regulation of immune responses, including T-cell proliferation impairment and promotion of regulatory T-cell (Treg) expansion via indoleamine 2,3-dioxygenase (IDO) upregulation. Our findings also indicate that STAT3 activation in DCs, as mediated by CAF-derived interleukin (IL)-6, is essential to IDO production. Moreover, IDO inhibitor, STAT3 and IL-6 blocking antibodies can reverse this hepatic CAF-DC regulatory function. Therefore, our results provide new insights into the mechanisms by which CAFs induce tumor immune escape as well as a novel cancer immunotherapeutic approach (for example, targeting CAFs, IDO or IL-6).

  1. Classical dendritic cells are required for dietary antigen-mediated peripheral regulatory T cell and tolerance induction

    PubMed Central

    Esterházy, Daria; Loschko, Jakob; London, Mariya; Jove, Veronica; Oliveira, Thiago Y.; Mucida, Daniel

    2016-01-01

    Oral tolerance prevents pathological inflammatory responses towards innocuous foreign antigens via peripheral regulatory T cells (pTreg cells). However, whether a particular subset of antigen-presenting cells (APCs) is required during dietary antigen exposure to instruct naïve CD4+ T cells to differentiate into pTreg cells has not been defined. Using myeloid lineage-specific APC depletion in mice, we found that monocyte-derived APCs are dispensable, while classical dendritic cells (cDCs) are critical for pTreg cell induction and oral tolerance. CD11b− cDCs from the gut-draining lymph nodes efficiently induced pTreg cells, and conversely, loss of IRF8-dependent CD11b− cDCs impaired their polarization, although oral tolerance remained intact. These data reveal the hierarchy of cDC subsets in pTreg cell induction and their redundancy during oral tolerance development. PMID:27019226

  2. Generation of regulatory dendritic cells and CD4+Foxp3+ T cells by probiotics administration suppresses immune disorders.

    PubMed

    Kwon, Ho-Keun; Lee, Choong-Gu; So, Jae-Seon; Chae, Chang-Suk; Hwang, Ji-Sun; Sahoo, Anupama; Nam, Jong Hee; Rhee, Joon Haeng; Hwang, Ki-Chul; Im, Sin-Hyeog

    2010-02-01

    The beneficial effects of probiotics have been described in many diseases, but the mechanism by which they modulate the immune system is poorly understood. In this study, we identified a mixture of probiotics that up-regulates CD4(+)Foxp3(+) regulatory T cells (Tregs). Administration of the probiotics mixture induced both T-cell and B-cell hyporesponsiveness and down-regulated T helper (Th) 1, Th2, and Th17 cytokines without apoptosis induction. It also induced generation of CD4(+)Foxp3(+) Tregs from the CD4(+)CD25(-) population and increased the suppressor activity of naturally occurring CD4(+)CD25(+) Tregs. Conversion of T cells into Foxp3(+) Tregs is directly mediated by regulatory dendritic cells (rDCs) that express high levels of IL-10, TGF-beta, COX-2, and indoleamine 2,3-dioxygenase. Administration of probiotics had therapeutical effects in experimental inflammatory bowel disease, atopic dermatitis, and rheumatoid arthritis. The therapeutical effect of the probiotics is associated with enrichment of CD4(+)Foxp3(+) Tregs in the inflamed regions. Collectively, the administration of probiotics that enhance the generation of rDCs and Tregs represents an applicable treatment of inflammatory immune disorders.

  3. CD8α+ Dendritic cells prime TCR-peptide-reactive regulatory CD4+FOXP3− T cells

    PubMed Central

    Smith, Trevor R. F.; Maricic, Igor; Ria, Francesco; Schneider, Susan; Kumar, Vipin

    2011-01-01

    Summary CD4+ T cells with immune regulatory function can be either FOXP3+ or FOXP3−. We have previously shown that priming of naturally occurring TCR-peptide-reactive regulatory CD4+FOXP3− T cells (Treg) specifically controls Vβ8.2+CD4+ T cells mediating experimental autoimmune encephalomyelitis (EAE). However, the mechanism by which these Treg are primed to recognize their cognate antigenic determinant, which is derived from the TCRVβ8.2-chain, is not known. In this study we show that antigen presenting cells (APC) derived from splenocytes of naïve mice are able to stimulate cloned CD4+ Treg in the absence of exogenous antigen, and their stimulation capacity is augmented during EAE. Among the APC populations DC were the most efficient in stimulating the Treg. Stimulation of CD4+ Treg was dependent upon processing and presentation of TCR peptides from ingested Vβ8.2TCR+ CD4+ T cells. Additionally, dendritic cells pulsed with TCR peptide or apoptotic Vβ8.2+ T cells are able to prime Treg in vivo and mediate protection from disease in a CD8-dependent fashion. These data highlight a novel mechanism for the priming of CD4+ Treg by CD8α+ DC, and suggest a pathway that can be exploited to prime antigen-specific regulation of T cell-mediated inflammatory disease. PMID:20394075

  4. Trypanosoma cruzi Infection Imparts a Regulatory Program in Dendritic Cells and T Cells via Galectin-1-Dependent Mechanisms.

    PubMed

    Poncini, Carolina V; Ilarregui, Juan M; Batalla, Estela I; Engels, Steef; Cerliani, Juan P; Cucher, Marcela A; van Kooyk, Yvette; González-Cappa, Stella M; Rabinovich, Gabriel A

    2015-10-01

    Galectin-1 (Gal-1), an endogenous glycan-binding protein, is widely distributed at sites of inflammation and microbial invasion. Despite considerable progress regarding the immunoregulatory activity of this lectin, the role of endogenous Gal-1 during acute parasite infections is uncertain. In this study, we show that Gal-1 functions as a negative regulator to limit host-protective immunity following intradermal infection with Trypanosoma cruzi. Concomitant with the upregulation of immune inhibitory mediators, including IL-10, TGF-β1, IDO, and programmed death ligand 2, T. cruzi infection induced an early increase of Gal-1 expression in vivo. Compared to their wild-type (WT) counterpart, Gal-1-deficient (Lgals1(-/-)) mice exhibited reduced mortality and lower parasite load in muscle tissue. Resistance of Lgals1(-/-) mice to T. cruzi infection was associated with a failure in the activation of Gal-1-driven tolerogenic circuits, otherwise orchestrated by WT dendritic cells, leading to secondary dysfunction in the induction of CD4(+)CD25(+)Foxp3(+) regulatory T cells. This effect was accompanied by an increased number of CD8(+) T cells and higher frequency of IFN-γ-producing CD4(+) T cells in muscle tissues and draining lymph nodes as well as reduced parasite burden in heart and hindlimb skeletal muscle. Moreover, dendritic cells lacking Gal-1 interrupted the Gal-1-mediated tolerogenic circuit and reinforced T cell-dependent anti-parasite immunity when adoptively transferred into WT mice. Thus, endogenous Gal-1 may influence T. cruzi infection by fueling tolerogenic circuits that hinder anti-parasite immunity.

  5. Induction of T helper 3 regulatory cells by dendritic cells infected with porcine reproductive and respiratory syndrome virus

    SciTech Connect

    Silva-Campa, Erika; Flores-Mendoza, Lilian; Resendiz, Monica; Pinelli-Saavedra, Araceli; Mata-Haro, Veronica; Mwangi, Waithaka; Hernandez, Jesus

    2009-05-10

    Delayed development of virus-specific immune response has been observed in pigs infected with the porcine reproductive and respiratory syndrome virus (PRRSV). Several studies support the hypothesis that the PRRSV is capable of modulating porcine immune system, but the mechanisms involved are yet to be defined. In this study, we evaluated the induction of T regulatory cells by PRRSV-infected dendritic cells (DCs). Our results showed that PRRSV-infected DCs significantly increased Foxp3{sup +}CD25{sup +} T cells, an effect that was reversible by IFN-alpha treatment, and this outcome was reproducible using two distinct PRRSV strains. Analysis of the expressed cytokines suggested that the induction of Foxp3{sup +}CD25{sup +} T cells is dependent on TGF-beta but not IL-10. In addition, a significant up-regulation of Foxp3 mRNA, but not TBX21 or GATA3, was detected. Importantly, our results showed that the induced Foxp3{sup +}CD25{sup +} T cells were able to suppress the proliferation of PHA-stimulated PBMCs. The T cells induced by the PRRSV-infected DCs fit the Foxp3{sup +}CD25{sup +} T helper 3 (Th3) regulatory cell phenotype described in the literature. The induction of this cell phenotype depended, at least in part, on PRRSV viability because IFN-alpha treatment or virus inactivation reversed these effects. In conclusion, this data supports the hypothesis that the PRRSV succeeds to establish and replicate in porcine cells early post-infection, in part, by inducing Th3 regulatory cells as a mechanism of modulating the porcine immune system.

  6. Interruption of dendritic cell-mediated TIM-4 signaling induces regulatory T cells and promotes skin allograft survival.

    PubMed

    Yeung, Melissa Y; McGrath, Martina M; Nakayama, Masafumi; Shimizu, Tetsunosuke; Boenisch, Olaf; Magee, Ciara N; Abdoli, Rozita; Akiba, Hisaya; Ueno, Takuya; Turka, Laurence A; Najafian, Nader

    2013-10-15

    Dendritic cells (DCs) are the central architects of the immune response, inducing inflammatory or tolerogenic immunity, dependent on their activation status. As such, DCs are highly attractive therapeutic targets and may hold the potential to control detrimental immune responses. TIM-4, expressed on APCs, has complex functions in vivo, acting both as a costimulatory molecule and a phosphatidylserine receptor. The effect of TIM-4 costimulation on T cell activation remains unclear. In this study, we demonstrate that Ab blockade of DC-expressed TIM-4 leads to increased induction of induced regulatory T cells (iTregs) from naive CD4(+) T cells, both in vitro and in vivo. iTreg induction occurs through suppression of IL-4/STAT6/Gata3-induced Th2 differentiation. In addition, blockade of TIM-4 on previously activated DCs still leads to increased iTreg induction. iTregs induced under TIM-4 blockade have equivalent potency to control and, upon adoptive transfer, significantly prolong skin allograft survival in vivo. In RAG(-/-) recipients of skin allografts adoptively transferred with CD4(+) T cells, we show that TIM-4 blockade in vivo is associated with a 3-fold prolongation in allograft survival. Furthermore, in this mouse model of skin transplantation, increased induction of allospecific iTregs and a reduction in T effector responses were observed, with decreased Th1 and Th2 responses. This enhanced allograft survival and protolerogenic skewing of the alloresponse is critically dependent on conversion of naive CD4(+) to Tregs in vivo. Collectively, these studies identify blockade of DC-expressed TIM-4 as a novel strategy that holds the capacity to induce regulatory immunity in vivo.

  7. Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD.

    PubMed

    Leveque-El Mouttie, Lucie; Koyama, Motoko; Le Texier, Laetitia; Markey, Kate A; Cheong, Melody; Kuns, Rachel D; Lineburg, Katie E; Teal, Bianca E; Alexander, Kylie A; Clouston, Andrew D; Blazar, Bruce R; Hill, Geoffrey R; MacDonald, Kelli P A

    2016-08-11

    Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD. PMID:27338097

  8. Clec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity

    PubMed Central

    Uto, Tomofumi; Fukaya, Tomohiro; Takagi, Hideaki; Arimura, Keiichi; Nakamura, Takeshi; Kojima, Naoya; Malissen, Bernard; Sato, Katsuaki

    2016-01-01

    Dendritic cells (DCs) comprise several subsets that are critically involved in the initiation and regulation of immunity. Clec4A4/DC immunoreceptor 2 (DCIR2) is a C-type lectin receptor (CLR) exclusively expressed on CD8α− conventional DCs (cDCs). However, how Clec4A4 controls immune responses through regulation of the function of CD8α− cDCs remains unclear. Here we show that Clec4A4 is a regulatory receptor for the activation of CD8α− cDCs that impairs inflammation and T-cell immunity. Clec4a4−/−CD8α− cDCs show enhanced cytokine production and T-cell priming following Toll-like receptor (TLR)-mediated activation. Furthermore, Clec4a4−/− mice exhibit TLR-mediated hyperinflammation. On antigenic immunization, Clec4a4−/− mice show not only augmented T-cell responses but also progressive autoimmune pathogenesis. Conversely, Clec4a4−/− mice exhibit resistance to microbial infection, accompanied by enhanced T-cell responses against microbes. Thus, our findings highlight roles of Clec4A4 in regulation of the function of CD8α− cDCs for control of the magnitude and quality of immune response. PMID:27068492

  9. Thymus-derived regulatory T cells restrain pro-inflammatory Th1 responses by downregulating CD70 on dendritic cells

    PubMed Central

    Dhainaut, Maxime; Coquerelle, Caroline; Uzureau, Sophie; Denoeud, Julie; Acolty, Valérie; Oldenhove, Guillaume; Galuppo, Adrien; Sparwasser, Tim; Thielemans, Kris; Pays, Etienne; Yagita, Hideo; Borst, Jannie; Moser, Muriel

    2015-01-01

    The severity and intensity of autoimmune disease in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) patients and in scurfy mice emphasize the critical role played by thymus-derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here, we demonstrate that tTregs selectively inhibit CD27/CD70-dependent Th1 priming, while leaving the IL-12-dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN-γ-secreting CD4+ T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27-dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responses. PMID:25787857

  10. Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD.

    PubMed

    Leveque-El Mouttie, Lucie; Koyama, Motoko; Le Texier, Laetitia; Markey, Kate A; Cheong, Melody; Kuns, Rachel D; Lineburg, Katie E; Teal, Bianca E; Alexander, Kylie A; Clouston, Andrew D; Blazar, Bruce R; Hill, Geoffrey R; MacDonald, Kelli P A

    2016-08-11

    Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD.

  11. Allostimulatory Effects of Dendritic Cells with Characteristic Features of a Regulatory Phenotype

    PubMed Central

    Jacobs, C. W. M.; van der Vlag, J.; Hilbrands, L. B.

    2016-01-01

    Introduction Tolerogenic dendritic cells (DCs) have the potential to prolong graft survival after transplantation. Tolerogenic DCs are in general characterized by a low expression of co-stimulatory molecule and a high IL-10:IL-12 production ratio. Based on promising results with earlier used alternatively activated DCs, we aimed to generate in culture potentially tolerogenic DC by simultaneously blocking GSK3 by lithium chloride (LiCl) and stimulating TLR2 by PAM3CysSerLys4. Materials and Methods Bone marrow-derived LiClPAM3 DCs were generated by the addition of LiCl 24 hours before harvesting, and one hour later PAM3CysSerLys4. The phenotype of the DCs was assessed by determining the expression of co-stimulatory molecules in flow cytometry and cytokine production in ELISA, whereas their functional properties were tested in a mixed lymphocyte reaction. A fully MHC mismatched heterotopic heart transplant preceded by infusion of donor-derived LiClPAM3 DC was performed to assess the tolerogenic potential of LiClPAM3 DCs in vivo. Results LiClPAM3 DCs displayed a tolerogenic phenotype accompanied with a low expression of co-stimulatory molecules and a high IL-10:IL-12 production ratio. However, in mixed lymphocyte reaction, LiClPAM3 DCs appeared superior in T cell stimulation, and induced Th1 and Th17 differentiation. Moreover, mice pretreated with LiClPAM3 DC displayed a reduced graft survival. Analysis of LiClPAM3 DC culture supernatant revealed high levels of CXCL-1, which was also found in supernatants of co-cultures of LiClPAM3 DC and T cells. Nevertheless, we could not show a role for CXCL-1 in T cell proliferation or activation in vitro. Discussion LiClPAM3 DCs display in vitro a tolerogenic phenotype with a high IL-10:IL-12 ratio, but appeared to be highly immunogenic, since allograft rejection was accelerated. As yet unidentified LiClPAM3 DC-derived factors, may explain the immunogenic character of LiClPAM3 DCs in vivo. PMID:27525971

  12. Disruption of TIM-4 in dendritic cell ameliorates hepatic warm IR injury through the induction of regulatory T cells.

    PubMed

    Li, Ji; Zhao, Xin; Liu, Xiaoliang; Liu, Huanqiu

    2015-08-01

    Hepatic ischaemia reperfusion (IR) injury results from the infiltration of multiple immune cells especially dendritic cells (DC). T-cell immunoglobulin-domain and mucin-domain 4 (TIM-4) is a type I cell-surface glycoprotein which is extensively expressed on antigen presenting cells (APC) like DC and macrophages. TIM-4 has been demonstrated to be implicated in mucosal allergy, skin allograft rejection and tumour-immune tolerance. However, the role of TIM-4 expressed on DC in hepatic IR injury remains largely unknown. In the present study, we aimed to investigate whether and how DC expressed TIM-4 was involved in hepatic IR injury. With segmental hepatic warm ischaemia mice models, we demonstrated that promoted DC infiltration and increased TIM-4 expression were induced by hepatic IR. Blockade of TIM-4 by anti-TIM-4 mAb (0.35mg/mouse) markedly ameliorated hepatic injury and reduced inflammatory cytokine secretion. Furthermore, in a DC:CD4+ T cell co-culture system, blockade of TIM-4 on DC significantly inhibited T helper-2 cell differentiation and facilitated induced CD4+ CD25+ Foxp3+ T regulatory cell (iTreg) expansion. Interleukin-4 (IL-4)/signal transducer and activator of transcription 6 (Stat 6) signalling was shown to be impeded by TIM-4 blockade and involved in iTreg generation. Additionally, adoptive transfer of iTreg produced by TIM-4 blockade into hepatic IR mice models remarkably attenuated liver injury. We conclude that TIM-4 on DC play a critical role in hepatic IR injury and may be an efficient target for the prevention of liver or other organ IR injury.

  13. Decreased Numbers of Blood Dendritic Cells and Defective Function of Regulatory T Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

    PubMed Central

    Rimbert, Marie; Hamidou, Mohamed; Braudeau, Cécile; Puéchal, Xavier; Teixeira, Luis; Caillon, Hélène; Néel, Antoine; Audrain, Marie; Guillevin, Loic; Josien, Régis

    2011-01-01

    Background Dendritic cells (DC) and regulatory cells (Treg) play pivotal roles in controlling both normal and autoimmune adaptive immune responses. DC are the main antigen-presenting cells to T cells, and they also control Treg functions. In this study, we examined the frequency and phenotype of DC subsets, and the frequency and function of Treg from patients with ANCA-associated vasculitis (AAV). Methodology/Principal Findings Blood samples from 19 untreated patients with AAV during flares and before any immunosuppressive treatment were analyzed, along with 15 AAV patients in remission and 18 age-matched healthy controls. DC and Treg numbers, and phenotypes were assessed by flow cytometry, and in vitro suppressive function of Treg was determined by co-culture assay. When compared to healthy volunteers, absolute numbers of conventional and plasmacytoid DC were decreased in AAV patients. During the acute phase this decrease was significantly more pronounced and was associated with an increased DC expression of CD62L. Absolute numbers of Treg (CD4+CD25highCD127low/− Tcells) were moderately decreased in patients. FOXP3 and CD39 were expressed at similar levels on Treg from patients as compared to controls. The suppressive function of Treg from AAV patients was dramatically decreased as compared to controls, and this defect was more pronounced during flares than remission. This Treg functional deficiency occurred in the absence of obvious Th17 deviation. Conclusion In conclusion, these data show that AAV flares are associated with both a decrease number and altered phenotype of circulating DC and point to a role for Treg functional deficiency in the pathogenesis of AAV. PMID:21494636

  14. INTERRUPTION OF DENDRITIC CELL-MEDIATED TIM-4 SIGNALING INDUCES REGULATORY T CELLS AND PROMOTES SKIN ALLOGRAFT SURVIVAL

    PubMed Central

    Yeung, Melissa Y.; McGrath, Martina M.; Nakayama, Masafumi; Shimizu, Tetsunosuke; Boenisch, Olaf; Magee, Ciara N.; Abdoli, Rozita; Akiba, Hisaya; Ueno, Takuya; Turka, Laurence A.; Najafian, Nader

    2013-01-01

    Dendritic cells (DCs) are the central architects of the immune response, inducing inflammatory or tolerogenic immunity, dependent upon their activation status. As such, DCs are highly attractive therapeutic targets and may hold the potential to control detrimental immune responses. TIM-4, expressed on antigen presenting cells, has complex functions in vivo, acting both as a costimulatory molecule and a phosphatidylserine (PS) receptor. The effect of TIM-4 costimulation on T cell activation remains unclear. Here, we demonstrate that antibody blockade of DC-expressed TIM-4 leads to increased induction of iTregs from naïve CD4+ T cells, both in vitro and in vivo. iTreg induction occurs through suppression of IL-4/STAT6/Gata3 induced Th2 differentiation. In addition, blockade of TIM-4 on previously activated DCs still leads to increased iTreg induction. iTregs induced under TIM-4 blockade have equivalent potency to control and upon adoptive transfer, significantly prolong skin allograft survival in vivo. In RAG−/− recipients of skin allografts adoptively transferred with CD4+ T cells, we show that TIM-4 blockade in vivo is associated with a three-fold prolongation in allograft survival. Furthermore, in this mouse model of skin transplantation, increased induction of allospecific iTregs and a reduction in T effector responses were observed, with decreased Th1 and Th2 responses. This enhanced allograft survival and pro-tolerogenic skewing of the alloresponse is critically dependent upon conversion of naïve CD4+ to Tregs in vivo. Collectively, these studies identify blockade of DC-expressed TIM-4 as a novel strategy which holds the capacity to induce regulatory immunity in vivo. PMID:24038092

  15. Murine Melanoma-Infiltrating Dendritic Cells Are Defective in Antigen Presenting Function Regardless of the Presence of CD4+CD25+ Regulatory T Cells

    PubMed Central

    Ataera, Haley; Hyde, Evelyn; Price, Kylie M.; Stoitzner, Patrizia; Ronchese, Franca

    2011-01-01

    Tumor-infiltrating dendritic cells are often ineffective at presenting tumor-derived antigen in vivo, a defect usually ascribed to the suppressive tumor environment. We investigated the effects of depleting CD4+CD25+ “natural” regulatory T cells (Treg) on the frequency, phenotype and function of total dendritic cell populations in B16.OVA tumors and in tumor-draining lymph nodes. Intraperitoneal injection of the anti-CD25 monoclonal antibody PC61 reduced Treg frequency in blood and tumors, but did not affect the frequency of tumor-infiltrating dendritic cells, or their expression of CD40, CD86 and MHCII. Tumor-infiltrating dendritic cells from PC61-treated or untreated mice induced the proliferation of allogeneic T cells in vitro, but could not induce proliferation of OVA-specific OTI and OTII T cells unless specific peptide antigen was added in culture. Some proliferation of naïve, OVA-specific OTI T cells, but not OTII T cells, was observed in the tumor-draining LN of mice carrying B16.OVA tumors, however, this was not improved by PC61 treatment. Experiments using RAG1−/− hosts adoptively transferred with OTI and CD25-depleted OTII cells also failed to show improved OTI and OTII T cell proliferation in vivo compared to C57BL/6 hosts. We conclude that the defective presentation of B16.OVA tumor antigen by tumor-infiltrating dendritic cells and in the tumor-draining lymph node is not due to the presence of “natural” CD4+CD25+ Treg. PMID:21390236

  16. Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15.

    PubMed

    Litjens, Nicolle H R; Boer, Karin; Zuijderwijk, Joke M; Klepper, Mariska; Peeters, Annemiek M A; Prens, Errol P; Verschoor, Wenda; Kraaijeveld, Rens; Ozgur, Zeliha; van den Hout-van Vroonhoven, Mirjam C; van IJcken, Wilfred F J; Baan, Carla C; Betjes, Michiel G H

    2015-06-01

    Expansion of Ag-specific naturally occurring regulatory T cells (nTregs) is required to obtain sufficient numbers of cells for cellular immunotherapy. In this study, different allogeneic stimuli were studied for their capacity to generate functional alloantigen-specific nTregs. A highly enriched nTreg fraction (CD4(+)CD25(bright)CD127(-) T cells) was alloantigen-specific expanded using HLA-mismatched immature, mature monocyte-derived dendritic cells (moDCs), or PBMCs. The allogeneic mature moDC-expanded nTregs were fully characterized by analysis of the demethylation status within the Treg-specific demethylation region of the FOXP3 gene and the expression of both protein and mRNA of FOXP3, HELIOS, CTLA4, and cytokines. In addition, the Ag-specific suppressive capacity of these expanded nTregs was tested. Allogeneic mature moDCs and skin-derived DCs were superior in inducing nTreg expansion compared with immature moDCs or PBMCs in an HLA-DR- and CD80/CD86-dependent way. Remarkably, the presence of exogenous IL-15 without IL-2 could facilitate optimal mature moDC-induced nTreg expansion. Allogeneic mature moDC-expanded nTregs were at low ratios (<1:320), potent suppressors of alloantigen-induced proliferation without significant suppression of completely HLA-mismatched, Ag-induced proliferation. Mature moDC-expanded nTregs were highly demethylated at the Treg-specific demethylation region within the FOXP3 gene and highly expressed of FOXP3, HELIOS, and CTLA4. A minority of the expanded nTregs produced IL-10, IL-2, IFN-γ, and TNF-α, but few IL-17-producing nTregs were found. Next-generation sequencing of mRNA of moDC-expanded nTregs revealed a strong induction of Treg-associated mRNAs. Human allogeneic mature moDCs are highly efficient stimulator cells, in the presence of exogenous IL-15, for expansion of stable alloantigen-specific nTregs with superior suppressive function. PMID:25917092

  17. N-3-(oxododecanoyl)-L-homoserine lactone promotes the induction of regulatory T-cells by preventing human dendritic cell maturation

    PubMed Central

    Li, Youqiang; Zhou, Huayou; Zhang, Yunyan; Huang, Bin; Qu, Pinghua; Zeng, Jianming; E, Shunmei; Zhang, Xuan; Liu, Jianping

    2015-01-01

    N-3-(Oxododecanoyl)-L-homoserine lactone (C12) is a small bacterial signaling molecule secreted by Pseudomonas aeruginosa (PA), which activates mammalian cells through TLR4-independent mechanisms. C12 acts as an immunosuppressant and it has been shown to modulate murine bone marrow-derived dendritic cell-mediated T-helper 2 (Th2) cell polarizations in vitro. In the present study, we initially examined the impact of C12 on the maturation of human monocyte-derived dendritic cells (Mo-DCs) and the induction of regulatory T-cells (iTregs) in culture. Our findings demonstrate that C12-treated Mo-DCs failed to undergo lipopolysaccharide (LPS)-induced maturation. At the molecular level, C12 blocked the upregulation of surface molecules, including CD11c, HLA-DR, CD40, and CD80, and it switched to an interleukin (IL)-10high, IL-12p70low phenotype. Moreover, C12 selectively inhibited the capacity of Mo-DCs to stimulate the proliferation of allogeneic CD4+ T-cells. Otherwise, the C12-treated Mo-DCs promoted the generation of CD4+CD25+Foxp3+-induced regulatory T-cells (iTregs) and enhanced their IL-10 and transforming growth factor (TGF)-β production associated with reduced interferon (IFN)-γ and IL-12p70 production. These findings provide new insights towards understanding the persistence of chronic inflammation in PA infection. PMID:25749498

  18. A Human Trypanosome Suppresses CD8+ T Cell Priming by Dendritic Cells through the Induction of Immune Regulatory CD4+ Foxp3+ T Cells.

    PubMed

    Ersching, Jonatan; Basso, Alexandre Salgado; Kalich, Vera Lucia Garcia; Bortoluci, Karina Ramalho; Rodrigues, Maurício M

    2016-06-01

    Although CD4+ Foxp3+ T cells are largely described in the regulation of CD4+ T cell responses, their role in the suppression of CD8+ T cell priming is much less clear. Because the induction of CD8+ T cells during experimental infection with Trypanosoma cruzi is remarkably delayed and suboptimal, we raised the hypothesis that this protozoan parasite actively induces the regulation of CD8+ T cell priming. Using an in vivo assay that eliminated multiple variables associated with antigen processing and dendritic cell activation, we found that injection of bone marrow-derived dendritic cells exposed to T. cruzi induced regulatory CD4+ Foxp3+ T cells that suppressed the priming of transgenic CD8+ T cells by peptide-loaded BMDC. This newly described suppressive effect on CD8+ T cell priming was independent of IL-10, but partially dependent on CTLA-4 and TGF-β. Accordingly, depletion of Foxp3+ cells in mice infected with T. cruzi enhanced the response of epitope-specific CD8+ T cells. Altogether, our data uncover a mechanism by which T. cruzi suppresses CD8+ T cell responses, an event related to the establishment of chronic infections. PMID:27332899

  19. A Human Trypanosome Suppresses CD8+ T Cell Priming by Dendritic Cells through the Induction of Immune Regulatory CD4+ Foxp3+ T Cells

    PubMed Central

    Ersching, Jonatan; Basso, Alexandre Salgado; Kalich, Vera Lucia Garcia; Bortoluci, Karina Ramalho

    2016-01-01

    Although CD4+ Foxp3+ T cells are largely described in the regulation of CD4+ T cell responses, their role in the suppression of CD8+ T cell priming is much less clear. Because the induction of CD8+ T cells during experimental infection with Trypanosoma cruzi is remarkably delayed and suboptimal, we raised the hypothesis that this protozoan parasite actively induces the regulation of CD8+ T cell priming. Using an in vivo assay that eliminated multiple variables associated with antigen processing and dendritic cell activation, we found that injection of bone marrow-derived dendritic cells exposed to T. cruzi induced regulatory CD4+ Foxp3+ T cells that suppressed the priming of transgenic CD8+ T cells by peptide-loaded BMDC. This newly described suppressive effect on CD8+ T cell priming was independent of IL-10, but partially dependent on CTLA-4 and TGF-β. Accordingly, depletion of Foxp3+ cells in mice infected with T. cruzi enhanced the response of epitope-specific CD8+ T cells. Altogether, our data uncover a mechanism by which T. cruzi suppresses CD8+ T cell responses, an event related to the establishment of chronic infections. PMID:27332899

  20. Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition.

    PubMed

    Weist, Brian M; Kurd, Nadia; Boussier, Jeremy; Chan, Shiao Wei; Robey, Ellen A

    2015-06-01

    The thymic production of regulatory T cells (Treg cells) requires interleukin 2 (IL-2) and agonist T cell antigen receptor (TCR) ligands and is controlled by competition for a limited developmental niche, but the thymic sources of IL-2 and the factors that limit access to the niche are poorly understood. Here we found that IL-2 produced by antigen-bearing dendritic cells (DCs) had a key role in Treg cell development and that existing Treg cells limited new development of Treg cells by competing for IL-2. Our data suggest that antigen-presenting cells (APCs) that can provide both IL-2 and a TCR ligand constitute the thymic niche and that competition by existing Treg cells for a limited supply of IL-2 provides negative feedback for new production of Treg cells. PMID:25939026

  1. The relation of plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) with HPV persistence in HIV-infected and HIV-uninfected women.

    PubMed

    Strickler, Howard D; Martinson, Jeffrey; Desai, Seema; Xie, Xianhong; Burk, Robert D; Anastos, Kathryn; Massad, L Stewart; Minkoff, Howard; Xue, Xiaonan; D'Souza, Gypsyamber; Levine, Alexandra M; Colie, Christine; Watts, D Heather; Palefsky, Joel M; Landay, Alan

    2014-02-01

    Other than CD4+ count, the immunologic factors that underlie the relationship of HIV/AIDS with persistent oncogenic HPV (oncHPV) and cervical cancer are not well understood. Plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) are of particular interest. pDCs have both effector and antigen presenting activity and, in HIV-positive patients, low pDC levels are associated with opportunistic infections. Tregs downregulate immune responses, and are present at high levels in HIV-positives. The current pilot study shows for the first time that low pDC and high Treg levels may be significantly associated with oncHPV persistence in both HIV-positive and HIV-negative women. Larger studies are now warranted.

  2. Skin-draining lymph nodes contain dermis-derived CD103(-) dendritic cells that constitutively produce retinoic acid and induce Foxp3(+) regulatory T cells.

    PubMed

    Guilliams, Martin; Crozat, Karine; Henri, Sandrine; Tamoutounour, Samira; Grenot, Pierre; Devilard, Elisabeth; de Bovis, Béatrice; Alexopoulou, Lena; Dalod, Marc; Malissen, Bernard

    2010-03-11

    Small intestinal CD103(+) dendritic cells (DCs) have the selective ability to promote de novo generation of regulatory T cells via the production of retinoic acid (RA). Considering that aldehyde dehydrogenase (ALDH) activity controls the production of RA, we used a flow cytometry-based assay to measure ALDH activity at the single-cell level and to perform a comprehensive analysis of the RA-producing DC populations present in lymphoid and nonlymphoid mouse tissues. RA-producing DCs were primarily of the tissue-derived, migratory DC subtype and can be readily found in the skin and in the lungs as well as in their corresponding draining lymph nodes. The RA-producing skin-derived DCs were capable of triggering the generation of regulatory T cells, a finding demonstrating that the presence of RA-producing, tolerogenic DCs is not restricted to the intestinal tract as previously thought. Unexpectedly, the production of RA by skin DCs was restricted to CD103(-) DCs, indicating that CD103 expression does not constitute a "universal" marker for RA-producing mouse DCs. Finally, Toll-like receptor (TLR) triggering or the presence of a commensal microflora was not essential for the induction of ALDH activity in the discrete ALDH(+) DC subsets that characterize tissues constituting environmental interfaces.

  3. Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age.

    PubMed

    Agrawal, Sudhanshu; Ganguly, Sreerupa; Tran, Alexander; Sundaram, Padmaja; Agrawal, Anshu

    2016-06-01

    Aged subjects display increased susceptibility to mucosal diseases. Retinoic Acid (RA) plays a major role in inducing tolerance in the mucosa. RA acts on Dendritic cells (DCs) to induce mucosal tolerance. Here we compared the response of DCs from aged and young individuals to RA with a view to understand the role of DCs in age-associated increased susceptibility to mucosal diseases. Our investigations revealed that compared to young DCs, RA stimulated DCs from aged subjects are defective in inducing IL-10 and T regulatory cells. Examinations of the underlying mechanisms indicated that RA exposure led to the upregulation of CD141 and GARP on DCs which rendered the DCs tolerogenic. CD141(hi), GARP(+) DCs displayed enhanced capacity to induce T regulatory cells compared to CD141(lo) and GARP(-) DCs. Unlike RA stimulated DCs from young, DCs from aged subjects exhibited diminished upregulation of both CD141 and GARP. The percentage of DCs expressing CD141 and GARP on RA treatment was significantly reduced in DCs from aged individuals. Furthermore, the remaining CD141(hi), GARP(+) DCs from aged individuals were also deficient in inducing T regs. In summary, reduced response of aged DCs to RA enhances mucosal inflammation in the elderly, increasing their susceptibility to mucosal diseases. PMID:27244900

  4. Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age

    PubMed Central

    Agrawal, Sudhanshu; Ganguly, Sreerupa; Tran, Alexander; Sundaram, Padmaja; Agrawal, Anshu

    2016-01-01

    Aged subjects display increased susceptibility to mucosal diseases. Retinoic Acid (RA) plays a major role in inducing tolerance in the mucosa. RA acts on Dendritic cells (DCs) to induce mucosal tolerance. Here we compared the response of DCs from aged and young individuals to RA with a view to understand the role of DCs in age-associated increased susceptibility to mucosal diseases. Our investigations revealed that compared to young DCs, RA stimulated DCs from aged subjects are defective in inducing IL-10 and T regulatory cells. Examinations of the underlying mechanisms indicated that RA exposure led to the upregulation of CD141 and GARP on DCs which rendered the DCs tolerogenic. CD141hi, GARP+ DCs displayed enhanced capacity to induce T regulatory cells compared to CD141lo and GARP− DCs. Unlike RA stimulated DCs from young, DCs from aged subjects exhibited diminished upregulation of both CD141 and GARP. The percentage of DCs expressing CD141 and GARP on RA treatment was significantly reduced in DCs from aged individuals. Furthermore, the remaining CD141hi, GARP+ DCs from aged individuals were also deficient in inducing T regs. In summary, reduced response of aged DCs to RA enhances mucosal inflammation in the elderly, increasing their susceptibility to mucosal diseases. PMID:27244900

  5. An increase in tolerogenic dendritic cell and natural regulatory T cell numbers during experimental autoimmune encephalomyelitis in Rras-/- mice results in attenuated disease.

    PubMed

    Ray, Avijit; Basu, Sreemanti; Miller, Nichole M; Chan, Andrew M; Dittel, Bonnie N

    2014-06-01

    R-Ras is a member of the Ras superfamily of small GTPases, which are regulators of various cellular processes, including adhesion, survival, proliferation, trafficking, and cytokine production. R-Ras is expressed by immune cells and has been shown to modulate dendritic cell (DC) function in vitro and has been associated with liver autoimmunity. We used Rras-deficient mice to study the mechanism whereby R-Ras contributes to autoimmunity using experimental autoimmune encephalomyelitis (EAE), a mouse model of the CNS autoimmune disease multiple sclerosis. We found that a lack of R-Ras in peripheral immune cells resulted in attenuated EAE disease. Further investigation revealed that, during EAE, absence of R-Ras promoted the formation of MHC II(low) DC concomitant with a significant increase in proliferation of natural regulatory T cells, resulting in an increase in their cell numbers in the periphery. Our study suggests a novel role for R-Ras in promoting autoimmunity through negative regulation of natural regulatory T cell numbers by inhibiting the development of MHCII(low) DC with tolerogenic potential.

  6. Retinoic acid treated human dendritic cells induce T regulatory cells via the expression of CD141 and GARP which is impaired with age.

    PubMed

    Agrawal, Sudhanshu; Ganguly, Sreerupa; Tran, Alexander; Sundaram, Padmaja; Agrawal, Anshu

    2016-06-01

    Aged subjects display increased susceptibility to mucosal diseases. Retinoic Acid (RA) plays a major role in inducing tolerance in the mucosa. RA acts on Dendritic cells (DCs) to induce mucosal tolerance. Here we compared the response of DCs from aged and young individuals to RA with a view to understand the role of DCs in age-associated increased susceptibility to mucosal diseases. Our investigations revealed that compared to young DCs, RA stimulated DCs from aged subjects are defective in inducing IL-10 and T regulatory cells. Examinations of the underlying mechanisms indicated that RA exposure led to the upregulation of CD141 and GARP on DCs which rendered the DCs tolerogenic. CD141(hi), GARP(+) DCs displayed enhanced capacity to induce T regulatory cells compared to CD141(lo) and GARP(-) DCs. Unlike RA stimulated DCs from young, DCs from aged subjects exhibited diminished upregulation of both CD141 and GARP. The percentage of DCs expressing CD141 and GARP on RA treatment was significantly reduced in DCs from aged individuals. Furthermore, the remaining CD141(hi), GARP(+) DCs from aged individuals were also deficient in inducing T regs. In summary, reduced response of aged DCs to RA enhances mucosal inflammation in the elderly, increasing their susceptibility to mucosal diseases.

  7. Regulatory Dendritic Cells Restrain NK Cell IFN-γ Production through Mechanisms Involving NKp46, IL-10, and MHC Class I-Specific Inhibitory Receptors.

    PubMed

    Spallanzani, Raúl G; Torres, Nicolás I; Avila, Damián E; Ziblat, Andrea; Iraolagoitia, Ximena L Raffo; Rossi, Lucas E; Domaica, Carolina I; Fuertes, Mercedes B; Rabinovich, Gabriel A; Zwirner, Norberto W

    2015-09-01

    Cross-talk between mature dendritic cells (mDC) and NK cells through the cell surface receptors NKp30 and DNAM-1 leads to their reciprocal activation. However, the impact of regulatory dendritic cells (regDC) on NK cell function remains unknown. As regDC constrain the immune response in different physiological and pathological conditions, the aim of this work was to investigate the functional outcome of the interaction between regDC and NK cells and the associated underlying mechanisms. RegDC generated from monocyte-derived DC treated either with LPS and dexamethasone, vitamin D3, or vitamin D3 and dexamethasone instructed NK cells to secrete lower amounts of IFN-γ than NK cells exposed to mDC. Although regDC triggered upregulation of the activation markers CD69 and CD25 on NK cells, they did not induce upregulation of CD56 as mDC, and silenced IFN-γ secretion through mechanisms involving insufficient secretion of IL-18, but not IL-12 or IL-15 and/or induction of NK cell apoptosis. Blocking experiments demonstrated that regDC curb IFN-γ secretion by NK cells through a dominant suppressive mechanism involving IL-10, NK cell inhibitory receptors, and, unexpectedly, engagement of the activating receptor NKp46. Our findings unveil a previously unrecognized cross-talk through which regDC shape NK cell function toward an alternative activated phenotype unable to secrete IFN-γ, highlighting the plasticity of NK cells in response to tolerogenic stimuli. In addition, our findings contribute to identify a novel inhibitory role for NKp46 in the control of NK cell function, and have broad implications in the resolution of inflammatory responses and evasion of antitumor responses. PMID:26232426

  8. Reduced Dendritic Cells Expressing CD200R1 in Children with Inflammatory Bowel Disease: Correlation with Th17 and Regulatory T Cells

    PubMed Central

    Elshal, Mohamed F.; Aldahlawi, Alia M.; Saadah, Omar I.; McCoy, J. Philip

    2015-01-01

    Loss of tolerance of the adaptive immune system towards indigenous flora contributes to the development of inflammatory bowel diseases (IBD). Defects in dendritic cell (DC)-mediated innate and adoptive immune responses are conceivable. The aim of this study was to investigate the expression of the inhibitory molecules CD200R1 and their ligand CD200 on DCs, to clarify the role of the DCs in the pathogenesis of IBD. Thirty-seven pediatric IBD patients (23 with Crohn’s disease (CD) and 14 with ulcerative colitis (UC)) with mean age 13.25 ± 2.9 years were included. Fourteen age-matched healthy pediatric volunteers (five males and nine females) served as a control group (HC). The percentage of CD11c+ myeloid dendritic cells (mDCs) and CD123+ plasmacytoid DCs (pDCs) expressing CD200R1 and CD200 were evaluated in peripheral blood using flow cytometry and were correlated with routine biochemical, serological markers, serum levels of cytokines and with the percentages of circulating regulatory T cells (Treg) and CD4+ producing IL-17 (Th17). IBD patients showed a significant decrease in the percentage of pDCs and mDCs expressing CD200R1 compared to that of HC. Patients with UC showed increased expressions of the CD200 molecule on pDCs as compared to HC. DCs expressing CD200R1 were found to be correlated positively with Treg and negatively with TH17 and erythrocyte sedimentation rate (ESR). Our findings suggest that IBD is associated with dysregulation in the CD200R1/CD200 axis and that the decrease in DCs expressing CD200R1 may contribute to the imbalance of Th17 and Treg cells and in the pathogenesis of IBD. PMID:26690123

  9. Myeloid Dendritic Cells (DCs) of Mice Susceptible to Paracoccidioidomycosis Suppress T Cell Responses whereas Myeloid and Plasmacytoid DCs from Resistant Mice Induce Effector and Regulatory T Cells

    PubMed Central

    Pina, Adriana; Frank de Araujo, Eliseu; Felonato, Maíra; Loures, Flávio V.; Feriotti, Claudia; Bernardino, Simone; Barbuto, José Alexandre M.

    2013-01-01

    The protective adaptive immune response in paracoccidioidomycosis, a mycosis endemic among humans, is mediated by T cell immunity, whereas impaired T cell responses are associated with severe, progressive disease. The early host response to Paracoccidioides brasiliensis infection is not known since the disease is diagnosed at later phases of infection. Our laboratory established a murine model of infection where susceptible mice reproduce the severe disease, while resistant mice develop a mild infection. This work aimed to characterize the influence of dendritic cells in the innate and adaptive immunity of susceptible and resistant mice. We verified that P. brasiliensis infection induced in bone marrow-derived dendritic cells (DCs) of susceptible mice a prevalent proinflammatory myeloid phenotype that secreted high levels of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-β, whereas in resistant mice, a mixed population of myeloid and plasmacytoid DCs secreting proinflammatory cytokines and expressing elevated levels of secreted and membrane-bound transforming growth factor β was observed. In proliferation assays, the proinflammatory DCs from B10.A mice induced anergy of naïve T cells, whereas the mixed DC subsets from resistant mice induced the concomitant proliferation of effector and regulatory T cells (Tregs). Equivalent results were observed during pulmonary infection. The susceptible mice displayed preferential expansion of proinflammatory myeloid DCs, resulting in impaired proliferation of effector T cells. Conversely, the resistant mice developed myeloid and plasmacytoid DCs that efficiently expanded gamma interferon-, IL-4-, and IL-17-positive effector T cells associated with increased development of Tregs. Our work highlights the deleterious effect of excessive innate proinflammatory reactions and provides new evidence for the importance of immunomodulation during pulmonary paracoccidioidomycosis. PMID:23340311

  10. Reduced Dendritic Cells Expressing CD200R1 in Children with Inflammatory Bowel Disease: Correlation with Th17 and Regulatory T Cells.

    PubMed

    Elshal, Mohamed F; Aldahlawi, Alia M; Saadah, Omar I; McCoy, J Philip

    2015-12-04

    Loss of tolerance of the adaptive immune system towards indigenous flora contributes to the development of inflammatory bowel diseases (IBD). Defects in dendritic cell (DC)-mediated innate and adoptive immune responses are conceivable. The aim of this study was to investigate the expression of the inhibitory molecules CD200R1 and their ligand CD200 on DCs, to clarify the role of the DCs in the pathogenesis of IBD. Thirty-seven pediatric IBD patients (23 with Crohn's disease (CD) and 14 with ulcerative colitis (UC)) with mean age 13.25 ± 2.9 years were included. Fourteen age-matched healthy pediatric volunteers (five males and nine females) served as a control group (HC). The percentage of CD11c⁺ myeloid dendritic cells (mDCs) and CD123⁺ plasmacytoid DCs (pDCs) expressing CD200R1 and CD200 were evaluated in peripheral blood using flow cytometry and were correlated with routine biochemical, serological markers, serum levels of cytokines and with the percentages of circulating regulatory T cells (Treg) and CD4⁺ producing IL-17 (Th17). IBD patients showed a significant decrease in the percentage of pDCs and mDCs expressing CD200R1 compared to that of HC. Patients with UC showed increased expressions of the CD200 molecule on pDCs as compared to HC. DCs expressing CD200R1 were found to be correlated positively with Treg and negatively with TH17 and erythrocyte sedimentation rate (ESR). Our findings suggest that IBD is associated with dysregulation in the CD200R1/CD200 axis and that the decrease in DCs expressing CD200R1 may contribute to the imbalance of Th17 and Treg cells and in the pathogenesis of IBD.

  11. The amelioration of composite tissue allograft rejection by TIM-3-modified dendritic cell: Regulation of the balance of regulatory and effector T cells.

    PubMed

    Wang, Yaojun; Zheng, Zhao; Zhu, Xiongxiang; Han, Juntao; Dong, Maolong; Tao, Ke; Wang, Hongtao; Wang, Yunchuan; Hu, Dahai

    2016-01-01

    T cell-dependent immune responses play a central role in allograft rejection. Exploring ways to disarm alloreactive T cells represents a potential strategy to promote long-term allograft acceptance and survival. T cell Ig domain and mucin domain 3 (TIM-3) has previously been demonstrated as a central regulator of T helper 1 (Th1) responses and immune tolerance. Hence, TIM-3 may be an important molecule for decreasing immunological rejection during composite tissue allotransplantation (CTA). In this study, BALB/c and C57BL/6 mice were chosen as the experimental animals. The effects of TIM-3 on allograft rejection were explored using TIM-3-modified mature dendritic cells (TIM-3 mDCs). A laser speckle blood flow (LSBF) imager was used to evaluate blood distribution of the BALB/c mice. ELISA, MTT, ELISPOT assays and flow cytometry analysis were carried out for further researches. We found that TIM-3 could obviously prolong the survival time of the transplanted limbs. And TIM-3 could mitigate the immune response and thus enhance immune tolerance after CTA. Also, TIM-3 can induce lymphocyte hyporesponsiveness, including facilitating lymphocyte apoptosis, decreasing lymphocyte proliferation, and influencing the secretion of inflammatory cytokines by CD4(+) T cells. Furthermore, TIM-3 overexpression could induce CD4(+) T cells to differentiate into regulatory T cells (Tregs), which recalibrate the effector and regulatory arms of the alloimmune response. In summary, we concluded that TIM-3 can mitigate allograft rejection and thus enhance immune tolerance by inducing lymphocyte hyporesponsiveness and increasing the number of Tregs of the alloimmune response. TIM-3 may be a potential therapeutic molecule for allograft rejection in CTA.

  12. A 33D1+ Dendritic Cell/Autoreactive CD4+ T Cell Circuit Maintains IL-2-Dependent Regulatory T Cells in the Spleen.

    PubMed

    Stolley, J Michael; Campbell, Daniel J

    2016-10-01

    Phenotypically and functionally diverse regulatory T (Tr) cell subsets populate lymphoid and nonlymphoid tissues, where their maintenance and function are governed by unique homeostatic signals. Whereas Tr cells resident in nonlymphoid tissues depend on continual TCR signaling for their survival and function, phenotypically naive Tr cells occupying secondary lymphoid organs are largely supported by paracrine IL-2 signaling. Crucially, the absence of either of these distinct Tr cell subsets results in pathogenic autoimmunity, underscoring their nonredundant roles in the preservation of self-tolerance. However, the cellular and molecular factors precipitating IL-2 release and subsequent maintenance of secondary lymphoid organ-resident Tr cells are still poorly understood. In this study, we report that IL-2-dependent Tr cells in the spleen compete for a limiting supply of paracrine IL-2 generated by autoreactive CD4(+) T cells in response to MHC class II-restricted autoantigen activation by 33D1(+)CD11b(int) dendritic cells. Manipulating this cellular circuit culminating in IL-2 production could have clinical benefits in settings in which diminished Tr cell abundance is desired.

  13. Helicobacter pylori induces in-vivo expansion of human regulatory T cells through stimulating interleukin-1β production by dendritic cells.

    PubMed

    Mitchell, P J; Afzali, B; Fazekasova, H; Chen, D; Ali, N; Powell, N; Lord, G M; Lechler, R I; Lombardi, G

    2012-12-01

    Helicobacter pylori is one of the most common infections in the world. Despite inciting inflammation, immunological clearance of the pathogen is often incomplete. CD4(+) CD25(hi) forkhead box protein 3 (FoxP3(+)) regulatory T cells (T(regs)) are potent suppressors of different types of immune responses and have been implicated in limiting inflammatory responses to H. pylori. Investigating the influence of H. pylori on T(reg) function and proliferation, we found that H. pylori-stimulated dendritic cells (DCs) induced proliferation in T(regs) and impaired their suppressive capability. This effect was mediated by interleukin (IL)-1β produced by H. pylori-stimulated DCs. These data correlated with in-vivo observations in which H. pylori(+) gastric mucosa contained more T(regs) in active cell division than uninfected stomachs. Inciting local proliferation of T(regs) and inhibiting their suppressive function may represent a mechanism for the chronic gastritis and carcinogenesis attributable to H. pylori.

  14. Human dendritic cells acquire a semimature phenotype and lymph node homing potential through interaction with CD4+CD25+ regulatory T cells.

    PubMed

    Bayry, Jagadeesh; Triebel, Frédéric; Kaveri, Srini V; Tough, David F

    2007-04-01

    Interactions between dendritic cells (DC) and T cells are known to involve the delivery of signals in both directions. We sought to characterize the effects on human DC of contact with different subsets of activated CD4+ T cells. The results showed that interaction with CD25(high)CD4+ regulatory T cells (Tregs) caused DC to take on very different properties than contact with naive or memory phenotype T cells. Whereas non-Tregs stimulated DC maturation, culture with Tregs produced DC with a mixed phenotype. By many criteria, Tregs inhibited DC maturation, inducing down-regulation of costimulatory molecules and T cell stimulatory activity. However, DC exposed to Tregs also showed some changes typically associated with DC maturation, namely, increased expression of CCR7 and MHC class II molecules, and gained the ability to migrate in response to the CCR7 ligand CCL19. Both soluble factors and cell-associated molecules were shown to be involved in Treg modulation of DC, with lymphocyte activation gene 3 (LAG-3) playing a predominant role in driving maturation-associated changes. The data show that Tregs induce the generation of semimature DC with the potential to migrate into lymphoid organs, suggesting a possible mechanism by which Tregs down-modulate immune responses. PMID:17371975

  15. Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients

    PubMed Central

    Banerjee, Devi K.; Dhodapkar, Madhav V.; Matayeva, Elyana; Steinman, Ralph M.; Dhodapkar, Kavita M.

    2006-01-01

    CD4+CD25+FOXP3+ regulatory T cells (Treg's) play an important role in the maintenance of immune tolerance. The mechanisms controlling the induction and maintenance of Treg's in humans need to be defined. We find that human myeloid dendritic cells (DCs) are superior to other antigen presenting cells for the maintenance of FOXP3+ Treg's in culture. Coculture of DCs with autologous T cells leads to an increase in both the number of Treg's, as well as the expression of FOXP3 protein per cell both in healthy donors and myeloma patients. DC-mediated expansion of FOXP3high Treg's is enhanced by endogenous but not exogenous interleukin-2 (IL-2), and DC-T-cell contact, including the CD80/CD86 membrane costimulatory molecules. DCs also stimulate the formation of Treg's from CD25- T cells. The efficacy of induction of Treg's by DCs depends on the nature of the DC maturation stimulus, with inflammatory cytokine-treated DCs (Cyt-DCs) being the most effective Treg inducers. DC-induced Treg's from both healthy donors and patients with myeloma are functional and effectively suppress T-cell responses. A single injection of cytokine-matured DCs led to rapid enhancement of FOXP3+ Treg's in vivo in 3 of 3 myeloma patients. These data reveal a role for DCs in increasing the number of functional FOXP3high Treg's in humans. PMID:16763205

  16. CD8α+β− and CD8α+β+ plasmacytoid dendritic cells induce Foxp3+ regulatory T cells and prevent the induction of airway hyperreactivity

    PubMed Central

    Lombardi, Vincent; Speak, Anneliese O.; Kerzerho, Jérôme; Szely, Natacha; Akbari, Omid

    2012-01-01

    Dendritic cells (DCs) control the balance between protection against pathogens and tolerance to innocuous or self-antigens. Here, we demonstrate for the first time that mouse plasmacytoid DCs (pDCs) can be segregated into three distinct populations, exhibiting phenotypic and functional differences, according to their surface expression of CD8α or CD8β as CD8α−β−, CD8α+β− or CD8α+β+. In a mouse model of lung inflammation, adoptive transfer of CD8α+β− or CD8α+β+ pDCs prevents the development of airway hyperreactivity. The tolerogenic features of these subsets are associated with increased production of retinoic acid, which leads to the enhanced induction of Foxp3+ regulatory T cells compared to CD8α−β− pDCs. Our data thus identify subsets of pDCs with potent tolerogenic functions that may contribute to the maintenance of tolerance in mucosal sites such as the lungs. PMID:22472775

  17. Murine dendritic cell rapamycin-resistant and rictor-independent mTOR controls IL-10, B7-H1, and regulatory T-cell induction

    PubMed Central

    Rosborough, Brian R.; Raïch-Regué, Dàlia; Matta, Benjamin M.; Lee, Keunwook; Gan, Boyi; DePinho, Ronald A.; Hackstein, Holger; Boothby, Mark

    2013-01-01

    Mammalian target of rapamycin (mTOR) is an important, yet poorly understood integrative kinase that regulates immune cell function. mTOR functions in 2 independent complexes: mTOR complex (mTORC) 1 and 2. The immunosuppressant rapamycin (RAPA) inhibits mTORC1 but not mTORC2 and causes a paradoxical reduction in anti-inflammatory interleukin (IL) 10 and B7-homolog 1 (B7-H1) expression by dendritic cells (DCs). Using catalytic mTOR inhibitors and DCs lacking mTORC2, we show that restraint of signal transducer and activator of transcription 3–mediated IL-10 and B7-H1 expression during DC maturation involves a RAPA-insensitive and mTORC2-independent mTOR mechanism. Relatedly, catalytic mTOR inhibition promotes B7-H1–dependent and IL-1β–dependent DC induction of regulatory T cells (Tregs). Thus, we define an immunoregulatory pathway in which RAPA-sensitive mTORC1 in DCs promotes effector T-cell expansion and RAPA-insensitive mTORC1 restrains Treg induction. These findings identify the first known RAPA-insensitive mTOR pathway that is not mediated solely by mTORC2 and have implications for the use of catalytic mTOR inhibitors in inflammatory disease settings. PMID:23444404

  18. Preserved dendritic cell HLA-DR expression and reduced regulatory T cell activation in asymptomatic Plasmodium falciparum and P. vivax infection.

    PubMed

    Kho, Steven; Marfurt, Jutta; Noviyanti, Rintis; Kusuma, Andreas; Piera, Kim A; Burdam, Faustina H; Kenangalem, Enny; Lampah, Daniel A; Engwerda, Christian R; Poespoprodjo, Jeanne R; Price, Ric N; Anstey, Nicholas M; Minigo, Gabriela; Woodberry, Tonia

    2015-08-01

    Clinical illness with Plasmodium falciparum or Plasmodium vivax compromises the function of dendritic cells (DC) and expands regulatory T (Treg) cells. Individuals with asymptomatic parasitemia have clinical immunity, restricting parasite expansion and preventing clinical disease. The role of DC and Treg cells during asymptomatic Plasmodium infection is unclear. During a cross-sectional household survey in Papua, Indonesia, we examined the number and activation of blood plasmacytoid DC (pDC), CD141(+), and CD1c(+) myeloid DC (mDC) subsets and Treg cells using flow cytometry in 168 afebrile children (of whom 15 had P. falciparum and 36 had P. vivax infections) and 162 afebrile adults (of whom 20 had P. falciparum and 20 had P. vivax infections), alongside samples from 16 patients hospitalized with uncomplicated malaria. Unlike DC from malaria patients, DC from children and adults with asymptomatic, microscopy-positive P. vivax or P. falciparum infection increased or retained HLA-DR expression. Treg cells in asymptomatic adults and children exhibited reduced activation, suggesting increased immune responsiveness. The pDC and mDC subsets varied according to clinical immunity (asymptomatic or symptomatic Plasmodium infection) and, in asymptomatic infection, according to host age and parasite species. In conclusion, active control of asymptomatic infection was associated with and likely contingent upon functional DC and reduced Treg cell activation.

  19. Possible regulatory role of dendritic spikes in induction of long-term potentiation at hippocampal schaffer collateral-CA1 synapses.

    PubMed

    Isomura, Y; Kato, N

    2000-11-10

    The amplitude of backpropagating action potentials (BAPs) is attenuated, either activity- or neurotransmitter-dependently in the apical dendrite of hippocampal pyramidal neurons. To test the possibility that this BAP attenuation may contribute to regulating the inducibility of long-term potentiation (LTP), BAPs evoked by theta-burst stimulation (TBS), a standard protocol for LTP induction, to apical dendrite synapses were subjected to perturbation by conditioning stimuli to basal dendrite synapses. During this conditioned TBS (cTBS), the amplitude of BAPs was noticeably attenuated, but that of somatic action potentials was not. In the distal dendrite area, cTBS-induced LTP was much smaller than that induced by TBS. By contrast, no difference was observed between TBS- and cTBS-induced LTP in the proximal dendrite area. These findings suggest that the activity-dependent attenuation of BAPs, propagating along the apical dendrite, may serve to regulate hippocampal synaptic plasticity.

  20. Dendritic Cell-Specific Deletion of β-Catenin Results in Fewer Regulatory T-Cells without Exacerbating Autoimmune Collagen-Induced Arthritis

    PubMed Central

    Alves, C. Henrique; Ober-Blöbaum, Julia L.; Brouwers-Haspels, Inge; Asmawidjaja, Patrick S.; Mus, Adriana M. C.; Razawy, Wida; Molendijk, Marlieke; Clausen, Björn E.; Lubberts, Erik

    2015-01-01

    Dendritic cells (DCs) are professional antigen presenting cells that have the dual ability to stimulate immunity and maintain tolerance. However, the signalling pathways mediating tolerogenic DC function in vivo remain largely unknown. The β-catenin pathway has been suggested to promote a regulatory DC phenotype. The aim of this study was to unravel the role of β-catenin signalling to control DC function in the autoimmune collagen-induced arthritis model (CIA). Deletion of β-catenin specifically in DCs was achieved by crossing conditional knockout mice with a CD11c-Cre transgenic mouse line. Bone marrow-derived DCs (BMDCs) were generated and used to study the maturation profile of these cells in response to a TLR2 or TLR4 ligand stimulation. CIA was induced by intra-dermal immunization with 100 μg chicken type II collagen in complete Freund’s adjuvant on days 0 and 21. CIA incidence and severity was monitored macroscopically and by histology. The T cell profile as well as their cytokine production were analysed by flow cytometry. Lack of β-catenin specifically in DCs did not affect the spontaneous, TLR2- or TLR4-induced maturation and activation of BMDCs or their cytokine production. Moreover, no effect on the incidence and severity of CIA was observed in mice lacking β-catenin in CD11c+ cells. A decreased frequency of splenic CD3+CD8+ T cells and of regulatory T cells (Tregs) (CD4+CD25highFoxP3+), but no changes in the frequency of splenic Th17 (CCR6+CXCR3-CCR4+), Th2 (CCR6-CXCR3-CCR4+) and Th1 (CCR6-CXCR3+CCR4-) cells were observed in these mice under CIA condition. Furthermore, the expression of IL-17A, IL-17F, IL-22, IL-4 or IFNγ was also not affected. Our data indicate that ablation of β-catenin expression in DCs did not alter the course and severity of CIA. We conclude that although deletion of β-catenin resulted in a lower frequency of Tregs, this decrease was not sufficient to aggravate the onset and severity of CIA. PMID:26587585

  1. Clonorchis sinensis-derived total protein attenuates airway inflammation in murine asthma model by inducing regulatory T cells and modulating dendritic cell functions

    SciTech Connect

    Jeong, Young-Il; Kim, Seung Hyun; Ju, Jung Won; Cho, Shin Hyeong; Lee, Won Ja; Park, Jin Wook; Park, Yeong-Min; Lee, Sang Eun

    2011-04-22

    Highlights: {yields} Treatment with Clonorchis sinensis-derived total protein attenuates OVA-induced airway inflammation and AHR to methacholine. {yields} Induction of CD4{sup +}CD25{sup +}Foxp3{sup +} T cells and IL-10 along with suppression of splenocyte proliferation by C. sinensis-derived total protein. {yields} C. sinensis-derived total protein interferes with the expression of co-stimulatory molecules in DCs. -- Abstract: Asthma is characterized by Th2-mediated inflammation, resulting in airway hyperresponsiveness (AHR) through airway remodeling. Recent epidemiological and experimental reports have suggested an inverse relationship between the development of allergy and helminth infections. Infection by Clonorchis sinensis, a liver fluke that resides in the bile duct of humans, is endemic predominantly in Asia including Korea and China. Using a murine model for asthma, we investigated the effects of C. sinensis-derived total protein (Cs-TP) on allergen-induced airway inflammation and the mechanism underlying the protective effects of Cs-TP administration on asthma. Treatment with Cs-TP attenuated OVA-induced airway inflammation and methacholine-induced AHR, as well as eosinophilia development, lymphocyte infiltration into the lung, and goblet cell metaplasia. This protective effect of Cs-TP is associated with markedly reduced OVA-specific IgE and Th1/Th2 cytokine production. Moreover, Cs-TP increased the number of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T (Treg) cells as well as their suppressive activity. In fact, proliferation of OVA-restimulated splenocytes was suppressed significantly. Cs-TP also inhibited the expression of such co-stimulatory molecules as CD80, CD86, and CD40 in LPS- or OVA-stimulated dendritic cells (DCs), suggesting that Cs-TP could interfere with the capacity of airway DCs to prime naive T cells. These data demonstrate the capacity of C. sinensis to ameliorate allergic asthma and broaden our understanding of the paradoxical

  2. In situ analysis of FOXP3+ regulatory T cells and myeloid dendritic cells in human colorectal cancer tissue and tumor-draining lymph node

    PubMed Central

    GAI, XIAO-DONG; LI, CHUN; SONG, YANG; LEI, YAN-MING; YANG, BAO-XUE

    2013-01-01

    Forkhead box protein 3 (FOXP3) regulatory T cells (Tregs) are important in the maintenance of tumor immunity tolerance. Myeloid dendritic cells (mDCs) are antigen-presenting cells (APCs) specialized to initiate and regulate immunity. Tregs and mDCs are suspected of influencing the interaction between the tumor and immune system, and thus the course of tumors. However, the implication and interaction of their concurrent infitration in colorectal cancer (CRC) remain unknown. The aim of this study was to determine FOXP3+ Tregs and CD11c+ mDCs infiltration in CRC and tumor-draining lymph node (TDLN) and to explore the clinical and pathological implication of suppressor and effector immune cell subsets. Immunohistochemical assay was conducted to assess FOXP3+ Tregs and CD11c+ mDCs infiltration in tumor tissue and in metastasis-free TDLN (mfTDLN) and metastatic TDLN (mTDLN). The results showed that FOXP3+ Tregs and CD11c+ mDCs infiltration was higher in tumor tissue compared to adjacent normal mucosa (P<0.001). FOXP3+ Tregs infiltration was associated with advanced tumor-node-metastasis (TNM) stage and lymph node metastasis (P<0.001 and P<0.001, for TNM stage and lymph node metastasis, respectively), whereas less CD11c+ mDCs infiltration of tumor in situ was associated with deeper tumor invasion, advanced TNM stages and lymph node metastasis (P<0.05, P<0.001 and P<0.001, for tumor invasion depth, TNM stages and lymph node metastasis, respectively). Compared to mfTDLN, mTDLN was significantly enriched in FOXP3+ Tregs (P<0.001) and reduced in CD11c+ mDCs (P<0.001). The statistical analysis demonstrated no significant correlations in Tregs and mDCs infiltration. These results suggest that more FOXP3+ Tregs and less CD11c+ mDCs infiltration have stronger prognostic significance in CRC. The presence of tumor cells in mTDLN may contribute to a tolerogenic milieu and facilitate the survival of metastatic tumor cells. PMID:24648920

  3. Dendrite inhibitor

    DOEpatents

    Miller, W.E.

    1988-06-07

    An apparatus for removing dendrites or other crystalline matter from the surface of a liquid in a matter transport process, and an electrolytic cell including such an apparatus. A notch may be provided to allow continuous exposure of the liquid surface, and a bore may be further provided to permit access to the liquid. 2 figs.

  4. Dendrite inhibitor

    DOEpatents

    Miller, William E.

    1989-01-01

    An apparatus for removing dendrites or other crystalline matter from the surface of a liquid in a matter transport process, and an electrolytic cell including such an apparatus. A notch may be provided to allow continuous exposure of the liquid surface, and a bore may be further provided to permit access to the liquid.

  5. Dendrite Model

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Donald Gilles, the Discipline Scientist for Materials Science in NASA's Microgravity Materials Science and Applications Department, demonstrates to Carl Dohrman a model of dendrites, the branch-like structures found in many metals and alloys. Dohrman was recently selected by the American Society for Metals International as their 1999 ASM International Foundation National Merit Scholar. The University of Illinois at Urbana-Champaign freshman recently toured NASA's materials science facilities at the Marshall Space Flight Center.

  6. Uptake of donor lymphocytes treated with 8-methoxypsoralen and ultraviolet A light by recipient dendritic cells induces CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells and down-regulates cardiac allograft rejection

    SciTech Connect

    Zheng, De-Hua; Dou, Li-Ping; Wei, Yu-Xiang; Du, Guo-Sheng; Zou, Yi-Ping; Song, Ji-Yong; Zhu, Zhi-Dong; Cai, Ming; Qian, Ye-Yong; Shi, Bing-Yi

    2010-05-14

    Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy and has been demonstrated to be beneficial for graft-vs-host disease and solid-organ allograft rejection. ECP involves reinfusion of a patient's autologous peripheral blood leukocytes treated ex vivo with 8-methoxypsoralen and UVA light radiation (PUVA). Previous studies focused only on ECP treatment of recipient immune cells. Our study is the first to extend the target of ECP treatment to donor immune cells. The results of in vitro co-culture experiments demonstrate uptake of donor PUVA-treated splenic lymphocytes (PUVA-SPs) by recipient immature dendritic cells (DCs). Phagocytosis of donor PUVA-SPs does not stimulate phenotype maturation of recipient DCs. In the same co-culture system, donor PUVA-SPs enhanced production of interleukin-10 and interferon-{gamma} by recipient DCs and impaired the subsequent capability of recipient DCs to stimulate recipient naive T cells. Phagocytosis of donor PUVA-SP (PUVA-SP DCs) by recipient DCs shifted T-cell responses in favor of T helper 2 cells. Infusion of PUVA-SP DCs inhibited cardiac allograft rejection in an antigen-specific manner and induced CD4{sup +}CD25{sup high}Foxp3{sup +} regulatory T cells. In conclusion, PUVA-SP DCs simultaneously deliver the donor antigen and the regulatory signal to the transplant recipient, and thus can be used to develop a novel DC vaccine for negative immune regulation and immune tolerance induction.

  7. Immature dendritic cells convert anergic nonregulatory T cells into Foxp3- IL-10+ regulatory T cells by engaging CD28 and CTLA-4.

    PubMed

    Pletinckx, Katrien; Vaeth, Martin; Schneider, Theresa; Beyersdorf, Niklas; Hünig, Thomas; Berberich-Siebelt, Friederike; Lutz, Manfred B

    2015-02-01

    Anergic T cells can survive for long time periods passively in a hyporesponsive state without obvious active functions. Thus, the immunological reason for their maintenance is unclear. Here, we induced peptide-specific anergy in T cells from mice by coculturing these cells with immature murine dendritic cells (DCs). We found that these anergic, nonsuppressive IL-10(-) Foxp3(-) CTLA-4(+) CD25(low) Egr2(+) T cells could be converted into suppressive IL-10(+) Foxp3(-) CTLA-4(+) CD25(high) Egr2(+) cells resembling type-1 Treg cells (Tr1) when stimulated a second time by immature DCs in vitro. Addition of TGF-β during anergy induction favored Foxp3(+) Treg-cell induction, while TGF-β had little effect when added to the second stimulation. Expression of both CD28 and CTLA-4 molecules on anergic T cells was required to allow their conversion into Tr1-like cells. Suppressor activity was enabled via CD28-mediated CD25 upregulation, acting as an IL-2 sink, together with a CTLA-4-mediated inhibition of NFATc1/α activation to shut down IL-2-mediated proliferation. Together, these data provide evidence and mechanistical insights into how persistent anergic T cells may serve as a resting memory pool for Tr1-like cells.

  8. The TLR7 agonist induces tumor regression both by promoting CD4+T cells proliferation and by reversing T regulatory cell-mediated suppression via dendritic cells

    PubMed Central

    Wang, Xiaofeng; Wu, Xiongyan; Chen, Xuehua; Li, Jianfang; Zhu, Zhenggang; Liu, Bingya; Su, Liping

    2015-01-01

    Treg-induced immunosuppression is now recognized as a key element in enabling tumors to escape immune-mediated destruction. Although topical TLR7 therapies such as imiquimod have been proved successful in the treatment of dermatological malignancy and a number of conditions beyond the FDA-approved indications, the mechanism behind the effect of TLR7 on effector T cell and Treg cell function in cancer immunosurveillance is still not well understood. Here, we found that Loxoribin, one of the TLR7 ligands, could inhibit tumor growth in xenograft models of colon cancer and lung cancer, and these anti-tumor effects of Loxoribin were mediated by promoting CD4+T cell proliferation and reversing Treg-mediated suppression via dendritic cells (DCs). However, deprivation of IL-6 using a neutralizing antibody abrogated the ability of Loxoribin-treated DCs, which reversed the Treg cell-mediated suppression. Furthermore, adoptive transfer of Loxoribin-treated DCs inhibited the tumor growth in vivo. Thus, this study links TLR7 signaling to the functional control of effector T cells and Treg cells and identifies Loxoribin as a new therapeutic strategy in cancer treatment, which may offer new opportunities to improve the outcome of cancer immunotherapy. PMID:25593198

  9. Human dendritic cell DC-SIGN and TLR-2 mediate complementary immune regulatory activities in response to Lactobacillus rhamnosus JB-1.

    PubMed

    Konieczna, Patrycja; Schiavi, Elisa; Ziegler, Mario; Groeger, David; Healy, Selena; Grant, Ray; O'Mahony, Liam

    2015-01-01

    The microbiota is required for optimal host development and ongoing immune homeostasis. Lactobacilli are common inhabitants of the mammalian large intestine and immunoregulatory effects have been described for certain, but not all, strains. The mechanisms underpinning these protective effects are beginning to be elucidated. One such protective organism is Lactobacillus rhamnosus JB-1 (Lb. rhamnosus JB-1). Lb. murinus has no such anti-inflammatory protective effects and was used as a comparator organism. Human monocyte-derived dendritic cells (MDDCs) were co-incubated with bacteria and analysed over time for bacterial adhesion and intracellular processing, costimulatory molecule expression, cytokine secretion and induction of lymphocyte polarization. Neutralising antibodies were utilized to identify the responsible MDDC receptors. Lb. rhamnosus JB-1 adhered to MDDCs, but internalization and intracellular processing was significantly delayed, compared to Lb. murinus which was rapidly internalized and processed. Lb. murinus induced CD80 and CD86 expression, accompanied by high levels of cytokine secretion, while Lb. rhamnosus JB-1 was a poor inducer of costimulatory molecule expression and cytokine secretion. Lb. rhamnosus JB-1 primed MDDCs induced Foxp3 expression in autologous lymphocytes, while Lb. murinus primed MDDCs induced Foxp3, T-bet and Ror-γt expression. DC-SIGN was required for Lb. rhamnosus JB-1 adhesion and influenced IL-12 secretion, while TLR-2 influenced IL-10 and IL-12 secretion. Here we demonstrate that the delayed kinetics of bacterial processing by MDDCs correlates with MDDC activation and stimulation of lymphocytes. Thus, inhibition or delay of intracellular processing may be a novel strategy by which certain commensals may avoid the induction of proinflammatory responses.

  10. Helminth Antigens Enable CpG-Activated Dendritic Cells to Inhibit the Symptoms of Collagen-induced Arthritis through Foxp3+ Regulatory T Cells

    PubMed Central

    Carranza, Franco; Falcón, Cristian Roberto; Nuñez, Nicolás; Knubel, Carolina; Correa, Silvia Graciela; Bianco, Ismael; Maccioni, Mariana; Fretes, Ricardo; Triquell, María Fernanda; Motrán, Claudia Cristina; Cervi, Laura

    2012-01-01

    Dendritic cells (DC) have the potential to control the outcome of autoimmunity by modulating the immune response. In this study, we tested the ability of Fasciola hepatica total extract (TE) to induce tolerogenic properties in CpG-ODN (CpG) maturated DC, to then evaluate the therapeutic potential of these cells to diminish the inflammatory response in collagen induced arthritis (CIA). DBA/1J mice were injected with TE plus CpG treated DC (T/C-DC) pulsed with bovine collagen II (CII) between two immunizations with CII and clinical scores CIA were determined. The levels of CII-specific IgG2 and IgG1 in sera, the histological analyses in the joints, the cytokine profile in the draining lymph node (DLN) cells and in the joints, and the number, and functionality of CD4+CD25+Foxp3+ T cells (Treg) were evaluated. Vaccination of mice with CII pulsed T/C-DC diminished the severity and incidence of CIA symptoms and the production of the inflammatory cytokine, while induced the production of anti-inflammatory cytokines. The therapeutic effect was mediated by Treg cells, since the adoptive transfer of CD4+CD25+ T cells, inhibited the inflammatory symptoms in CIA. The in vitro blockage of TGF-β in cultures of DLN cells plus CII pulsed T/C-DC inhibited the expansion of Treg cells. Vaccination with CII pulsed T/C-DC seems to be a very efficient approach to diminish exacerbated immune response in CIA, by inducing the development of Treg cells, and it is therefore an interesting candidate for a cell-based therapy for rheumatoid arthritis (RA). PMID:22848374

  11. Dominating expression of negative regulatory factors downmodulates major histocompatibility complex Class-II expression on dendritic cells in chronic hepatitis C infection

    PubMed Central

    Tomer, Shallu; Chawla, Yogesh K; Duseja, Ajay; Arora, Sunil K

    2016-01-01

    AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells (DCs) in chronic hepatitis C (CHC) patients infected with genotype 3 virus. METHODS: This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c (BDCA1)+ DC isolation Kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus (HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time PCR. RESULTS: Non-responders [sustained virological response (SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1 (6-fold) and negative regulators of JAK-STAT pathway such as SOCS (6-fold) as compared to responders (SVR+ve) to antiviral therapy. The down-regulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex (MHC) Class-II family as HLA-DP, HLA-DQ (2-fold) and superoxide dismutase (2-fold). Cells grown in the presence of HCV viral proteins had genes down-regulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors (4-fold) were up-regulated as compared to cells grown in absence of viral proteins. CONCLUSION: Underexpressed MHC class-II genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs. PMID:27298560

  12. Human Dendritic Cell DC-SIGN and TLR-2 Mediate Complementary Immune Regulatory Activities in Response to Lactobacillus rhamnosus JB-1

    PubMed Central

    Konieczna, Patrycja; Schiavi, Elisa; Ziegler, Mario; Groeger, David; Healy, Selena; Grant, Ray; O’Mahony, Liam

    2015-01-01

    The microbiota is required for optimal host development and ongoing immune homeostasis. Lactobacilli are common inhabitants of the mammalian large intestine and immunoregulatory effects have been described for certain, but not all, strains. The mechanisms underpinning these protective effects are beginning to be elucidated. One such protective organism is Lactobacillus rhamnosus JB-1 (Lb. rhamnosus JB-1). Lb. murinus has no such anti-inflammatory protective effects and was used as a comparator organism. Human monocyte-derived dendritic cells (MDDCs) were co-incubated with bacteria and analysed over time for bacterial adhesion and intracellular processing, costimulatory molecule expression, cytokine secretion and induction of lymphocyte polarization. Neutralising antibodies were utilized to identify the responsible MDDC receptors. Lb. rhamnosus JB-1 adhered to MDDCs, but internalization and intracellular processing was significantly delayed, compared to Lb. murinus which was rapidly internalized and processed. Lb. murinus induced CD80 and CD86 expression, accompanied by high levels of cytokine secretion, while Lb. rhamnosus JB-1 was a poor inducer of costimulatory molecule expression and cytokine secretion. Lb. rhamnosus JB-1 primed MDDCs induced Foxp3 expression in autologous lymphocytes, while Lb. murinus primed MDDCs induced Foxp3, T-bet and Ror-γt expression. DC-SIGN was required for Lb. rhamnosus JB-1 adhesion and influenced IL-12 secretion, while TLR-2 influenced IL-10 and IL-12 secretion. Here we demonstrate that the delayed kinetics of bacterial processing by MDDCs correlates with MDDC activation and stimulation of lymphocytes. Thus, inhibition or delay of intracellular processing may be a novel strategy by which certain commensals may avoid the induction of proinflammatory responses. PMID:25816321

  13. Inhibition of NF-kappa B during human dendritic cell differentiation generates anergy and regulatory T-cell activity for one but not two human leukocyte antigen DR mismatches.

    PubMed

    Hernandez, Ana; Burger, Melissa; Blomberg, Bonnie B; Ross, William A; Gaynor, Jeffrey J; Lindner, Inna; Cirocco, Robert; Mathew, James M; Carreno, Manuel; Jin, Yidi; Lee, Kelvin P; Esquenazi, Violet; Miller, Joshua

    2007-09-01

    We examined the in vitro inhibition of human monocyte-derived dendritic cells (DC) maturation via NF-kappaB blockade on T-cell allostimulation, cytokine production, and regulatory T-cell generation. DC were generated from CD14+ monocytes isolated from peripheral blood using GM-CSF and IL-4 for differentiation and TNF-alpha, IL-1beta, and PGE2 as maturational stimuli with or without the NF-kappaB inhibitors, BAY 11-7082 (BAY-DC) or Aspirin (ASA-DC). Stimulator and responder cells were one versus two HLA-DR mismatched in direct versus indirect presentation assays. Both BAY-DC and ASA-DC expressed high levels of HLA-DR and CD86 but always expressed less CD40 compared with controls. Some experiments showed slightly lower levels of CD80. Both BAY- and ASA-allogeneic DC and autologous alloantigen pulsed DC were weaker stimulators of T cells (by MLR) compared with controls, and there was reduced IL-2 and IFN-gamma production by T cells stimulated with BAY-DC or ASA-DC (by ELISPOT) (more marked results were always observed with ASA-treated DC). In addition, NF-kappaB blockade of DC maturation caused the generation of T cells with regulatory function (T regs) but only when T cells were stimulated by either allogeneic (direct presentation) or alloantigen pulsed autologous DC (indirect presentation) with one HLA-DR mismatch and not with two HLA-DR mismatches (either direct or indirect presentation). However, the T regs generated from these ASA-DC showed similar FoxP3 mRNA expression to those from nontreated DC. Extension of this study to human organ transplantation suggests potential therapies using one DR-matched NF-kappaB blocked DC to help generate clinical tolerance.

  14. Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells.

    PubMed

    Goudin, Nicolas; Chappert, Pascal; Mégret, Jérome; Gross, David-Alexandre; Rocha, Benedita; Azogui, Orly

    2016-01-01

    Natural regulatory T (Treg) cells interfere with multiple functions, which are crucial for the development of strong anti-tumour responses. In a model of 4T1 mammary carcinoma, depletion of CD25+Tregs results in tumour regression in Balb/c mice, but the mechanisms underlying this process are not fully understood. Here, we show that partial Treg depletion leads to the generation of a particular effector CD8 T cell subset expressing CD11c and low level of PD-1 in tumour draining lymph nodes. These cells have the capacity to migrate into the tumour, to kill DCs, and to locally regulate the anti-tumour response. These events are concordant with a substantial increase in CD11b+ resident dendritic cells (DCs) subsets in draining lymph nodes followed by CD8+ DCs. These results indicate that Treg depletion leads to tumour regression by unmasking an increase of DC subsets as a part of a program that optimizes the microenvironment by orchestrating the activation, amplification, and migration of high numbers of fully differentiated CD8+CD11c+PD1lo effector T cells to the tumour sites. They also indicate that a critical pattern of DC subsets correlates with the evolution of the anti-tumour response and provide a template for Treg depletion and DC-based therapy. PMID:27341421

  15. Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells

    PubMed Central

    Goudin, Nicolas; Chappert, Pascal; Mégret, Jérome; Gross, David-Alexandre; Rocha, Benedita

    2016-01-01

    Natural regulatory T (Treg) cells interfere with multiple functions, which are crucial for the development of strong anti-tumour responses. In a model of 4T1 mammary carcinoma, depletion of CD25+Tregs results in tumour regression in Balb/c mice, but the mechanisms underlying this process are not fully understood. Here, we show that partial Treg depletion leads to the generation of a particular effector CD8 T cell subset expressing CD11c and low level of PD-1 in tumour draining lymph nodes. These cells have the capacity to migrate into the tumour, to kill DCs, and to locally regulate the anti-tumour response. These events are concordant with a substantial increase in CD11b+ resident dendritic cells (DCs) subsets in draining lymph nodes followed by CD8+ DCs. These results indicate that Treg depletion leads to tumour regression by unmasking an increase of DC subsets as a part of a program that optimizes the microenvironment by orchestrating the activation, amplification, and migration of high numbers of fully differentiated CD8+CD11c+PD1lo effector T cells to the tumour sites. They also indicate that a critical pattern of DC subsets correlates with the evolution of the anti-tumour response and provide a template for Treg depletion and DC-based therapy. PMID:27341421

  16. PRRSV-infected monocyte-derived dendritic cells express high levels of SLA-DR and CD80/86 but do not stimulate PRRSV-naïve regulatory T cells to proliferate.

    PubMed

    Rodríguez-Gómez, Irene M; Käser, Tobias; Gómez-Laguna, Jaime; Lamp, Benjamin; Sinn, Leonie; Rümenapf, Till; Carrasco, Librado; Saalmüller, Armin; Gerner, Wilhelm

    2015-01-01

    In vitro generated monocyte-derived dendritic cells (moDCs) have frequently been used to study the influence of porcine reproductive and respiratory syndrome virus (PRRSV) infection on antigen presenting cells. However, obtained results have often been conflicting in regard to expression of co-stimulatory molecules and interaction with T cells. In this study we performed a detailed phenotypic characterisation of PRRSV-infected moDCs and non-infected moDCs. For CD163 and CD169, which are involved in PRRSV-entry into host cells, our results show that prior to infection porcine moDCs express high levels of CD163 but only very low levels for CD169. Following infection with either PRRSV-1 or PRRSV-2 strains after 24 h, PRRSV-nucleoprotein (N-protein)(+) and N-protein(-) moDCs derived from the same microculture were analyzed for expression of swine leukocyte antigen-DR (SLA-DR) and CD80/86. N-protein(+) moDCs consistently expressed higher levels of SLA-DR and CD80/86 compared to N-protein(-) moDCs. We also investigated the influence of PRRSV-infected moDCs on proliferation and frequency of Foxp3(+) regulatory T cells present within CD4(+) T cells in in vitro co-cultures. Neither CD3-stimulated nor unstimulated CD4(+) T cells showed differences in regard to proliferation and frequency of Foxp3(+) T cells following co-cultivation with either PRRSV-1 or PRRSV-2 infected moDCs. Our results suggest that a more detailed characterisation of PRRSV-infected moDCs will lead to more consistent results across different laboratories and PRRSV strains as indicated by the major differences in SLA-DR and CD80/86 expression between PRRSV-infected and non-infected moDCs present in the same microculture. PMID:25990845

  17. PRRSV-infected monocyte-derived dendritic cells express high levels of SLA-DR and CD80/86 but do not stimulate PRRSV-naïve regulatory T cells to proliferate.

    PubMed

    Rodríguez-Gómez, Irene M; Käser, Tobias; Gómez-Laguna, Jaime; Lamp, Benjamin; Sinn, Leonie; Rümenapf, Till; Carrasco, Librado; Saalmüller, Armin; Gerner, Wilhelm

    2015-05-20

    In vitro generated monocyte-derived dendritic cells (moDCs) have frequently been used to study the influence of porcine reproductive and respiratory syndrome virus (PRRSV) infection on antigen presenting cells. However, obtained results have often been conflicting in regard to expression of co-stimulatory molecules and interaction with T cells. In this study we performed a detailed phenotypic characterisation of PRRSV-infected moDCs and non-infected moDCs. For CD163 and CD169, which are involved in PRRSV-entry into host cells, our results show that prior to infection porcine moDCs express high levels of CD163 but only very low levels for CD169. Following infection with either PRRSV-1 or PRRSV-2 strains after 24 h, PRRSV-nucleoprotein (N-protein)(+) and N-protein(-) moDCs derived from the same microculture were analyzed for expression of swine leukocyte antigen-DR (SLA-DR) and CD80/86. N-protein(+) moDCs consistently expressed higher levels of SLA-DR and CD80/86 compared to N-protein(-) moDCs. We also investigated the influence of PRRSV-infected moDCs on proliferation and frequency of Foxp3(+) regulatory T cells present within CD4(+) T cells in in vitro co-cultures. Neither CD3-stimulated nor unstimulated CD4(+) T cells showed differences in regard to proliferation and frequency of Foxp3(+) T cells following co-cultivation with either PRRSV-1 or PRRSV-2 infected moDCs. Our results suggest that a more detailed characterisation of PRRSV-infected moDCs will lead to more consistent results across different laboratories and PRRSV strains as indicated by the major differences in SLA-DR and CD80/86 expression between PRRSV-infected and non-infected moDCs present in the same microculture.

  18. Plasmacytoid dendritic cells and type 1 interferon promote peripheral expansion of forkhead box protein 3(+) regulatory T cells specific for the ubiquitous RNA-binding nuclear antigen La/Sjögren's syndrome (SS)-B.

    PubMed

    Pan, Z-J; Horton, C G; Lawrence, C; Farris, A D

    2016-10-01

    RNA-binding nuclear antigens are a major class of self-antigen to which immune tolerance is lost in rheumatic diseases. Serological tolerance to one such antigen, La/Sjögren's syndrome (SS)-B (La), is controlled by CD4(+) T cells. This study investigated peripheral tolerance to human La (hLa) by tracking the fate of hLa-specific CD4(+) T cells expressing the transgenic (Tg) 3B5.8 T cell receptor (TCR) after adoptive transfer into lymphocyte-replete recipient mice expressing hLa as a neo-self-antigen. After initial antigen-specific cell division, hLa-specific donor CD4(+) T cells expressed forkhead box protein 3 (FoxP3). Donor cells retrieved from hLa Tg recipients displayed impaired proliferation and secreted interleukin (IL)-10 in vitro in response to antigenic stimulation. Transfer of highly purified FoxP3-negative donor cells demonstrated that accumulation of hLa-specific regulatory T cells (Treg ) was due primarily to expansion of small numbers of donor Treg . Depletion of recipient plasmacytoid dendritic cells (pDC), but not B cells, severely hampered the accumulation of FoxP3(+) donor Treg in hLa Tg recipients. Recipient pDC expressed tolerogenic markers and higher levels of co-stimulatory and co-inhibitory molecules than B cells. Adoptive transfer of hLa peptide-loaded pDC into mice lacking expression of hLa recapitulated the accumulation of hLa-specific Treg . Blockade of the type 1 interferon (IFN) receptor in hLa Tg recipients of hLa-specific T cells impaired FoxP3(+) donor T cell accumulation. Therefore, peripheral expansion of Treg specific for an RNA-binding nuclear antigen is mediated by antigen-presenting pDC in a type 1 IFN-dependent manner. These results reveal a regulatory function of pDC in controlling autoreactivity to RNA-binding nuclear antigens.

  19. Isothermal Dendritic Growth Experiment - PVA Dendrites

    NASA Technical Reports Server (NTRS)

    1997-01-01

    The Isothermal Dendritic Growth Experiment (IDGE), flown on three Space Shuttle missions, is yielding new insights into virtually all industrially relevant metal and alloy forming operations. IDGE used transparent organic liquids that form dendrites (treelike structures) similar to those inside metal alloys. Comparing Earth-based and space-based dendrite growth velocity, tip size and shape provides a better understanding of the fundamentals of dentritic growth, including gravity's effects. Shalowgraphic images of pivalic acid (PVA) dendrites forming from the melt show the subtle but distinct effects of gravity-driven heat convection on dentritic growth. In orbit, the dendrite grows as its latent heat is liberated by heat conduction. This yields a blunt dendrite tip. On Earth, heat is carried away by both conduction and gravity-driven convection. This yields a sharper dendrite tip. In addition, under terrestrial conditions, the sidebranches growing in the direction of gravity are augmented as gravity helps carry heat out of the way of the growing sidebranches as opposed to microgravity conditions where no augmentation takes place. IDGE was developed by Rensselaer Polytechnic Institute and NASA/Glenn Research Center. Advanced follow-on experiments are being developed for flight on the International Space Station. Photo Credit: NASA/Glenn Research Center

  20. Free dendritic growth

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.

    1984-01-01

    Free dendritic growth refers to the unconstrained development of crystals within a supercooled melt, which is the classical 'dendrite problem'. Great strides have been taken in recent years in both the theoretical understanding of dendritic growth and its experimental status. The development of this field will be sketched, showing that transport theory and interfacial thermodynamics (capillarity theory) were sufficient ingredients to develop a truly predictive model of dendrite formation. The convenient, but incorrect, notion of 'maximum velocity' was used for many years to estimate the behavior of dendritic transformations until supplanted by modern dynamic stability theory. The proper combinations of transport theory and morphological stability seem to able to predict the salient aspects of dendritic growth, especially in the neighborhood of the tip. The overall development of cast microstructures, such as equiaxed zone formation, rapidly solidified microstructures, etc., also seems to contain additional non-deterministic features which lie outside the current theories discussed here.

  1. The PD-L1/CD86 ratio is increased in dendritic cells co-infected with porcine circovirus type 2 and porcine reproductive and respiratory syndrome virus, and the PD-L1/PD-1 axis is associated with anergy, apoptosis, and the induction of regulatory T-cells in porcine lymphocytes.

    PubMed

    Richmond, O; Cecere, T E; Erdogan, E; Meng, X J; Piñeyro, P; Subramaniam, S; Todd, S M; LeRoith, T

    2015-11-18

    Porcine circovirus type 2 (PCV2) and porcine reproductive and respiratory syndrome virus (PRRSV) continue to have a negative economic impact on global swine production operations. Host immune modulations that potentiate disease during PCV2 and/or PRRSV infections are important areas of ongoing research. In this study, we evaluated the expression levels of PD-L1, CD86, and IL-10 in order to phenotype dendritic cells following viral infection with PCV2b and/or PRRSV. The results showed that the inhibitory marker PD-L1 was significantly increased in monocyte derived dendritic cells (MoDC) in both singular PCV2 infection and PCV2/PRRSV co-infections. MoDC expression of stimulatory marker CD86 was significantly increased during singular PCV2 infections, while it was significantly decreased in the treatment groups co-infected with both PCV2 and PRRSV. IL-10 production was highest among MoDCs that were co-infected with PCV2 and PRRSV. These results indicate that dendritic cells develop a regulatory phenotype following PCV2/PRRSV co-infections. We further investigated the role of the PD-L1/PD-1 axis in lymphocyte anergy, apoptosis, and the induction of regulatory T-cells in porcine mononuclear cell populations. Lymphocyte populations with normal PD-1 expression had higher percentages of anergic, apoptotic lymphocytes and CD4(+)CD25(HIGH)FoxP3(+) regulatory T-cells when compared to a PD-1 deficient lymphocyte population. These results implicate the PD-L1/PD-1 axis in negative regulation of lymphocyte responses in pigs. PMID:26446939

  2. Dendritic polyurea polymers.

    PubMed

    Tuerp, David; Bruchmann, Bernd

    2015-01-01

    Dendritic polymers, subsuming dendrimers as well as hyperbranched or highly branched polymers are well established in the field of polymer chemistry. This review article focuses on urea based dendritic polymers and summarizes their synthetic routes through both isocyanate and isocyanate-free processes. Furthermore, this article highlights applications where dendritic polyureas show their specific chemical and physical potential. For these purposes scientific publications as well as patent literature are investigated to generate a comprehensive overview on this topic.

  3. Molecular mechanisms of dendrite stability

    PubMed Central

    Koleske, Anthony J.

    2014-01-01

    In the developing brain, dendrite branches and dendritic spines form and turn over dynamically. By contrast, most dendrite arbors and dendritic spines in the adult brain are stable for months, years and possibly even decades. Emerging evidence reveals that dendritic spine and dendrite arbor stability have crucial roles in the correct functioning of the adult brain and that loss of stability is associated with psychiatric disorders and neurodegenerative diseases. Recent findings have provided insights into the molecular mechanisms that underlie long-term dendrite stabilization, how these mechanisms differ from those used to mediate structural plasticity and how they are disrupted in disease. PMID:23839597

  4. Isothermal Dendritic Growth Experiment - SCN Dendrites

    NASA Technical Reports Server (NTRS)

    1995-01-01

    The Isothermal Dendritic Growth Experiment (IDGE), flown on three Space Shuttle missions, is yielding new insights into virtually all industrially relevant metal and alloy forming operations. IDGE used transparent organic liquids that form dendrites (treelike structures) similar to the crystals that form inside metal alloys. Comparing Earth-based and space-based dentrite growth velocity, tip size and shape provid a better understanding of the fundamentals of dentritic growth, including gravity's effects. These shadowgraphic images show succinonitrile (SCN) dentrites growing in a melt (liquid). The space-grown crystals also have cleaner, better defined sidebranches. IDGE was developed by Rensselaer Polytechnic Institude (RPI) and NASA/ Glenn Research Center(GRC). Advanced follow-on experiments are being developed for flight on the International Space Station. Photo gredit: NASA/Glenn Research Center

  5. On the dendrites and dendritic transitions in undercooled germanium

    SciTech Connect

    Lau, C.F.; Kui, H.W. . Dept. of Physics)

    1993-07-01

    Undercooled molten Ge was allowed to solidify at initial bulk undercoolings, [Delta]T, from 10 to 200C under dehydrated boron oxide flux. It turned out that in addition to the (211) twin dendrite found by Billig and the (100) twin-free dendrite discovered by Devaud and Turnbill, there is a third novel twin dendrite, the (110) twin dendrite. The twin planes in a (110) dendrite always appear in multiple numbers and the orientation is (111). These different kinds of dendrites exist at different initial interfacial undercoolings and the transition temperatures for (110) to (211), (211) to (100) are [Delta]T = 61 and 93C, respectively.

  6. Optimization principles of dendritic structure

    PubMed Central

    Cuntz, Hermann; Borst, Alexander; Segev, Idan

    2007-01-01

    Background Dendrites are the most conspicuous feature of neurons. However, the principles determining their structure are poorly understood. By employing cable theory and, for the first time, graph theory, we describe dendritic anatomy solely on the basis of optimizing synaptic efficacy with minimal resources. Results We show that dendritic branching topology can be well described by minimizing the path length from the neuron's dendritic root to each of its synaptic inputs while constraining the total length of wiring. Tapering of diameter toward the dendrite tip – a feature of many neurons – optimizes charge transfer from all dendritic synapses to the dendritic root while housekeeping the amount of dendrite volume. As an example, we show how dendrites of fly neurons can be closely reconstructed based on these two principles alone. PMID:17559645

  7. Metabolism Is Central to Tolerogenic Dendritic Cell Function

    PubMed Central

    Sim, Wen Jing; Ahl, Patricia Jennifer; Connolly, John Edward

    2016-01-01

    Immunological tolerance is a fundamental tenant of immune homeostasis and overall health. Self-tolerance is a critical component of the immune system that allows for the recognition of self, resulting in hyporeactivity instead of immunogenicity. Dendritic cells are central to the establishment of dominant immune tolerance through the secretion of immunosuppressive cytokines and regulatory polarization of T cells. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Recent studies have demonstrated that dendritic cell maturation leads to a shift toward a glycolytic metabolic state and preferred use of glucose as a carbon source. In contrast, tolerogenic dendritic cells favor oxidative phosphorylation and fatty acid oxidation. This dichotomous metabolic reprogramming of dendritic cells drives differential cellular function and plays a role in pathologies, such as autoimmune disease. Pharmacological alterations in metabolism have promising therapeutic potential. PMID:26980944

  8. Dendritic Polymers for Theranostics

    PubMed Central

    Ma, Yuan; Mou, Quanbing; Wang, Dali; Zhu, Xinyuan; Yan, Deyue

    2016-01-01

    Dendritic polymers are highly branched polymers with controllable structures, which possess a large population of terminal functional groups, low solution or melt viscosity, and good solubility. Their size, degree of branching and functionality can be adjusted and controlled through the synthetic procedures. These tunable structures correspond to application-related properties, such as biodegradability, biocompatibility, stimuli-responsiveness and self-assembly ability, which are the key points for theranostic applications, including chemotherapeutic theranostics, biotherapeutic theranostics, phototherapeutic theranostics, radiotherapeutic theranostics and combined therapeutic theranostics. Up to now, significant progress has been made for the dendritic polymers in solving some of the fundamental and technical questions toward their theranostic applications. In this review, we briefly summarize how to control the structures of dendritic polymers, the theranostics-related properties derived from their structures and their theranostics-related applications. PMID:27217829

  9. Lithium Dendrite Formation

    SciTech Connect

    2015-03-06

    Scientists at the Department of Energy’s Oak Ridge National Laboratory have captured the first real-time nanoscale images of lithium dendrite structures known to degrade lithium-ion batteries. The ORNL team’s electron microscopy could help researchers address long-standing issues related to battery performance and safety. Video shows annular dark-field scanning transmission electron microscopy imaging (ADF STEM) of lithium dendrite nucleation and growth from a glassy carbon working electrode and within a 1.2M LiPF6 EC:DM battery electrolyte.

  10. Isothermal Dendritic Growth Experiment Video

    NASA Technical Reports Server (NTRS)

    1997-01-01

    This video, captured during the Isothermal Dendritic Growth Experiment (IDGE) flown on STS-87 as a part of the fourth United States Microgravity payload, shows the growth of a dendrite, and the surface solidification that occurred on the front and back windows of the growth chamber. Dendrites are tiny, tree like structures that form as metals solidify.

  11. Transport Processes in Dendritic Crystallization

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.

    1984-01-01

    Free dentritic growth refers to the unconstrained development of crystals within a supercooled melt, which is the classical dendrite problem. The development of theoretical understanding of dendritic growth and its experimental status is sketched showing that transport theory and interfacial thermodynamics (capillarity theory) are insufficient ingredients to develop a truly predictive model of dendrite formation. The convenient, but incorrect, notion of maximum velocity was used for many years to estimate the behavior of dendritic transformations until supplanted by modern dynamic stability theory. The proper combinations of transport theory and morphological stability seem to be able to predict the salient aspects of dendritic growth, especially in the neighborhood of the tip.

  12. Modification of dendritic development.

    PubMed

    Feria-Velasco, Alfredo; del Angel, Alma Rosa; Gonzalez-Burgos, Ignacio

    2002-01-01

    Since 1890 Ramón y Cajal strongly defended the theory that dendrites and their processes and spines had a function of not just nutrient transport to the cell body, but they had an important conductive role in neural impulse transmission. He extensively discussed and supported this theory in the Volume 1 of his extraordinary book Textura del Sistema Nervioso del Hombre y de los Vertebrados. Also, Don Santiago significantly contributed to a detailed description of the various neural components of the hippocampus and cerebral cortex during development. Extensive investigation has been done in the last Century related to the functional role of these complex brain regions, and their association with learning, memory and some limbic functions. Likewise, the organization and expression of neuropsychological qualities such as memory, exploratory behavior and spatial orientation, among others, depend on the integrity and adequate functional activity of the cerebral cortex and hippocampus. It is known that brain serotonin synthesis and release depend directly and proportionally on the availability of its precursor, tryptophan (TRY). By using a chronic TRY restriction model in rats, we studied their place learning ability in correlation with the dendritic spine density of pyramidal neurons in field CA1 of the hippocampus during postnatal development. We have also reported alterations in the maturation pattern of the ability for spontaneous alternation and task performance evaluating short-term memory, as well as adverse effects on the density of dendritic spines of hippocampal CA1 field pyramidal neurons and on the dendritic arborization and the number of dendritic spines of pyramidal neurons from the third layer of the prefrontal cortex using the same model of TRY restriction. The findings obtained in these studies employing a modified Golgi method, can be interpreted as a trans-synaptic plastic response due to understimulation of serotoninergic receptors located in the

  13. Magnetic and dendritic catalysts.

    PubMed

    Wang, Dong; Deraedt, Christophe; Ruiz, Jaime; Astruc, Didier

    2015-07-21

    The recovery and reuse of catalysts is a major challenge in the development of sustainable chemical processes. Two methods at the frontier between homogeneous and heterogeneous catalysis have recently emerged for addressing this problem: loading the catalyst onto a dendrimer or onto a magnetic nanoparticle. In this Account, we describe representative examples of these two methods, primarily from our research group, and compare them. We then describe new chemistry that combines the benefits of these two methods of catalysis. Classic dendritic catalysis has involved either attaching the catalyst covalently at the branch termini or within the dendrimer core. We have used chelating pyridyltriazole ligands to insolubilize catalysts at the termini of dendrimers, providing an efficient, recyclable heterogeneous catalysts. With the addition of dendritic unimolecular micelles olefin metathesis reactions catalyzed by commercial Grubbs-type ruthenium-benzylidene complexes in water required unusually low amounts of catalyst. When such dendritic micelles include intradendritic ligands, both the micellar effect and ligand acceleration promote faster catalysis in water. With these types of catalysts, we could carry out azide alkyne cycloaddition ("click") chemistry with only ppm amounts of CuSO4·5H2O and sodium ascorbate under ambient conditions. Alternatively we can attach catalysts to the surface of superparamagnetic iron oxide nanoparticles (SPIONs), essentially magnetite (Fe3O4) or maghemite (γ-Fe2O3), offering the opportunity to recover the catalysts using magnets. Taking advantage of the merits of both of these strategies, we and others have developed a new generation of recyclable catalysts: dendritic magnetically recoverable catalysts. In particular, some of our catalysts with a γ-Fe2O3@SiO2 core and 1,2,3-triazole tethers and loaded with Pd nanoparticles generate strong positive dendritic effects with respect to ligand loading, catalyst loading, catalytic activity and

  14. Silicon dendritic web material

    NASA Technical Reports Server (NTRS)

    Meier, D. L.; Campbell, R. B.; Sienkiewicz, L. J.; Rai-Choudhury, P.

    1982-01-01

    The development of a low cost and reliable contact system for solar cells and the fabrication of several solar cell modules using ultrasonic bonding for the interconnection of cells and ethylene vinyl acetate as the potting material for module encapsulation are examined. The cells in the modules were made from dendritic web silicon. To reduce cost, the electroplated layer of silver was replaced with an electroplated layer of copper. The modules that were fabricated used the evaporated Ti, Pd, Ag and electroplated Cu (TiPdAg/Cu) system. Adherence of Ni to Si is improved if a nickel silicide can be formed by heat treatment. The effectiveness of Ni as a diffusion barrier to Cu and the ease with which nickel silicide is formed is discussed. The fabrication of three modules using dendritic web silicon and employing ultrasonic bonding for interconnecting calls and ethylene vinyl acetate as the potting material is examined.

  15. Isolation of dendritic cells.

    PubMed

    Inaba, K; Swiggard, W J; Steinman, R M; Romani, N; Schuler, G

    2001-05-01

    This unit presents two methods for preparing dendritic cells (DCs), a highly specialized type of antigen-presenting cell (APC). The first method involves the isolation of DCs from mouse spleen, resulting in a cell population that is highly enriched in accessory cell and APC function. A support protocol for collagenase digestion of splenocyte suspensions is described to increase the yield of dendritic cells. The second method involves generating large numbers of DCs from mouse bone marrow progenitor cells. In that technique, bone marrow cells are cultured in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) to yield 5-10 10(6) cells, 60% of which express DC surface markers (e.g., B-7-2/CD86). Additional techniques for isolating DCs from mouse spleens or other mouse tissues, as well as from human tissues, are also discussed.

  16. Isolation of dendritic cells.

    PubMed

    Inaba, Kayo; Swiggard, William J; Steinman, Ralph M; Romani, Nikolaus; Schuler, Gerold; Brinster, Carine

    2009-08-01

    This unit presents two methods for preparing dendritic cells (DCs), a highly specialized type of antigen-presenting cell (APC). The first method involves the isolation of DCs from mouse spleen, resulting in a cell population that is highly enriched in accessory cell and APC function. A support protocol for collagenase digestion of splenocyte suspensions is described to increase the yield of dendritic cells. The second method involves generating large numbers of DCs from mouse bone marrow progenitor cells. In that technique, bone marrow cells are cultured in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) to yield 5-10 x 10(6) cells, 60% of which express DC surface markers (e.g., B-7-2/CD86). Additional techniques for isolating DCs from mouse spleens or other mouse tissues, as well as from human tissues, are also discussed.

  17. Silicon dendritic web growth

    NASA Technical Reports Server (NTRS)

    Duncan, S.

    1984-01-01

    Technological goals for a silicon dendritic web growth program effort are presented. Principle objectives for this program include: (1) grow long web crystals front continuously replenished melt; (2) develop temperature distribution in web and melt; (3) improve reproductibility of growth; (4) develop configurations for increased growth rates (width and speed); (5) develop new growth system components as required for improved growth; and (6) evaluate quality of web growth.

  18. Web-dendritic ribbon growth

    NASA Technical Reports Server (NTRS)

    Hilborn, R. B., Jr.; Faust, J. W., Jr.

    1976-01-01

    A web furnace was constructed for pulling dendritic-web samples. The effect of changes in the furnace thermal geometry on the growth of dendritic-web was studied. Several attempts were made to grow primitive dendrites for use as the dendritic seed crystals for web growth and to determine the optimum twin spacing in the dendritic seed crystal for web growth. Mathematical models and computer programs were used to determine the thermal geometries in the susceptor, crucible melt, meniscus, and web. Several geometries were determined for particular furnace geometries and growth conditions. The information obtained was used in conjunction with results from the experimental growth investigations in order to achieve proper conditions for sustained pulling of two dendrite web ribbons. In addition, the facilities for obtaining the following data were constructed: twin spacing, dislocation density, web geometry, resistivity, majority charge carrier type, and minority carrier lifetime.

  19. Rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3L exhibit distinct phenotypical and functional characteristics.

    PubMed

    N'diaye, Marie; Warnecke, Andreas; Flytzani, Sevasti; Abdelmagid, Nada; Ruhrmann, Sabrina; Olsson, Tomas; Jagodic, Maja; Harris, Robert A; Guerreiro-Cacais, Andre Ortlieb

    2016-03-01

    Dendritic cells are professional APCs that play a central role in the initiation of immune responses. The limited ex vivo availability of dendritic cells inspires the widespread use of bone marrow-derived dendritic cells as an alternative in research. However, the functional characteristics of bone marrow-derived dendritic cells are incompletely understood. Therefore, we compared functional and phenotypic characteristics of rat bone marrow-derived dendritic cells generated with GM-CSF/IL-4 or FLT3 ligand bone marrow-derived dendritic cells. A comparison of surface markers revealed that FLT3 ligand-bone marrow-derived dendritic cells expressed signal regulatory protein α, CD103, and CD4 and baseline levels of MHC class II, CD40, and CD86, which were highly up-regulated upon stimulation. Conversely, GM-CSF/IL-4-bone marrow-derived dendritic cells constitutively expressed signal regulatory protein α, CD11c, and CD11b but only mildly up-regulated MHC class II, CD40, or CD86 following stimulation. Expression of dendritic cell-associated core transcripts was restricted to FLT3 ligand-bone marrow-derived dendritic cells . GM-CSF/IL-4-bone marrow-derived dendritic cells were superior at phagocytosis but were outperformed by FLT3 ligand-bone marrow-derived dendritic cells at antigen presentation and T cell stimulation in vitro. Stimulated GM-CSF/IL-4-bone marrow-derived dendritic cells secreted more TNF, CCL5, CCL20, and NO, whereas FLT3 ligand-bone marrow-derived dendritic cells secreted more IL-6 and IL-12. Finally, whereas GM-CSF/IL-4-bone marrow-derived dendritic cell culture supernatants added to resting T cell cultures promoted forkhead box p3(+) regulatory T cell populations, FLT3 ligand-bone marrow-derived dendritic cell culture supernatants drove Th17 differentiation. We conclude that rat GM-CSF/IL-4-bone marrow-derived dendritic cells and FLT3 ligand-bone marrow-derived dendritic cells are functionally distinct. Our data support the current rationale that FLT3

  20. Dendritic Cells: Cellular Mediators for Immunological Tolerance

    PubMed Central

    Chung, Chun Yuen J.; Ysebaert, Dirk; Berneman, Zwi N.

    2013-01-01

    In general, immunological tolerance is acquired upon treatment with non-specific immunosuppressive drugs. This indiscriminate immunosuppression of the patient often causes serious side-effects, such as opportunistic infectious diseases. Therefore, the need for antigen-specific modulation of pathogenic immune responses is of crucial importance in the treatment of inflammatory diseases. In this perspective, dendritic cells (DCs) can have an important immune-regulatory function, besides their notorious antigen-presenting capacity. DCs appear to be essential for both central and peripheral tolerance. In the thymus, DCs are involved in clonal deletion of autoreactive immature T cells by presenting self-antigens. Additionally, tolerance is achieved by their interactions with T cells in the periphery and subsequent induction of T cell anergy, T cell deletion, and induction of regulatory T cells (Treg). Various studies have described, modulation of DC characteristics with the purpose to induce antigen-specific tolerance in autoimmune diseases, graft-versus-host-disease (GVHD), and transplantations. Promising results in animal models have prompted researchers to initiate first-in-men clinical trials. The purpose of current review is to provide an overview of the role of DCs in the immunopathogenesis of autoimmunity, as well as recent concepts of dendritic cell-based therapeutic opportunities in autoimmune diseases. PMID:23762100

  1. IDGE: Isothermal Dendritic Growth Experiment

    NASA Technical Reports Server (NTRS)

    1994-01-01

    The Isothermal Dendritic Growth Experiment (IDGE) flew on STS-62 to study the microscopic, tree-like structures (dendrites) that form within metals as they solidify from molten materials. The size, shape, and orientation of these dendrites affect the strength and usefulness of metals. Data from this experiment will be used to test and improve the mathematical models that support the industrial production of metals.

  2. Dendritic spine alterations in schizophrenia.

    PubMed

    Moyer, Caitlin E; Shelton, Micah A; Sweet, Robert A

    2015-08-01

    Schizophrenia is a chronic illness affecting approximately 0.5-1% of the world's population. The etiology of schizophrenia is complex, including multiple genes, and contributing environmental effects that adversely impact neurodevelopment. Nevertheless, a final common result, present in many subjects with schizophrenia, is impairment of pyramidal neuron dendritic morphology in multiple regions of the cerebral cortex. In this review, we summarize the evidence of reduced dendritic spine density and other dendritic abnormalities in schizophrenia, evaluate current data that informs the neurodevelopment timing of these impairments, and discuss what is known about possible upstream sources of dendritic spine loss in this illness.

  3. Dendrite development: a surprising origin.

    PubMed

    Ehlers, Michael D

    2005-08-15

    Neurons extend elaborate dendrites studded with spines. Unexpectedly, this cellular sculpting is regulated by the origin recognition complex -- the core machinery for initiating DNA replication. PMID:16103221

  4. Dendritic Alloy Solidification Experiment (DASE)

    NASA Technical Reports Server (NTRS)

    Beckermann, C.; Karma, A.; Steinbach, I.; deGroh, H. C., III

    2001-01-01

    A space experiment, and supporting ground-based research, is proposed to study the microstructural evolution in free dendritic growth from a supercooled melt of the transparent model alloy succinonitrile-acetone (SCN-ACE). The research is relevant to equiaxed solidification of metal alloy castings. The microgravity experiment will establish a benchmark for testing of equiaxed dendritic growth theories, scaling laws, and models in the presence of purely diffusive, coupled heat and solute transport, without the complicating influences of melt convection. The specific objectives are to: determine the selection of the dendrite tip operating state, i.e. the growth velocity and tip radius, for free dendritic growth of succinonitrile-acetone alloys; determine the growth morphology and sidebranching behavior for freely grown alloy dendrites; determine the effects of the thermal/solutal interactions in the growth of an assemblage of equiaxed alloy crystals; determine the effects of melt convection on the free growth of alloy dendrites; measure the surface tension anisotropy strength of succinon itrile -acetone alloys establish a theoretical and modeling framework for the experiments. Microgravity experiments on equiaxed dendritic growth of alloy dendrites have not been performed in the past. The proposed experiment builds on the Isothermal Dendritic Growth Experiment (IDGE) of Glicksman and coworkers, which focused on the steady growth of a single crystal from pure supercooled melts (succinonitrile and pivalic acid). It also extends the Equiaxed Dendritic Solidification Experiment (EDSE) of the present investigators, which is concerned with the interactions and transients arising in the growth of an assemblage of equiaxed crystals (succinonitrile). However, these experiments with pure substances are not able to address the issues related to coupled heat and solute transport in growth of alloy dendrites.

  5. Human intestinal dendritic cells as controllers of mucosal immunity.

    PubMed

    Bernardo, David

    2013-01-01

    Dendritic cells are the most potent, professional antigen-presenting cells in the body; following antigen presentation they control the type (proinflammatory/regulatory) of immune response that will take place, as well as its location. Given their high plasticity and maturation ability in response to local danger signals derived from innate immunity, dendritic cells are key actors in the connection between innate immunity and adaptive immunity responses. In the gut dendritic cells control immune tolerance mechanisms against food and/or commensal flora antigens, and are also capable of initiating an active immune response in the presence of invading pathogens. Dendritic cells are thus highly efficient in controlling the delicate balance between tolerance and immunity in an environment so rich in antigens as the gut, and any factor involving these cells may impact their function, ultimately leading to the development of bowel conditions such as celiac disease or inflammatory bowel disease. In this review we shall summarize our understanding of human intestinal dendritic cells, their ability to express and induce migration markers, the various environmental factors modulating their properties, their subsets in the gut, and the problems entailed by their study, including identification strategies, differences between humans and murine models, and phenotypical variations along the gastrointestinal tract.

  6. Dendritic cell metabolism

    PubMed Central

    Pearce, Edward J.; Everts, Bart

    2015-01-01

    The past 15 years have seen enormous advances in our understanding of the receptor and signalling systems that allow dendritic cells (DCs) to respond to pathogens or other danger signals and initiate innate and adaptive immune responses. We are now beginning to appreciate that many of these pathways not only stimulate changes in the expression of genes that control DC immune functions, but also affect metabolic pathways, thereby integrating the cellular requirements of the activation process. In this Review, we focus on this relatively new area of research and attempt to describe an integrated view of DC immunometabolism. PMID:25534620

  7. Dendritic Growth Velocities in Microgravity

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.; Koss, M. B.; Winsa, E. A.

    1994-01-01

    We measured dendritic tip velocities in pure succinonitrile (SCN) in microgravity. using a sequence of telemetered binary images sent to Earth from the Space Shuttle Columbia (STS-62). Growth velocities were measured as a function of the supercooling over the range 0.05-1.5 K. Microgravity observations show that buoyancy-induced convection alters the growth kinetics of SCN dendrites at supercooling as high as 1.3 K. Also, the dendrite velocity data measured under microgravity agree well with the Ivantsov paraboloidal diffusion solution when coupled to a scaling constant of sigma(sup *) = 0.0157.

  8. Transient Dendritic Solidification Experiment (TDSE)

    NASA Technical Reports Server (NTRS)

    2000-01-01

    The Transient Dendritic Solidification Expepriment (TDSE) is being developed as a candidate for flight aboard the International Space Station. TDSE will study the growth of dendrites (treelike crystalline structures) in a transparent material (succinonitrile or SCN) that mimics the behavior of widely used iron-based metals. Basic work by three Space Shuttle missions of the Isothermal Dendritic Growth Expepriment (IDGE) is yielding new insights into virtually all industrially relevant metal and alloy forming operations. The TDSE is similar to IDGE, but will maintain a constant temperature while varying pressure on the dendrites. Shown here is an exploded view of major elements of TDSE. A similar view is available with labels. The principal investigator is Matthew Koss of College of the Holy Cross in Worcester, MA. Photo credit: NASA/Marshall Space Flight Center (MSFC)

  9. Transient Dendritic Solidification Experiment (TDSE)

    NASA Technical Reports Server (NTRS)

    2000-01-01

    The Transient Dendritic Solidification Experiment (TDSE) is being developed as a candidate for flight aboard the International Space Station. TDSE will study the growth of dendrites (treelike crystalline structures) in a transparent material (succinonitrile or SCN) that mimics the behavior or widely used iron-based metals. Basic work by three Space Shuttle missions of the Isothermal Dendritic Growth Experiment (IDGE) is yielding new insights into virtually all industrially relevant metal and alloy forming operations. The TDSE is similar to IDGE, but will maintain a constant temperature while varying pressure on the dendrites. Shown here is an exploded view of major elements of the TDSE. A similar view is availble without labels. The principal investigator is Matthew Koss of College of the Holy Cross in Worcester, MA. Photo credit: NASA/Marshall Space Flight Center (MSFC)

  10. Optimal Current Transfer in Dendrites

    PubMed Central

    Bird, Alex D.

    2016-01-01

    Integration of synaptic currents across an extensive dendritic tree is a prerequisite for computation in the brain. Dendritic tapering away from the soma has been suggested to both equalise contributions from synapses at different locations and maximise the current transfer to the soma. To find out how this is achieved precisely, an analytical solution for the current transfer in dendrites with arbitrary taper is required. We derive here an asymptotic approximation that accurately matches results from numerical simulations. From this we then determine the diameter profile that maximises the current transfer to the soma. We find a simple quadratic form that matches diameters obtained experimentally, indicating a fundamental architectural principle of the brain that links dendritic diameters to signal transmission. PMID:27145441

  11. Dendritic cells and immunity against cancer

    PubMed Central

    Palucka, Karolina; Ueno, Hideki; Fay, Joseph; Banchereau, Jacques

    2010-01-01

    SUMMARY T cells can reject established tumors when adoptively transferred into patients, thereby demonstrating the power of the immune system for cancer therapy. However, it has proven difficult to maintain adoptively transferred T cells in the long term. Vaccines have the potential to induce tumor-specific effector and memory T cells. However, clinical efficacy of current vaccines is limited, possibly because tumors skew the immune system by means of myeloid-derived suppressor cells, inflammatory type 2 T cells and regulatory T cells (Tregs), all of which prevent the generation of effector cells. To improve the clinical efficacy of cancer vaccines in patients with metastatic disease, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome Tregs and allow the breakdown of the immunosuppressive tumor microenvironment. This can be achieved by exploiting the fast increasing knowledge about the dendritic cell (DC) system, including the existence of distinct DC subsets which respond differentially to distinct activation signals, (functional plasticity), both contributing to the generation of unique adaptive immune responses. We foresee that these novel cancer vaccines will be used as monotherapy in patients with resected disease, and in combination with drugs targeting regulatory/suppressor pathways in patients with metastatic disease. PMID:21158979

  12. Lysophosphatidic acid induces osteocyte dendrite outgrowth

    SciTech Connect

    Karagiosis, Sue A.; Karin, Norm J.

    2007-05-25

    A method was developed to measure dendrite formation in bone cells. Lysophosphatidic acid (LPA) was found to stimulate dendrite outgrowth. It is postulated that LPA plays a role in regulating the osteocyte network in vivo.

  13. Gravitational effects in dendritic growth

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.; Singh, N. B.; Chopra, M.

    1983-01-01

    The theories of diffusion-controlled dendritic crystallization will be reviewed briefly, along with recently published critical experiments on the kinetics and morphology of dendritic growth in pure substances. The influence of the gravitational body force on dendrite growth kinetics will be shown to be highly dependent on the growth orientation with respect to the gravity vector and on the level of the thermal supercooling. In fact, an abrupt transition occurs at a critical supercooling, above which diffusional transport dominates the growth process and below which convective transport dominates. Our most recent work on binary mixtures shows that dilute solute additions influence the crystallization process indirectly, by altering the interfacial stability, rather than by directly affecting the transport mode. Directions for future studies in this field will also be discussed.

  14. Spindle-F Is the Central Mediator of Ik2 Kinase-Dependent Dendrite Pruning in Drosophila Sensory Neurons

    PubMed Central

    Lai, Yu-Ting; Chiang, Kai-Wen; Hsieh, Hsin-Lun; Wu, Yi-Ping; Ke, Jian-Ming; Lee, Myong-Chol; Liao, Shih-Sian; Shih, Hsueh-Tzu; Tang, Chiou-Yang; Yang, Shi-Bing; Cheng, Hsu-Chen; Wu, June-Tai; Jan, Yuh-Nung; Lee, Hsiu-Hsiang

    2015-01-01

    During development, certain Drosophila sensory neurons undergo dendrite pruning that selectively eliminates their dendrites but leaves the axons intact. How these neurons regulate pruning activity in the dendrites remains unknown. Here, we identify a coiled-coil protein Spindle-F (Spn-F) that is required for dendrite pruning in Drosophila sensory neurons. Spn-F acts downstream of IKK-related kinase Ik2 in the same pathway for dendrite pruning. Spn-F exhibits a punctate pattern in larval neurons, whereas these Spn-F puncta become redistributed in pupal neurons, a step that is essential for dendrite pruning. The redistribution of Spn-F from puncta in pupal neurons requires the phosphorylation of Spn-F by Ik2 kinase to decrease Spn-F self-association, and depends on the function of microtubule motor dynein complex. Spn-F is a key component to link Ik2 kinase to dynein motor complex, and the formation of Ik2/Spn-F/dynein complex is critical for Spn-F redistribution and for dendrite pruning. Our findings reveal a novel regulatory mechanism for dendrite pruning achieved by temporal activation of Ik2 kinase and dynein-mediated redistribution of Ik2/Spn-F complex in neurons. PMID:26540204

  15. Dendritic polyglycerols for biomedical applications.

    PubMed

    Calderón, Marcelo; Quadir, Mohiuddin Abdul; Sharma, Sunil Kumar; Haag, Rainer

    2010-01-12

    The application of nanotechnology in medicine and pharmaceuticals is a rapidly advancing field that is quickly gaining acceptance and recognition as an independent area of research called "nanomedicine". Urgent needs in this field, however, are biocompatible and bioactive materials for antifouling surfaces and nanoparticles for drug delivery. Therefore, extensive attention has been given to the design and development of new macromolecular structures. Among the various polymeric architectures, dendritic ("treelike") polymers have experienced an exponential development due to their highly branched, multifunctional, and well-defined structures. This Review describes the diverse syntheses and biomedical applications of dendritic polyglycerols (PGs). These polymers exhibit good chemical stability and inertness under biological conditions and are highly biocompatible. Oligoglycerols and their fatty acid esters are FDA-approved and are already being used in a variety of consumer applications, e.g., cosmetics and toiletries, food industries, cleaning and softening agents, pharmaceuticals, polymers and polymer additives, printing photographing materials, and electronics. Herein, we present the current status of dendritic PGs as functional dendritic architectures with particular focus on their application in nanomedicine, in drug, dye, and gene delivery, as well as in regenerative medicine in the form of non-fouling surfaces and matrix materials.

  16. Advanced dendritic web growth development

    NASA Technical Reports Server (NTRS)

    Hopkins, R. H.

    1985-01-01

    A program to develop the technology of the silicon dendritic web ribbon growth process is examined. The effort is being concentrated on the area rate and quality requirements necessary to meet the JPL/DOE goals for terrestrial PV applications. Closed loop web growth system development and stress reduction for high area rate growth is considered.

  17. Wiring dendrites in layers and columns.

    PubMed

    Luo, Jiangnan; McQueen, Philip G; Shi, Bo; Lee, Chi-Hon; Ting, Chun-Yuan

    2016-06-01

    The most striking structure in the nervous system is the complex yet stereotyped morphology of the neuronal dendritic tree. Dendritic morphologies and the connections they make govern information flow and integration in the brain. The fundamental mechanisms that regulate dendritic outgrowth and branching are subjects of extensive study. In this review, we summarize recent advances in the molecular and cellular mechanisms for routing dendrites in layers and columns, prevalent organizational structures in the brain. We highlight how dendritic patterning influences the formation of synaptic circuits. PMID:27315108

  18. Plasmacytoid dendritic cells are crucial in Bifidobacterium adolescentis-mediated inhibition of Yersinia enterocolitica infection.

    PubMed

    Wittmann, Alexandra; Autenrieth, Ingo B; Frick, Julia-Stefanie

    2013-01-01

    In industrialized countries bacterial intestinal infections are commonly caused by enteropathogenic Enterobacteriaceae. The interaction of the microbiota with the host immune system determines the adequacy of an appropriate response against pathogens. In this study we addressed whether the probiotic Bifidobacterium adolescentis is protective during intestinal Yersinia enterocolitica infection. Female C57BL/6 mice were fed with B. adolescentis, infected with Yersinia enterocolitica, or B. adolescentis fed and subsequently infected with Yersinia enterocolitica. B. adolescentis fed and Yersinia infected mice were protected from Yersinia infection as indicated by a significantly reduced weight loss and splenic Yersinia load when compared to Yersinia infected mice. Moreover, protection from infection was associated with increased intestinal plasmacytoid dendritic cell and regulatory T-cell frequencies. Plasmacytoid dendritic cell function was investigated using depletion experiments by injecting B. adolescentis fed, Yersinia infected C57BL/6 mice with anti-mouse PDCA-1 antibody, to deplete plasmacytoid dendritic cells, or respective isotype control. The B. adolescentis-mediated protection from Yersinia dissemination to the spleen was abrogated after plasmacytoid dendritic cell depletion indicating a crucial function for pDC in control of intestinal Yersinia infection. We suggest that feeding of B. adolescentis modulates the intestinal immune system in terms of increased plasmacytoid dendritic cell and regulatory T-cell frequencies, which might account for the B. adolescentis-mediated protection from Yersinia enterocolitica infection.

  19. Dendritic solidification of alloys in low gravity

    NASA Astrophysics Data System (ADS)

    Curreri, P. A.; Lee, J. E.; Stefanescu, D. M.

    1988-11-01

    Gravity-driven convective flow influences dendrite morphology, interdendritic fluid flow, dendrite interface morphology, casting macrosegregation, formation of channel type casting defects, and casting grain structure. Dendritic solidification experiments during multiple parabolic aircraft maneuvers for iron-carbon type alloys and superalloys show increased dendritic spacing in low-gravity periods. Larger dendrite spacings for low-gravity solidification have also been reported for sounding rocket and space laboratory experiments for metal-model and binary alloys. Convection decreases local solidification time and increases the rate of interdendritic solute removal. The elimination of convection in low gravity is thus expected to increase dendritic spacing. Convection's effect on dendritic arm coarsening is expected to be dependent on the coarsening mechanism. Decreased coarsening in low gravity found for Al-Cu is indicative of coarsening predominately by arm coalescence.

  20. Directing dendritic cell immunotherapy towards successful cancer treatment

    PubMed Central

    Sabado, Rachel Lubong; Bhardwaj, Nina

    2010-01-01

    The use of dendritic cells (DCs) for tumor immunotherapy represents a powerful approach for harnessing the patient's own immune system to eliminate tumor cells. However, suboptimal conditions for generating potent immunostimulatory DCs, as well as the induction of tolerance and suppression mediated by the tumors and its microenvironment have contributed to limited success. Combining DC vaccines with new approaches that enhance immunogenicity and overcome the regulatory mechanisms underlying peripheral tolerance may be the key to achieving effective and durable anti-tumor immune responses that translate to better clinical outcomes. PMID:20473346

  1. Dendritic cell function in vivo during the steady state: a role in peripheral tolerance.

    PubMed

    Steinman, Ralph M; Hawiger, Daniel; Liu, Kang; Bonifaz, Laura; Bonnyay, David; Mahnke, Karsten; Iyoda, Tomonori; Ravetch, Jeffrey; Dhodapkar, Madhav; Inaba, Kayo; Nussenzweig, Michel

    2003-04-01

    The avoidance of autoimmunity requires mechanisms to actively silence or tolerize self reactive T cells in the periphery. During infection, dendritic cells are not only capturing microbial antigens, but also are processing self antigens from dying cells as well as innocuous environmental proteins. Since the dendritic cells are maturing in response to microbial and other stimuli, peptides will be presented from both noxious and innocuous antigens. Therefore it would be valuable to have mechanisms whereby dendritic cells, prior to infection, establish tolerance to those self and environmental antigens that can be processed upon pathogen encounter. In the steady state, prior to acute infection and inflammation, dendritic cells are in an immature state and not fully differentiated to carry out their known roles as inducers of immunity. These immature cells are not inactive, however. They continuously circulate through tissues and into lymphoid organs, capturing self antigens as well as innocuous environmental proteins. Recent experiments have provided direct evidence that antigen-loaded immature dendritic in vivo silence T cells either by deleting them or by expanding regulatory T cells. In this way, it is proposed that the immune system overcomes at least some of the risk of developing autoimmunity and chronic inflammation. It is proposed that dendritic cells play a major role in defining immunologic self, not only centrally in the thymus but also in the periphery.

  2. LMTK1 regulates dendritic formation by regulating movement of Rab11A-positive endosomes

    PubMed Central

    Takano, Tetsuya; Urushibara, Tomoki; Yoshioka, Nozomu; Saito, Taro; Fukuda, Mitsunori; Tomomura, Mineko; Hisanaga, Shin-ichi

    2014-01-01

    Neurons extend two types of neurites—axons and dendrites—that differ in structure and function. Although it is well understood that the cytoskeleton plays a pivotal role in neurite differentiation and extension, the mechanisms by which membrane components are supplied to growing axons or dendrites is largely unknown. We previously reported that the membrane supply to axons is regulated by lemur kinase 1 (LMTK1) through Rab11A-positive endosomes. Here we investigate the role of LMTK1 in dendrite formation. Down-regulation of LMTK1 increases dendrite growth and branching of cerebral cortical neurons in vitro and in vivo. LMTK1 knockout significantly enhances the prevalence, velocity, and run length of anterograde movement of Rab11A-positive endosomes to levels similar to those expressing constitutively active Rab11A-Q70L. Rab11A-positive endosome dynamics also increases in the cell body and growth cone of LMTK1-deficient neurons. Moreover, a nonphosphorylatable LMTK1 mutant (Ser34Ala, a Cdk5 phosphorylation site) dramatically promotes dendrite growth. Thus LMTK1 negatively controls dendritic formation by regulating Rab11A-positive endosomal trafficking in a Cdk5-dependent manner, indicating the Cdk5-LMTK1-Rab11A pathway as a regulatory mechanism of dendrite development as well as axon outgrowth. PMID:24672056

  3. Involvement of α2-antiplasmin in dendritic growth of hippocampal neurons.

    PubMed

    Kawashita, Eri; Kanno, Yosuke; Asayama, Haruka; Okada, Kiyotaka; Ueshima, Shigeru; Matsuo, Osamu; Matsuno, Hiroyuki

    2013-07-01

    The α2-Antiplasmin (α2AP) protein is known as a principal physiological inhibitor of plasmin, but we previously demonstrated that it acts as a regulatory factor for cellular functions independent of plasmin. α2AP is highly expressed in the hippocampus, suggesting a potential role for α2AP in hippocampal neuronal functions. However, the role for α2AP was unclear. This study is the first to investigate the involvement of α2AP in the dendritic growth of hippocampal neurons. The expression of microtubule-associated protein 2, which contributes to neurite initiation and neuronal growth, was lower in the neurons from α2AP⁻/⁻ mice than in the neurons from α2AP⁺/⁺ mice. Exogenous treatment with α2AP enhanced the microtubule-associated protein 2 expression, dendritic growth and filopodia formation in the neurons. This study also elucidated the mechanism underlying the α2AP-induced dendritic growth. Aprotinin, another plasmin inhibitor, had little effect on the dendritic growth of neurons, and α2AP induced its expression in the neurons from plaminogen⁻/⁻ mice. The activation of p38 MAPK was involved in the α2AP-induced dendritic growth. Therefore, our findings suggest that α2AP induces dendritic growth in hippocampal neurons through p38 MAPK activation, independent of plasmin, providing new insights into the role of α2AP in the CNS.

  4. Microtubule nucleation and organization in dendrites.

    PubMed

    Delandre, Caroline; Amikura, Reiko; Moore, Adrian W

    2016-07-01

    Dendrite branching is an essential process for building complex nervous systems. It determines the number, distribution and integration of inputs into a neuron, and is regulated to create the diverse dendrite arbor branching patterns characteristic of different neuron types. The microtubule cytoskeleton is critical to provide structure and exert force during dendrite branching. It also supports the functional requirements of dendrites, reflected by differential microtubule architectural organization between neuron types, illustrated here for sensory neurons. Both anterograde and retrograde microtubule polymerization occur within growing dendrites, and recent studies indicate that branching is enhanced by anterograde microtubule polymerization events in nascent branches. The polarities of microtubule polymerization events are regulated by the position and orientation of microtubule nucleation events in the dendrite arbor. Golgi outposts are a primary microtubule nucleation center in dendrites and share common nucleation machinery with the centrosome. In addition, pre-existing dendrite microtubules may act as nucleation sites. We discuss how balancing the activities of distinct nucleation machineries within the growing dendrite can alter microtubule polymerization polarity and dendrite branching, and how regulating this balance can generate neuron type-specific morphologies. PMID:27097122

  5. Lipid dynamics at dendritic spines.

    PubMed

    Dotti, Carlos Gerardo; Esteban, Jose Antonio; Ledesma, María Dolores

    2014-01-01

    Dynamic changes in the structure and composition of the membrane protrusions forming dendritic spines underlie memory and learning processes. In recent years a great effort has been made to characterize in detail the protein machinery that controls spine plasticity. However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants. Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signaling. In this review we gather information available on the lipid composition at dendritic spine membranes and on its dynamics. We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity.

  6. Convective flow during dendritic growth

    NASA Technical Reports Server (NTRS)

    Glicksman, M. E.; Huang, S. C.

    1979-01-01

    A review is presented of the major experimental findings obtained from recent ground-based research conducted under the SPAR program. Measurements of dendritic growth at small supercoolings indicate that below approximately 1.5 K a transition occurs from diffusive control to convective control in succinonitrile, a model system chosen for this study. The key theoretical ideas concerning diffusive and convective heat transport during dendritic growth are discussed, and it is shown that a transition in the transport control should occur when the characteristic length for diffusion becomes larger than the characteristic length for convection. The experimental findings and the theoretical ideas discussed suggest that the Fluid Experiment System could provide appropriate experimental diagnostics for flow field visualization and quantification of the fluid dynamical effects presented here.

  7. Method of inhibiting dislocation generation in silicon dendritic webs

    DOEpatents

    Spitznagel, John A.; Seidensticker, Raymond G.; McHugh, James P.

    1990-11-20

    A method of tailoring the heat balance of the outer edge of the dendrites adjacent the meniscus to produce thinner, smoother dendrites, which have substantially less dislocation sources contiguous with the dendrites, by changing the view factor to reduce radiation cooling or by irradiating the dendrites with light from a quartz lamp or a laser to raise the temperature of the dendrites.

  8. Targeting dendritic cells in allergen immunotherapy.

    PubMed

    Novak, Natalija

    2006-05-01

    Allergen immunotherapy is a well-established strategy for treating allergic diseases with the goal of inducing allergen-specific tolerance. Identified mechanisms contributing to the therapeutic effect of immunotherapy include a shift of T helper 2 (Th2)-type immune responses to a modified Th2 immune response, a change of the balance of IgE-producing B cells to the production of IgG subtypes, in addition to increased IL-10 and TGF-beta secretion and activation of the suppressive functions of regulatory T-cells. Dendritic cells (DCs), which as outposts of the immune system are capable of T-cell priming through efficient allergen uptake by IgE receptors expressed on their cell surface. Most of the hypotheses concerning the function of DCs as facilitators of allergen-specific tolerance in allergen immunotherapy remain speculative. Therefore, studies must focus on the functional changes of DCs under immunotherapy to close the gap of knowledge about their exact role. These experimental data should help confirm the hypothesis of DCs as efficient silencers and potential target cells and take advantage of the bivalent character and tolerogenic properties of DCs. PMID:16701146

  9. DENDRITIC CELLS: ARE THEY CLINICALLY RELEVANT?

    PubMed Central

    Palucka, Karolina; Ueno, Hideki; Roberts, Lee; Fay, Joseph; Banchereau, Jacques

    2010-01-01

    Cancer vaccines have undergone a renaissance due to recent clinical trials showing promising immunological data and some clinical benefit to patients. Current trials exploiting dendritic cells (DCs) as vaccines have shown durable tumor regressions in a fraction of patients. Clinical efficacy of current vaccines is hampered by myeloid-derived suppressor cells, inflammatory type 2 T cells and regulatory T cells (Tregs), all of which prevent the generation of effector cells. To improve the clinical efficacy of DC vaccines, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome Tregs and allow the breakdown of the immunosuppressive tumor microenvironment. This can be achieved by exploiting the fast increasing knowledge about the DC system, including the existence of distinct DC subsets. Critical to the design of better vaccines is the concept of distinct DC subsets and distinct DC activation pathways, all contributing to the generation of unique adaptive immune responses. Such novel DC vaccines will be used as monotherapy in patients with resected disease and in combination with antibodies and/or drugs targeting suppressor pathways and modulation of the tumor environment in patients with metastatic disease. PMID:20693842

  10. Transcranial magnetic stimulation (TMS) inhibits cortical dendrites.

    PubMed

    Murphy, Sean C; Palmer, Lucy M; Nyffeler, Thomas; Müri, René M; Larkum, Matthew E

    2016-03-18

    One of the leading approaches to non-invasively treat a variety of brain disorders is transcranial magnetic stimulation (TMS). However, despite its clinical prevalence, very little is known about the action of TMS at the cellular level let alone what effect it might have at the subcellular level (e.g. dendrites). Here, we examine the effect of single-pulse TMS on dendritic activity in layer 5 pyramidal neurons of the somatosensory cortex using an optical fiber imaging approach. We find that TMS causes GABAB-mediated inhibition of sensory-evoked dendritic Ca(2+) activity. We conclude that TMS directly activates fibers within the upper cortical layers that leads to the activation of dendrite-targeting inhibitory neurons which in turn suppress dendritic Ca(2+) activity. This result implies a specificity of TMS at the dendritic level that could in principle be exploited for investigating these structures non-invasively.

  11. Dendritic web silicon for solar cell application

    NASA Technical Reports Server (NTRS)

    Seidensticker, R. G.

    1977-01-01

    The dendritic web process for growing long thin ribbon crystals of silicon and other semiconductors is described. Growth is initiated from a thin wirelike dendrite seed which is brought into contact with the melt surface. Initially, the seed grows laterally to form a button at the melt surface; when the seed is withdrawn, needlelike dendrites propagate from each end of the button into the melt, and the web portion of the crystal is formed by the solidification of the liquid film supported by the button and the bounding dendrites. Apparatus used for dendritic web growth, material characteristics, and the two distinctly different mechanisms involved in the growth of a single crystal are examined. The performance of solar cells fabricated from dendritic web material is indistinguishable from the performance of cells fabricated from Czochralski grown material.

  12. Cell-intrinsic drivers of dendrite morphogenesis

    PubMed Central

    Puram, Sidharth V.; Bonni, Azad

    2013-01-01

    The proper formation and morphogenesis of dendrites is fundamental to the establishment of neural circuits in the brain. Following cell cycle exit and migration, neurons undergo organized stages of dendrite morphogenesis, which include dendritic arbor growth and elaboration followed by retraction and pruning. Although these developmental stages were characterized over a century ago, molecular regulators of dendrite morphogenesis have only recently been defined. In particular, studies in Drosophila and mammalian neurons have identified numerous cell-intrinsic drivers of dendrite morphogenesis that include transcriptional regulators, cytoskeletal and motor proteins, secretory and endocytic pathways, cell cycle-regulated ubiquitin ligases, and components of other signaling cascades. Here, we review cell-intrinsic drivers of dendrite patterning and discuss how the characterization of such crucial regulators advances our understanding of normal brain development and pathogenesis of diverse cognitive disorders. PMID:24255095

  13. The Equiaxed Dendritic Solidification Experiment (EDSE)

    NASA Technical Reports Server (NTRS)

    1999-01-01

    The Equiaxed Dendritic Solidification Experiment (EDSE) is a material sciences investigation under the Formation of Microstructures/pattern formation discipline. The objective is to study the microstructural evolution of and thermal interactions between several equiaxed crystals growing dendritically in a supercooled melt of a pure and transparent substance under diffusion controlled conditions. Dendrites growing at .4 supercooling from a 2 stinger growth chamber for the EDSE in the Microgravity Development Lab (MDL).

  14. Dendrite preventing separator for secondary lithium batteries

    NASA Technical Reports Server (NTRS)

    Shen, David H. (Inventor); Surampudi, Subbarao (Inventor); Huang, Chen-Kuo (Inventor); Halpert, Gerald (Inventor)

    1993-01-01

    Dendrites are prevented from shorting a secondary lithium battery by use of a first porous separator, such as porous polypropylene, adjacent to the lithium anode that is unreactive with lithium and a second porous fluoropolymer separator between the cathode and the first separator, such as polytetrafluoroethylene, that is reactive with lithium. As the tip of a lithium dendrite contacts the second separator, an exothermic reaction occurs locally between the lithium dendrite and the fluoropolymer separator. This results in the prevention of the dendrite propagation to the cathode.

  15. Dendrite preventing separator for secondary lithium batteries

    NASA Technical Reports Server (NTRS)

    Shen, David H. (Inventor); Surampudi, Subbarao (Inventor); Huang, Chen-Kuo (Inventor); Halpert, Gerald (Inventor)

    1995-01-01

    Dendrites are prevented from shorting a secondary lithium battery by use of a first porous separator such as porous polypropylene adjacent the lithium anode that is unreactive with lithium and a second porous fluoropolymer separator between the cathode and the first separator such as polytetrafluoroethylene that is reactive with lithium. As the tip of a lithium dendrite contacts the second separator, an exothermic reaction occurs locally between the lithium dendrite and the fluoropolymer separator. This results in the prevention of the dendrite propagation to the cathode.

  16. Hierarchical assembly of diphenylalanine into dendritic nanoarchitectures.

    PubMed

    Han, Tae Hee; Oh, Jun Kyun; Lee, Gyoung-Ja; Pyun, Su-Il; Kim, Sang Ouk

    2010-09-01

    Highly ordered, multi-dimensional dendritic nanoarchitectures were created via self-assembly of diphenylalanine from an acidic buffer solution. The self-similarity of dendritic structures was characterized by examining their fractal dimensions with the box-counting method. The fractal dimension was determined to be 1.7, which demonstrates the fractal dimension of structures generated by diffusion limited aggregation on a two-dimensional substrate surface. By confining the dendritic assembly of diphenylalanine within PDMS microchannels, the self-similar dendritic growth could be hierarchically directed to create linearly assembled nanoarchitectures. Our approach offers a novel pathway for creating and directing hierarchical nanoarchitecture from biomolecular assembly. PMID:20605423

  17. Precipitation dendrites in turbulent pipe flows

    NASA Astrophysics Data System (ADS)

    Angheluta, Luiza; Hawkins, Christopher; Hammer, Øyvind; Jamtveit, Bjørn

    2013-04-01

    Surface precipitation in pipelines, as well as freezing in water pipes is of great concern in many industrial applications where scaling phenomena becomes a control problem of pipe-clogging or an efficiency reduction in transport. Flow blockage often occurs even when only a small fraction is deposited non-uniformly on the walls in the form of dendrites. Dendritic patterns are commonly encountered in surface precipitation from supersaturated solutions, e.g. calcite dendrites, as well as in solidification from undercooled liquids, e.g. freezing of water into ice dendrites. We explore the mathematical similarities between precipitation and freezing processes and, in particular, investigate the effect of fluid flow on the precipitation dendrites on pipe walls. We use a phase field approach to model surface growth coupled with a lattice Boltzmann method that simulates a channel flow at varying Reynolds number. The dendrites orientation and shape depend non-trivially on the ratio between advection and diffusion, i.e. the Peclet number, as well as the Reynolds number. Roughness induced vortices near growing dendrites at high flow rates further affect the branch splitting of dendrites. We show how the transport rate in a pipeline may depend on the different dendritic morphologies, and provide estimates for the flow conditions that correspond to most efficient transport regimes.

  18. Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation

    PubMed Central

    Plümpe, Tobias; Ehninger, Dan; Steiner, Barbara; Klempin, Friederike; Jessberger, Sebastian; Brandt, Moritz; Römer, Benedikt; Rodriguez, Gerardo Ramirez; Kronenberg, Golo; Kempermann, Gerd

    2006-01-01

    Background In the course of adult hippocampal neurogenesis most regulation takes place during the phase of doublecortin (DCX) expression, either as pro-proliferative effect on precursor cells or as survival-promoting effect on postmitotic cells. We here obtained quantitative data about the proliferative population and the dynamics of postmitotic dendrite development during the period of DCX expression. The question was, whether any indication could be obtained that the initiation of dendrite development is timely bound to the exit from the cell cycle. Alternatively, the temporal course of morphological maturation might be subject to additional regulatory events. Results We found that (1) 20% of the DCX population were precursor cells in cell cycle, whereas more than 70% were postmitotic, (2) the time span until newborn cells had reached the most mature stage associated with DCX expression varied between 3 days and several weeks, (3) positive or negative regulation of precursor cell proliferation did not alter the pattern and dynamics of dendrite development. Dendrite maturation was largely independent of close contacts to astrocytes. Conclusion These data imply that dendrite maturation of immature neurons is initiated at varying times after cell cycle exit, is variable in duration, and is controlled independently of the regulation of precursor cell proliferation. We conclude that in addition to the major regulatory events in cell proliferation and selective survival, additional micro-regulatory events influence the course of adult hippocampal neurogenesis. PMID:17105671

  19. Mode of dendrite growth in undercooled alloy melts

    SciTech Connect

    Li, J.; Yang, G.; Zhou, Y.

    1998-01-01

    The mode of dendrite growth in the undercooled Ni-50 at% Cu alloy was investigated. At lower undercoolings, the dendrite growth is mainly controlled by solute diffusion, and the formed dendritic morphologies are similar to those of the conventional as-cast equiaxed crystals, except that here the branches are much denser. At higher undercoolings, however, the severe solutal trapping that results from high dendrite growth velocity weakens the effect of solute diffusion on the dendrite growth. In this case, the dendrites branch in the bunching form. The dendrite spacings were measured, and the results were interpreted with the current dendrite growth theories.

  20. Tick salivary cystatin sialostatin L2 suppresses IFN responses in mouse dendritic cells.

    PubMed

    Lieskovská, J; Páleníková, J; Širmarová, J; Elsterová, J; Kotsyfakis, M; Campos Chagas, A; Calvo, E; Růžek, D; Kopecký, J

    2015-02-01

    Type I interferon (IFN), mainly produced by dendritic cells (DCs), is critical in the host defence against tick-transmitted pathogens. Here, we report that salivary cysteine protease inhibitor from the hard tick Ixodes scapularis, sialostatin L2, affects IFN-β mediated immune reactions in mouse dendritic cells. Following IFN receptor ligation, the Janus activated kinases/signal transducer and activator of transcription (JAK/STAT) pathway is activated. We show that sialostatin L2 attenuates phosphorylation of STATs in spleen dendritic cells upon addition of recombinant IFN-β. LPS-stimulated dendritic cells release IFN-β which in turn leads to the induction of IFN-stimulated genes (ISG) through JAK/STAT pathway activation. The induction of two ISG, interferon regulatory factor 7 (IRF-7) and IP-10, was suppressed by sialostatin L2 in LPS-stimulated dendritic cells. Finally, the interference of sialostatin L2 with IFN action led to the enhanced replication of tick-borne encephalitis virus in DC. In summary, we present here that tick salivary cystatin negatively affects IFN-β responses which may consequently increase the pathogen load after transmission via tick saliva.

  1. In vivo dendrite regeneration after injury is different from dendrite development.

    PubMed

    Thompson-Peer, Katherine L; DeVault, Laura; Li, Tun; Jan, Lily Yeh; Jan, Yuh Nung

    2016-08-01

    Neurons receive information along dendrites and send signals along axons to synaptic contacts. The factors that control axon regeneration have been examined in many systems, but dendrite regeneration has been largely unexplored. Here we report that, in intact Drosophila larvae, a discrete injury that removes all dendrites induces robust dendritic growth that recreates many features of uninjured dendrites, including the number of dendrite branches that regenerate and responsiveness to sensory stimuli. However, the growth and patterning of injury-induced dendrites is significantly different from uninjured dendrites. We found that regenerated arbors cover much less territory than uninjured neurons, fail to avoid crossing over other branches from the same neuron, respond less strongly to mechanical stimuli, and are pruned precociously. Finally, silencing the electrical activity of the neurons specifically blocks injury-induced, but not developmental, dendrite growth. By elucidating the essential features of dendrites grown in response to acute injury, our work builds a framework for exploring dendrite regeneration in physiological and pathological conditions. PMID:27542831

  2. Early events in axon/dendrite polarization.

    PubMed

    Cheng, Pei-lin; Poo, Mu-ming

    2012-01-01

    Differentiation of axons and dendrites is a critical step in neuronal development. Here we review the evidence that axon/dendrite formation during neuronal polarization depends on the intrinsic cytoplasmic asymmetry inherited by the postmitotic neuron, the exposure of the neuron to extracellular chemical factors, and the action of anisotropic mechanical forces imposed by the environment. To better delineate the functions of early signals among a myriad of cellular components that were shown to influence axon/dendrite formation, we discuss their functions by distinguishing their roles as determinants, mediators, or modulators and consider selective degradation of these components as a potential mechanism for axon/dendrite polarization. Finally, we examine whether these early events of axon/dendrite formation involve local autocatalytic activation and long-range inhibition, as postulated by Alan Turing for the morphogenesis of patterned biological structure.

  3. Early events in axon/dendrite polarization.

    PubMed

    Cheng, Pei-lin; Poo, Mu-ming

    2012-01-01

    Differentiation of axons and dendrites is a critical step in neuronal development. Here we review the evidence that axon/dendrite formation during neuronal polarization depends on the intrinsic cytoplasmic asymmetry inherited by the postmitotic neuron, the exposure of the neuron to extracellular chemical factors, and the action of anisotropic mechanical forces imposed by the environment. To better delineate the functions of early signals among a myriad of cellular components that were shown to influence axon/dendrite formation, we discuss their functions by distinguishing their roles as determinants, mediators, or modulators and consider selective degradation of these components as a potential mechanism for axon/dendrite polarization. Finally, we examine whether these early events of axon/dendrite formation involve local autocatalytic activation and long-range inhibition, as postulated by Alan Turing for the morphogenesis of patterned biological structure. PMID:22715881

  4. GMP-Grade mRNA Electroporation of Dendritic Cells for Clinical Use.

    PubMed

    Derdelinckx, Judith; Berneman, Zwi N; Cools, Nathalie

    2016-01-01

    mRNA-electroporated dendritic cells (DC) are demonstrating clinical benefit in patients in many therapeutic areas, including cancer and infectious diseases. According to current good manufacturing guidelines, cell-based medicinal products have to be defined for identity, purity, potency, stability, and viability. In order to comply with the directives and guidelines defined by the regulatory authorities, we report here a standardized and reproducible method for the manufacturing of clinical-grade mRNA-transfected DC. PMID:27236797

  5. Impact of dendritic size and dendritic topology on burst firing in pyramidal cells.

    PubMed

    van Elburg, Ronald A J; van Ooyen, Arjen

    2010-05-13

    Neurons display a wide range of intrinsic firing patterns. A particularly relevant pattern for neuronal signaling and synaptic plasticity is burst firing, the generation of clusters of action potentials with short interspike intervals. Besides ion-channel composition, dendritic morphology appears to be an important factor modulating firing pattern. However, the underlying mechanisms are poorly understood, and the impact of morphology on burst firing remains insufficiently known. Dendritic morphology is not fixed but can undergo significant changes in many pathological conditions. Using computational models of neocortical pyramidal cells, we here show that not only the total length of the apical dendrite but also the topological structure of its branching pattern markedly influences inter- and intraburst spike intervals and even determines whether or not a cell exhibits burst firing. We found that there is only a range of dendritic sizes that supports burst firing, and that this range is modulated by dendritic topology. Either reducing or enlarging the dendritic tree, or merely modifying its topological structure without changing total dendritic length, can transform a cell's firing pattern from bursting to tonic firing. Interestingly, the results are largely independent of whether the cells are stimulated by current injection at the soma or by synapses distributed over the dendritic tree. By means of a novel measure called mean electrotonic path length, we show that the influence of dendritic morphology on burst firing is attributable to the effect both dendritic size and dendritic topology have, not on somatic input conductance, but on the average spatial extent of the dendritic tree and the spatiotemporal dynamics of the dendritic membrane potential. Our results suggest that alterations in size or topology of pyramidal cell morphology, such as observed in Alzheimer's disease, mental retardation, epilepsy, and chronic stress, could change neuronal burst firing and

  6. Dendritic cell SIRPα regulates homeostasis of dendritic cells in lymphoid organs.

    PubMed

    Washio, Ken; Kotani, Takenori; Saito, Yasuyuki; Respatika, Datu; Murata, Yoji; Kaneko, Yoriaki; Okazawa, Hideki; Ohnishi, Hiroshi; Fukunaga, Atsushi; Nishigori, Chikako; Matozaki, Takashi

    2015-06-01

    Signal regulatory protein α (SIRPα), an immunoglobulin superfamily protein that is expressed predominantly in myeloid lineage cells such as dendritic cells (DCs) or macrophages, mediates cell-cell signaling. In the immune system, SIRPα is thought to be important for homeostasis of DCs, but it remains unclear whether SIRPα intrinsic to DCs is indeed indispensable for such functional role. Thus, we here generated the mice, in which SIRPα was specifically ablated in CD11c(+) DCs (Sirpa(Δ) (DC) ). Sirpa(Δ) (DC) mice manifested a marked reduction of CD4(+) CD8α(-) conventional DCs (cDCs) in the secondary lymphoid organs, as well as of Langerhans cells in the epidermis. Such reduction of cDCs in Sirpa(Δ) (DC) mice was comparable to that apparent with the mice, in which SIRPα was systemically ablated. Expression of SIRPα in DCs was well correlated with that of either endothelial cell-selective adhesion molecule (ESAM) or Epstein-Barr virus-induced molecule 2 (EBI2), both of which were also implicated in the regulation of DC homeostasis. Indeed, ESAM(+) or EBI2(+) cDCs were markedly reduced in the spleen of Sirpa(Δ) (DC) mice. Thus, our results suggest that SIRPα intrinsic to CD11c(+) DCs is essential for homeostasis of cDCs in the secondary lymphoid organs and skin.

  7. Double dendrite growth in solidification.

    PubMed

    Utter, Brian; Bodenschatz, E

    2005-07-01

    We present experiments on the doublon growth morphology in directional solidification. Samples used are succinonitrile with small amounts of poly(ethylene oxide), acetone, or camphor as the solute. Doublons, or symmetry-broken dendrites, are generic diffusion-limited growth structures expected at large undercooling and low anisotropy. Low anisotropy growth is achieved by selecting a grain near the {111} plane leading to either seaweed (dense branching morphology) or doublon growth depending on experimental parameters. We find selection of doublons to be strongly dependent on solute concentration and sample orientation. Doublons are selected at low concentrations (low solutal undercooling) in contrast to the prediction of doublons at large thermal undercooling in pure materials. Doublons also exhibit preferred growth directions and changing the orientation of a specific doublonic grain changes the character and stability of the doublons. We observe transitions between seaweed and doublon growth with changes in concentration and sample orientation.

  8. Dendritic cell immunotherapy: clinical outcomes

    PubMed Central

    Apostolopoulos, Vasso; Pietersz, Geoffrey A; Tsibanis, Anastasios; Tsikkinis, Annivas; Stojanovska, Lily; McKenzie, Ian FC; Vassilaros, Stamatis

    2014-01-01

    The use of tumour-associated antigens for cancer immunotherapy studies is exacerbated by tolerance to these self-antigens. Tolerance may be broken by using ex vivo monocyte-derived dendritic cells (DCs) pulsed with self-antigens. Targeting tumour-associated antigens directly to DCs in vivo is an alternative and simpler strategy. The identification of cell surface receptors on DCs, and targeting antigens to DC receptors, has become a popular approach for inducing effective immune responses against cancer antigens. Many years ago, we demonstrated that targeting the mannose receptor on macrophages using the carbohydrate mannan to DCs led to appropriate immune responses and tumour protection in animal models. We conducted Phase I, I/II and II, clinical trials demonstrating the effectiveness of oxidised mannan-MUC1 in patients with adenocarcinomas. Here we summarise DC targeting approaches and their efficacy in human clinical trials. PMID:25505969

  9. Evidence for Eigenfrequencies in Dendritic Growth Dynamics

    NASA Astrophysics Data System (ADS)

    Lacombe, Jeffrey C.; Koss, Matthew B.; Giummarra, Cindie; Frei, Julie E.; Lupulescu, Afina O.; Glicksman, Martin E.

    Microgravity dendritic growth experiments, conducted aboard the space shuttle Columbia, are described. In-situ video images reveal that pivalic acid dendrites growing in the diffusion-controlled environment of low-earth orbit exhibit a range of transient or non-steady-state behaviors. The observed transient features of the growth process are being studied with the objective of understanding the mechanisms responsible for these behaviors. Included in these observations is possible evidence for characteristic frequencies or limit cycles in the growth behavior near the tip of the dendrites. These data, and their interpretations, will be discussed.

  10. Active dendrites support efficient initiation of dendritic spikes in hippocampal CA3 pyramidal neurons

    PubMed Central

    Kim, Sooyun; Guzman, Segundo J; Hu, Hua; Jonas, Peter

    2013-01-01

    CA3 pyramidal neurons are important for memory formation and pattern completion in the hippocampal network. It is generally thought that proximal synapses from the mossy fibers activate these neurons most efficiently, whereas distal inputs from the perforant path have a weaker modulatory influence. We used confocally targeted patch-clamp recording from dendrites and axons to map the activation of rat CA3 pyramidal neurons at the subcellular level. Our results reveal two distinct dendritic domains. In the proximal domain, action potentials initiated in the axon backpropagate actively with large amplitude and fast time course. In the distal domain, Na+ channel–mediated dendritic spikes are efficiently initiated by waveforms mimicking synaptic events. CA3 pyramidal neuron dendrites showed a high Na+-to-K+ conductance density ratio, providing ideal conditions for active backpropagation and dendritic spike initiation. Dendritic spikes may enhance the computational power of CA3 pyramidal neurons in the hippocampal network. PMID:22388958

  11. Epigenetic program and transcription factor circuitry of dendritic cell development.

    PubMed

    Lin, Qiong; Chauvistré, Heike; Costa, Ivan G; Gusmao, Eduardo G; Mitzka, Saskia; Hänzelmann, Sonja; Baying, Bianka; Klisch, Theresa; Moriggl, Richard; Hennuy, Benoit; Smeets, Hubert; Hoffmann, Kurt; Benes, Vladimir; Seré, Kristin; Zenke, Martin

    2015-11-16

    Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC. Specific histone marks in CDP reveal a DC-primed epigenetic signature, which is maintained and reinforced during DC differentiation. Epigenetic marks and transcription factor PU.1 occupancy increasingly coincide upon DC differentiation. By integrating PU.1 occupancy and gene expression we devised a transcription factor regulatory circuitry for DC commitment and subset specification. The circuitry provides the transcription factor hierarchy that drives the sequel MPP-CDP-cDC/pDC, including Irf4, Irf8, Tcf4, Spib and Stat factors. The circuitry also includes feedback loops inferred for individual or multiple factors, which stabilize distinct stages of DC development and DC subsets. In summary, here we describe the basic regulatory circuitry of transcription factors that drives DC development.

  12. Epigenetic program and transcription factor circuitry of dendritic cell development

    PubMed Central

    Lin, Qiong; Chauvistré, Heike; Costa, Ivan G.; Gusmao, Eduardo G.; Mitzka, Saskia; Hänzelmann, Sonja; Baying, Bianka; Klisch, Theresa; Moriggl, Richard; Hennuy, Benoit; Smeets, Hubert; Hoffmann, Kurt; Benes, Vladimir; Seré, Kristin; Zenke, Martin

    2015-01-01

    Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC. Specific histone marks in CDP reveal a DC-primed epigenetic signature, which is maintained and reinforced during DC differentiation. Epigenetic marks and transcription factor PU.1 occupancy increasingly coincide upon DC differentiation. By integrating PU.1 occupancy and gene expression we devised a transcription factor regulatory circuitry for DC commitment and subset specification. The circuitry provides the transcription factor hierarchy that drives the sequel MPP-CDP-cDC/pDC, including Irf4, Irf8, Tcf4, Spib and Stat factors. The circuitry also includes feedback loops inferred for individual or multiple factors, which stabilize distinct stages of DC development and DC subsets. In summary, here we describe the basic regulatory circuitry of transcription factors that drives DC development. PMID:26476451

  13. Modulation of dendritic cell maturation and function by B lymphocytes.

    PubMed

    Bayry, Jagadeesh; Lacroix-Desmazes, Sébastien; Kazatchkine, Michel D; Hermine, Olivier; Tough, David F; Kaveri, Srini V

    2005-07-01

    Investigating the signals that regulate the function of dendritic cells (DC), the sentinels of the immune system, is critical to understanding the role of DC in the regulation of immune responses. Accumulating lines of evidence indicate that in addition to innate stimuli and T cell-derived signals, B lymphocytes exert a profound regulatory effect in vitro and in vivo on the Ag-presenting function of DC. The identification of B cells as a cellular source of cytokines, chemokines, and autoantibodies that are critically involved in the process of maturation, migration, and function of DC provides a rationale for immunotherapeutic intervention of autoimmune and inflammatory conditions by targeting B cells. Conversely, efficient cross-presentation of Ags by DC pulsed with immune complexes provides an alternative approach in the immunotherapy of cancer and infectious diseases. PMID:15972625

  14. Functional impact of dendritic branch point morphology

    PubMed Central

    Ferrante, Michele; Migliore, Michele; Ascoli, Giorgio A.

    2013-01-01

    Cortical pyramidal cells store multiple features of complex synaptic input in individual dendritic branches and independently regulate the coupling between dendritic and somatic spikes. Branch points in apical trees exhibit wide ranges of sizes and shapes, and the large diameter ratio between trunk and oblique dendrites exacerbates impedance mismatch. The morphological diversity of dendritic bifurcations could thus locally tune neuronal excitability and signal integration. However, these aspects have never been investigated. Here, we first quantified the morphological variability of branch points from two-photon images of rat CA1 pyramidal neurons. We then investigated the geometrical features affecting spike initiation, propagation, and timing with a computational model validated by glutamate uncaging experiments. The results suggest that even subtle membrane readjustments at branch point could drastically alter the ability of synaptic input to generate, propagate, and time action potentials. PMID:23365251

  15. Dendritic spine dysgenesis in Autism Related Disorders

    PubMed Central

    Phillips, Mary; Pozzo-Miller, Lucas

    2015-01-01

    The activity-dependent structural and functional plasticity of dendritic spines has led to the long-standing belief that these neuronal compartments are the subcellular sites of learning and memory. Of relevance to human health, central neurons in several neuropsychiatric illnesses, including autism related disorders, have atypical numbers and morphologies of dendritic spines. These so-called dendritic spine dysgeneses found in individuals with autism related disorders are consistently replicated in experimental mouse models. Dendritic spine dysgenesis reflects the underlying synaptopathology that drives clinically relevant behavioral deficits in experimental mouse models, providing a platform for testing new therapeutic approaches. By examining molecular signaling pathways, synaptic deficits, and spine dysgenesis in experimental mouse models of autism related disorders we find strong evidence for mTOR to be a critical point of convergence and promising therapeutic target. PMID:25578949

  16. Dendritic cells are stressed out in tumor.

    PubMed

    Maj, Tomasz; Zou, Weiping

    2015-09-01

    A recently paper published in Cell reports that dendritic cells (DCs) are dysfunctional in the tumor environment. Tumor impairs DC function through induction of endoplasmic reticulum stress response and subsequent disruption of lipid metabolic homeostasis.

  17. Dendritic Growth in Nematic Liquid Crystals

    NASA Astrophysics Data System (ADS)

    Martin, Joshua; Garg, Shila

    2000-03-01

    The experimental study of the onset of electrohydrodynamic convection (EHC) through a dendritic growth is reported. If a magnetic Freedericksz-distorted liquid crystal of negative dielectric anisotropy is subjected to an electric field parallel to the magnetic field, EHC sets in through the nucleation of dendrites [1,2]. Measurements of tip speeds of the dendrites as a function of applied voltage at a fixed magnetic field are made. The goal is to explore the effect of the magnetic and electric fields on the dendritic growth. In addition, pattern dynamics is monitored once the final state of spatio-temporal chaos is reached by the system. [1] J. T. Gleeson, Nature 385, 511 (1997). [2] J. T. Gleeson, Physica A 239, 211 (1997). This research was supported by NSF grants DMR 9704579 and DMR 9619406.

  18. Dendritic spine dysgenesis in autism related disorders.

    PubMed

    Phillips, Mary; Pozzo-Miller, Lucas

    2015-08-01

    The activity-dependent structural and functional plasticity of dendritic spines has led to the long-standing belief that these neuronal compartments are the subcellular sites of learning and memory. Of relevance to human health, central neurons in several neuropsychiatric illnesses, including autism related disorders, have atypical numbers and morphologies of dendritic spines. These so-called dendritic spine dysgeneses found in individuals with autism related disorders are consistently replicated in experimental mouse models. Dendritic spine dysgenesis reflects the underlying synaptopathology that drives clinically relevant behavioral deficits in experimental mouse models, providing a platform for testing new therapeutic approaches. By examining molecular signaling pathways, synaptic deficits, and spine dysgenesis in experimental mouse models of autism related disorders we find strong evidence for mTOR to be a critical point of convergence and promising therapeutic target. PMID:25578949

  19. Dendritic spine dysgenesis in Rett syndrome

    PubMed Central

    Xu, Xin; Miller, Eric C.; Pozzo-Miller, Lucas

    2014-01-01

    Spines are small cytoplasmic extensions of dendrites that form the postsynaptic compartment of the majority of excitatory synapses in the mammalian brain. Alterations in the numerical density, size, and shape of dendritic spines have been correlated with neuronal dysfunction in several neurological and neurodevelopmental disorders associated with intellectual disability, including Rett syndrome (RTT). RTT is a progressive neurodevelopmental disorder associated with intellectual disability that is caused by loss of function mutations in the transcriptional regulator methyl CpG-binding protein 2 (MECP2). Here, we review the evidence demonstrating that principal neurons in RTT individuals and Mecp2-based experimental models exhibit alterations in the number and morphology of dendritic spines. We also discuss the exciting possibility that signaling pathways downstream of brain-derived neurotrophic factor (BDNF), which is transcriptionally regulated by MeCP2, offer promising therapeutic options for modulating dendritic spine development and plasticity in RTT and other MECP2-associated neurodevelopmental disorders. PMID:25309341

  20. Dendritic cells in autoimmune thyroid disease.

    PubMed

    Kabel, P J; Voorbij, H A; van der Gaag, R D; Wiersinga, W M; de Haan, M; Drexhage, H A

    1987-01-01

    Dendritic cells form a morphologically distinct class of cells characterized by shape, reniform nucleus, absent to weak acid-phosphatase activity and strong Class II MHC determinant positivity. Functionally they are the most efficient cells in antigen presentation to T-lymphocytes which indicates their role in the initiation of an immune response. Using immunehistochemical techniques we studied the presence of dendritic cells in normal Wistar rat and human thyroids, in thyroids of BBW rats developing thyroid autoimmunity and in Graves' goitres. Dendritic cells could be identified in all thyroids studied and were positioned underneath the thyrocytes in between the follicles. Skin dendritic cells travel via lymphatics to draining lymph nodes, thus forming an antigen presenting cell system. It is likely that a similar cell system exists on the level of the thyroid for dendritic cells have also been detected in thyroid draining lymph nodes. In normal thyroid tissue of both human and rat dendritic cells were relatively scarce. During the initial phases of the thyroid autoimmune response in the BBW rat (before the appearance of Tg-antibodies in the circulation) numbers of thyroid dendritic cells increased. Intrathyroidal T-helper cells, B-cells or plasma cells could not be found. The thyroid draining lymph node contained large numbers of plasma cells. During the later stages of the thyroid autoimmune response in the BB/W rat (after the appearance of Tg-antibodies in the circulation) and in Graves' goitres dendritic cells were not only present in high number, but 20-30% were seen in contact with now-present intrathyroidal T-helper lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3475920

  1. Non-synaptic dendritic spines in neocortex.

    PubMed

    Arellano, J I; Espinosa, A; Fairén, A; Yuste, R; DeFelipe, J

    2007-03-16

    A long-held assumption states that each dendritic spine in the cerebral cortex forms a synapse, although this issue has not been systematically investigated. We performed complete ultrastructural reconstructions of a large (n=144) population of identified spines in adult mouse neocortex finding that only 3.6% of the spines clearly lacked synapses. Nonsynaptic spines were small and had no clear head, resembling dendritic filopodia, and could represent a source of new synaptic connections in the adult cerebral cortex.

  2. Dendritic cells in autoimmune thyroid disease.

    PubMed

    Kabel, P J; Voorbij, H A; van der Gaag, R D; Wiersinga, W M; de Haan, M; Drexhage, H A

    1987-01-01

    Dendritic cells form a morphologically distinct class of cells characterized by shape, reniform nucleus, absent to weak acid-phosphatase activity and strong Class II MHC determinant positivity. Functionally they are the most efficient cells in antigen presentation to T-lymphocytes which indicates their role in the initiation of an immune response. Using immunehistochemical techniques we studied the presence of dendritic cells in normal Wistar rat and human thyroids, in thyroids of BBW rats developing thyroid autoimmunity and in Graves' goitres. Dendritic cells could be identified in all thyroids studied and were positioned underneath the thyrocytes in between the follicles. Skin dendritic cells travel via lymphatics to draining lymph nodes, thus forming an antigen presenting cell system. It is likely that a similar cell system exists on the level of the thyroid for dendritic cells have also been detected in thyroid draining lymph nodes. In normal thyroid tissue of both human and rat dendritic cells were relatively scarce. During the initial phases of the thyroid autoimmune response in the BBW rat (before the appearance of Tg-antibodies in the circulation) numbers of thyroid dendritic cells increased. Intrathyroidal T-helper cells, B-cells or plasma cells could not be found. The thyroid draining lymph node contained large numbers of plasma cells. During the later stages of the thyroid autoimmune response in the BB/W rat (after the appearance of Tg-antibodies in the circulation) and in Graves' goitres dendritic cells were not only present in high number, but 20-30% were seen in contact with now-present intrathyroidal T-helper lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Transcranial magnetic stimulation (TMS) inhibits cortical dendrites

    PubMed Central

    Murphy, Sean C; Palmer, Lucy M; Nyffeler, Thomas; Müri, René M; Larkum, Matthew E

    2016-01-01

    One of the leading approaches to non-invasively treat a variety of brain disorders is transcranial magnetic stimulation (TMS). However, despite its clinical prevalence, very little is known about the action of TMS at the cellular level let alone what effect it might have at the subcellular level (e.g. dendrites). Here, we examine the effect of single-pulse TMS on dendritic activity in layer 5 pyramidal neurons of the somatosensory cortex using an optical fiber imaging approach. We find that TMS causes GABAB-mediated inhibition of sensory-evoked dendritic Ca2+ activity. We conclude that TMS directly activates fibers within the upper cortical layers that leads to the activation of dendrite-targeting inhibitory neurons which in turn suppress dendritic Ca2+ activity. This result implies a specificity of TMS at the dendritic level that could in principle be exploited for investigating these structures non-invasively. DOI: http://dx.doi.org/10.7554/eLife.13598.001 PMID:26988796

  4. Architecture of apical dendrites in the murine neocortex: dual apical dendritic systems.

    PubMed

    Escobar, M I; Pimienta, H; Caviness, V S; Jacobson, M; Crandall, J E; Kosik, K S

    1986-04-01

    A monoclonal antibody (5F9) against microtubule-associated protein 2 is a selective and sensitive marker for neocortical dendrites in the mouse. The marker stains all dendrites. It affords a particularly comprehensive picture of the patterns of arrangements of apical dendrites which are most intensely stained with this antibody. Dual systems of apical dendrites arise from the polymorphic neurons of layer VI, on the one hand, and the pyramidal neurons of layers II-V, on the other. Terminal arborization of the former is concentrated principally at the interface of layers V and IV, while that of the latter is in the molecular layer. Apical dendrites of both systems are grouped into fascicles. In supragranular layers and in upper layer VI-lower layer V, where apical dendrites are most abundant, the fascicles coalesce into septa. These generate a honeycomb-like pattern, subdividing these cortical levels into columnar spaces of approximately 20-40 micron diameter. At the level of layer IV, where the number of apical dendrites is greatly reduced, the fascicles are isolated bundles. These bundles have the form of circular, elliptical or rectangular columns in the primary somatosensory, temporal and frontal regions, respectively. Those in the barrel field are preferentially concentrated in the sides of barrels and the interbarrel septa. The configurations of the dendritic fascicles, particularly the midcortical bundles, may conform to the spatial configuration of investing axons of interneurons.

  5. Neuroblastoma and dendritic cell function.

    PubMed

    Redlinger, Richard E; Mailliard, Robbie B; Barksdale, Edward M

    2004-02-01

    Neuroblastoma, the most common extracranial solid tumor of childhood, remains a challenge for clinicians and investigators in pediatric surgical oncology. The absence of effective conventional therapies for most patients with neuroblastoma justifies the application of novel, biology-based, experimental approaches to the treatment of this deadly disease. The observation that some aggressive neuroblastomas, particularly in infants, may spontaneously regress suggested that immune-mediated mechanisms may be important in the biology of this disease. Advances in the understanding of the cognate interactions between T cells, antigen-presenting cells and tumors have demonstrated the sentinel role of dendritic cells (DC), the most potent antigen presenting cells, in initiating the cellular immune response to cancer. Until recently the function of DC in pediatric solid tumors, especially neuroblastoma, had not been extensively studied. This review discusses the role of DC in initiating and coordinating the immune response against cancer, the ability of neuroblastoma to induce DC dysregulation at multiple levels by inhibiting DC maturation and function, and the current vaccine strategies being designed to employ the unique ability of DC to promote neuroblastoma regression.

  6. Targeting vaccines to dendritic cells.

    PubMed

    Foged, Camilla; Sundblad, Anne; Hovgaard, Lars

    2002-03-01

    Dendritic cells (DC) are specialized antigen presenting cells (APC) with a remarkable ability to take up antigens and stimulate major histocompatibility complex (MHC)-restricted specific immune responses. Recent discoveries have shown that their role in initiating primary immune responses seems to be far superior to that of B-cells and macrophages. DC are localized at strategic places in the body at sites used by pathogens to enter the organism, and are thereby in an optimal position to capture antigens. In general, vaccination strategies try to mimic the invasiveness of the pathogens. DC are considered to play a central role for the provocation of primary immune responses by vaccination. A rational way of improving the potency and safety of new and already existing vaccines could therefore be to direct vaccines specifically to DC. There is a need for developing multifunctional vaccine drug delivery systems (DDS) with adjuvant effect that target DC directly and induce optimal immune responses. This paper will review the current knowledge of DC physiology as well as the progress in the field of novel vaccination strategies that directly or indirectly aim at targeting DC.

  7. Perinatal opiate treatment delays growth of cortical dendrites.

    PubMed

    Ricalde, A A; Hammer, R P

    1990-07-31

    Basilar dendritic arborizations of layer II-III pyramidal neurons in primary somatosensory cortex of 5-day-old male rats were reconstructed following perinatal morphine, morphine/naltrexone, or saline vehicle administration. Morphine treatment was observed to reduce total dendritic length. This effect was limited to higher order dendritic branches, with terminal dendrites manifesting the greatest reduction of length. The action of morphine was presumably mediated by opiate receptors, since concurrent naltrexone administration completely reversed morphine effects on dendritic length and branching. These results suggest that opiates act during late ontogenesis to affect dendritic growth in cerebral cortex. PMID:2172870

  8. Dendritic crystal growth in pure /sup 4/He

    SciTech Connect

    Franck, J.P.; Jung, J.

    1986-08-01

    Dendritic crystal growth of pure hcp and fcc /sup 4/He was observed at pressures between 210 and 6500 bar. Dendrite morphology depends on fluid supercooling and crystal phase. At large supercooling, dendrites with side arms are observed, whereas at low supercooling dendrites grow without side arms. The morpholpogy of hcp /sup 4/He dendrites is strongly influenced by crystalline anisotropy. Comparison with present theories of dendrite growth show good agreement with the power law dependencies of velocity, tip radius, and Peclet number on supercooling. Numerically, theory predicts much larger velocities than are observed. The stability parameter sigma is found to be much smaller than theoretically predicted.

  9. Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Is Sufficient To Induce Dendritic Cells That Inhibit Colitis.

    PubMed

    Hang, Long; Blum, Arthur M; Kumar, Sangeeta; Urban, Joseph F; Mitreva, Makedonka; Geary, Timothy G; Jardim, Armando; Stevenson, Mary M; Lowell, Clifford A; Weinstock, Joel V

    2016-10-01

    Helminthic infections modulate host immunity and may protect people in less-developed countries from developing immunological diseases. In a murine colitis model, the helminth Heligmosomoides polygyrus bakeri prevents colitis via induction of regulatory dendritic cells (DCs). The mechanism driving the development of these regulatory DCs is unexplored. There is decreased expression of the intracellular signaling pathway spleen tyrosine kinase (Syk) in intestinal DCs from H. polygyrus bakeri-infected mice. To explore the importance of this observation, it was shown that intestinal DCs from DC-specific Syk(-/-) mice were powerful inhibitors of murine colitis, suggesting that loss of Syk was sufficient to convert these cells into their regulatory phenotype. DCs sense gut flora and damaged epithelium via expression of C-type lectin receptors, many of which signal through the Syk signaling pathway. It was observed that gut DCs express mRNA encoding for C-type lectin (CLEC) 7A, CLEC9A, CLEC12A, and CLEC4N. H. polygyrus bakeri infection downmodulated CLEC mRNA expression in these cells. Focusing on CLEC7A, which encodes for the dectin-1 receptor, flow analysis showed that H. polygyrus bakeri decreases dectin-1 expression on the intestinal DC subsets that drive Th1/Th17 development. DCs become unresponsive to the dectin-1 agonist curdlan and fail to phosphorylate Syk after agonist stimulation. Soluble worm products can block CLEC7A and Syk mRNA expression in gut DCs from uninfected mice after a brief in vitro exposure. Thus, downmodulation of Syk expression and phosphorylation in intestinal DCs could be important mechanisms through which helminths induce regulatory DCs that limit colitis. PMID:27559049

  10. Activity affects dendritic shape and synapse elimination during steroid controlled dendritic retraction in Manduca sexta.

    PubMed

    Duch, Carsten; Mentel, Tim

    2004-11-01

    Insect metamorphosis is a compelling example for dendritic and synaptic remodeling as larval and adult behaviors place distinct demands on the CNS. During the metamorphosis of the moth, Manduca sexta, many larval motoneurons are remodeled to serve a new function in the adult. During late larval life, steroid hormones trigger axonal and dendritic regression as well as larval synapse elimination. These regressive events are accompanied by stereotypical changes in motor behavior during the so-called wandering stages. Both normally occurring changes in dendritic shape and in motor output have previously been analyzed quantitatively for the individually identified motoneuron MN5. This study tested whether activity affected steroid-induced dendritic regression and synapse disassembly in MN5 by means of chronically implanted extracellular electrodes. Stimulating MN5 in vivo in intact, normally developing animals during a developmental period when it usually shows no activity significantly slowed the regression of high-order dendrites. Both physiological and anatomical analysis demonstrated that reduced dendritic regression was accompanied by a significant reduction in larval synapse disassembly. Therefore, steroid-induced alterations of dendritic shape and synaptic connectivity are modified by activity-dependent mechanisms. This interaction might be a common mechanism for rapid adjustments of rigid, inflexible, hormonal programs.

  11. Successful Isothermal Dendritic Growth Experiment (IDGE) Proves Current Theories of Dendritic Solidification are Flawed

    NASA Technical Reports Server (NTRS)

    1996-01-01

    The scientific objective of the Isothermal Dendritic Growth Experiment (IDGE) is to test fundamental assumptions about dendritic solidification of molten materials. "Dendrites"-- from the ancient Greek word for tree--are tiny branching structures that form inside molten metal alloys when they solidify during manufacturing. The size, shape, and orientation of the dendrites have a major effect on the strength, ductility (ability to be molded or shaped), and usefulness of an alloy. Nearly all of the cast metal alloys used in everyday products (such as automobiles and airplanes) are composed of thousands to millions of tiny dendrites. Gravity, present on Earth, causes convection currents in molten alloys that disturb dendritic solidification and make its precise study impossible. In space, gravity is negated by the orbiting of the space shuttle. Consequently, IDGE (which was conducted on the space shuttle) gathered the first precise data regarding undisturbed dendritic solidification. IDGE is a microgravity materials science experiment that uses an apparatus which was designed, built, tested, and operated by people from the NASA Lewis Research Center. This experiment was conceived by the principal investigator, Professor Martin E. Glicksman, from Rensselaer Polytechnic Institute in Troy, New York. The experiment was a team effort of Lewis civil servants, contractors from Aerospace Design & Fabrication Inc. (ADF), and personnel at Rensselaer.

  12. Suppression of zinc dendrites in zinc electrode power cells

    NASA Technical Reports Server (NTRS)

    Damjanovic, A.; Diggle, J. W.

    1970-01-01

    Addition of various tetraalkyl quarternary ammonium salts, to alkaline zincate electrolyte of cell, prevents formation of zinc dendrites during charging of zinc electrode. Electrode capacity is not impaired and elimination of dendrites prolongs cell life.

  13. Forward- and backpropagation in a silicon dendrite.

    PubMed

    Rasche, C; Douglas, R J

    2001-01-01

    We have developed an analog very-large-scale integrated (aVLSI) electronic circuit that emulates a compartmental model of a neuronal dendrite. The horizontal conductances of the compartmental model are implemented as a switched capacitor network. The transmembrane conductances are implemented as transconductance amplifiers. The electrotonic properties of our silicon cable are qualitatively similar to those of the ideal passive cable that is commonly used to model mathematically the electrotonic behavior of neurons. In particular the propagation of excitatory postsynaptic potentials is realistic, and we are easily able to emulate such classical synaptic integration models as direction selectivity. We are also able to emulate the backpropagation into the dendrite of single somatic spikes and bursts of spikes. Thus, this silicon dendrite is suitable for incorporation in detailed silicon neurons operating in real-time; in particular for the emulation of forward- and backpropagating electrical activities found in real neurons. PMID:18244392

  14. Studying Signal Transduction in Single Dendritic Spines

    PubMed Central

    Yasuda, Ryohei

    2012-01-01

    Many forms of synaptic plasticity are triggered by biochemical signaling that occurs in small postsynaptic compartments called dendritic spines, each of which typically houses the postsynaptic terminal associated with a single glutamatergic synapse. Recent advances in optical techniques allow investigators to monitor biochemical signaling in single dendritic spines and thus reveal the signaling mechanisms that link synaptic activity and the induction of synaptic plasticity. This is mostly in the study of Ca2+-dependent forms of synaptic plasticity for which many of the steps between Ca2+ influx and changes to the synapse are now known. This article introduces the new techniques used to investigate signaling in single dendritic spines and the neurobiological insights that they have produced. PMID:22843821

  15. Loss of Microtubule-Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia

    PubMed Central

    Shelton, Micah A.; Newman, Jason T.; Gu, Hong; Sampson, Allan R.; Fish, Kenneth N.; MacDonald, Matthew L; Moyer, Caitlin E.; DiBitetto, James V; Dorph-Petersen, Karl-Anton; Penzes, Peter; Lewis, David A.; Sweet, Robert A.

    2015-01-01

    Background Microtubule-associated protein 2 (MAP2) is a neuronal protein that plays a role in maintaining dendritic structure through its interaction with microtubules. In schizophrenia (Sz), a number of studies have revealed that MAP2’s typically robust immunoreactivity (IR) is significantly reduced across several cortical regions. Previous studies have not explored the relationship between MAP2-IR reduction and lower dendritic spine density, which is frequently reported in schizophrenia nor has MAP2-IR loss been investigated in the primary auditory cortex (Brodmann Area 41), a site of conserved pathology in Sz. Methods Using quantitative spinning disk confocal microscopy in two cohorts of Sz subjects and matched control subjects (Sz, n=20; C, n=20), we measured MAP2-IR as well as dendritic spine density and spine number in deep layer 3 of BA41. Results Sz subjects exhibited a significant reduction in MAP2-IR. The reductions in MAP2-IR were not associated with neuron loss, loss of MAP2 protein, clinical confounders, or technical factors. Dendritic spine density and number were also reduced in Sz and correlated with MAP2-IR. Twelve (60%) Sz subjects exhibited MAP2-IR values lower than the lowest values in controls; only in this group were spine density and number significantly reduced. Conclusions These findings demonstrate that MAP2-IR loss is closely linked to dendritic spine pathology in Sz. Because MAP2 shares substantial sequence, regulatory, and functional homology with MAP tau, the wealth of knowledge regarding tau biology and the rapidly expanding field of tau therapeutics provide resources for identifying how MAP2 is altered in Sz and possible leads to novel therapeutics. PMID:25818630

  16. Dendritic Cells Stimulated by Cationic Liposomes.

    PubMed

    Vitor, Micaela Tamara; Bergami-Santos, Patrícia Cruz; Cruz, Karen Steponavicius Piedade; Pinho, Mariana Pereira; Barbuto, José Alexandre Marzagão; De La Torre, Lucimara Gaziola

    2016-01-01

    Immunotherapy of cancer aims to harness the immune system to detect and destroy cancer cells. To induce an immune response against cancer, activated dendritic cells (DCs) must present tumor antigens to T lymphocytes of patients. However, cancer patients' DCs are frequently defective, therefore, they are prone to induce rather tolerance than immune responses. In this context, loading tumor antigens into DCs and, at the same time, activating these cells, is a tempting goal within the field. Thus, we investigated the effects of cationic liposomes on the DCs differentiation/maturation, evaluating their surface phenotype and ability to stimulate T lymphocytes proliferation in vitro. The cationic liposomes composed by egg phosphatidylcholine, 1,2-dioleoyl-3-trimethylammonium propane and 1,2-dioleoylphosphatidylethanolamine (50/25/25% molar) were prepared by the thin film method followed by extrusion (65 nm, polydispersity of 0.13) and by the dehydration-rehydration method (95% of the population 107 nm, polydispersity of 0.52). The phenotypic analysis of dendritic cells and the analysis of T lymphocyte proliferation were performed by flow cytometry and showed that both cationic liposomes were incorporated and activated dendritic cells. Extruded liposomes were better incorporated and induced higher CD86 expression for dendritic cells than dehydrated-rehydrated vesicles. Furthermore, dendritic cells which internalized extruded liposomes also provided stronger T lymphocyte stimulation. Thus, cationic liposomes with a smaller size and polydispersity seem to be better incorporated by dendritic cells. Hence, these cationic liposomes could be used as a potential tool in further cancer immunotherapy strategies and contribute to new strategies in immunotherapy. PMID:27398454

  17. Convection Effects in Three-dimensional Dendritic Growth

    NASA Technical Reports Server (NTRS)

    Lu, Yili; Beckermann, C.; Karma, A.

    2003-01-01

    A phase-field model is developed to simulate free dendritic growth coupled with fluid flow for a pure material in three dimensions. The preliminary results presented here illustrate the strong influence of convection on the three-dimensional (3D) dendrite growth morphology. The detailed knowledge of the flow and temperature fields in the melt around the dendrite from the simulations allows for a detailed understanding of the convection effects on dendritic growth.

  18. Seaweed to dendrite transition in directional solidification.

    PubMed

    Provatas, Nikolas; Wang, Quanyong; Haataja, Mikko; Grant, Martin

    2003-10-10

    We simulate directional solidification using a phase-field model solved with adaptive mesh refinement. For small surface tension anisotropy directed at 45 degrees relative to the pulling direction we observe a crossover from a seaweed to a dendritic morphology as the thermal gradient is lowered, consistent with recent experimental findings. We show that the morphology of crystal structures can be unambiguously characterized through the local interface velocity distribution. We derive semiempirically an estimate for the crossover from seaweed to dendrite as a function of thermal gradient and pulling speed.

  19. Apparatus for growing a dendritic web

    DOEpatents

    Duncan, Charles S.; Piotrowski, Paul A.; Skutch, Maria E.; McHugh, James P.

    1983-06-21

    A melt system including a susceptor-crucible assembly having improved gradient control when melt replenishment is used during dendritic web growth. The improvement lies in the formation of a thermal barrier in the base of the receptor which is in the form of a vertical slot in the region of the susceptor underlying the crucible at the location of a compartmental separator dividing the crucible into a growth compartment and a melt replenishment compartment. The result achieved is a step change in temperature gradient in the melt thereby providing a more uniform temperature in the growth compartment from which the dendritic web is drawn.

  20. The Isothermal Dendritic Growth Experiment (IDGE)

    NASA Technical Reports Server (NTRS)

    Glicksman, Martin E.; Koss, M. B.; Lupulescu, A. O.; LaCombe, J. C.; Frei, J. E.; Malarik, D. C.

    1999-01-01

    The Isothermal Dendritic Growth Experiment (IDGE) constituted a series of three NASA-supported microgravity experiments, all of which flew aboard the space shuttle, Columbia. This experimental space flight series was designed and operated to grow and record dendrite solidification in the absence of gravity-induced convective heat transfer, and thereby produce a wealth of benchmark-quality data for testing solidification scaling laws. The data and analysis performed on the dendritic growth speed and tip size in Succinontrie (SCN) demonstrates that although the theory yields predictions that are reasonably in agreement with experiment, there are significant discrepancies. However, some of these discrepancies can be explained by accurately describing the diffusion of heat. The key finding involves recognition that the actual three-dimensional shape of dendrites includes time-dependent side-branching and a tip region that is not a paraboloid of revolution. Thus, the role of heat transfer in dendritic growth is validated, with the caveat that a more realistic model of the dendrite then a paraboloid is needed to account for heat flow in an experimentally observed dendrite. We are currently conducting additional analysis to further confirm and demonstrate these conclusions. The data and analyses for the growth selection physics remain much less definitive. From the first flight, the data indicated that the selection parameter, sigma*, is not exactly a constant, but exhibits a slight dependence on the supercooling. Additional data from the second flight are being examined to investigate the selection of a unique dendrite speed, tip size and shape. The IDGE flight series is now complete. We are currently completing analyses and moving towards final data archiving. It is gratifying to see that the IDGE published results and archived data sets are being used actively by other scientists and engineers. In addition, we are also pleased to report that the techniques and IDGE

  1. Dendritic microstructure in argon atomized superalloy powders

    NASA Technical Reports Server (NTRS)

    Tewari, S. N.; Kumar, Mahundra

    1986-01-01

    The dendritic microstructure of atomized nickel base superalloy powders (Ni-20 pct Cr, NIMONIC-80A, ASTROALOY, and ZHS6-K) was studied. Prealloyed vacuum induction melted ingots were argon-atomized, the powders were cooled to room temperature, and various powder-size fractions were examined by optical metallography. Linear correlations were obtained for the powder size dependence of the secondary dendrite arm spacing, following the expected d-alpha (R) to the m power dependence on the particle size for all four superalloy compositions. However, the Ni-20 pct Cr alloy, which had much coarser arm spacing as compared to the other three alloys, had a much larger value of m.

  2. Silicon dendritic web growth thermal analysis task

    NASA Technical Reports Server (NTRS)

    Richter, R.; Bhandari, P.

    1985-01-01

    A thermal analysis model is presented which describes the dendritic ribbon process. The model uses a melt-dendrite interface which projects out of the bulk melt as the basic interpretation of the ribbon production process. This is a marked departure from the interpretations of the interface phenomena which were used previously. The model was extensively illustrated with diagrams and pictures of ribbon samples. This model should have great impact on the analyses of experimental data as well as on future design modifications of ribbon-pulling equipment.

  3. [Application of dendritic cells in clinical tumor therapy].

    PubMed

    Li, Yan; Xian, Li-jian

    2002-04-01

    The active immunotherapy of dendritic cells is hot in tumor therapy research area. This article is a review of the source of dendritic cells, loading antigen, immunotherapy pathway, clinical application, choice of patients, and so on. It makes preparation for further research of dendritic cells. PMID:12452029

  4. Stimulation of dendritic cells enhances immune response after photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Castano, Ana P.; Hamblin, Michael R.

    2009-02-01

    Photodynamic therapy (PDT) involves the administration of photosensitizers followed by illumination of the primary tumor with red light producing reactive oxygen species that cause vascular shutdown and tumor cell necrosis and apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, priming of the immune system to recognize tumor-associated antigens (TAA). The induction of specific CD8+ Tlymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. This process is however, often sub-optimal, in part due to tumor-induced DC dysfunction. Instead of DC that can become mature and activated and have a potent antigen-presenting and immune stimulating phenotype, immature dendritic cells (iDC) are often found in tumors and are part of an immunosuppressive milieu including regulatory T-cells and immunosuppressive cytokines such as TGF-beta and IL10. We here report on the use of a potent DC activating agent, an oligonucleotide (ODN) that contains a non-methylated CpG motif and acts as an agonist of toll like receptor (TLR) 9. TLR activation is a danger signal to notify the immune system of the presence of invading pathogens. CpG-ODN (but not scrambled non-CpG ODN) increased bone-marrow DC activation after exposure to PDT-killed tumor cells, and significantly increased tumor response to PDT and mouse survival after peri-tumoral administration. CpG may be a valuable immunoadjuvant to PDT especially for tumors that produce DC dysfunction.

  5. Hyper-dendritic nanoporous zinc foam anodes

    SciTech Connect

    Chamoun, Mylad; Hertzberg, Benjamin J.; Gupta, Tanya; Davies, Daniel; Bhadra, Shoham; Van Tassell, Barry.; Erdonmez, Can; Steingart, Daniel A.

    2015-04-24

    The low cost, significant reducing potential, and relative safety of the zinc electrode is a common hope for a reductant in secondary batteries, but it is limited mainly to primary implementation due to shape change. In this work we exploit such shape change for the benefit of static electrodes through the electrodeposition of hyper-dendritic nanoporous zinc foam. Electrodeposition of zinc foam resulted in nanoparticles formed on secondary dendrites in a three-dimensional network with a particle size distribution of 54.1 - 96.0 nm. The nanoporous zinc foam contributed to highly oriented crystals, high surface area and more rapid kinetics in contrast to conventional zinc in alkaline mediums. The anode material presented had a utilization of ~ 88% at full depth-of-discharge at various rates indicating a superb rate-capability. The rechargeability of Zn⁰/Zn²⁺ showed significant capacity retention over 100 cycles at a 40% depth-of-discharge to ensure that the dendritic core structure was imperforated. The dendritic architecture was densified upon charge-discharge cycling and presented superior performance compared to bulk zinc electrodes.

  6. Hyper-dendritic nanoporous zinc foam anodes

    DOE PAGESBeta

    Chamoun, Mylad; Hertzberg, Benjamin J.; Gupta, Tanya; Davies, Daniel; Bhadra, Shoham; Van Tassell, Barry.; Erdonmez, Can; Steingart, Daniel A.

    2015-04-24

    The low cost, significant reducing potential, and relative safety of the zinc electrode is a common hope for a reductant in secondary batteries, but it is limited mainly to primary implementation due to shape change. In this work we exploit such shape change for the benefit of static electrodes through the electrodeposition of hyper-dendritic nanoporous zinc foam. Electrodeposition of zinc foam resulted in nanoparticles formed on secondary dendrites in a three-dimensional network with a particle size distribution of 54.1 - 96.0 nm. The nanoporous zinc foam contributed to highly oriented crystals, high surface area and more rapid kinetics in contrastmore » to conventional zinc in alkaline mediums. The anode material presented had a utilization of ~ 88% at full depth-of-discharge at various rates indicating a superb rate-capability. The rechargeability of Zn⁰/Zn²⁺ showed significant capacity retention over 100 cycles at a 40% depth-of-discharge to ensure that the dendritic core structure was imperforated. The dendritic architecture was densified upon charge-discharge cycling and presented superior performance compared to bulk zinc electrodes.« less

  7. Detecting Danger: The Dendritic Cell Algorithm

    NASA Astrophysics Data System (ADS)

    Greensmith, Julie; Aickelin, Uwe; Cayzer, Steve

    The "Dendritic Cell Algorithm" (DCA) is inspired by the function of the dendritic cells of the human immune system. In nature, dendritic cells are the intrusion detection agents of the human body, policing the tissue and organs for potential invaders in the form of pathogens. In this research, an abstract model of dendritic cell (DC) behavior is developed and subsequently used to form an algorithm—the DCA. The abstraction process was facilitated through close collaboration with laboratory-based immunologists, who performed bespoke experiments, the results of which are used as an integral part of this algorithm. The DCA is a population-based algorithm, with each agent in the system represented as an "artificial DC". Each DC has the ability to combine multiple data streams and can add context to data suspected as anomalous. In this chapter, the abstraction process and details of the resultant algorithm are given. The algorithm is applied to numerous intrusion detection problems in computer security including the detection of port scans and botnets, where it has produced impressive results with relatively low rates of false positives.

  8. Characterization of chicken dendritic cell markers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Animal and Natural Resources Institute, ARS-USDA, Beltsville, MD, USA. New mouse monoclonal antibodies which detect CD80 and CD83 were developed to characterize chicken dendritic cells (DCs). The characteristics of these molecules have been studied in human, swine, ovine, feline, and canine but not ...

  9. Thermosolutal convection and macrosegregation in dendritic alloys

    NASA Technical Reports Server (NTRS)

    Poirier, David R.; Heinrich, J. C.

    1993-01-01

    A mathematical model of solidification, that simulates the formation of channel segregates or freckles, is presented. The model simulates the entire solidification process, starting with the initial melt to the solidified cast, and the resulting segregation is predicted. Emphasis is given to the initial transient, when the dendritic zone begins to develop and the conditions for the possible nucleation of channels are established. The mechanisms that lead to the creation and eventual growth or termination of channels are explained in detail and illustrated by several numerical examples. A finite element model is used for the simulations. It uses a single system of equations to deal with the all-liquid region, the dendritic region, and the all-solid region. The dendritic region is treated as an anisotropic porous medium. The algorithm uses the bilinear isoparametric element, with a penalty function approximation and a Petrov-Galerkin formulation. The major task was to develop the solidification model. In addition, other tasks that were performed in conjunction with the modeling of dendritic solidification are briefly described.

  10. Defect characterization of silicon dendritic web ribbons

    NASA Technical Reports Server (NTRS)

    Cheng, L. J.

    1985-01-01

    Progress made in the study of defect characterization of silicon dendritic web ribbon is presented. Chemical etching is used combined with optical microscopy, as well as the electron beam induced current (EBIC) technique. Thermal annealing effect on carrier lifetime is examined.

  11. Supramolecular dendritic polymers: from synthesis to applications.

    PubMed

    Dong, Ruijiao; Zhou, Yongfeng; Zhu, Xinyuan

    2014-07-15

    CONSPECTUS: Supramolecular dendritic polymers (SDPs), which perfectly combine the advantages of dendritic polymers with those of supramolecular polymers, are a novel class of non-covalently bonded, highly branched macromolecules with three-dimensional globular topology. Because of their dynamic/reversible nature, unique topological structure, and exceptional physical/chemical properties (e.g., low viscosity, high solubility, and a large number of functional terminal groups), SDPs have attracted increasing attention in recent years in both academic and industrial fields. In particular, the reversibility of non-covalent interactions endows SDPs with the ability to undergo dynamic switching of structure, morphology, and function in response to various external stimuli, such as pH, temperature, light, stress, and redox agents, which further provides a flexible and robust platform for designing and developing smart supramolecular polymeric materials and functional supramolecular devices. The existing SDPs can be systematically classified into the following six major types according to their topological features: supramolecular dendrimers, supramolecular dendronized polymers, supramolecular hyperbranched polymers, supramolecular linear-dendritic block copolymers, supramolecular dendritic-dendritic block copolymers, and supramolecular dendritic multiarm copolymers. These different types of SDPs possess distinct morphologies, unique architectures, and specific functions. Benefiting from their versatile topological structures as well as stimuli-responsive properties, SDPs have displayed not only unique characteristics or advantages in supramolecular self-assembly behaviors (e.g., controllable morphologies, specific performance, and facile functionalization) but also great potential to be promising candidates in various fields. In this Account, we summarize the recent progress in the synthesis, functionalization, and self-assembly of SDPs as well as their potential

  12. Regulatory Anatomy

    PubMed Central

    2015-01-01

    This article proposes the term “safety logics” to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, legal documents, technological devices, organizational structures, and work practices aimed at minimizing risk. I use this term to reorient the analytical attention with respect to safety regulation. Instead of evaluating whether safety is achieved, the point is to explore the types of “safety” produced through these logics as well as to consider the sometimes unintended consequences of such safety work. In fact, the EU rules have been giving rise to complaints from practitioners finding the directives problematic and inadequate. In this article, I explore the problems practitioners face and why they arise. In short, I expose the regulatory anatomy of the policy landscape. PMID:26139952

  13. Regulatory RNAs

    PubMed Central

    Vazquez-Anderson, Jorge; Contreras, Lydia M

    2013-01-01

    RNAs have many important functional properties, including that they are independently controllable and highly tunable. As a result of these advantageous properties, their use in a myriad of sophisticated devices has been widely explored. Yet, the exploitation of RNAs for synthetic applications is highly dependent on the ability to characterize the many new molecules that continue to be discovered by large-scale sequencing and high-throughput screening techniques. In this review, we present an exhaustive survey of the most recent synthetic bacterial riboswitches and small RNAs while emphasizing their virtues in gene expression management. We also explore the use of these RNA components as building blocks in the RNA synthetic biology toolbox and discuss examples of synthetic RNA components used to rewire bacterial regulatory circuitry. We anticipate that this field will expand its catalog of smart devices by mimicking and manipulating natural RNA mechanisms and functions. PMID:24356572

  14. Regulatory Physiology

    NASA Technical Reports Server (NTRS)

    Lane, Helen W.; Whitson, Peggy A.; Putcha, Lakshmi; Baker, Ellen; Smith, Scott M.; Stewart, Karen; Gretebeck, Randall; Nimmagudda, R. R.; Schoeller, Dale A.; Davis-Street, Janis

    1999-01-01

    As noted elsewhere in this report, a central goal of the Extended Duration Orbiter Medical Project (EDOMP) was to ensure that cardiovascular and muscle function were adequate to perform an emergency egress after 16 days of spaceflight. The goals of the Regulatory Physiology component of the EDOMP were to identify and subsequently ameliorate those biochemical and nutritional factors that deplete physiological reserves or increase risk for disease, and to facilitate the development of effective muscle, exercise, and cardiovascular countermeasures. The component investigations designed to meet these goals focused on biochemical and physiological aspects of nutrition and metabolism, the risk of renal (kidney) stone formation, gastrointestinal function, and sleep in space. Investigations involved both ground-based protocols to validate proposed methods and flight studies to test those methods. Two hardware tests were also completed.

  15. CD45 epitope mapping of human CD1a+ dendritic cells and peripheral blood dendritic cells.

    PubMed Central

    Wood, G. S.; Freudenthal, P. S.; Edinger, A.; Steinman, R. M.; Warnke, R. A.

    1991-01-01

    The authors studied the pattern of leukocyte common antigen (CD45) epitope expression on dendritic cells in sections of human epidermis, tonsillar epithelium, dermatopathic lymph nodes, and in isolates from blood. The monoclonal antibodies (MAb) used were specific for all known CD45 epitopes, including the seven different CD45 common epitopes as well as the four known CD45R epitopes (two CD45RA, one CD45RB, and one CD45RO). Dendritic cells in all sites were uniformly reactive for the CD45 common epitopes tested except 2B11, which may recognize a CD45R rather than CD45 epitope. By single-label immunoperoxidase and double-label immunofluorescence epitope mapping of CD1a+ dendritic cells in tissue sections, it was generally difficult or impossible to detect expression of CD45RA, CD45RB, CD45RO, or 2B11. In blood dendritic cells, however, low levels of these CD45R epitopes were detected consistently using single-label immunoperoxidase staining of cytocentrifuge preparations. Monocytes were similar to blood dendritic cells except that the staining with MAb to CD45RO and 2B11 was slightly stronger. The authors conclude that dendritic cells differ from most subpopulations of lymphocytes in that CD45 common epitopes are readily detectable but the existing RA, RB, and RO epitopes are either undetectable or expressed at relatively low levels. These studies raise the possibility that CD1a+ dendritic cells may express a novel dominant CD45 isoform. Images Figure 1 Figure 2 PMID:1711291

  16. Dendritic development of newly generated neurons in the adult brain.

    PubMed

    Ribak, Charles E; Shapiro, Lee A

    2007-10-01

    Ramon y Cajal described the fundamental morphology of the dendritic and axonal growth cones of neurons during development. However, technical limitations at the time prevented him from describing such growth cones from newborn neurons in the adult brain. The phenomenon of adult neurogenesis is briefly reviewed, and the structural description of dendritic and axonal outgrowth for these newly generated neurons in the adult brain is discussed. Axonal outgrowth into the hilus and CA3 region of the hippocampus occurs later than the outgrowth of dendrites into the molecular layer, and the ultrastructural analysis of axonal outgrowth has yet to be completed. In contrast, growth cones on dendrites from newborn neurons in the adult dentate gyrus have been described and this observation suggests that dendrites in adult brains grow in a similar way to those found in immature brains. However, dendrites in adult brains have to navigate through a denser neuropil and a more complex cell layer. Therefore, some aspects of dendritic outgrowth of neurons born in the adult dentate gyrus are different as compared to that found in development. These differences include the radial process of radial glial cells acting as a lattice to guide apical dendritic growth through the granule cell layer and a much thinner dendrite to grow through the neuropil of the molecular layer. Therefore, similarities and differences exist for dendritic outgrowth from newborn neurons in the developing and adult brain.

  17. Developmental mechanisms that regulate retinal ganglion cell dendritic morphology

    PubMed Central

    Tian, Ning

    2011-01-01

    One of the fundamental features of retinal ganglion cells (RGCs) is that dendrites of individual RGCs are confined to one or a few narrow strata within the inner plexiform layer (IPL), and each RGC synapses only with a small group of presynaptic bipolar and amacrine cells with axons/dendrites ramified in the same strata to process distinct visual features. The underlying mechanisms which control the development of this laminar-restricted distribution pattern of RGC dendrites have been extensively studied, and it is still an open question whether the dendritic pattern of RGCs is determined by molecular cues or by activity-dependent refinement. Accumulating evidence suggests that both molecular cues and activity-dependent refinement might regulate RGC dendrites in a cell subtype-specific manner. However, identification of morphological subtypes of RGCs before they have achieved their mature dendritic pattern is a major challenge in the study of RGC dendritic development. This problem is now being circumvented through the use of molecular markers in genetically engineered mouse lines to identify RGC subsets early during development. Another unanswered fundamental question in the study of activity-dependent refinement of RGC dendrites is how changes in synaptic activity lead to the changes in dendritic morphology. Recent studies have started to shed light on the molecular basis of activity-dependent dendritic refinement of RGCs by showing that some molecular cascades control the cytoskeleton reorganization of RGCs. PMID:21542137

  18. Dendritic growth tip velocities and radii of curvature in microgravity

    SciTech Connect

    Koss, M.B.; LaCombe, J.C.; Tennenhouse, L.A.; Glicksman, M.E.; Winsa, E.A.

    1999-12-01

    Dendritic growth is the common mode of solidification encountered when metals and alloys freeze under low thermal gradients. The growth of dendrites in pure melts depends on the transport of latent heat from the moving crystal-melt interface and the influence of weaker effects like the interfacial energy. Experimental data for critical tests of dendritic growth theories remained limited because dendritic growth can be complicated by convection. The Isothermal Dendritic Growth Experiment (IDGE) was developed specifically to test dendritic growth theories by performing measurements with succinonitrile (SCN) in microgravity, thus eliminating buoyancy-induced convection. The first flight of the IDGE in 1994 operated for 9 days at a mean quasi-static acceleration of 0.7 x 10{sup {minus}6} g{sub 0}. The velocity and radius data show that at supercoolings above approximately 0.4 K, dendritic growth in SCN under microgravity conditions is diffusion limited. By contrast, under terrestrial conditions, dendritic growth of SCN is dominated y convection for supercoolings below 1.7 K. The theoretical and experimental Peclet numbers exhibit modest disagreement, indicating that transport theories of dendritic solidification require some modification. Finally, the kinetic selection rule for dendritic growth, VR{sup 2} = constant, where V is the velocity of the tip and R is the radius of curvature at the tip, appears to be independent of the gravity environment, with a slight dependence on the supercooling.

  19. Evaluating Local Primary Dendrite Arm Spacing Characterization Techniques Using Synthetic Directionally Solidified Dendritic Microstructures

    NASA Astrophysics Data System (ADS)

    Tschopp, Mark A.; Miller, Jonathan D.; Oppedal, Andrew L.; Solanki, Kiran N.

    2015-10-01

    Microstructure characterization continues to play an important bridge to understanding why particular processing routes or parameters affect the properties of materials. This statement certainly holds true in the case of directionally solidified dendritic microstructures, where characterizing the primary dendrite arm spacing is vital to developing the process-structure-property relationships that can lead to the design and optimization of processing routes for defined properties. In this work, four series of simulations were used to examine the capability of a few Voronoi-based techniques to capture local microstructure statistics (primary dendrite arm spacing and coordination number) in controlled (synthetically generated) microstructures. These simulations used both cubic and hexagonal microstructures with varying degrees of disorder (noise) to study the effects of length scale, base microstructure, microstructure variability, and technique parameters on the local PDAS distribution, local coordination number distribution, bulk PDAS, and bulk coordination number. The Voronoi tesselation technique with a polygon-side-length criterion correctly characterized the known synthetic microstructures. By systematically studying the different techniques for quantifying local primary dendrite arm spacings, we have evaluated their capability to capture this important microstructure feature in different dendritic microstructures, which can be an important step for experimentally correlating with both processing and properties in single crystal nickel-based superalloys.

  20. Somato-dendritic Synaptic Plasticity and Error-backpropagation in Active Dendrites

    PubMed Central

    Schiess, Mathieu; Urbanczik, Robert; Senn, Walter

    2016-01-01

    In the last decade dendrites of cortical neurons have been shown to nonlinearly combine synaptic inputs by evoking local dendritic spikes. It has been suggested that these nonlinearities raise the computational power of a single neuron, making it comparable to a 2-layer network of point neurons. But how these nonlinearities can be incorporated into the synaptic plasticity to optimally support learning remains unclear. We present a theoretically derived synaptic plasticity rule for supervised and reinforcement learning that depends on the timing of the presynaptic, the dendritic and the postsynaptic spikes. For supervised learning, the rule can be seen as a biological version of the classical error-backpropagation algorithm applied to the dendritic case. When modulated by a delayed reward signal, the same plasticity is shown to maximize the expected reward in reinforcement learning for various coding scenarios. Our framework makes specific experimental predictions and highlights the unique advantage of active dendrites for implementing powerful synaptic plasticity rules that have access to downstream information via backpropagation of action potentials. PMID:26841235

  1. Simulation of dendritic growth reveals necessary and sufficient parameters to describe the shapes of dendritic trees

    NASA Astrophysics Data System (ADS)

    Trottier, Olivier; Ganguly, Sujoy; Bowne-Anderson, Hugo; Liang, Xin; Howard, Jonathon

    For the last 120 years, the development of neuronal shapes has been of great interest to the scientific community. Over the last 30 years, significant work has been done on the molecular processes responsible for dendritic development. In our ongoing research, we use the class IV sensory neurons of the Drosophila melanogaster larva as a model system to understand the growth of dendritic arbors. Our main goal is to elucidate the mechanisms that the neuron uses to determine the shape of its dendritic tree. We have observed the development of the class IV neuron's dendritic tree in the larval stage and have concluded that morphogenesis is defined by 3 distinct processes: 1) branch growth, 2) branching and 3) branch retraction. As the first step towards understanding dendritic growth, we have implemented these three processes in a computational model. Our simulations are able to reproduce the branch length distribution, number of branches and fractal dimension of the class IV neurons for a small range of parameters.

  2. A Genome-Wide Screen for Dendritically Localized RNAs Identifies Genes Required for Dendrite Morphogenesis.

    PubMed

    Misra, Mala; Edmund, Hendia; Ennis, Darragh; Schlueter, Marissa A; Marot, Jessica E; Tambasco, Janet; Barlow, Ida; Sigurbjornsdottir, Sara; Mathew, Renjith; Vallés, Ana Maria; Wojciech, Waldemar; Roth, Siegfried; Davis, Ilan; Leptin, Maria; Gavis, Elizabeth R

    2016-01-01

    Localizing messenger RNAs at specific subcellular sites is a conserved mechanism for targeting the synthesis of cytoplasmic proteins to distinct subcellular domains, thereby generating the asymmetric protein distributions necessary for cellular and developmental polarity. However, the full range of transcripts that are asymmetrically distributed in specialized cell types, and the significance of their localization, especially in the nervous system, are not known. We used the EP-MS2 method, which combines EP transposon insertion with the MS2/MCP in vivo fluorescent labeling system, to screen for novel localized transcripts in polarized cells, focusing on the highly branched Drosophila class IV dendritic arborization neurons. Of a total of 541 lines screened, we identified 55 EP-MS2 insertions producing transcripts that were enriched in neuronal processes, particularly in dendrites. The 47 genes identified by these insertions encode molecularly diverse proteins, and are enriched for genes that function in neuronal development and physiology. RNAi-mediated knockdown confirmed roles for many of the candidate genes in dendrite morphogenesis. We propose that the transport of mRNAs encoded by these genes into the dendrites allows their expression to be regulated on a local scale during the dynamic developmental processes of dendrite outgrowth, branching, and/or remodeling. PMID:27260999

  3. Sensitivity of Dendritic Cells to Microenvironment Signals

    PubMed Central

    Motta, Juliana Maria; Rumjanek, Vivian Mary

    2016-01-01

    Dendritic cells are antigen-presenting cells capable of either activating the immune response or inducing and maintaining immune tolerance. They do this by integrating stimuli from the environment and changing their functional status as a result of plasticity. The modifications suffered by these cells have consequences in the way the organism may respond. In the present work two opposing situations known to affect dendritic cells are analyzed: tumor growth, leading to a microenvironment that favors the induction of a tolerogenic profile, and organ transplantation, which leads to a proinflammatory profile. Lessons learned from these situations may help to understand the mechanisms of modulation resulting not only from the above circumstances, but also from other pathologies. PMID:27088097

  4. Asteroid core crystallization by inward dendritic growth

    NASA Technical Reports Server (NTRS)

    Haack, Henning; Scott, Edward R. D.

    1992-01-01

    The physics of the asteroid core crystallization process in metallic asteroids is investigated, with special attention given to the initial conditions for core crystallization, the manner of crystallization, the mechanisms acting in the stirring of the liquid, and the effects of elements such as sulfur on crystallization of Fe-Ni. On the basis of theoretical considerations and the published data on iron meteorites, it is suggested that the mode of crystallization in asteroid core was different from the apparent outward concentric crystallization of the earth core, in that the crystallization of asteroidal cores commenced at the base of the mantle and proceeded inward. The inward crystallization resulted in complex dendritic growth. These dendrites may have grown to lengths of hundreds of meters or perhaps even as large as the core radius, thereby dividing the core into separate magma chambers.

  5. Lid for improved dendritic web growth

    DOEpatents

    Duncan, Charles S.; Kochka, Edgar L.; Piotrowski, Paul A.; Seidensticker, Raymond G.

    1992-03-24

    A lid for a susceptor in which a crystalline material is melted by induction heating to form a pool or melt of molten material from which a dendritic web of essentially a single crystal of the material is pulled through an elongated slot in the lid and the lid has a pair of generally round openings adjacent the ends of the slot and a groove extends between each opening and the end of the slot. The grooves extend from the outboard surface of the lid to adjacent the inboard surface providing a strip contiguous with the inboard surface of the lid to produce generally uniform radiational heat loss across the width of the dendritic web adjacent the inboard surface of the lid to reduce thermal stresses in the web and facilitate the growth of wider webs at a greater withdrawal rate.

  6. Endoplasmic reticulum calcium stores in dendritic spines

    PubMed Central

    Segal, Menahem; Korkotian, Eduard

    2014-01-01

    Despite decades of research, the role of calcium stores in dendritic spines structure, function and plasticity is still debated. The reasons for this may have to do with the multitude of overlapping calcium handling machineries in the neuron, including stores, voltage and ligand gated channels, pumps and transporters. Also, different cells in the brain are endowed with calcium stores that are activated by different receptor types, and their differential compartmentalization in dendrites, spines and presynaptic terminals complicates their analysis. In the present review we address several key issues, including the role of calcium stores in synaptic plasticity, their role during development, in stress and in neurodegenerative diseases. Apparently, there is increasing evidence for a crucial role of calcium stores, especially of the ryanodine species, in synaptic plasticity and neuronal survival. PMID:25071469

  7. Physiologic control of IDO competence in splenic dendritic cells.

    PubMed

    Baban, Babak; Chandler, Phillip R; Johnson, Burles A; Huang, Lei; Li, Minghui; Sharpe, Marlon L; Francisco, Loise M; Sharpe, Arlene H; Blazar, Bruce R; Munn, David H; Mellor, Andrew L

    2011-09-01

    Dendritic cells (DCs) competent to express the regulatory enzyme IDO in mice are a small but distinctive subset of DCs. Previously, we reported that a high-dose systemic CpG treatment to ligate TLR9 in vivo induced functional IDO exclusively in splenic CD19(+) DCs, which stimulated resting Foxp3-lineage regulatory T cells (Tregs) to rapidly acquire potent suppressor activity. In this paper, we show that IDO was induced in spleen and peripheral lymph nodes after CpG treatment in a dose-dependent manner. Induced IDO suppressed local T cell responses to exogenous Ags and inhibited proinflammatory cytokine expression in response to TLR9 ligation. IDO induction did not occur in T cell-deficient mice or in mice with defective B7 or programmed death (PD)-1 costimulatory pathways. Consistent with these findings, CTLA4 or PD-1/PD-ligand costimulatory blockade abrogated IDO induction and prevented Treg activation via IDO following high-dose CpG treatment. Consequently, CD4(+)CD25(+) T cells uniformly expressed IL-17 shortly after TLR9 ligation. These data support the hypothesis that constitutive interactions from activated T cells or Tregs and IDO-competent DCs via concomitant CTLA4→B7 and PD-1→PD-ligand signals maintain the default potential to regulate T cell responsiveness via IDO. Acute disruption of these nonredundant interactions abrogated regulation via IDO, providing novel perspectives on the proinflammatory effects of costimulatory blockade therapies. Moreover, interactions between IDO-competent DCs and activated T cells in lymphoid tissues may attenuate proinflammatory responses to adjuvants such as TLR ligands.

  8. The discovery of dendritic spines by Cajal.

    PubMed

    Yuste, Rafael

    2015-01-01

    Dendritic spines were considered an artifact of the Golgi method until a brash Spanish histologist, Santiago Ramón y Cajal, bet his scientific career arguing that they were indeed real, correctly deducing their key role in mediating synaptic connectivity. This article reviews the historical context of the discovery of spines and the reasons behind Cajal's obsession with them, all the way till his deathbed. PMID:25954162

  9. Role of Dendritic Cells in Immune Dysfunction

    NASA Technical Reports Server (NTRS)

    Savary, Cherylyn A.

    1997-01-01

    Specific aims include: (1) Application of the bioreactor to enhance cytokine-regulated proliferation and maturation of dendritic cells (DC); (2) Based on clues from spaceflight: compare the frequency and function of DC in normal donors and immunocompromised cancer patients; and (3) Initiate studies on the efficiency of cytokine therapy and DC-assisted immunotherapy (using bioreactor-expanded DC) in animal models of experimental fungal infections.

  10. The diverging roles of dendritic cells in kidney allotransplantation.

    PubMed

    Podestà, Manuel Alfredo; Cucchiari, David; Ponticelli, Claudio

    2015-07-01

    Dendritic cells (DCs) are a family of antigen presenting cells that play a paramount role in bridging innate and adaptive immunity. In murine models several subtypes of DCs have been identified, including classical DCs, monocyte-derived DCs, and plasmacytoid DCs. Quiescent, immature DCs and some subtypes of plasmacytoid cells favor the expression of regulatory T cells, but in an inflammatory milieu DCs become mature and after intercepting the antigen migrate to lymphatic system where they present the antigen to naïve T cells. Transplant rejection largely depends on the phenotype and maturation of DCs. The ischemia-reperfusion injury causes the release of endogenous molecules that are recognized as danger signals by the pattern recognition receptor of the innate immunity with subsequent activation of inflammatory cells and mediators. In this environment DCs become mature and migrate to lymphonodes where they present the alloantigen to T cells and direct their differentiation towards Th1 and Th17 effector cells. On the other hand, manipulation of DCs may favor T cell differentiation towards tolerant Th2 and T regulators (Treg). Experimental studies in murine models showed the possibility of inducing an operational tolerance by injecting immature tolerogenic DCs. Recently, such a possibility has been also confirmed in primates. Although manipulation of DCs may represent an important step ahead in kidney transplantation, a number of technical and ethical issues should be solved before its clinical application.

  11. Plasmacytoid dendritic cells: development, functions, and role in atherosclerotic inflammation

    PubMed Central

    Chistiakov, Dimitry A.; Orekhov, Alexander N.; Sobenin, Igor A.; Bobryshev, Yuri V.

    2014-01-01

    Plasmacytoid dendritic cells (pDCs) are a specialized subset of DCs that links innate and adaptive immunity. They sense viral and bacterial pathogens and release high levels of Type I interferons (IFN-I) in response to infection. pDCs were shown to contribute to inflammatory responses in the steady state and in pathology. In atherosclerosis, pDCs are involved in priming vascular inflammation and atherogenesis through production of IFN-I and chemokines that attract inflammatory cells to inflamed sites. pDCs also contribute to the proinflammatory activation of effector T cells, cytotoxic T cells, and conventional DCs. However, tolerogenic populations of pDCs are found that suppress atherosclerosis-associated inflammation through down-regulation of function and proliferation of proinflammatory T cell subsets and induction of regulatory T cells with potent immunomodulatory properties. Notably, atheroprotective tolerogenic DCs could be induced by certain self-antigens or bacterial antigens that suggests for great therapeutic potential of these DCs for development of DC-based anti-atherogenic vaccines. PMID:25120492

  12. Connecting the mechanisms of T-cell regulation: dendritic cells as the missing link.

    PubMed

    Cobbold, Stephen P; Adams, Elizabeth; Nolan, Kathleen F; Regateiro, Frederico S; Waldmann, Herman

    2010-07-01

    A variety of different molecular mechanisms have been proposed to explain the suppressive action of regulatory T cells, including the production of anti-inflammatory cytokines, negative costimulatory ligands, indoleamine 2,3-dioxygenase-mediated tryptophan catabolism, CD73-mediated adenosine generation, and downregulation of antigen-presenting cells. Until now it has been unclear how important each of these different mechanisms might be and how they are coordinated. In this review, we examine the hypothesis that it is the interaction between regulatory T cells and dendritic cells that creates a local microenvironment depleted of essential amino acids and rich in adenosine that leads to the amplification of a range of different tolerogenic signals. These signals are all eventually integrated by mammalian target of rapamycin inhibition, which enables the induction of new forkhead box protein 3-expressing Tregs. If correct, this provides a molecular explanation for the in vivo phenomena of linked suppression and infectious tolerance. PMID:20636819

  13. Epidermis-Derived Semaphorin Promotes Dendrite Self-Avoidance by Regulating Dendrite-Substrate Adhesion in Drosophila Sensory Neurons.

    PubMed

    Meltzer, Shan; Yadav, Smita; Lee, Jiae; Soba, Peter; Younger, Susan H; Jin, Peng; Zhang, Wei; Parrish, Jay; Jan, Lily Yeh; Jan, Yuh-Nung

    2016-02-17

    Precise patterning of dendritic arbors is critical for the wiring and function of neural circuits. Dendrite-extracellular matrix (ECM) adhesion ensures that the dendrites of Drosophila dendritic arborization (da) sensory neurons are properly restricted in a 2D space, and thereby facilitates contact-mediated dendritic self-avoidance and tiling. However, the mechanisms regulating dendrite-ECM adhesion in vivo are poorly understood. Here, we show that mutations in the semaphorin ligand sema-2b lead to a dramatic increase in self-crossing of dendrites due to defects in dendrite-ECM adhesion, resulting in a failure to confine dendrites to a 2D plane. Furthermore, we find that Sema-2b is secreted from the epidermis and signals through the Plexin B receptor in neighboring neurons. Importantly, we find that Sema-2b/PlexB genetically and physically interacts with TORC2 complex, Tricornered (Trc) kinase, and integrins. These results reveal a novel role for semaphorins in dendrite patterning and illustrate how epidermal-derived cues regulate neural circuit assembly.

  14. Synergistic action of dendritic mitochondria and creatine kinase maintains ATP homeostasis and actin dynamics in growing neuronal dendrites.

    PubMed

    Fukumitsu, Kansai; Fujishima, Kazuto; Yoshimura, Azumi; Wu, You Kure; Heuser, John; Kengaku, Mineko

    2015-04-01

    The distribution of mitochondria within mature, differentiated neurons is clearly adapted to their regional physiological needs and can be perturbed under various pathological conditions, but the function of mitochondria in developing neurons has been less well studied. We have studied mitochondrial distribution within developing mouse cerebellar Purkinje cells and have found that active delivery of mitochondria into their dendrites is a prerequisite for proper dendritic outgrowth. Even when mitochondria in the Purkinje cell bodies are functioning normally, interrupting the transport of mitochondria into their dendrites severely disturbs dendritic growth. Additionally, we find that the growth of atrophic dendrites lacking mitochondria can be rescued by activating ATP-phosphocreatine exchange mediated by creatine kinase (CK). Conversely, inhibiting cytosolic CKs decreases dendritic ATP levels and also disrupts dendrite development. Mechanistically, this energy depletion appears to perturb normal actin dynamics and enhance the aggregation of cofilin within growing dendrites, reminiscent of what occurs in neurons overexpressing the dephosphorylated form of cofilin. These results suggest that local ATP synthesis by dendritic mitochondria and ATP-phosphocreatine exchange act synergistically to sustain the cytoskeletal dynamics necessary for dendritic development.

  15. Plasmacytoid dendritic cell role in cutaneous malignancies.

    PubMed

    Saadeh, Dana; Kurban, Mazen; Abbas, Ossama

    2016-07-01

    Plasmacytoid dendritic cells (pDCs) correspond to a specialized dendritic cell population that exhibit plasma cell morphology, express CD4, CD123, HLA-DR, blood-derived dendritic cell antigen-2 (BDCA-2), and Toll-like receptor (TLR)7 and TLR9 within endosomal compartments. Through their production of type I interferons (IFNs) and other pro-inflammatory cytokines, pDCs provide anti-viral resistance and link the innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer (NK) cells. While lacking from normal skin, pDCs are usually recruited to the skin in several cutaneous pathologies where they appear to be involved in the pathogenesis of several infectious, inflammatory/autoimmune, and neoplastic entities. Among the latter group, pDCs have the potential to induce anti-tumour immunity; however, the complex interaction of pDCs with tumor cells and their micro-environment appears to contribute to immunologic tolerance. In this review, we aim at highlighting the role played by pDCs in cutaneous malignancies with special emphasis on the underlying mechanisms.

  16. The Isothermal Dendritic Growth Experiment Archive

    NASA Astrophysics Data System (ADS)

    Koss, Matthew

    2009-03-01

    The growth of dendrites is governed by the interplay between two simple and familiar processes---the irreversible diffusion of energy, and the reversible work done in the formation of new surface area. To advance our understanding of these processes, NASA sponsored a project that flew on the Space Shuttle Columbia is 1994, 1996, and 1997 to record and analyze benchmark data in an apparent-microgravity ``laboratory.'' In this laboratory, energy transfer by gravity driven convection was essentially eliminated and one could test independently, for the first time, both components of dendritic growth theory. The analysis of this data shows that although the diffusion of energy can be properly accounted for, the results from interfacial physics appear to be in disagreement and alternate models should receive increased attention. Unfortunately, currently and for the foreseeable future, there is no access or financial support to develop and conduct additional experiments of this type. However, the benchmark data of 35mm photonegatives, video, and all supporting instrument data are now available at the IDGE Archive at the College of the Holy Cross. This data may still have considerable relevance to researchers working specifically with dendritic growth, and more generally those working in the synthesis, growth & processing of materials, multiscale computational modeling, pattern formation, and systems far from equilibrium.

  17. Involvement of diacylglycerol kinase β in the spine formation at distal dendrites of striatal medium spiny neurons.

    PubMed

    Hozumi, Yasukazu; Kakefuda, Kenichi; Yamasaki, Miwako; Watanabe, Masahiko; Hara, Hideaki; Goto, Kaoru

    2015-01-12

    Spine formation, a salient feature underlying neuronal plasticity to adapt to a changing environment, is regulated by complex machinery involving membrane signal transduction. The diacylglycerol kinase (DGK) family, which is involved in membrane lipid metabolism, catalyzes the phosphorylation of a lipid second messenger, diacylglycerol (DG). Of the DGKs, DGKβ is characterized by predominant expression in a specific brain region: the striatum. We previously demonstrated that DGKβ is expressed selectively in medium spiny neurons (MSNs) and that it is highly enriched in the perisynaptic membrane on dendritic spines contacted with excitatory terminals. Moreover, DGKβ regulates spinogenesis through actin-based remodeling in an activity-dependent manner. However, the detailed mechanisms of spinogenesis regulation and its functional significance remain unclear. To address these issues, we performed Golgi-Cox staining to examine morphological aspects of MSNs in the striatum of DGKβ-knockout (KO) mice. Results show that striatal MSNs of DGKβ-KO mice exhibited lower dendritic spine density at distal dendrites than wild-type mice did. We also sought protein targets that interact with DGKβ and identified the GluA2 AMPA receptor subunit as a novel DGKβ binding partner. In addition, DGKβ-deficient brain exhibits significant reduction of TARP γ-8, which represents a transmembrane AMPA receptor regulatory protein. These findings suggest that DGKβ regulates the spine formation at distal dendrites in MSNs.

  18. Location-dependent synaptic plasticity rules by dendritic spine cooperativity.

    PubMed

    Weber, Jens P; Andrásfalvy, Bertalan K; Polito, Marina; Magó, Ádám; Ujfalussy, Balázs B; Makara, Judit K

    2016-01-01

    Nonlinear interactions between coactive synapses enable neurons to discriminate between spatiotemporal patterns of inputs. Using patterned postsynaptic stimulation by two-photon glutamate uncaging, here we investigate the sensitivity of synaptic Ca(2+) signalling and long-term plasticity in individual spines to coincident activity of nearby synapses. We find a proximodistally increasing gradient of nonlinear NMDA receptor (NMDAR)-mediated amplification of spine Ca(2+) signals by a few neighbouring coactive synapses along individual perisomatic dendrites. This synaptic cooperativity does not require dendritic spikes, but is correlated with dendritic Na(+) spike propagation strength. Furthermore, we show that repetitive synchronous subthreshold activation of small spine clusters produces input specific, NMDAR-dependent cooperative long-term potentiation at distal but not proximal dendritic locations. The sensitive synaptic cooperativity at distal dendritic compartments shown here may promote the formation of functional synaptic clusters, which in turn can facilitate active dendritic processing and storage of information encoded in spatiotemporal synaptic activity patterns. PMID:27098773

  19. Special fractal growth of dendrite copper using a hydrothermal method

    NASA Astrophysics Data System (ADS)

    Zheng, Yan; Zhang, Zhejuan; Guo, Pingsheng; He, Pingang; Sun, Zhuo

    2011-08-01

    Special fractal dendrite Cu nanostructures have been synthesized through a simple hydrothermal method, and the effects of the volume ratio between glycerol and water and the concentration of H 3PO 3 on the morphologies of dendrite Cu have been studied in detail. The Field emission scanning electron microscopy (FESEM), Transmission electron microscopy (TEM) and X-ray diffraction (XRD) have been used to characterize these Cu products. The results indicate that rhombic diamond and different morphologies of fractal dendrite were prepared because of the accumulation of Cu nuclei based on the diffusion-limited aggregation (DLA) and the nucleation-limited aggregation (NLA) model. Fortunately, symmetrical leaf-like dendrite Cu nanostructures different from Cu dendrites reported before have been obtained. Additionally, an explanation for the growth of fractal dendrite Cu has been discussed carefully.

  20. Neural pattern formation in networks with dendritic structure

    NASA Astrophysics Data System (ADS)

    Bressloff, P. C.; De Souza, B.

    1998-04-01

    We present a detailed analysis of a recently proposed model of neural pattern formation that is based on the combined effect of diffusion along a neuron's dendritic tree and recurrent interactions along axo-dendritic synaptic connections. For concreteness, we consider a one-dimensional array of analog neurons with the dendritic tree idealized as a one-dimensional cable. Linear stability analysis and bifurcation theory together with numerical simulations are used to establish conditions for the onset of a Turing instability leading to the formation of stable spatial patterns of network output activity. It is shown that the presence of dendritic structure can induce dynamic (time-periodic) spatial pattern formation. Moreover, correlations between the dendritic location of a synapse and the relative positions of neurons in the network are shown to result in spatially oscillating patterns of activity along the dendrites of each neuron.

  1. Location-dependent synaptic plasticity rules by dendritic spine cooperativity

    PubMed Central

    Weber, Jens P.; Andrásfalvy, Bertalan K.; Polito, Marina; Magó, Ádám; Ujfalussy, Balázs B.; Makara, Judit K.

    2016-01-01

    Nonlinear interactions between coactive synapses enable neurons to discriminate between spatiotemporal patterns of inputs. Using patterned postsynaptic stimulation by two-photon glutamate uncaging, here we investigate the sensitivity of synaptic Ca2+ signalling and long-term plasticity in individual spines to coincident activity of nearby synapses. We find a proximodistally increasing gradient of nonlinear NMDA receptor (NMDAR)-mediated amplification of spine Ca2+ signals by a few neighbouring coactive synapses along individual perisomatic dendrites. This synaptic cooperativity does not require dendritic spikes, but is correlated with dendritic Na+ spike propagation strength. Furthermore, we show that repetitive synchronous subthreshold activation of small spine clusters produces input specific, NMDAR-dependent cooperative long-term potentiation at distal but not proximal dendritic locations. The sensitive synaptic cooperativity at distal dendritic compartments shown here may promote the formation of functional synaptic clusters, which in turn can facilitate active dendritic processing and storage of information encoded in spatiotemporal synaptic activity patterns. PMID:27098773

  2. Random positions of dendritic spines in human cerebral cortex.

    PubMed

    Morales, Juan; Benavides-Piccione, Ruth; Dar, Mor; Fernaud, Isabel; Rodríguez, Angel; Anton-Sanchez, Laura; Bielza, Concha; Larrañaga, Pedro; DeFelipe, Javier; Yuste, Rafael

    2014-07-23

    Dendritic spines establish most excitatory synapses in the brain and are located in Purkinje cell's dendrites along helical paths, perhaps maximizing the probability to contact different axons. To test whether spine helixes also occur in neocortex, we reconstructed >500 dendritic segments from adult human cortex obtained from autopsies. With Fourier analysis and spatial statistics, we analyzed spine position along apical and basal dendrites of layer 3 pyramidal neurons from frontal, temporal, and cingulate cortex. Although we occasionally detected helical positioning, for the great majority of dendrites we could not reject the null hypothesis of spatial randomness in spine locations, either in apical or basal dendrites, in neurons of different cortical areas or among spines of different volumes and lengths. We conclude that in adult human neocortex spine positions are mostly random. We discuss the relevance of these results for spine formation and plasticity and their functional impact for cortical circuits.

  3. Dendritic spine detection using curvilinear structure detector and LDA classifier.

    PubMed

    Zhang, Yong; Zhou, Xiaobo; Witt, Rochelle M; Sabatini, Bernardo L; Adjeroh, Donald; Wong, Stephen T C

    2007-06-01

    Dendritic spines are small, bulbous cellular compartments that carry synapses. Biologists have been studying the biochemical pathways by examining the morphological and statistical changes of the dendritic spines at the intracellular level. In this paper a novel approach is presented for automated detection of dendritic spines in neuron images. The dendritic spines are recognized as small objects of variable shape attached or detached to multiple dendritic backbones in the 2D projection of the image stack along the optical direction. We extend the curvilinear structure detector to extract the boundaries as well as the centerlines for the dendritic backbones and spines. We further build a classifier using Linear Discriminate Analysis (LDA) to classify the attached spines into valid and invalid types to improve the accuracy of the spine detection. We evaluate the proposed approach by comparing with the manual results in terms of backbone length, spine number, spine length, and spine density.

  4. Random Positions of Dendritic Spines in Human Cerebral Cortex

    PubMed Central

    Morales, Juan; Benavides-Piccione, Ruth; Dar, Mor; Fernaud, Isabel; Rodríguez, Angel; Anton-Sanchez, Laura; Bielza, Concha; Larrañaga, Pedro; DeFelipe, Javier

    2014-01-01

    Dendritic spines establish most excitatory synapses in the brain and are located in Purkinje cell's dendrites along helical paths, perhaps maximizing the probability to contact different axons. To test whether spine helixes also occur in neocortex, we reconstructed >500 dendritic segments from adult human cortex obtained from autopsies. With Fourier analysis and spatial statistics, we analyzed spine position along apical and basal dendrites of layer 3 pyramidal neurons from frontal, temporal, and cingulate cortex. Although we occasionally detected helical positioning, for the great majority of dendrites we could not reject the null hypothesis of spatial randomness in spine locations, either in apical or basal dendrites, in neurons of different cortical areas or among spines of different volumes and lengths. We conclude that in adult human neocortex spine positions are mostly random. We discuss the relevance of these results for spine formation and plasticity and their functional impact for cortical circuits. PMID:25057209

  5. Random positions of dendritic spines in human cerebral cortex.

    PubMed

    Morales, Juan; Benavides-Piccione, Ruth; Dar, Mor; Fernaud, Isabel; Rodríguez, Angel; Anton-Sanchez, Laura; Bielza, Concha; Larrañaga, Pedro; DeFelipe, Javier; Yuste, Rafael

    2014-07-23

    Dendritic spines establish most excitatory synapses in the brain and are located in Purkinje cell's dendrites along helical paths, perhaps maximizing the probability to contact different axons. To test whether spine helixes also occur in neocortex, we reconstructed >500 dendritic segments from adult human cortex obtained from autopsies. With Fourier analysis and spatial statistics, we analyzed spine position along apical and basal dendrites of layer 3 pyramidal neurons from frontal, temporal, and cingulate cortex. Although we occasionally detected helical positioning, for the great majority of dendrites we could not reject the null hypothesis of spatial randomness in spine locations, either in apical or basal dendrites, in neurons of different cortical areas or among spines of different volumes and lengths. We conclude that in adult human neocortex spine positions are mostly random. We discuss the relevance of these results for spine formation and plasticity and their functional impact for cortical circuits. PMID:25057209

  6. Galectin-1 Regulates Tissue Exit of Specific Dendritic Cell Populations*

    PubMed Central

    Thiemann, Sandra; Man, Jeanette H.; Chang, Margaret H.; Lee, Benhur; Baum, Linda G.

    2015-01-01

    During inflammation, dendritic cells emigrate from inflamed tissue across the lymphatic endothelium into the lymphatic vasculature and travel to regional lymph nodes to initiate immune responses. However, the processes that regulate dendritic cell tissue egress and migration across the lymphatic endothelium are not well defined. The mammalian lectin galectin-1 is highly expressed by vascular endothelial cells in inflamed tissue and has been shown to regulate immune cell tissue entry into inflamed tissue. Here, we show that galectin-1 is also highly expressed by human lymphatic endothelial cells, and deposition of galectin-1 in extracellular matrix selectively regulates migration of specific human dendritic cell subsets. The presence of galectin-1 inhibits migration of immunogenic dendritic cells through the extracellular matrix and across lymphatic endothelial cells, but it has no effect on migration of tolerogenic dendritic cells. The major galectin-1 counter-receptor on both dendritic cell populations is the cell surface mucin CD43; differential core 2 O-glycosylation of CD43 between immunogenic dendritic cells and tolerogenic dendritic cells appears to contribute to the differential effect of galectin-1 on migration. Binding of galectin-1 to immunogenic dendritic cells reduces phosphorylation and activity of the protein-tyrosine kinase Pyk2, an effect that may also contribute to reduced migration of this subset. In a murine lymphedema model, galectin-1−/− animals had increased numbers of migratory dendritic cells in draining lymph nodes, specifically dendritic cells with an immunogenic phenotype. These findings define a novel role for galectin-1 in inhibiting tissue emigration of immunogenic, but not tolerogenic, dendritic cells, providing an additional mechanism by which galectin-1 can dampen immune responses. PMID:26216879

  7. Evidence for tip velocity oscillations in dendritic solidification

    NASA Astrophysics Data System (ADS)

    Lacombe, J. C.; Koss, M. B.; Frei, J. E.; Giummarra, C.; Lupulescu, A. O.; Glicksman, M. E.

    2002-03-01

    Dendritic growth experiments were conducted in the reduced-convection environment aboard the space shuttle Columbia on STS-87. Spectral analysis was performed on 30-frame/s video data during growths of isothermal dendrites. Results indicate that pivalic acid dendrites exhibit a subtle oscillatory behavior of the axial growth velocity near the tip, with a frequency component that is associated with the sidebranch formation process.

  8. Evidence for tip velocity oscillations in dendritic solidification.

    PubMed

    LaCombe, J C; Koss, M B; Frei, J E; Giummarra, C; Lupulescu, A O; Glicksman, M E

    2002-03-01

    Dendritic growth experiments were conducted in the reduced-convection environment aboard the space shuttle Columbia on STS-87. Spectral analysis was performed on 30-frame/s video data during growths of isothermal dendrites. Results indicate that pivalic acid dendrites exhibit a subtle oscillatory behavior of the axial growth velocity near the tip, with a frequency component that is associated with the sidebranch formation process. PMID:11909070

  9. Dendritic integration in pyramidal neurons during network activity and disease.

    PubMed

    Palmer, Lucy M

    2014-04-01

    Neurons have intricate dendritic morphologies which come in an array of shapes and sizes. Not only do they give neurons their unique appearance, but dendrites also endow neurons with the ability to receive and transform synaptic inputs. We now have a wealth of information about the functioning of dendrites which suggests that the integration of synaptic inputs is highly dependent on both dendritic properties and neuronal input patterns. It has been shown that dendrites can perform non-linear processing, actively transforming synaptic input into Na(+) spikes, Ca(2+) plateau spikes and NMDA spikes. These membrane non-linearities can have a large impact on the neuronal output and have been shown to be regulated by numerous factors including synaptic inhibition. Many neuropathological diseases involve changes in how dendrites receive and package synaptic input by altering dendritic spine characteristics, ion channel expression and the inhibitory control of dendrites. This review focuses on the role of dendrites in integrating and transforming input and what goes wrong in the case of neuropathological diseases.

  10. Mapping homeostatic synaptic plasticity using cable properties of dendrites.

    PubMed

    Queenan, B N; Lee, K J; Tan, H; Huganir, R L; Vicini, S; Pak, D T S

    2016-02-19

    When chronically silenced, cortical and hippocampal neurons homeostatically upregulate excitatory synaptic function. However, the subcellular position of such changes on the dendritic tree is not clear. We exploited the cable-filtering properties of dendrites to derive a parameter, the dendritic filtering index (DFI), to map the spatial distribution of synaptic currents. Our analysis indicates that young rat cortical neurons globally scale AMPA receptor-mediated currents, while mature hippocampal neurons do not, revealing distinct homeostatic strategies between brain regions and developmental stages. The DFI presents a useful tool for mapping the dendritic origin of synaptic currents and the location of synaptic plasticity changes.

  11. The Evolution of Dendrite Morphology during Isothermal Coarsening

    NASA Technical Reports Server (NTRS)

    Alkemper, Jens; Mendoza, Roberto; Kammer, Dimitris; Voorhees, Peter W.

    2003-01-01

    Dendrite coarsening is a common phenomenon in casting processes. From the time dendrites are formed until the inter-dendritic liquid is completely solidified dendrites are changing shape driven by variations in interfacial curvature along the dendrite and resulting in a reduction of total interfacial area. During this process the typical length-scale of the dendrite can change by orders of magnitude and the final microstructure is in large part determined by the coarsening parameters. Dendrite coarsening is thus crucial in setting the materials parameters of ingots and of great commercial interest. This coarsening process is being studied in the Pb-Sn system with Sn-dendrites undergoing isothermal coarsening in a Pb-Sn liquid. Results are presented for samples of approximately 60% dendritic phase, which have been coarsened for different lengths of times. Presented are three-dimensional microstructures obtained by serial-sectioning and an analysis of these microstructures with regard to interface orientation and interfacial curvatures. These graphs reflect the evolution of not only the microstructure itself, but also of the underlying driving forces of the coarsening process. As a visualization of the link between the microstructure and the driving forces a three-dimensional microstructure with the interfaces colored according to the local interfacial mean curvature is shown.

  12. Actin in dendritic spines: connecting dynamics to function

    PubMed Central

    2010-01-01

    Dendritic spines are small actin-rich protrusions from neuronal dendrites that form the postsynaptic part of most excitatory synapses and are major sites of information processing and storage in the brain. Changes in the shape and size of dendritic spines are correlated with the strength of excitatory synaptic connections and heavily depend on remodeling of its underlying actin cytoskeleton. Emerging evidence suggests that most signaling pathways linking synaptic activity to spine morphology influence local actin dynamics. Therefore, specific mechanisms of actin regulation are integral to the formation, maturation, and plasticity of dendritic spines and to learning and memory. PMID:20457765

  13. Bent dendrite growth in undercooled Fe-B alloy melts

    NASA Astrophysics Data System (ADS)

    Karrasch, C.; Volkmann, T.; Valloton, J.; Kolbe, M.; Herlach, DM

    2016-03-01

    Dendritic growth is the main solidification mode in alloy casting. In order to control dendrite growth for materials design from the melt it is important to fully understand the influence of process conditions. This study stands as an experimental note observing bent dendrite growth in Fe-B alloys and suggesting possible explanations as induced by fluid flow, thermal, and concentrational diffusion or impurities. Electromagnetic levitation technique (EML) is used for containerless processing of undercooled melts under 1g and reduced gravity conditions in parabolic flight. Further investigations are needed to find a suitable explanation for the observed bent dendrite growth behaviour.

  14. Ternary eutectic dendrites: Pattern formation and scaling properties

    SciTech Connect

    Rátkai, László; Szállás, Attila; Pusztai, Tamás; Mohri, Tetsuo; Gránásy, László

    2015-04-21

    Extending previous work [Pusztai et al., Phys. Rev. E 87, 032401 (2013)], we have studied the formation of eutectic dendrites in a model ternary system within the framework of the phase-field theory. We have mapped out the domain in which two-phase dendritic structures grow. With increasing pulling velocity, the following sequence of growth morphologies is observed: flat front lamellae → eutectic colonies → eutectic dendritesdendrites with target pattern → partitionless dendrites → partitionless flat front. We confirm that the two-phase and one-phase dendrites have similar forms and display a similar scaling of the dendrite tip radius with the interface free energy. It is also found that the possible eutectic patterns include the target pattern, and single- and multiarm spirals, of which the thermal fluctuations choose. The most probable number of spiral arms increases with increasing tip radius and with decreasing kinetic anisotropy. Our numerical simulations confirm that in agreement with the assumptions of a recent analysis of two-phase dendrites [Akamatsu et al., Phys. Rev. Lett. 112, 105502 (2014)], the Jackson-Hunt scaling of the eutectic wavelength with pulling velocity is obeyed in the parameter domain explored, and that the natural eutectic wavelength is proportional to the tip radius of the two-phase dendrites. Finally, we find that it is very difficult/virtually impossible to form spiraling two-phase dendrites without anisotropy, an observation that seems to contradict the expectations of Akamatsu et al. Yet, it cannot be excluded that in isotropic systems, two-phase dendrites are rare events difficult to observe in simulations.

  15. Dendritic Polyglycerol Sulfate Inhibits Microglial Activation and Reduces Hippocampal CA1 Dendritic Spine Morphology Deficits.

    PubMed

    Maysinger, Dusica; Gröger, Dominic; Lake, Andrew; Licha, Kai; Weinhart, Marie; Chang, Philip K-Y; Mulvey, Rose; Haag, Rainer; McKinney, R Anne

    2015-09-14

    Hyperactivity of microglia and loss of functional circuitry is a common feature of many neurological disorders including those induced or exacerbated by inflammation. Herein, we investigate the response of microglia and changes in hippocampal dendritic postsynaptic spines by dendritic polyglycerol sulfate (dPGS) treatment. Mouse microglia and organotypic hippocampal slices were exposed to dPGS and an inflammogen (lipopolysaccharides). Measurements of intracellular fluorescence and confocal microscopic analyses revealed that dPGS is avidly internalized by microglia but not CA1 pyramidal neurons. Concentration and time-dependent response studies consistently showed no obvious toxicity of dPGS. The adverse effects induced by proinflammogen LPS exposure were reduced and dendritic spine morphology was normalized with the addition of dPGS. This was accompanied by a significant reduction in nitrite and proinflammatory cytokines (TNF-α and IL-6) from hyperactive microglia suggesting normalized circuitry function with dPGS treatment. Collectively, these results suggest that dPGS acts anti-inflammatory, inhibits inflammation-induced degenerative changes in microglia phenotype and rescues dendritic spine morphology. PMID:26218295

  16. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota

    PubMed Central

    Cong, Y; Liu, Z

    2015-01-01

    The intestinal lumen harbors nearly 100 trillion commensal bacteria that exert crucial function for health. An elaborate balance between immune responses and tolerance to intestinal microbiota is required to maintain intestinal homeostasis. This process depends on diverse regulatory mechanisms, including both innate and adaptive immunity. Dysregulation of the homeostasis between intestinal immune systems and microbiota has been shown to be associated with the development of inflammatory bowel diseases (IBD) in genetically susceptible populations. In this review, we discuss the recent progress reported in studies of distinct types of regulatory immune cells in the gut, including intestinal intraepithelial lymphocytes, Foxp3+ regulatory T cells, regulatory B cells, alternatively activated macrophages, dendritic cells, and innate lymphoid cells, and how dysfunction of this immune regulatory system contributes to intestinal diseases such as IBD. Moreover, we discuss the manipulation of these regulatory immune cells as a potential therapeutic method for management of intestinal inflammatory disorders. PMID:26080708

  17. Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p.

    PubMed

    Ding, Guoping; Zhou, Liangjing; Qian, Yingming; Fu, Mingnian; Chen, Jian; Chen, Jionghuang; Xiang, Jianyang; Wu, Zhengrong; Jiang, Guixing; Cao, Liping

    2015-10-01

    It has been reported tumor-derived exosomes can transfer miRNAs to recipient cells in the tumor microenvironment, promoting tumor invasion and metastasis. The present research aimed to explore how pancreatic cancer (PC) derived exosomal miRNAs inhibited mRNA expression of dendritic cells and induced immune tolerance. Our study revealed that 9 PC-related miRNAs were increased and 208 mRNAs were inhibited in exosome-stimulated dendritic cells (exo-iDCs) compared to immature dendritic cells (iDCs). A target prediction between the 9 miRNAs and 208 mRNAs was performed by bioinformatics database analysis. From the target prediction, it was predicted and validated that regulatory factor X-associated protein (RFXAP), an important transcription factor for MHC II, was inhibited by miR-212-3p transferred from PC-secreted exosomes, resulting in decreased MHC II expression. Moreover, a clinical study showed a negative correlation between miR-212-3p and RFXAP in PC tissue. From these data, we concluded that PC-related miRNAs can be transferred to dendritic cells via exosome and inhibit target mRNA expression. More importantly, PC-derived exosomes inhibit RFXAP expression via miR-212-3p, which decrease MHC II expression and induce immune tolerance of dendritic cells. RFXAP deficiency has never been reported in solid tumors. The functions and mechanisms of RFXAP in tumors deserve future explorations.

  18. Organization of TNIK in dendritic spines

    PubMed Central

    Burette, Alain C.; Phend, Kristen D.; Burette, Susan; Lin, Qingcong; Liang, Musen; Foltz, Gretchen; Taylor, Noël; Wang, Qi; Brandon, Nicholas J.; Bates, Brian; Ehlers, Michael D.; Weinberg, Richard J.

    2015-01-01

    TRAF2- and NCK-interacting kinase (TNIK) has been identified as an interactor of the psychiatric risk factor, Disrupted in Schizophrenia 1 (DISC1). As a step toward deciphering its function in the brain, we performed high-resolution light and electron microscopic immunocytochemistry. We demonstrate here that TNIK is expressed in neurons throughout the adult mouse brain. In striatum and cerebral cortex, TNIK concentrates in dendritic spines, especially in the vicinity of the lateral edge of the synapse. Thus, TNIK is highly enriched at a microdomain critical for glutamatergic signaling and implicated in the regulation of synaptic strength. PMID:25753355

  19. Plasticity of Dendritic Spines: Subcompartmentalization of Signaling

    PubMed Central

    Colgan, Lesley A.; Yasuda, Ryohei

    2014-01-01

    The ability to induce and study neuronal plasticity in single dendritic spines has greatly advanced our understanding of the signaling mechanisms that mediate long-term potentiation. It is now clear that in addition to compartmentalization by the individual spine, subcompartmentalization of biochemical signals occurs at specialized microdomains within the spine. The spatiotemporal coordination of these complex cascades allows for the concomitant remodeling of the postsynaptic density actin spinoskeleton and for the regulation of membrane traffic to express functional and structural plasticity. Here, we highlight recent findings in the signaling cascades at spine microdomains as well as the challenges and approaches to studying plasticity at the spine level. PMID:24215443

  20. Contribution of sublinear and supralinear dendritic integration to neuronal computations.

    PubMed

    Tran-Van-Minh, Alexandra; Cazé, Romain D; Abrahamsson, Therése; Cathala, Laurence; Gutkin, Boris S; DiGregorio, David A

    2015-01-01

    Nonlinear dendritic integration is thought to increase the computational ability of neurons. Most studies focus on how supralinear summation of excitatory synaptic responses arising from clustered inputs within single dendrites result in the enhancement of neuronal firing, enabling simple computations such as feature detection. Recent reports have shown that sublinear summation is also a prominent dendritic operation, extending the range of subthreshold input-output (sI/O) transformations conferred by dendrites. Like supralinear operations, sublinear dendritic operations also increase the repertoire of neuronal computations, but feature extraction requires different synaptic connectivity strategies for each of these operations. In this article we will review the experimental and theoretical findings describing the biophysical determinants of the three primary classes of dendritic operations: linear, sublinear, and supralinear. We then review a Boolean algebra-based analysis of simplified neuron models, which provides insight into how dendritic operations influence neuronal computations. We highlight how neuronal computations are critically dependent on the interplay of dendritic properties (morphology and voltage-gated channel expression), spiking threshold and distribution of synaptic inputs carrying particular sensory features. Finally, we describe how global (scattered) and local (clustered) integration strategies permit the implementation of similar classes of computations, one example being the object feature binding problem. PMID:25852470

  1. BC1 RNA motifs required for dendritic transport in vivo

    PubMed Central

    Robeck, Thomas; Skryabin, Boris V.; Rozhdestvensky, Timofey S.; Skryabin, Anastasiya B.; Brosius, Jürgen

    2016-01-01

    BC1 RNA is a small brain specific non-protein coding RNA. It is transported from the cell body into dendrites where it is involved in the fine-tuning translational control. Due to its compactness and established secondary structure, BC1 RNA is an ideal model for investigating the motifs necessary for dendritic localization. Previously, microinjection of in vitro transcribed BC1 RNA mutants into the soma of cultured primary neurons suggested the importance of RNA motifs for dendritic targeting. These ex vivo experiments identified a single bulged nucleotide (U22) and a putative K-turn (GA motif) structure required for dendritic localization or distal transport, respectively. We generated six transgenic mouse lines (three founders each) containing neuronally expressing BC1 RNA variants on a BC1 RNA knockout mouse background. In contrast to ex vivo data, we did not find indications of reduction or abolition of dendritic BC1 RNA localization in the mutants devoid of the GA motif or the bulged nucleotide. We confirmed the ex vivo data, which showed that the triloop terminal sequence had no consequence on dendritic transport. Interestingly, changing the triloop supporting structure completely abolished dendritic localization of BC1 RNA. We propose a novel RNA motif important for dendritic transport in vivo. PMID:27350115

  2. Dendrites and Cognition: A Negative Pilot Study in the Rat.

    ERIC Educational Resources Information Center

    Anderson, Britt

    1995-01-01

    The dendritic structure of layer II-III pyramidal neurons of the parietal cortex in 41 Long-Evans rats was compared to behavioral assessments of attention to novelty, response flexibility, and reasoning. A significant correlation between dendritic arborization and behavioral performance was not demonstrated. (SLD)

  3. BC1 RNA motifs required for dendritic transport in vivo.

    PubMed

    Robeck, Thomas; Skryabin, Boris V; Rozhdestvensky, Timofey S; Skryabin, Anastasiya B; Brosius, Jürgen

    2016-01-01

    BC1 RNA is a small brain specific non-protein coding RNA. It is transported from the cell body into dendrites where it is involved in the fine-tuning translational control. Due to its compactness and established secondary structure, BC1 RNA is an ideal model for investigating the motifs necessary for dendritic localization. Previously, microinjection of in vitro transcribed BC1 RNA mutants into the soma of cultured primary neurons suggested the importance of RNA motifs for dendritic targeting. These ex vivo experiments identified a single bulged nucleotide (U22) and a putative K-turn (GA motif) structure required for dendritic localization or distal transport, respectively. We generated six transgenic mouse lines (three founders each) containing neuronally expressing BC1 RNA variants on a BC1 RNA knockout mouse background. In contrast to ex vivo data, we did not find indications of reduction or abolition of dendritic BC1 RNA localization in the mutants devoid of the GA motif or the bulged nucleotide. We confirmed the ex vivo data, which showed that the triloop terminal sequence had no consequence on dendritic transport. Interestingly, changing the triloop supporting structure completely abolished dendritic localization of BC1 RNA. We propose a novel RNA motif important for dendritic transport in vivo. PMID:27350115

  4. Contribution of sublinear and supralinear dendritic integration to neuronal computations

    PubMed Central

    Tran-Van-Minh, Alexandra; Cazé, Romain D.; Abrahamsson, Therése; Cathala, Laurence; Gutkin, Boris S.; DiGregorio, David A.

    2015-01-01

    Nonlinear dendritic integration is thought to increase the computational ability of neurons. Most studies focus on how supralinear summation of excitatory synaptic responses arising from clustered inputs within single dendrites result in the enhancement of neuronal firing, enabling simple computations such as feature detection. Recent reports have shown that sublinear summation is also a prominent dendritic operation, extending the range of subthreshold input-output (sI/O) transformations conferred by dendrites. Like supralinear operations, sublinear dendritic operations also increase the repertoire of neuronal computations, but feature extraction requires different synaptic connectivity strategies for each of these operations. In this article we will review the experimental and theoretical findings describing the biophysical determinants of the three primary classes of dendritic operations: linear, sublinear, and supralinear. We then review a Boolean algebra-based analysis of simplified neuron models, which provides insight into how dendritic operations influence neuronal computations. We highlight how neuronal computations are critically dependent on the interplay of dendritic properties (morphology and voltage-gated channel expression), spiking threshold and distribution of synaptic inputs carrying particular sensory features. Finally, we describe how global (scattered) and local (clustered) integration strategies permit the implementation of similar classes of computations, one example being the object feature binding problem. PMID:25852470

  5. Musical representation of dendritic spine distribution: a new exploratory tool.

    PubMed

    Toharia, Pablo; Morales, Juan; de Juan, Octavio; Fernaud, Isabel; Rodríguez, Angel; DeFelipe, Javier

    2014-04-01

    Dendritic spines are small protrusions along the dendrites of many types of neurons in the central nervous system and represent the major target of excitatory synapses. For this reason, numerous anatomical, physiological and computational studies have focused on these structures. In the cerebral cortex the most abundant and characteristic neuronal type are pyramidal cells (about 85 % of all neurons) and their dendritic spines are the main postsynaptic target of excitatory glutamatergic synapses. Thus, our understanding of the synaptic organization of the cerebral cortex largely depends on the knowledge regarding synaptic inputs to dendritic spines of pyramidal cells. Much of the structural data on dendritic spines produced by modern neuroscience involves the quantitative analysis of image stacks from light and electron microscopy, using standard statistical and mathematical tools and software developed to this end. Here, we present a new method with musical feedback for exploring dendritic spine morphology and distribution patterns in pyramidal neurons. We demonstrate that audio analysis of spiny dendrites with apparently similar morphology may "sound" quite different, revealing anatomical substrates that are not apparent from simple visual inspection. These morphological/music translations may serve as a guide for further mathematical analysis of the design of the pyramidal neurons and of spiny dendrites in general.

  6. Mechanisms underlying subunit independence in pyramidal neuron dendrites

    PubMed Central

    Behabadi, Bardia F.; Mel, Bartlett W.

    2014-01-01

    Pyramidal neuron (PN) dendrites compartmentalize voltage signals and can generate local spikes, which has led to the proposal that their dendrites act as independent computational subunits within a multilayered processing scheme. However, when a PN is strongly activated, back-propagating action potentials (bAPs) sweeping outward from the soma synchronize dendritic membrane potentials many times per second. How PN dendrites maintain the independence of their voltage-dependent computations, despite these repeated voltage resets, remains unknown. Using a detailed compartmental model of a layer 5 PN, and an improved method for quantifying subunit independence that incorporates a more accurate model of dendritic integration, we first established that the output of each dendrite can be almost perfectly predicted by the intensity and spatial configuration of its own synaptic inputs, and is nearly invariant to the rate of bAP-mediated “cross-talk” from other dendrites over a 100-fold range. Then, through an analysis of conductance, voltage, and current waveforms within the model cell, we identify three biophysical mechanisms that together help make independent dendritic computation possible in a firing neuron, suggesting that a major subtype of neocortical neuron has been optimized for layered, compartmentalized processing under in-vivo–like spiking conditions. PMID:24357611

  7. Musical representation of dendritic spine distribution: a new exploratory tool.

    PubMed

    Toharia, Pablo; Morales, Juan; de Juan, Octavio; Fernaud, Isabel; Rodríguez, Angel; DeFelipe, Javier

    2014-04-01

    Dendritic spines are small protrusions along the dendrites of many types of neurons in the central nervous system and represent the major target of excitatory synapses. For this reason, numerous anatomical, physiological and computational studies have focused on these structures. In the cerebral cortex the most abundant and characteristic neuronal type are pyramidal cells (about 85 % of all neurons) and their dendritic spines are the main postsynaptic target of excitatory glutamatergic synapses. Thus, our understanding of the synaptic organization of the cerebral cortex largely depends on the knowledge regarding synaptic inputs to dendritic spines of pyramidal cells. Much of the structural data on dendritic spines produced by modern neuroscience involves the quantitative analysis of image stacks from light and electron microscopy, using standard statistical and mathematical tools and software developed to this end. Here, we present a new method with musical feedback for exploring dendritic spine morphology and distribution patterns in pyramidal neurons. We demonstrate that audio analysis of spiny dendrites with apparently similar morphology may "sound" quite different, revealing anatomical substrates that are not apparent from simple visual inspection. These morphological/music translations may serve as a guide for further mathematical analysis of the design of the pyramidal neurons and of spiny dendrites in general. PMID:24395057

  8. Special fractal growth of dendrite copper using a hydrothermal method

    SciTech Connect

    Zheng Yan; Zhang Zhejuan; Guo Pingsheng; He Pingang; Sun Zhuo

    2011-08-15

    Special fractal dendrite Cu nanostructures have been synthesized through a simple hydrothermal method, and the effects of the volume ratio between glycerol and water and the concentration of H{sub 3}PO{sub 3} on the morphologies of dendrite Cu have been studied in detail. The Field emission scanning electron microscopy (FESEM), Transmission electron microscopy (TEM) and X-ray diffraction (XRD) have been used to characterize these Cu products. The results indicate that rhombic diamond and different morphologies of fractal dendrite were prepared because of the accumulation of Cu nuclei based on the diffusion-limited aggregation (DLA) and the nucleation-limited aggregation (NLA) model. Fortunately, symmetrical leaf-like dendrite Cu nanostructures different from Cu dendrites reported before have been obtained. Additionally, an explanation for the growth of fractal dendrite Cu has been discussed carefully. - Graphical abstract: Uniform dendritic Cu are grown through controlling V{sub glycerol/water} in range of 0.6-1.2 and the concentration of H{sub 3}PO{sub 3} in range of 0.06-0.3 M. The rhombic cluster Cu are obtained by decreasing the amount of glycerol. Highlights: > Volume ratio of glycerol/water and concentration of H{sub 3}PO{sub 3} were varied, respectively. > Morphologies of dendritic Cu have some changes. > Leaf-like and rhombic cluster Cu were obtained. > The concentration changes affect the aggregation of Cu crystallites. > The aggregation and crystallographic orientation cause leaf-like Cu nanostructures.

  9. Contribution of sublinear and supralinear dendritic integration to neuronal computations.

    PubMed

    Tran-Van-Minh, Alexandra; Cazé, Romain D; Abrahamsson, Therése; Cathala, Laurence; Gutkin, Boris S; DiGregorio, David A

    2015-01-01

    Nonlinear dendritic integration is thought to increase the computational ability of neurons. Most studies focus on how supralinear summation of excitatory synaptic responses arising from clustered inputs within single dendrites result in the enhancement of neuronal firing, enabling simple computations such as feature detection. Recent reports have shown that sublinear summation is also a prominent dendritic operation, extending the range of subthreshold input-output (sI/O) transformations conferred by dendrites. Like supralinear operations, sublinear dendritic operations also increase the repertoire of neuronal computations, but feature extraction requires different synaptic connectivity strategies for each of these operations. In this article we will review the experimental and theoretical findings describing the biophysical determinants of the three primary classes of dendritic operations: linear, sublinear, and supralinear. We then review a Boolean algebra-based analysis of simplified neuron models, which provides insight into how dendritic operations influence neuronal computations. We highlight how neuronal computations are critically dependent on the interplay of dendritic properties (morphology and voltage-gated channel expression), spiking threshold and distribution of synaptic inputs carrying particular sensory features. Finally, we describe how global (scattered) and local (clustered) integration strategies permit the implementation of similar classes of computations, one example being the object feature binding problem.

  10. Immune Monitoring Using mRNA-Transfected Dendritic Cells.

    PubMed

    Borch, Troels Holz; Svane, Inge Marie; Met, Özcan

    2016-01-01

    Dendritic cells are known to be the most potent antigen presenting cell in the immune system and are used as cellular adjuvants in therapeutic anticancer vaccines using various tumor-associated antigens or their derivatives. One way of loading antigen into the dendritic cells is by mRNA electroporation, ensuring presentation of antigen through major histocompatibility complex I and potentially activating T cells, enabling them to kill the tumor cells. Despite extensive research in the field, only one dendritic cell-based vaccine has been approved. There is therefore a great need to elucidate and understand the immunological impact of dendritic cell vaccination in order to improve clinical benefit. In this chapter, we describe a method for performing immune monitoring using peripheral blood mononuclear cells and autologous dendritic cells transfected with tumor-associated antigen-encoding mRNA. PMID:27236804

  11. Synthesis and field emission properties of Cu dendritic nanostructures

    NASA Astrophysics Data System (ADS)

    Xu, Jianwen; Yu, Ke; Zhu, Ziqiang

    2010-03-01

    Cu dendritic nanostructures were synthesized on ITO glass substructure by electrochemical deposition. SEM images showed that these Cu dendritic nanostuctures revealed a clear and well-defined dendritic fractal structure with a pronounced trunk and highly ordered branches distributed on both sides of the trunk. The diffusion-limited aggregation (DLA) model was used to explain the fractal growth of Cu dendritic nanostructures. Field emission properties of these Cu dendritic nanostructures were measured, which have possessed good performance with the turn-on field of 7.5 V/μm (defined as the electric field required to be detected at a current density of 0.1 mA/cm 2) and the field enhancement factor β of 1094.

  12. Regulation of Th2 Cell Immunity by Dendritic Cells.

    PubMed

    Na, Hyeongjin; Cho, Minkyoung; Chung, Yeonseok

    2016-02-01

    Th2 cell immunity is required for host defense against helminths, but it is detrimental in allergic diseases in humans. Unlike Th1 cell and Th17 cell subsets, the mechanism by which dendritic cells modulate Th2 cell responses has been obscure, in part because of the inability of dendritic cells to provide IL-4, which is indispensable for Th2 cell lineage commitment. In this regard, immune cells other than dendritic cells, such as basophils and innate lymphoid cells, have been suggested as Th2 cell inducers. More recently, multiple independent researchers have shown that specialized subsets of dendritic cells mediate Th2 cell responses. This review will discuss the current understanding related to the regulation of Th2 cell responses by dendritic cells and other immune cells. PMID:26937227

  13. Dendrite coherency during equiaxed solidification in binary aluminum alloys

    SciTech Connect

    Chai, G.; Baeckerud, L.; Roelland, T.; Arnberg, L.

    1995-04-01

    Dendrite coherency, or dendrite impingement, is important to the formation of the solidification structure and castability of alloys. Dendrite coherency in the systems Al-xMn, Al-xCu, Al-xFe, and Al-xSi (x = 0 to 5 wt pct) has been studied by continuous torque measurement in solidifying samples. The fraction solid at the dendrite coherency point, fs*, varies with the alloy system and the solute concentration in the alloy, from 18 to 56 pct for the present alloys investigated. An increase in solute concentration decreases the coherency fraction solid, fs*. An alloy system with a large slope of the liquidus line has a high coherency fraction solid. A theoretical approach has been developed to account for the effects of the alloy system and solute concentration on the dendrite coherency in the alloy. The grain sizes of the alloys were evaluated using the parameters at coherency point.

  14. Human dendritic cells as targets of dengue virus infection.

    PubMed

    Marovich, M; Grouard-Vogel, G; Louder, M; Eller, M; Sun, W; Wu, S J; Putvatana, R; Murphy, G; Tassaneetrithep, B; Burgess, T; Birx, D; Hayes, C; Schlesinger-Frankel, S; Mascola, J

    2001-12-01

    Dengue virus infections are an emerging global threat. Severe dengue infection is manifested as dengue hemorrhagic fever and dengue shock syndrome, both of which can be fatal complications. Factors predisposing to complicated disease and pathogenesis of severe infections are discussed. Using immunohistochemistry, immunofluorescence, flow cytometry, and ELISA techniques, we studied the cellular targets of dengue virus infection, at both the clinical (in vivo) and the laboratory (in vitro) level. Resident skin dendritic cells are targets of dengue virus infection as demonstrated in a skin biopsy from a dengue vaccine recipient. We show that factors influencing infection of monocytes/macrophages and dendritic cells are different. Immature dendritic cells were found to be the cells most permissive for dengue infection and maybe early targets for infection. Immature dendritic cells exposed to dengue virus produce TNF-alpha protein. Some of these immature dendritic cells undergo TNF-alpha mediated maturation as a consequence of exposure to the dengue virus. PMID:11924831

  15. Spatially Distributed Dendritic Resonance Selectively Filters Synaptic Input

    PubMed Central

    Segev, Idan; Shamma, Shihab

    2014-01-01

    An important task performed by a neuron is the selection of relevant inputs from among thousands of synapses impinging on the dendritic tree. Synaptic plasticity enables this by strenghtening a subset of synapses that are, presumably, functionally relevant to the neuron. A different selection mechanism exploits the resonance of the dendritic membranes to preferentially filter synaptic inputs based on their temporal rates. A widely held view is that a neuron has one resonant frequency and thus can pass through one rate. Here we demonstrate through mathematical analyses and numerical simulations that dendritic resonance is inevitably a spatially distributed property; and therefore the resonance frequency varies along the dendrites, and thus endows neurons with a powerful spatiotemporal selection mechanism that is sensitive both to the dendritic location and the temporal structure of the incoming synaptic inputs. PMID:25144440

  16. Astrocytes refine cortical connectivity at dendritic spines

    PubMed Central

    Risher, W Christopher; Patel, Sagar; Kim, Il Hwan; Uezu, Akiyoshi; Bhagat, Srishti; Wilton, Daniel K; Pilaz, Louis-Jan; Singh Alvarado, Jonnathan; Calhan, Osman Y; Silver, Debra L; Stevens, Beth; Calakos, Nicole; Soderling, Scott H; Eroglu, Cagla

    2014-01-01

    During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines. DOI: http://dx.doi.org/10.7554/eLife.04047.001 PMID:25517933

  17. Morphological change tracking of dendritic spines based on structural features.

    PubMed

    Son, J; Song, S; Lee, S; Chang, S; Kim, M

    2011-03-01

    Identification and tracking of dendritic spine morphology from two-dimensional time-lapsed images plays an important role in neurobiological research. Such analysis can enable us to derive a correlation between morphological characteristics and molecular mechanism of dendritic spine development and remodelling. Moreover, Neuronal morphology of hippocampal Cornu Ammonis 1 region is critical for understanding the Alzheimer's disease. Therefore, we need to extract and trace the dendritic spines accurately for examining their development and remodelling processes, which are related to functions of hippocampal Cornu Ammonis 1. There are some problems to be solved in related researches. Noise due to the properties of optical microscopes makes it difficult to identify and trace dendritic spines accurately. To solve these problems, in this paper we present a local spine detection technique minimizing noise influence in two-dimensional optical microscopy images. Also, we suggest an efficient mapping method for tracking the dynamics of dendritic spines to measure their morphological changes quantitatively. First, to utilize structural feature of spines, which are small protrusions of tree-like dendrites, we extract the tips of each dendritic branch and use this position as an initial contour position for a deformable model-based segmentation. We then use a geodesic active contour model to detect the spines accurately. Secondly, we apply an optical flow method, which takes into account both structure and movement of objects, to map every time-series image frame. Proposed method provides accurate measurements of dendritic spine length, volume, shape classification for time-lapse images of dendrites of hippocampal neurons. We compared the proposed spine detection algorithm with manual method performed by biologists and noncommercial software NeuronIQ. In particular, this method is able to segment dendritic spines better than existing methods with high sensitivity in adjacent

  18. Regulatory T cells and transplantation tolerance.

    PubMed

    Cobbold, S P

    2008-01-01

    Rodent models of transplantation have demonstrated that it is possible to induce specific immunological tolerance of donor antigens and indefinite graft survival in the absence of any continued immunosuppression. If this situation could be achieved clinically it would avoid many of the longer term complications of organ grafting, such as the increased risk of infection and cancer and the nephrotoxicity of many immunosuppressive agents. In this review we shall consider the interplay between regulatory T cells, dendritic cells and the graft itself and the resulting local protective mechanisms that are coordinated to maintain the tolerant state. We will discuss how both anti-inflammatory cytokines and negative costimulatory interactions can elicit a number of interrelated mechanisms to regulate both T cell and antigen-presenting cell activity. The induction and maintenance of tolerance via acquired local immune privilege has implications for the design of therapeutic regimens and the monitoring of the tolerant status of patients being weaned off immunosuppression. PMID:18651537

  19. Novel immunomodulatory effects of adiponectin on dendritic cell functions.

    PubMed

    Tsang, Julia Yuen Shan; Li, Daxu; Ho, Derek; Peng, Jiao; Xu, Aimin; Lamb, Jonathan; Chen, Yan; Tam, Paul Kwong Hang

    2011-05-01

    Adiponectin (ADN) is an adipocytokine with anti-inflammatory properties. Although it has been reported that ADN can inhibit the immunostimulatory function of monocytes and macrophages, little is known of its effect on dendritic cells (DC). Recent data suggest that ADN can regulate immune responses. DCs are uniquely specialised antigen presenting cells that play a central role in the initiation of immunity and tolerance. In this study, we have investigated the immuno- modulatory effects of ADN on DC functions. We found that ADN has only moderate effect on the differentiation of murine bone marrow (BM) derived DCs but altered the phenotype of DCs. The expression of major histocompatibilty complex class II (MHCII), CD80 and CD86 on ADN conditioned DCs (ADN-DCs) was lower than that on untreated cells. The production of IL-12p40 was also suppressed in ADN-DCs. Interestingly, ADN treated DCs showed an increase in the expression of the inhibitory molecule, programmed death-1 ligand (PDL-1) compared to untreated cells. In vitro co-culture of ADN-DCs with allogeneic T cells led to a decrease in T cell proliferation and reduction of IL-2 production. Concomitant with that, a higher percentage of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) was detected in co-cultures of T cells and ADN-DCs. Blocking PD-1/PDL-1 pathway could partially restore T cell function. These findings suggest that the immunomodulatory effect of ADN on immune responses could be at least partially be mediated by its ability to alter DC function. The PD-1/PDL-1 pathway and the enhancement of Treg expansion are implicated in the immunomodulatory mechanisms.

  20. The Role of Dendritic Cells in S. pneumoniae Transport to Follicular Dendritic Cells.

    PubMed

    Heesters, Balthasar A; Carroll, Michael C

    2016-09-20

    Affinity-mature B cells require cognate antigen, retained by follicular dendritic cells (FDCs), for clonal selection within germinal centers. Studies on how FDCs in lymphoid tissues acquire antigen have relied primarily on model protein antigens. To examine delivery of intact bacteria to FDCs, we used inactivated Streptococcus pneumonia (SP). We found that both medullary macrophages and a subset of SIGN-R1-positive dendritic cells (DCs) in the lymph node capture SP from the draining afferent lymphatics. The presence of DCs is required for initial complement activation, opsonization of the bacteria, and efficient transport of SP to FDCs. Moreover, we observed a major role for transport of bacteria to FDCs by naive B cells via a CD21-dependent pathway. We propose a mechanism by which efficient transport of SP to FDCs is dependent on DCs for initial binding and activation of complement and either direct transport to FDCs or transfer to naive B cells. PMID:27653679

  1. Interferon gamma induces retrograde dendritic retraction and inhibits synapse formation.

    PubMed

    Kim, In-Jung; Beck, Hiroko Nagasawa; Lein, Pamela J; Higgins, Dennis

    2002-06-01

    The expression of interferon gamma (IFNgamma) increases after neural injury, and it is sustained in chronic inflammatory conditions such as multiple sclerosis and infection with human immunodeficiency virus. To understand how exposure to this proinflammatory cytokine might affect neural function, we examined its effects on cultures of neurons derived from the central and peripheral nervous systems. IFNgamma inhibits initial dendritic outgrowth in cultures of embryonic rat sympathetic and hippocampal neurons, and this inhibitory effect on process growth is associated with a decrease in the rate of synapse formation. In addition, in older cultures of sympathetic neurons, IFNgamma also selectively induces retraction of existing dendrites, ultimately leading to an 88% decrease in the size of the arbor. Dendritic retraction induced by IFNgamma represents a specific cellular response because it occurs without affecting axonal outgrowth or cell survival, and it is not observed with tumor necrosis factor alpha or other inflammatory cytokines. IFNgamma-induced dendritic retraction is associated with the phosphorylation and nuclear translocation of signal transducer and activator of transcription 1 (STAT1), and expression of a dominant-negative STAT1 construct attenuates the inhibitory effect of IFNgamma. Moreover, retrograde dendritic retraction is observed when distal axons are selectively exposed to IFNgamma. These data imply that IFNgamma-mediated STAT1 activation induces both dendritic atrophy and synaptic loss and that this occurs both at the sites of IFNgamma release and at remote loci. Regressive actions of IFNgamma on dendrites may contribute to the neuropathology of inflammatory diseases.

  2. Axin Regulates Dendritic Spine Morphogenesis through Cdc42-Dependent Signaling

    PubMed Central

    Chen, Yu; Liang, Zhuoyi; Fei, Erkang; Chen, Yuewen; Zhou, Xiaopu; Fang, Weiqun; Fu, Wing-Yu; Fu, Amy K. Y.; Ip, Nancy Y.

    2015-01-01

    During development, scaffold proteins serve as important platforms for orchestrating signaling complexes to transduce extracellular stimuli into intracellular responses that regulate dendritic spine morphology and function. Axin (“axis inhibitor”) is a key scaffold protein in canonical Wnt signaling that interacts with specific synaptic proteins. However, the cellular functions of these protein–protein interactions in dendritic spine morphology and synaptic regulation are unclear. Here, we report that Axin protein is enriched in synaptic fractions, colocalizes with the postsynaptic marker PSD-95 in cultured hippocampal neurons, and interacts with a signaling protein Ca2+/calmodulin-dependent protein kinase II (CaMKII) in synaptosomal fractions. Axin depletion by shRNA in cultured neurons or intact hippocampal CA1 regions significantly reduced dendritic spine density. Intriguingly, the defective dendritic spine morphogenesis in Axin-knockdown neurons could be restored by overexpression of the small Rho-GTPase Cdc42, whose activity is regulated by CaMKII. Moreover, pharmacological stabilization of Axin resulted in increased dendritic spine number and spontaneous neurotransmission, while Axin stabilization in hippocampal neurons reduced the elimination of dendritic spines. Taken together, our findings suggest that Axin promotes dendritic spine stabilization through Cdc42-dependent cytoskeletal reorganization. PMID:26204446

  3. A multiphase solute diffusion model for dendritic alloy solidification

    SciTech Connect

    Wang, C.Y.; Beckermann, C.

    1993-12-01

    A solute diffusion model, aimed at predicting microstructure formation in metal castings, is proposed for dendritic solidification of alloys. The model accounts for the different length scales existing in a dendritic structure. This is accomplished by utilizing a multiphase approach, in which not only the various physical phases but also phases associated with different length scales are considered separately. The macroscopic conservation equations are derived for each phase using the volume averaging technique, with constitutive relations developed for the interfacial transfer terms. It is shown that the multiphase model can rigorously incorporate the growth of dendrite tips and coarsening of dendrite arms. In addition, the distinction of different length scales enables the inclusion of realistic descriptions of the dendrite topology and relations to key metallurgical parameters. Another novel aspect of the model is that a single set of conservation equations for solute diffusion is developed for both equiaxed and columnar dendritic solidification. Finally, illustrative calculations for equiaxed, columnar, and mixed columnar-equiaxed solidification are carried out to provide quantitative comparisons with previous studies, and a variety of fundamental phenomena such as recalescence, dendrite tip undercooling, and columnar-to-equiaxed transition (CET) are predicted.

  4. Dendritic mitochondria reach stable positions during circuit development

    PubMed Central

    Faits, Michelle C; Zhang, Chunmeng; Soto, Florentina; Kerschensteiner, Daniel

    2016-01-01

    Mitochondria move throughout neuronal dendrites and localize to sites of energy demand. The prevailing view of dendritic mitochondria as highly motile organelles whose distribution is continually adjusted by neuronal activity via Ca2+-dependent arrests is based on observations in cultured neurons exposed to artificial stimuli. Here, we analyze the movements of mitochondria in ganglion cell dendrites in the intact retina. We find that whereas during development 30% of mitochondria are motile at any time, as dendrites mature, mitochondria all but stop moving and localize stably to synapses and branch points. Neither spontaneous nor sensory-evoked activity and Ca2+ transients alter motility of dendritic mitochondria; and pathological hyperactivity in a mouse model of retinal degeneration elevates rather than reduces motility. Thus, our findings indicate that dendritic mitochondria reach stable positions during a critical developmental period of high motility, and challenge current views about the role of activity in regulating mitochondrial transport in dendrites. DOI: http://dx.doi.org/10.7554/eLife.11583.001 PMID:26742087

  5. Accelerators, Brakes, and Gears of Actin Dynamics in Dendritic Spines

    PubMed Central

    Pontrello, Crystal G.; Ethell, Iryna M.

    2010-01-01

    Dendritic spines are actin-rich structures that accommodate the postsynaptic sites of most excitatory synapses in the brain. Although dendritic spines form and mature as synaptic connections develop, they remain plastic even in the adult brain, where they can rapidly grow, change, or collapse in response to normal physiological changes in synaptic activity that underlie learning and memory. Pathological stimuli can adversely affect dendritic spine shape and number, and this is seen in neurodegenerative disorders and some forms of mental retardation and autism as well. Many of the molecular signals that control these changes in dendritic spines act through the regulation of filamentous actin (F-actin), some through direct interaction with actin, and others via downstream effectors. For example, cortactin, cofilin, and gelsolin are actin-binding proteins that directly regulate actin dynamics in dendritic spines. Activities of these proteins are precisely regulated by intracellular signaling events that control their phosphorylation state and localization. In this review, we discuss how actin-regulating proteins maintain the balance between F-actin assembly and disassembly that is needed to stabilize mature dendritic spines, and how changes in their activities may lead to rapid remodeling of dendritic spines. PMID:20463852

  6. Input transformation by dendritic spines of pyramidal neurons

    PubMed Central

    Araya, Roberto

    2014-01-01

    In the mammalian brain, most inputs received by a neuron are formed on the dendritic tree. In the neocortex, the dendrites of pyramidal neurons are covered by thousands of tiny protrusions known as dendritic spines, which are the major recipient sites for excitatory synaptic information in the brain. Their peculiar morphology, with a small head connected to the dendritic shaft by a slender neck, has inspired decades of theoretical and more recently experimental work in an attempt to understand how excitatory synaptic inputs are processed, stored and integrated in pyramidal neurons. Advances in electrophysiological, optical and genetic tools are now enabling us to unravel the biophysical and molecular mechanisms controlling spine function in health and disease. Here I highlight relevant findings, challenges and hypotheses on spine function, with an emphasis on the electrical properties of spines and on how these affect the storage and integration of excitatory synaptic inputs in pyramidal neurons. In an attempt to make sense of the published data, I propose that the raison d'etre for dendritic spines lies in their ability to undergo activity-dependent structural and molecular changes that can modify synaptic strength, and hence alter the gain of the linearly integrated sub-threshold depolarizations in pyramidal neuron dendrites before the generation of a dendritic spike. PMID:25520626

  7. Input transformation by dendritic spines of pyramidal neurons.

    PubMed

    Araya, Roberto

    2014-01-01

    In the mammalian brain, most inputs received by a neuron are formed on the dendritic tree. In the neocortex, the dendrites of pyramidal neurons are covered by thousands of tiny protrusions known as dendritic spines, which are the major recipient sites for excitatory synaptic information in the brain. Their peculiar morphology, with a small head connected to the dendritic shaft by a slender neck, has inspired decades of theoretical and more recently experimental work in an attempt to understand how excitatory synaptic inputs are processed, stored and integrated in pyramidal neurons. Advances in electrophysiological, optical and genetic tools are now enabling us to unravel the biophysical and molecular mechanisms controlling spine function in health and disease. Here I highlight relevant findings, challenges and hypotheses on spine function, with an emphasis on the electrical properties of spines and on how these affect the storage and integration of excitatory synaptic inputs in pyramidal neurons. In an attempt to make sense of the published data, I propose that the raison d'etre for dendritic spines lies in their ability to undergo activity-dependent structural and molecular changes that can modify synaptic strength, and hence alter the gain of the linearly integrated sub-threshold depolarizations in pyramidal neuron dendrites before the generation of a dendritic spike.

  8. Collapsin response mediator protein 5 (CRMP5) induces mitophagy, thereby regulating mitochondrion numbers in dendrites.

    PubMed

    Brot, Sébastien; Auger, Carole; Bentata, Rabia; Rogemond, Véronique; Ménigoz, Stéphane; Chounlamountri, Naura; Girard-Egrot, Agnès; Honnorat, Jérôme; Moradi-Améli, Mahnaz

    2014-01-24

    Degradation of damaged mitochondria by mitophagy is an essential process to ensure cell homeostasis. Because neurons, which have a high energy demand, are particularly dependent on the mitochondrial dynamics, mitophagy represents a key mechanism to ensure correct neuronal function. Collapsin response mediator proteins 5 (CRMP5) belongs to a family of cytosolic proteins involved in axon guidance and neurite outgrowth signaling during neural development. CRMP5, which is highly expressed during brain development, plays an important role in the regulation of neuronal polarity by inhibiting dendrite outgrowth at early developmental stages. Here, we demonstrated that CRMP5 was present in vivo in brain mitochondria and is targeted to the inner mitochondrial membrane. The mitochondrial localization of CRMP5 induced mitophagy. CRMP5 overexpression triggered a drastic change in mitochondrial morphology, increased the number of lysosomes and double membrane vesicles termed autophagosomes, and enhanced the occurrence of microtubule-associated protein 1 light chain 3 (LC3) at the mitochondrial level. Moreover, the lipidated form of LC3, LC3-II, which triggers autophagy by insertion into autophagosomes, enhanced mitophagy initiation. Lysosomal marker translocates at the mitochondrial level, suggesting autophagosome-lysosome fusion, and induced the reduction of mitochondrial content via lysosomal degradation. We show that during early developmental stages the strong expression of endogenous CRMP5, which inhibits dendrite growth, correlated with a decrease of mitochondrial content. In contrast, the knockdown or a decrease of CRMP5 expression at later stages enhanced mitochondrion numbers in cultured neurons, suggesting that CRMP5 modulated these numbers. Our study elucidates a novel regulatory mechanism that utilizes CRMP5-induced mitophagy to orchestrate proper dendrite outgrowth and neuronal function.

  9. PHENOTYPE AND POLARIZATION OF AUTOLOGOUS T CELLS BY BIOMATERIAL-TREATED DENDRITIC CELLS

    PubMed Central

    Park, Jaehyung; Gerber, Michael H.; Babensee, Julia E.

    2014-01-01

    Given the central role of dendritic cells (DCs) in directing T cell phenotypes, the ability of biomaterial-treated DCs to dictate autologous T cell phenotype was investigated. Here, we demonstrate that differentially biomaterial-treated DCs differentially directed autologous T cell phenotype and polarization, depending on the biomaterial used to pre-treat the DCs. Immature DCs (iDCs) were derived from human peripheral blood monocytes, and treated with biomaterial films of alginate, agarose, chitosan, hyaluronic acid, or 75:25 poly(lactic-co-glycolic acid) (PLGA), followed by co-culture of these biomaterial-treated DCs and autologous T cells. When autologous T cells were co-cultured with DCs treated with biomaterial film/antigen (ovalbumin, OVA) combinations, different biomaterial films induced differential levels of T cell marker (CD4, CD8, CD25, CD69) expression, as well as differential cytokine profiles [interferon (IFN)-γ, interleukin (IL)-12p70, IL-10, IL-4] in the polarization of T helper types. Dendritic cells treated with agarose films/OVA induced CD4+CD25+FoxP3+ (T regulatory cells) expression, comparable to untreated iDCs, on autologous T cells in the DC-T co-culture system. Furthermore, in this co-culture, agarose treatment induced release of IL-12p70 and IL-10 at higher levels, as compared to DC treatment with other biomaterial films/OVA, suggesting Th1 and Th2 polarization, respectively. Dendritic cells treated with PLGA film/OVA treatment induced release of IFN-γ at higher levels compared to that observed for co-cultures with iDCs or DCs treated with all other biomaterial films. These results indicate that DC treatment with different biomaterial films has potential as a tool for immunomodulation by directing autologous T cell responses. PMID:24616366

  10. Fractal structures of dendrites in GaSe crystals

    NASA Astrophysics Data System (ADS)

    Kolesnikov, N. N.; Borisenko, E. B.; Borisenko, D. N.; Bozhko, S. I.

    2008-07-01

    Solidification of melts at substantial supercooling is associated with instability on the growth front. This causes growth of dendrites, which form as a branched tree in a crystal. In the layered melt-grown GaSe crystals dendrites are observed, if growth rates are rather high [N.N. Kolesnikov, E.B. Borisenko, D.N. Borisenko, V.K. Gartman, Influence of growth conditions on microstructure and properties of GaSe crystals, J. Crystal Growth 300 (2) (2007) 294-298]. Models based on solution of the thermal diffusion problem are traditionally used to describe dendrite growth. Solution of this problem requires information about several physical parameters, such as diffusion coefficient, heat conductivity coefficient and supercooling at the solid/liquid interface. The study of scale invariance of dendrites formed in a crystal provides a new approach to solution of the dynamic growth problem. The calculated fractal dimensionality of the experimentally observed dendrites in GaSe crystals is D=1.7. It coincides with dimensionality of the clusters obtained through computer simulation in terms of the model of diffusion-limited aggregation (DLA). This result provides a new approach to description of the dynamics of dendrite growth. We have shown that the dendrite growth mechanism in the layered semiconductor crystals can be described by a two-dimensional DLA model. It is shown that probabilistic simulation can be used to show the development of a dendrite in any material. In contrast to the classical theories of dendrite growth, this approach does not require information on physical parameters.

  11. Melanin-producing dendritic cells and histogenesis of malignant melanoma.

    PubMed

    Paul, E; Illig, L

    1976-12-15

    In a total of 70 malignant melanomas we searched for dendritic-branched fluorescent pigment cells. Hereby we found that dendritic-branched tumor cells are especially characteristic in cases of lentigo maligna. In the flat parts of these lesions, these cells are the predominant cell type. Dendrites in the pseudonests or nodular parts of lentigo maligna can only seldom be detected. The prevailing cell type in superficial spreading melanoma and in primary nodular melanoma is the round or oval unbranched tumor cell. In some cases of nodular melanoma, cells with short dendrites could be seen. In superficial spreading melanoma, dendritic tumor cells could be observed particularly in such tumor parts, in which the malignant cells were scattered between the keratinocytes. Melanocytes can evidently produce dendrites between cells of the sebaceous gland. In the marginal parts or in parts of regression of some superficial spreading melanomas, a great area of dendritic tumor cells could also be detected in the basal parts of the epidermis. Altogether, however, in superficial spreading melanoma and in nodular melanoma they occur only rarely. Dendritic-branched cells are also visible in lymph-node metastases of SSM and NM. The fact that the dendritic tumor cells can be observed in all 3 types of tumors (according to Clark and coworkers) gives a rise to a new discussion of the dualistic theory of melanoma-histogenesis of Mishima. Although this theory could not be disproved, up to now on the basis of the present results, an unitarian development of all types of mnelanoma from melanocytes seems to be possible.

  12. Quantifying the Number of Discriminable Coincident Dendritic Input Patterns through Dendritic Tree Morphology

    PubMed Central

    Zippo, Antonio G.; Biella, Gabriele E. M.

    2015-01-01

    Current developments in neuronal physiology are unveiling novel roles for dendrites. Experiments have shown mechanisms of non-linear synaptic NMDA dependent activations, able to discriminate input patterns through the waveforms of the excitatory postsynaptic potentials. Contextually, the synaptic clustering of inputs is the principal cellular strategy to separate groups of common correlated inputs. Dendritic branches appear to work as independent discriminating units of inputs potentially reflecting an extraordinary repertoire of pattern memories. However, it is unclear how these observations could impact our comprehension of the structural correlates of memory at the cellular level. This work investigates the discrimination capabilities of neurons through computational biophysical models to extract a predicting law for the dendritic input discrimination capability (M). By this rule we compared neurons from a neuron reconstruction repository (neuromorpho.org). Comparisons showed that primate neurons were not supported by an equivalent M preeminence and that M is not uniformly distributed among neuron types. Remarkably, neocortical neurons had substantially less memory capacity in comparison to those from non-cortical regions. In conclusion, the proposed rule predicts the inherent neuronal spatial memory gathering potentially relevant anatomical and evolutionary considerations about the brain cytoarchitecture. PMID:26100354

  13. Fundamentals of dendritic solidification. I - Steady-state tip growth. II - Development of sidebranch structure

    NASA Technical Reports Server (NTRS)

    Huang, S.-C.; Glicksman, M. E.

    1981-01-01

    Systematic measurements of dendrite tip radius and growth velocity in succinonitrile reveal that consideration of dendrite tip stability should be incorporated into the heat transfer theory to determine the steady-state dendritic growth condition. The dendritic stability criterion measured is 2 alpha d0/VR squared = 0.0195, where V is the dendritic growth velocity, R is the dendritic tip radius, alpha is the liquid thermal diffusivity, and d0 is a capillary length defined in the text. Several dendritic stability models are reviewed and discussed in comparison to the present experimental results.

  14. Role of Dendritic Cells in Immune Dysfunction

    NASA Technical Reports Server (NTRS)

    Savary, Cherylyn A.

    1998-01-01

    The specific aims of the project were: (1) Application of the NASA bioreactor to enhance cytokine-regulated proliferation and maturation of dendritic cells (DC). (2) Compare the frequency and function of DC in normal donors and immunocompromised cancer patients. (3) Analyze the effectiveness of cytokine therapy and DC-assisted immunotherapy (using bioreactor-expanded DC) in a murine model of experimental fungal disease. Our investigations have provided new insight into DC immunobiology and have led to the development of methodology to evaluate DC in blood of normal donors and patients. Information gained from these studies has broadened our understanding of possible mechanisms involved in the immune dysfunction of space travelers and earth-bound cancer patients, and could contribute to the design of novel therapies to restore/preserve immunity in these individuals. Several new avenues of investigation were also revealed. The results of studies completed during Round 2 are summarized.

  15. Unsteady growth of ammonium chloride dendrites

    NASA Astrophysics Data System (ADS)

    Martyushev, L. M.; Terentiev, P. S.; Soboleva, A. S.

    2016-02-01

    Growth of ammonium chloride dendrites from aqueous solution is experimentally investigated. The growth rate υ and the radius ρ of curvature of branches are measured as a function of the relative supersaturation Δ for steady and unsteady growth conditions. It is shown that the experimental results are quantitatively described by the dependences ρ=a/Δ+b, υ=сΔ2, where the factors for primary branches are a=(1.3±0.2)·10-7 m, b=(2.5±0.4)·10-7 m, and c=(2.2±0.3)·10-4 m/s. The factor c is found to be approximately 7 times smaller for the side branches than that for the primary branches.

  16. Platinum dendritic nanoparticles with magnetic behavior

    SciTech Connect

    Li, Wenxian; Sun, Ziqi; Nevirkovets, Ivan P.; Dou, Shi-Xue; Tian, Dongliang

    2014-07-21

    Magnetic nanoparticles have attracted increasing attention for biomedical applications in magnetic resonance imaging, high frequency magnetic field hyperthermia therapies, and magnetic-field-gradient-targeted drug delivery. In this study, three-dimensional (3D) platinum nanostructures with large surface area that features magnetic behavior have been demonstrated. The well-developed 3D nanodendrites consist of plentiful interconnected nano-arms ∼4 nm in size. The magnetic behavior of the 3D dendritic Pt nanoparticles is contributed by the localization of surface electrons due to strongly bonded oxygen/Pluronic F127 and the local magnetic moment induced by oxygen vacancies on the neighboring Pt and O atoms. The magnetization of the nanoparticles exhibits a mixed paramagnetic and ferromagnetic state, originating from the core and surface, respectively. The 3D nanodendrite structure is suitable for surface modification and high amounts of drug loading if the transition temperature was enhanced to room temperature properly.

  17. Free dendritic growth in viscous melts - Cyclohexanol

    NASA Technical Reports Server (NTRS)

    Singh, N. B.; Glicksman, M. E.

    1989-01-01

    Experiments were carried out to measure the growth speed, V, and dendritic tip radius, R, of highly purified cyclohexanol. The data show that VR-squared = constant over the entire experimentally observed supercooling range, Delta T is between 0.1 and 1 K. The stability parameter estimated from this result indicates that sigma(asterisk) = 0.027, a value in good agreement with the values of sigma(asterisk) found for the cubic plastic crystals succinonitrile pivalic acid. Cyclohexanol differs from other carefully measured plastic crystals in that the viscosity of its melt at the melting point is about 20 times higher, so gravity-induced convection remains weak even at small supercoolings.

  18. Macrophages, dendritic cells, and regression of atherosclerosis.

    PubMed

    Feig, Jonathan E; Feig, Jessica L

    2012-01-01

    Atherosclerosis is the number one cause of death in the Western world. It results from the interaction between modified lipoproteins and cells such as macrophages, dendritic cells (DCs), T cells, and other cellular elements present in the arterial wall. This inflammatory process can ultimately lead to the development of complex lesions, or plaques, that protrude into the arterial lumen. Ultimately, plaque rupture and thrombosis can occur leading to the clinical complications of myocardial infarction or stroke. Although each of the cell types plays roles in the pathogenesis of atherosclerosis, the focus of this review will be primarily on the macrophages and DCs. The role of these two cell types in atherosclerosis is discussed, with a particular emphasis on their involvement in atherosclerosis regression.

  19. Dendritic cell-based immunotherapy in mesothelioma.

    PubMed

    Cornelissen, Robin; Lievense, Lysanne A; Heuvers, Marlies E; Maat, Alexander P; Hendriks, Rudi W; Hoogsteden, Henk C; Hegmans, Joost P; Aerts, Joachim G

    2012-10-01

    Mesothelioma is a rare thoracic malignancy with a dismal prognosis. Current treatment options are scarce and clinical outcomes are rather disappointing. Due to the immunogenic nature of mesothelioma, several studies have investigated immunotherapeutic strategies to improve the prognosis of patients with mesothelioma. In the last decade, progress in knowledge of the modulation of the immune system to attack the tumor has been remarkable, but the optimal strategy for immunotherapy has yet to be unraveled. Because of their potent antigen-presenting capacity, dendritic cells are acknowledged as a promising agent in immunotherapeutic approaches in a number of malignancies. This review gives an update and provides a future perspective in which immunotherapy may improve the outcome of mesothelioma therapy.

  20. Unsteady growth of ammonium chloride dendrites

    NASA Astrophysics Data System (ADS)

    Martyushev, L. M.; Terentiev, P. S.; Soboleva, A. S.

    2016-02-01

    Growth of ammonium chloride dendrites from aqueous solution is experimentally investigated. The growth rate υ and the radius ρ of curvature of branches are measured as a function of the relative supersaturation Δ for steady and unsteady growth conditions. It is shown that the experimental results are quantitatively described by the dependences ρ=a/Δ+b, υ=cΔ2, where the factors for primary branches are a=(1.3±0.2)·10-7 m, b=(2.5±0.4)·10-7 m, and c=(2.2±0.3)·10-4 m/s. The factor c is found to be approximately 7 times smaller for the side branches than that for the primary branches.

  1. Harnessing Human Dendritic Cell Subsets for Medicine

    PubMed Central

    Ueno, Hideki; Schmitt, Nathalie; Klechevsky, Eynav; Pedroza-Gonzales, Alexander; Matsui, Toshimichi; Zurawski, Gerard; Oh, SangKon; Fay, Joseph; Pascual, Virginia; Banchereau, Jacques; Palucka, Karolina

    2010-01-01

    Summary Immunity results from a complex interplay between the antigen-nonspecific innate immune system and the antigen-specific adaptive immune system. The cells and molecules of the innate system employ non-clonal recognition receptors including lectins, Toll-like receptors, NOD-like receptors and helicases. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing antigens or their derived peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). DCs can induce such contrasting states as immunity and tolerance. The recent years have brought a wealth of information on the biology of DCs revealing the complexity of this cell system. Indeed, DC plasticity and subsets are prominent determinants of the type and quality of elicited immune responses. Here we summarize our recent studies aimed at a better understanding of the DC system to unravel the pathophysiology of human diseases and design novel human vaccines. PMID:20193020

  2. Dendritic cell control of tolerogenic responses

    PubMed Central

    Manicassamy, Santhakumar; Pulendran, Bali

    2011-01-01

    Summary One of the most fundamental problems in immunology is the seemingly schizophrenic ability of the immune system to launch robust immunity against pathogens, while acquiring and maintaining a state of tolerance to the body’s own tissues and the trillions of commensal microorganisms and food antigens that confront it every day. A fundamental role for the innate immune system, particularly dendritic cells (DCs), in orchestrating immunological tolerance has been appreciated, but emerging studies have highlighted the nature of the innate receptors and the signaling pathways that program DCs to a tolerogenic state. Furthermore, several studies have emphasized the major role played by cellular interactions, and the microenvironment in programming tolerogenic DCs. Here we review these studies and suggest that the innate control of tolerogenic responses can be viewed as different hierarchies of organization, in which DCs, their innate receptors and signaling networks, and their interactions with other cells and local microenvironments represent different levels of the hierarchy. PMID:21488899

  3. Regulation of dendritic branching by Cdc42 GAPs

    PubMed Central

    Simó, Sergi; Cooper, Jonathan A.

    2012-01-01

    Nerve cells form elaborate, highly branched dendritic trees that are optimized for the receipt of synaptic signals. Recent work published in this issue of Genes & Development by Rosario and colleagues (pp. 1743–1757) shows that a Cdc42-specific GTPase-activating protein (NOMA-GAP) regulates the branching of dendrites by neurons in the top layers of the mouse cortex. The results raise interesting questions regarding the specification of arbors in different cortical layers and the mechanisms of dendrite branching. PMID:22855828

  4. Communications: Mechanical Deformation of Dendrites by Fluid Flow

    NASA Technical Reports Server (NTRS)

    Pilling, J.; Hellawell, A.

    1996-01-01

    It is generally accepted that liquid agitation during alloy solidification assists in crystal multiplication, as in dendrite fragmentation and the detachment of side arms in the mushy region of a casting. Even without deliberate stirring by electromagnetic or mechanical means, there is often vigorous interdendritic fluid flow promoted by natural thermosolutal convection. In this analysis, we shall estimate the stress at the root of a secondary dendrite arm of aluminum arising from the action of a flow of molten metal past the dendrite arm.

  5. In vivo imaging of dendritic pruning in dentate granule cells.

    PubMed

    Gonçalves, J Tiago; Bloyd, Cooper W; Shtrahman, Matthew; Johnston, Stephen T; Schafer, Simon T; Parylak, Sarah L; Tran, Thanh; Chang, Tina; Gage, Fred H

    2016-06-01

    We longitudinally imaged the developing dendrites of adult-born mouse dentate granule cells (DGCs) in vivo and found that they underwent over-branching and pruning. Exposure to an enriched environment and constraint of dendritic growth by disrupting Wnt signaling led to increased branch addition and accelerated growth, which were, however, counteracted by earlier and more extensive pruning. Our results indicate that pruning is regulated in a homeostatic fashion to oppose excessive branching and promote a similar dendrite structure in DGCs. PMID:27135217

  6. Depolymerization of dendritic microtubules following incubation of cortical slices.

    PubMed

    Burgoyne, R D; Gray, E G; Sullivan, K; Barron, J

    1982-07-20

    Electron microscopical examination indicated that incubation of slices of rat cerebral cortex in Krebs buffer at room temperature of 37 degrees C led to a rapid and more or less complete depolymerization of dendritic microtubules. The loss of dendritic microtubules did not appear to be a consequence of anoxia. Myelinated axons showed only a partial loss of microtubules and the microtubules of preterminal axons were unaffected by incubation. These results indicate differential labilities of axonal and dendritic microtubules under these conditions of incubation. Such an effect of the incubation of slices in Krebs buffer indicates a need for caution in the interpretation of experiments on slice preparations.

  7. Multitasking in Gonadotropin-Releasing Hormone Neuron Dendrites.

    PubMed

    Iremonger, Karl J; Herbison, Allan E

    2015-01-01

    Gonadotropin-releasing hormone (GnRH) neurons integrate synaptic information in their dendrites in order to precisely control GnRH secretion and hence fertility. Recent discoveries concerning the structure and function of GnRH neuron dendrites have shed new light on the control of GnRH neuron excitability and GnRH secretion. This work suggests that GnRH neurons have a unique projection to the median eminence that possesses both dendritic and axonal properties. We propose that this 'dendron' projection allows GnRH neurons to multitask and integrate information in ways that would not be possible in a classically envisioned axon projection. PMID:25300776

  8. Dendrites of rod bipolar cells sprout in normal aging retina

    PubMed Central

    Liets, Lauren C.; Eliasieh, Kasra; van der List, Deborah A.; Chalupa, Leo M.

    2006-01-01

    The aging nervous system is known to manifest a variety of degenerative and regressive events. Here we report the unexpected growth of dendrites in the retinas of normal old mice. The dendrites of many rod bipolar cells in aging mice were observed to extend well beyond their normal strata within the outer plexiform layer to innervate the outer nuclear layer where they appeared to form contacts with the spherules of rod photoreceptors. Such dendritic sprouting increased with age and was evident at all retinal eccentricities. These results provide evidence of retinal plasticity associated with normal aging. PMID:16880381

  9. Probiotics, dendritic cells and bladder cancer.

    PubMed

    Feyisetan, Oladapo; Tracey, Christopher; Hellawell, Giles O

    2012-06-01

    What's known on the subject? and What does the study add? The suppressor effect of probiotics on superficial bladder cancer is an observed phenomenon but the specific mechanism is poorly understood. The evidence strongly suggests natural killer (NK) cells are the anti-tumour effector cells involved and NK cell activity correlates with the observed anti-tumour effect in mice. It is also known that dendritic cells (DC) cells are responsible for the recruitment and mobilization of NK cells so therefore it may be inferred that DC cells are most likely to be the interphase point at which probiotics act. In support of this, purification of NK cells was associated with a decrease in NK cells activity. The current use of intravesical bacille Calmette-Guérin in the management of superficial bladder cancer is based on the effect of a localised immune response. In the same way, understanding the mechanism of action of probiotics and the role of DC may potentially offer another avenue via which the immune system may be manipulated to resist bladder cancer. Probiotic foods have been available in the UK since 1996 with the arrival of the fermented milk drink (Yakult) from Japan. The presence of live bacterial ingredients (usually lactobacilli species) may confer health benefits when present in sufficient numbers. The role of probiotics in colo-rectal cancer may be related in part to the suppression of harmful colonic bacteria but other immune mechanisms are involved. Anti-cancer effects outside the colon were suggested by a Japanese report of altered rates of bladder tumour recurrence after ingestion of a particular probiotic. Dendritic cells play a central role to the general regulation of the immune response that may be modified by probiotics. The addition of probiotics to the diet may confer benefit by altering rates of bladder tumour recurrence and also alter the response to immune mechanisms involved with the application of intravesical treatments (bacille Calmette-Guérin).

  10. GATA2 regulates dendritic cell differentiation

    PubMed Central

    Onodera, Koichi; Fujiwara, Tohru; Onishi, Yasushi; Itoh-Nakadai, Ari; Okitsu, Yoko; Fukuhara, Noriko; Ishizawa, Kenichi; Shimizu, Ritsuko; Yamamoto, Masayuki

    2016-01-01

    Dendritic cells (DCs) are critical immune response regulators; however, the mechanism of DC differentiation is not fully understood. Heterozygous germ line GATA2 mutations induce GATA2-deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia/acute myeloid leukemia, and a profoundly reduced DC population, which is associated with increased susceptibility to viral infections, impaired phagocytosis, and decreased cytokine production. To define the role of GATA2 in DC differentiation and function, we studied Gata2 conditional knockout and haploinsufficient mice. Gata2 conditional deficiency significantly reduced the DC count, whereas Gata2 haploinsufficiency did not affect this population. GATA2 was required for the in vitro generation of DCs from Lin−Sca-1+Kit+ cells, common myeloid-restricted progenitors, and common dendritic cell precursors, but not common lymphoid-restricted progenitors or granulocyte-macrophage progenitors, suggesting that GATA2 functions in the myeloid pathway of DC differentiation. Moreover, expression profiling demonstrated reduced expression of myeloid-related genes, including mafb, and increased expression of T-lymphocyte–related genes, including Gata3 and Tcf7, in Gata2-deficient DC progenitors. In addition, GATA2 was found to bind an enhancer element 190-kb downstream region of Gata3, and a reporter assay exhibited significantly reduced luciferase activity after adding this enhancer region to the Gata3 promoter, which was recovered by GATA sequence deletion within Gata3 +190. These results suggest that GATA2 plays an important role in cell-fate specification toward the myeloid vs T-lymphocyte lineage by regulating lineage-specific transcription factors in DC progenitors, thereby contributing to DC differentiation. PMID:27259979

  11. Probiotics, dendritic cells and bladder cancer.

    PubMed

    Feyisetan, Oladapo; Tracey, Christopher; Hellawell, Giles O

    2012-06-01

    What's known on the subject? and What does the study add? The suppressor effect of probiotics on superficial bladder cancer is an observed phenomenon but the specific mechanism is poorly understood. The evidence strongly suggests natural killer (NK) cells are the anti-tumour effector cells involved and NK cell activity correlates with the observed anti-tumour effect in mice. It is also known that dendritic cells (DC) cells are responsible for the recruitment and mobilization of NK cells so therefore it may be inferred that DC cells are most likely to be the interphase point at which probiotics act. In support of this, purification of NK cells was associated with a decrease in NK cells activity. The current use of intravesical bacille Calmette-Guérin in the management of superficial bladder cancer is based on the effect of a localised immune response. In the same way, understanding the mechanism of action of probiotics and the role of DC may potentially offer another avenue via which the immune system may be manipulated to resist bladder cancer. Probiotic foods have been available in the UK since 1996 with the arrival of the fermented milk drink (Yakult) from Japan. The presence of live bacterial ingredients (usually lactobacilli species) may confer health benefits when present in sufficient numbers. The role of probiotics in colo-rectal cancer may be related in part to the suppression of harmful colonic bacteria but other immune mechanisms are involved. Anti-cancer effects outside the colon were suggested by a Japanese report of altered rates of bladder tumour recurrence after ingestion of a particular probiotic. Dendritic cells play a central role to the general regulation of the immune response that may be modified by probiotics. The addition of probiotics to the diet may confer benefit by altering rates of bladder tumour recurrence and also alter the response to immune mechanisms involved with the application of intravesical treatments (bacille Calmette

  12. Dendritic cell profile induced by Schistosoma mansoni antigen in cutaneous leishmaniasis patients.

    PubMed

    Lopes, Diego Mota; Fernandes, Jamille Souza; Cardoso, Thiago Marconi de Souza; Bafica, Aline Michele Barbosa; Oliveira, Sérgio Costa; Carvalho, Edgar M; Araujo, Maria Ilma; Cardoso, Luciana Santos

    2014-01-01

    The inflammatory response in cutaneous leishmaniasis (CL), although responsible for controlling the infection, is associated with the pathogenesis of disease. Conversely, the immune response induced by S. mansoni antigens is able to prevent immune-mediated diseases. The aim of this study was to evaluate the potential of the S. mansoni Sm29 antigen to change the profile of monocyte-derived dendritic cells (MoDCs) from subjects with cutaneous leishmaniasis (CL) in vitro. Monocytes derived from the peripheral blood mononuclear cells of twelve patients were cultured with GM-CSF and IL-4 for differentiation into dendritic cells and then stimulated with soluble Leishmania antigen (SLA) in the presence or absence of Sm29 antigen. The expression of surface molecules associated with maturation and activation (HLA-DR, CD40, CD83, CD80, and CD86), inflammation (IL-12, TNF), and downregulation (IL-10, IL-10R) was evaluated using flow cytometry. We observed that the frequencies of HLA-DR, CD83, CD80, and CD86 as well as of IL-10 and IL-10R on MoDCs were higher in cultures stimulated with Sm29, compared to the unstimulated cell cultures. Our results indicate that the Sm29 antigen is able to activate regulatory MoDCs in patients with cutaneous leishmaniasis. It might be useful to control the inflammatory process associated with this disease.

  13. Transient potassium channels augment degeneracy in hippocampal active dendritic spectral tuning

    PubMed Central

    Rathour, Rahul Kumar; Malik, Ruchi; Narayanan, Rishikesh

    2016-01-01

    Hippocampal pyramidal neurons express an intraneuronal map of spectral tuning mediated by hyperpolarization-activated cyclic-nucleotide-gated nonspecific-cation channels. Modeling studies have predicted a critical regulatory role for A-type potassium (KA) channels towards augmenting functional robustness of this map. To test this, we performed patch-clamp recordings from soma and dendrites of rat hippocampal pyramidal neurons, and measured spectral tuning before and after blocking KA channels using two structurally distinct pharmacological agents. Consistent with computational predictions, we found that blocking KA channels resulted in a significant reduction in resonance frequency and significant increases in input resistance, impedance amplitude and action-potential firing frequency across the somato-apical trunk. Furthermore, across all measured locations, blocking KA channels enhanced temporal summation of postsynaptic potentials and critically altered the impedance phase profile, resulting in a significant reduction in total inductive phase. Finally, pair-wise correlations between intraneuronal percentage changes (after blocking KA channels) in different measurements were mostly weak, suggesting differential regulation of different physiological properties by KA channels. Our results unveil a pivotal role for fast transient channels in regulating theta-frequency spectral tuning and intrinsic phase response, and suggest that degeneracy with reference to several coexisting functional maps is mediated by cross-channel interactions across the active dendritic arbor. PMID:27094086

  14. Dendritic Cell Profile Induced by Schistosoma mansoni Antigen in Cutaneous Leishmaniasis Patients

    PubMed Central

    Lopes, Diego Mota; Fernandes, Jamille Souza; Cardoso, Thiago Marconi de Souza; Bafica, Aline Michele Barbosa; Oliveira, Sérgio Costa; Carvalho, Edgar M.; Araujo, Maria Ilma; Cardoso, Luciana Santos

    2014-01-01

    The inflammatory response in cutaneous leishmaniasis (CL), although responsible for controlling the infection, is associated with the pathogenesis of disease. Conversely, the immune response induced by S. mansoni antigens is able to prevent immune-mediated diseases. The aim of this study was to evaluate the potential of the S. mansoni Sm29 antigen to change the profile of monocyte-derived dendritic cells (MoDCs) from subjects with cutaneous leishmaniasis (CL) in vitro. Monocytes derived from the peripheral blood mononuclear cells of twelve patients were cultured with GM-CSF and IL-4 for differentiation into dendritic cells and then stimulated with soluble Leishmania antigen (SLA) in the presence or absence of Sm29 antigen. The expression of surface molecules associated with maturation and activation (HLA-DR, CD40, CD83, CD80, and CD86), inflammation (IL-12, TNF), and downregulation (IL-10, IL-10R) was evaluated using flow cytometry. We observed that the frequencies of HLA-DR, CD83, CD80, and CD86 as well as of IL-10 and IL-10R on MoDCs were higher in cultures stimulated with Sm29, compared to the unstimulated cell cultures. Our results indicate that the Sm29 antigen is able to activate regulatory MoDCs in patients with cutaneous leishmaniasis. It might be useful to control the inflammatory process associated with this disease. PMID:25309922

  15. Transient potassium channels augment degeneracy in hippocampal active dendritic spectral tuning.

    PubMed

    Rathour, Rahul Kumar; Malik, Ruchi; Narayanan, Rishikesh

    2016-01-01

    Hippocampal pyramidal neurons express an intraneuronal map of spectral tuning mediated by hyperpolarization-activated cyclic-nucleotide-gated nonspecific-cation channels. Modeling studies have predicted a critical regulatory role for A-type potassium (KA) channels towards augmenting functional robustness of this map. To test this, we performed patch-clamp recordings from soma and dendrites of rat hippocampal pyramidal neurons, and measured spectral tuning before and after blocking KA channels using two structurally distinct pharmacological agents. Consistent with computational predictions, we found that blocking KA channels resulted in a significant reduction in resonance frequency and significant increases in input resistance, impedance amplitude and action-potential firing frequency across the somato-apical trunk. Furthermore, across all measured locations, blocking KA channels enhanced temporal summation of postsynaptic potentials and critically altered the impedance phase profile, resulting in a significant reduction in total inductive phase. Finally, pair-wise correlations between intraneuronal percentage changes (after blocking KA channels) in different measurements were mostly weak, suggesting differential regulation of different physiological properties by KA channels. Our results unveil a pivotal role for fast transient channels in regulating theta-frequency spectral tuning and intrinsic phase response, and suggest that degeneracy with reference to several coexisting functional maps is mediated by cross-channel interactions across the active dendritic arbor.

  16. Inducing tissue specific tolerance in autoimmune disease with tolerogenic dendritic cells.

    PubMed

    Suwandi, Jessica S; Toes, René E M; Nikolic, Tatjana; Roep, Bart O

    2015-01-01

    Current immunosuppressive therapy acts systemically, causing collateral damage and does not necessarily cope with the cause of rheumatoid arthritis. Tissue specific immune modulation may restore tolerance in patients with autoimmune diseases such as RA, but desires knowledge on relevant target autoantigens. We present the case of type 1 diabetes as prototype autoimmune disease with established autoantigens to set the stage for tissue-specific immune modulation using tolerogenic dendritic cells pulsed with autoantigen in RA. This approach induces autoantigen-specific regulatory T cells that exert their tissue-specific action through a combination of linked suppression and infectious tolerance, introducing a legacy of targeted, localised immune regulation in the proximity of the lesion. Several trials are in progress in RA employing various types of tolerogenic DCs. With knowledge on mode of action and confounding effects of concomitant immunosuppressive therapy, this strategy may provide novel immune intervention that may also prevent RA in high-risk subjects. PMID:26458178

  17. Dendritic Cell (DC)-Specific Targeting Reveals Stat3 as a Negative Regulator of DC Function

    PubMed Central

    Melillo, Jessica A.; Song, Li; Bhagat, Govind; Blazquez, Ana Belen; Plumlee, Courtney R.; Lee, Carolyn; Berin, Cecilia; Reizis, Boris; Schindler, Christian

    2011-01-01

    Dendritic cells (DCs) must achieve a critical balance between activation and tolerance, a process influenced by cytokines and growth factors. IL-10, which transduces signals through Stat3, has emerged as one important negative regulator of DC activation. To directly examine the role Stat3 plays in regulating DC activity, the Stat3 gene was targeted for deletion with a CD11c-cre transgene. Stat3 CKO mice developed cervical lymphadenopathy as well as a mild ileocolitis that persisted throughout life and was associated with impaired weight gain. Consistent with this, Stat3-deficient DCs demonstrated enhanced immune activity, including increased cytokine production, Ag-dependent T-cell activation and resistance to IL-10–mediated suppression. These results reveal a cell-intrinsic negative regulatory role of Stat3 in DCs and link increased DC activation with perturbed immune homeostasis and chronic mucosal inflammation. PMID:20124100

  18. Analysis of dendritic cell subpopulations in follicular lymphoma with respect to the tumor immune microenvironment.

    PubMed

    Chevalier, Nina; Mueller, Michael; Mougiakakos, Dimitrios; Ihorst, Gabriele; Marks, Reinhard; Schmitt-Graeff, Annette; Veelken, Hendrik

    2016-09-01

    The immune cell composition of the follicular lymphoma (FL) tumor microenvironment is increasingly recognized as an important determinant for clinical outcome. Here, we explored frequency and distribution of dendritic cell (DC) subtypes in relation to regulatory T cells (Treg) by immunohistochemistry in lymph node biopsies from patients with de novo FL. We found that neoplastic follicles contained lower DC and higher Treg frequencies than hyperplastic follicles in control lymph nodes. Treg numbers particularly correlated with the subset of conventional CD11c(+ )DCs. Additionally, both a high intra- to interfollicular ratio of CD11c(+ )DCs and increased intrafollicular Treg frequencies were associated with decreased overall survival. This suggests that functional interactions between these cells may be relevant for FL progression/recurrence. The presence of CD11c(+ )DCs in the tumor microenvironment may assist tumor infiltration by Tregs, thus contributing to the suppression of an otherwise beneficial T-cell-dominated FL microenvironment.

  19. Experimental models to investigate the function of dendritic cell subsets: challenges and implications.

    PubMed

    Hancock, D G; Guy, T V; Shklovskaya, E; Fazekas de St Groth, B

    2013-02-01

    The dendritic cell (DC) lineage is remarkably heterogeneous. It has been postulated that specialized DC subsets have evolved in order to select and support the multitude of possible T cell differentiation pathways. However, defining the function of individual DC subsets has proven remarkably difficult, and DC subset control of key T cell fates such as tolerance, T helper cell commitment and regulatory T cell induction is still not well understood. While the difficulty in assigning unique functions to particular DC subsets may be due to sharing of functions, it may also reflect a lack of appropriate physiological in-vivo models for studying DC function. In this paper we review the limitations associated with many of the current DC models and highlight some of the underlying difficulties involved in studying the function of murine DC subsets.

  20. Perspectives on Reprograming Cancer-Associated Dendritic Cells for Anti-Tumor Therapies

    PubMed Central

    Benencia, Fabian; Muccioli, Maria; Alnaeeli, Mawadda

    2014-01-01

    In recent years, the relevance of the tumor microenvironment (TME) in the progression of cancer has gained considerable attention. It has been shown that the TME is capable of inactivating various components of the immune system responsible for tumor clearance, thus favoring cancer cell growth and tumor metastasis. In particular, effects of the TME on antigen-presenting cells, such as dendritic cells (DCs) include rendering these cells unable to promote specific immune responses or transform them into suppressive cells capable of inducing regulatory T cells. In addition, under the influence of the TME, DCs can produce growth factors that induce neovascularization, therefore further contributing to tumor development. Interestingly, cancer-associated DCs harbor tumor antigens and thus have the potential to become anti-tumor vaccines in situ if properly reactivated. This perspective article provides an overview of the scientific background and experimental basis for reprograming cancer-associated DCs in situ to generate anti-tumor immune responses. PMID:24778991

  1. The Three-Dimensional Morphology of Growing Dendrites

    PubMed Central

    Gibbs, J. W.; Mohan, K. A.; Gulsoy, E. B.; Shahani, A. J.; Xiao, X.; Bouman, C. A.; De Graef, M.; Voorhees, P. W.

    2015-01-01

    The processes controlling the morphology of dendrites have been of great interest to a wide range of communities, since they are examples of an out-of-equilibrium pattern forming system, there is a clear connection with battery failure processes, and their morphology sets the properties of many metallic alloys. We determine the three-dimensional morphology of free growing metallic dendrites using a novel X-ray tomographic technique that improves the temporal resolution by more than an order of magnitude compared to conventional techniques. These measurements show that the growth morphology of metallic dendrites is surprisingly different from that seen in model systems, the morphology is not self-similar with distance back from the tip, and that this morphology can have an unexpectedly strong influence on solute segregation in castings. These experiments also provide benchmark data that can be used to validate simulations of free dendritic growth. PMID:26139473

  2. A simple transfer function for nonlinear dendritic integration.

    PubMed

    Singh, Matthew F; Zald, David H

    2015-01-01

    Relatively recent advances in patch clamp recordings and iontophoresis have enabled unprecedented study of neuronal post-synaptic integration ("dendritic integration"). Findings support a separate layer of integration in the dendritic branches before potentials reach the cell's soma. While integration between branches obeys previous linear assumptions, proximal inputs within a branch produce threshold nonlinearity, which some authors have likened to the sigmoid function. Here we show the implausibility of a sigmoidal relation and present a more realistic transfer function in both an elegant artificial form and a biophysically derived form that further considers input locations along the dendritic arbor. As the distance between input locations determines their ability to produce nonlinear interactions, models incorporating dendritic topology are essential to understanding the computational power afforded by these early stages of integration. We use the biophysical transfer function to emulate empirical data using biophysical parameters and describe the conditions under which the artificial and biophysically derived forms are equivalent.

  3. Observation of dendritic growth under the influence of forced convection

    NASA Astrophysics Data System (ADS)

    Roshchupkina, O.; Shevchenko, N.; Eckert, S.

    2015-06-01

    The directional solidification of Ga-25wt%In alloys within a Hele-Shaw cell was visualized by X-ray radioscopy. The investigations are focused on the impact of melt convection on the dendritic growth. Natural convection occurs during a bottom up solidification because lighter solute is rejected during crystallization. Forced convection was produced by a specific electromagnetic pump. The direction of forced melt flow is almost horizontal at the solidification front. Melt flow induces various effects on grain morphology primarily caused by convective transport of solute, such as a facilitation of the growth of primary trunks or lateral branches, dendrite remelting, fragmentation or freckle formation depending on the dendrite orientation, the flow direction and intensity. Forced flow eliminates solutal plumes and damps local fluctuations of solute. A preferential growth of the secondary arms occurs at the upstream side of the dendrites, whereas high solute concentration at the downstream side inhibits the formation of secondary branches.

  4. The three-dimensional morphology of growing dendrites

    SciTech Connect

    Gibbs, J. W.; Mohan, K. A.; Gulsoy, E. B.; Shahani, A. J.; Xiao, X.; Bouman, C. A.; De Graef, M.; Voorhees, P. W.

    2015-07-03

    The processes controlling the morphology of dendrites have been of great interest to a wide range of communities, since they are examples of an out-of-equilibrium pattern forming system, there is a clear connection with battery failure processes, and their morphology sets the properties of many metallic alloys. We determine the three-dimensional morphology of free growing metallic dendrites using a novel X-ray tomographic technique that improves the temporal resolution by more than an order of magnitude compared to conventional techniques. These measurements show that the growth morphology of metallic dendrites is surprisingly different from that seen in model systems, the morphology is not self-similar with distance back from the tip, and that this morphology can have an unexpectedly strong influence on solute segregation in castings. These experiments also provide benchmark data that can be used to validate simulations of free dendritic growth.

  5. The three-dimensional morphology of growing dendrites

    DOE PAGESBeta

    Gibbs, J. W.; Mohan, K. A.; Gulsoy, E. B.; Shahani, A. J.; Xiao, X.; Bouman, C. A.; De Graef, M.; Voorhees, P. W.

    2015-07-03

    The processes controlling the morphology of dendrites have been of great interest to a wide range of communities, since they are examples of an out-of-equilibrium pattern forming system, there is a clear connection with battery failure processes, and their morphology sets the properties of many metallic alloys. We determine the three-dimensional morphology of free growing metallic dendrites using a novel X-ray tomographic technique that improves the temporal resolution by more than an order of magnitude compared to conventional techniques. These measurements show that the growth morphology of metallic dendrites is surprisingly different from that seen in model systems, the morphologymore » is not self-similar with distance back from the tip, and that this morphology can have an unexpectedly strong influence on solute segregation in castings. These experiments also provide benchmark data that can be used to validate simulations of free dendritic growth.« less

  6. Dendritic spines: from structure to in vivo function

    PubMed Central

    Rochefort, Nathalie L; Konnerth, Arthur

    2012-01-01

    Dendritic spines arise as small protrusions from the dendritic shaft of various types of neuron and receive inputs from excitatory axons. Ever since dendritic spines were first described in the nineteenth century, questions about their function have spawned many hypotheses. In this review, we introduce understanding of the structural and biochemical properties of dendritic spines with emphasis on components studied with imaging methods. We then explore advances in in vivo imaging methods that are allowing spine activity to be studied in living tissue, from super-resolution techniques to calcium imaging. Finally, we review studies on spine structure and function in vivo. These new results shed light on the development, integration properties and plasticity of spines. PMID:22791026

  7. CUB and Sushi multiple domains 3 regulates dendrite development.

    PubMed

    Mizukami, Tomoharu; Kohno, Takao; Hattori, Mitsuharu

    2016-09-01

    CUB and Sushi multiple domains 3 (CSMD3) is a large protein expressed in fetal and adult brain. Recently, mutations of the CSMD3 gene were identified in schizophrenia and autism patients. However, biochemical properties and functions of the CSMD3 protein remain unknown. Here, we demonstrate that CSMD3 is an oligomeric type I transmembrane protein localized in the apical dendrites of hippocampal pyramidal neurons in the postnatal brain. In cultured hippocampal neurons, CSMD3 is expressed only after 7 days in vitro. Overexpression of CSMD3 induced dendritic branching in hippocampal neurons. Regulation of dendritic morphology by CSMD3 depended on the presence of its extracellular region, while CSMD3 intracellular region was dispensable for this activity. These results suggest that CSMD3 acts as a co-receptor of an unidentified membrane protein to regulate dendrite development. Therefore, malfunctions of CSMD3 may be one of the factors in the pathogenesis of psychiatric disorders.

  8. CUB and Sushi multiple domains 3 regulates dendrite development.

    PubMed

    Mizukami, Tomoharu; Kohno, Takao; Hattori, Mitsuharu

    2016-09-01

    CUB and Sushi multiple domains 3 (CSMD3) is a large protein expressed in fetal and adult brain. Recently, mutations of the CSMD3 gene were identified in schizophrenia and autism patients. However, biochemical properties and functions of the CSMD3 protein remain unknown. Here, we demonstrate that CSMD3 is an oligomeric type I transmembrane protein localized in the apical dendrites of hippocampal pyramidal neurons in the postnatal brain. In cultured hippocampal neurons, CSMD3 is expressed only after 7 days in vitro. Overexpression of CSMD3 induced dendritic branching in hippocampal neurons. Regulation of dendritic morphology by CSMD3 depended on the presence of its extracellular region, while CSMD3 intracellular region was dispensable for this activity. These results suggest that CSMD3 acts as a co-receptor of an unidentified membrane protein to regulate dendrite development. Therefore, malfunctions of CSMD3 may be one of the factors in the pathogenesis of psychiatric disorders. PMID:27033969

  9. Dendritic Spines as Tunable Regulators of Synaptic Signals

    PubMed Central

    Tønnesen, Jan; Nägerl, U. Valentin

    2016-01-01

    Neurons are perpetually receiving vast amounts of information in the form of synaptic input from surrounding cells. The majority of input occurs at thousands of dendritic spines, which mediate excitatory synaptic transmission in the brain, and is integrated by the dendritic and somatic compartments of the postsynaptic neuron. The functional role of dendritic spines in shaping biochemical and electrical signals transmitted via synapses has long been intensely studied. Yet, many basic questions remain unanswered, in particular regarding the impact of their nanoscale morphology on electrical signals. Here, we review our current understanding of the structure and function relationship of dendritic spines, focusing on the controversy of electrical compartmentalization and the potential role of spine structural changes in synaptic plasticity. PMID:27340393

  10. Structural defect characterization of silicon dendritic web ribbons

    NASA Technical Reports Server (NTRS)

    Cheng, L. J.

    1985-01-01

    An EBIC study of the cross section of silicon dendritic web ribbon has revealed that recombination-active structural defects are mainly concentrated in the inner part of the ribbon, particularly at and near the twin plane, whereas the material near the surface has significantly fewer defects. An analysis of the distribution of etch pits due to slip dislocations created by shear stress indicates that a minimum in the dislocation density is frequently observed in the ribbon adjacent to the dendrite.

  11. Dendritic biomimicry: microenvironmental hydrogen-bonding effects on tryptophan fluorescence.

    PubMed

    Koenig, S; Müller, L; Smith, D K

    2001-03-01

    Two series of dendritically modified tryptophan derivatives have been synthesised and their emission spectra measured in a range of different solvents. This paper presents the syntheses of these novel dendritic structures and discusses their emission spectra in terms of both solvent and dendritic effects. In the first series of dendrimers, the NH group of the indole ring is available for hydrogen bonding, whilst in the second series, the indole NH group has been converted to NMe. Direct comparison of the emission wavelengths of analogous NH and NMe derivatives indicates the importance of the Kamlet-Taft solvent beta3 parameter, which reflects the ability of the solvent to accept a hydrogen bond from the NH group, an effect not possible for the NMe series of dendrimers. For the NH dendrimers, the attachment of a dendritic shell to the tryptophan subunit leads to a red shift in emission wavelength. This dendritic effect only operates in non-hydrogen-bonding solvents. For the NMe dendrimers, however, the attachment of a dendritic shell has no effect on the emission spectra of the indole ring. This proves the importance of hydrogen bonding between the branched shell and the indole NH group in causing the dendritic effect. This is the first time a dendritic effect has been unambiguously assigned to individual hydrogen-bonding interactions and indicates that such intramolecular interactions are important in dendrimers, just as they are in proteins. Furthermore, this paper sheds light on the use of tryptophan residues as a probe of the microenvironment within proteins--in particular, it stresses the importance of hydrogen bonds formed by the indole NH group.

  12. Regulatory T cell effects in antitumor laser immunotherapy: a mathematical model and analysis

    NASA Astrophysics Data System (ADS)

    Dawkins, Bryan A.; Laverty, Sean M.

    2016-03-01

    Regulatory T cells (Tregs) have tremendous influence on treatment outcomes in patients receiving immunotherapy for cancerous tumors. We present a mathematical model incorporating the primary cellular and molecular components of antitumor laser immunotherapy. We explicitly model developmental classes of dendritic cells (DCs), cytotoxic T cells (CTLs), primary and metastatic tumor cells, and tumor antigen. Regulatory T cells have been shown to kill antigen presenting cells, to influence dendritic cell maturation and migration, to kill activated killer CTLs in the tumor microenvironment, and to influence CTL proliferation. Since Tregs affect explicitly modeled cells, but we do not explicitly model dynamics of Treg themselves, we use model parameters to analyze effects of Treg immunosuppressive activity. We will outline a systematic method for assigning clinical outcomes to model simulations and use this condition to associate simulated patient treatment outcome with Treg activity.

  13. Dendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Zhu, Bing; Luo, Liqing; Moore, G. R. Wayne; Paty, Donald W.; Cynader, Max S.

    2003-01-01

    Evidence has shown that excitotoxicity may contribute to the loss of central nervous system axons and oligodendrocytes in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Because dendrites and synapses are vulnerable to excitotoxicity, we examined these structures in acute and chronic models of EAE. Immunostaining for microtubule-associated protein-2 showed that extensive dendritic beading occurred in the white matter of the lumbosacral spinal cord (LSSC) during acute EAE episodes and EAE relapses. Retrograde labeling confirmed that most motoneuron dendrites were beaded in the white matter of the LSSC in acute EAE. In contrast, only mild swelling was observed in the gray matter of the LSSC. Dendritic beading showed marked recovery during EAE remission and after EAE recovery. In addition, synaptophysin, synapsin I, and PSD-95 immunoreactivities were significantly reduced in both the gray and white matter of the LSSC during acute EAE episodes and EAE relapses, but showed partial recovery during EAE remission and after EAE recovery. Pathologically, both dendritic beading and the reduction in synaptic protein immunoreactivity were well correlated with inflammatory cell infiltration in the LSSC at different EAE stages. We propose that dendritic and synaptic damage in the spinal cord may contribute to the neurological deficits in EAE. PMID:12707048

  14. Dendrites impact the encoding capabilities of the axon.

    PubMed

    Eyal, Guy; Mansvelder, Huibert D; de Kock, Christiaan P J; Segev, Idan

    2014-06-11

    This study highlights a new and powerful direct impact of the dendritic tree (the input region of neurons) on the encoding capability of the axon (the output region). We show that the size of the dendritic arbors (its impedance load) strongly modulates the shape of the action potential (AP) onset at the axon initial segment; it is accelerated in neurons with larger dendritic surface area. AP onset rapidness is key in determining the capability of the axonal spikes to encode (phase lock to) rapid changes in synaptic inputs. Hence, our findings imply that neurons with larger dendritic arbors have improved encoding capabilities. This "dendritic size effect" was explored both analytically as well as numerically, in simplified and detailed models of 3D reconstructed layer 2/3 cortical pyramidal cells of rats and humans. The cutoff frequency of spikes phase locking to modulated inputs increased from 100 to 200 Hz in pyramidal cells of young rats to 400-600 Hz in human cells. In the latter case, phase locking reached close to 1 KHz in in vivo-like conditions. This work highlights new and functionally profound cross talk between the dendritic tree and the axon initial segment, providing new understanding of neurons as sophisticated nonlinear input/output devices. PMID:24920612

  15. The unfolded protein response is required for dendrite morphogenesis

    PubMed Central

    Wei, Xing; Howell, Audrey S; Dong, Xintong; Taylor, Caitlin A; Cooper, Roshni C; Zhang, Jianqi; Zou, Wei; Sherwood, David R; Shen, Kang

    2015-01-01

    Precise patterning of dendritic fields is essential for the formation and function of neuronal circuits. During development, dendrites acquire their morphology by exuberant branching. How neurons cope with the increased load of protein production required for this rapid growth is poorly understood. Here we show that the physiological unfolded protein response (UPR) is induced in the highly branched Caenorhabditis elegans sensory neuron PVD during dendrite morphogenesis. Perturbation of the IRE1 arm of the UPR pathway causes loss of dendritic branches, a phenotype that can be rescued by overexpression of the ER chaperone HSP-4 (a homolog of mammalian BiP/ grp78). Surprisingly, a single transmembrane leucine-rich repeat protein, DMA-1, plays a major role in the induction of the UPR and the dendritic phenotype in the UPR mutants. These findings reveal a significant role for the physiological UPR in the maintenance of ER homeostasis during morphogenesis of large dendritic arbors. DOI: http://dx.doi.org/10.7554/eLife.06963.001 PMID:26052671

  16. An extracellular adhesion molecule complex patterns dendritic branching and morphogenesis.

    PubMed

    Dong, Xintong; Liu, Oliver W; Howell, Audrey S; Shen, Kang

    2013-10-10

    Robust dendrite morphogenesis is a critical step in the development of reproducible neural circuits. However, little is known about the extracellular cues that pattern complex dendrite morphologies. In the model nematode Caenorhabditis elegans, the sensory neuron PVD establishes stereotypical, highly branched dendrite morphology. Here, we report the identification of a tripartite ligand-receptor complex of membrane adhesion molecules that is both necessary and sufficient to instruct spatially restricted growth and branching of PVD dendrites. The ligand complex SAX-7/L1CAM and MNR-1 function at defined locations in the surrounding hypodermal tissue, whereas DMA-1 acts as the cognate receptor on PVD. Mutations in this complex lead to dramatic defects in the formation, stabilization, and organization of the dendritic arbor. Ectopic expression of SAX-7 and MNR-1 generates a predictable, unnaturally patterned dendritic tree in a DMA-1-dependent manner. Both in vivo and in vitro experiments indicate that all three molecules are needed for interaction. PMID:24120131

  17. Dendrites impact the encoding capabilities of the axon.

    PubMed

    Eyal, Guy; Mansvelder, Huibert D; de Kock, Christiaan P J; Segev, Idan

    2014-06-11

    This study highlights a new and powerful direct impact of the dendritic tree (the input region of neurons) on the encoding capability of the axon (the output region). We show that the size of the dendritic arbors (its impedance load) strongly modulates the shape of the action potential (AP) onset at the axon initial segment; it is accelerated in neurons with larger dendritic surface area. AP onset rapidness is key in determining the capability of the axonal spikes to encode (phase lock to) rapid changes in synaptic inputs. Hence, our findings imply that neurons with larger dendritic arbors have improved encoding capabilities. This "dendritic size effect" was explored both analytically as well as numerically, in simplified and detailed models of 3D reconstructed layer 2/3 cortical pyramidal cells of rats and humans. The cutoff frequency of spikes phase locking to modulated inputs increased from 100 to 200 Hz in pyramidal cells of young rats to 400-600 Hz in human cells. In the latter case, phase locking reached close to 1 KHz in in vivo-like conditions. This work highlights new and functionally profound cross talk between the dendritic tree and the axon initial segment, providing new understanding of neurons as sophisticated nonlinear input/output devices.

  18. Dendrite arborization requires the dynein cofactor NudE.

    PubMed

    Arthur, Ashley L; Yang, Sihui Z; Abellaneda, Allison M; Wildonger, Jill

    2015-06-01

    The microtubule-based molecular motor dynein is essential for proper neuronal morphogenesis. Dynein activity is regulated by cofactors, and the role(s) of these cofactors in shaping neuronal structure are still being elucidated. Using Drosophila melanogaster, we reveal that the loss of the dynein cofactor NudE results in abnormal dendrite arborization. Our data show that NudE associates with Golgi outposts, which mediate dendrite branching, suggesting that NudE normally influences dendrite patterning by regulating Golgi outpost transport. Neurons lacking NudE also have increased microtubule dynamics, reflecting a change in microtubule stability that is likely to also contribute to abnormal dendrite growth and branching. These defects in dendritogenesis are rescued by elevating levels of Lis1, another dynein cofactor that interacts with NudE as part of a tripartite complex. Our data further show that the NudE C-terminus is dispensable for dendrite morphogenesis and is likely to modulate NudE activity. We propose that a key function of NudE is to enhance an interaction between Lis1 and dynein that is crucial for motor activity and dendrite architecture.

  19. Cancer-Associated Myeloid Regulatory Cells

    PubMed Central

    De Vlaeminck, Yannick; González-Rascón, Anna; Goyvaerts, Cleo; Breckpot, Karine

    2016-01-01

    Myeloid cells are critically involved in the pathophysiology of cancers. In the tumor microenvironment (TME), they comprise tumor-associated macrophages (TAMs), neutrophils (TANs), dendritic cells, and myeloid-derived suppressor cells, which are further subdivided into a monocytic subset and a granulocytic subset. Some of these myeloid cells, in particular TAMs and TANs, are divided into type 1 or type 2 cells, according to the paradigm of T helper type 1 or type 2 cells. Type 1-activated cells are generally characterized as cells that aid tumor rejection, while all other myeloid cells are shown to favor tumor progression. Moreover, these cells are often at the basis of resistance to various therapies. Much research has been devoted to study the biology of myeloid cells. This endeavor has proven to be challenging, as the markers used to categorize myeloid cells in the TME are not restricted to particular subsets. Also from a functional and metabolic point of view, myeloid cells share many features. Finally, myeloid cells are endowed with a certain level of plasticity, which further complicates studying them outside their environment. In this article, we challenge the exclusive use of cell markers to unambiguously identify myeloid cell subsets in the TME. We further propose to divide myeloid cells into myeloid regulatory or stimulatory cells according to their pro- or antitumor function, because we contend that for therapeutic purposes it is not targeting the cell subsets but rather targeting their protumor traits; hence, myeloid regulatory cells will push antitumor immunotherapy to the next level. PMID:27065074

  20. Environmental regulatory update table

    SciTech Connect

    Brown, K.J.; Langston, M.E.; Tucker, C.S.; Reed, R.M.

    1987-06-01

    The Environmental Regulatory Update Table provides information on regulatory initiatives of interest to DOE operations and contractor staff with environmental management responsibilities. The table is updated each month with information from the Federal Register and other sources, including direct contact with regulatory agencies. Each table entry provides a chronological record of the rulemaking process for that initiative with an abstract and a projection of further action.

  1. Role of Plasmacytoid Dendritic Cells for Aberrant Class II Expression in Exocrine Glands from Estrogen-Deficient Mice of Healthy Background

    PubMed Central

    Arakaki, Rieko; Nagaoka, Ai; Ishimaru, Naozumi; Yamada, Akiko; Yoshida, Satoko; Hayashi, Yoshio

    2009-01-01

    Although it has been well documented that aberrant major histocompatibility complex class II molecules may contribute to the development of autoimmune disorders, the precise mechanisms responsible for their tissue-specific expression remain unknown. Here we show that estrogen deficiency induces aberrant class II major histocompatibility complex expression in exocrine glands via interactions between epithelial cells and plasmacytoid dendritic cells. Relatively modest but functionally significant expression levels of major histocompatibility complex class II and class II transactivator molecules were observed in the exocrine glands of ovariectomized (Ovx) C57BL/6 (B6) mice, but were not seen in the exocrine glands of control B6 mice. We observed that the salivary dendritic cells adjacent to the apoptotic epithelial cells positive for terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, were activated in Ovx mice, but were not activated in control mice. We obtained evidence that the salivary gland cells express both interferon regulatory factor-1 and class II transactivator type IV molecules in Ovx mice. Salivary gland cells from Ovx mice were also capable of inducing the activation of antigen-specific T cells from OT-II transgenic mice. These findings indicate that estrogen deficiency initiates class II transactivator type IV mRNA expression in exocrine glands via interactions between epithelial cells and plasmacytoid dendritic cells, suggesting that plasmacytoid dendritic cells play a pivotal role in gender-based autoimmune disorders in postmenopausal women. PMID:19359524

  2. Dendritic type, accessory cells within the mammalian thymic microenvironment. Antigen presentation in the dendritic neuro-endocrine-immune cellular network.

    PubMed

    Bodey, B; Bodey, B; Kaiser, H E

    1997-01-01

    During mammalian ontogenesis, the thymic "pure" endodermal epithelial anlage develops and differentiates into a complex cellular microenvironment. Beginning the 7-8th week of intrauterine development, thymic epithelial cells chemotactically regulate (induce) numerous waves of migration of stem cells into the thymus, including the CD34+, yolk sac-derived, committed hematopoietic stem cells. In vitro experiments have established that CD34+ CD38dim human thymocytes differentiate into T lymphocytes when co-cultured with mouse fetal thymic organs. Hematopoietic stem cells for myeloid and thymic stromal dendritic cells (DCs) are present within the minute population of CD34+ progenitors within the mammalian thymus. The common myeloid, DC, natural killer (NK) and T lymphocyte progenitors have also been identified within the CD34+ stem cell population in the human thymus. Interactions between the endocrine and immune systems have been reported in various regions of the mammalian body including the anterior pituitary (AP), the skin, and the central (thymus) and peripheral lymphatic system. The network of bone marrow derived DCs is a part of the reticuloendothelial system (RES) and DCs represent the cellular mediators of these regulatory endocrine-immune interactions. Folliculo-stellate cells (FSC) in the AP, Langerhans cells (LCs) in the skin and lymphatic system, "veiled" cells, lympho-dendritic and interdigitating cells (IDCs) in a number of tissues comprising the lymphatic system are the cell types of the DC meshwork of "professional" antigen presenting cells (APCs). Most of these cells express the immunocytochemical markers S-100, CD1. CD45, CD54, F418, MHC class I and II antigens, Fc and complement receptors. FSCs are non-hormone secreting cells which communicate directly with hormone producing cells, a form of neuro-endocrine-immune regulation. As a result, an attenuation of secretory responses follows stimulation of these cells. FSCs are also the cells in the AP

  3. Coordinate control of terminal dendrite patterning and dynamics by the membrane protein Raw

    PubMed Central

    Lee, Jiae; Peng, Yun; Lin, Wen-Yang; Parrish, Jay Z.

    2015-01-01

    The directional flow of information in neurons depends on compartmentalization: dendrites receive inputs whereas axons transmit them. Axons and dendrites likewise contain structurally and functionally distinct subcompartments. Axon/dendrite compartmentalization can be attributed to neuronal polarization, but the developmental origin of subcompartments in axons and dendrites is less well understood. To identify the developmental bases for compartment-specific patterning in dendrites, we screened for mutations that affect discrete dendritic domains in Drosophila sensory neurons. From this screen, we identified mutations that affected distinct aspects of terminal dendrite development with little or no effect on major dendrite patterning. Mutation of one gene, raw, affected multiple aspects of terminal dendrite patterning, suggesting that Raw might coordinate multiple signaling pathways to shape terminal dendrite growth. Consistent with this notion, Raw localizes to branch-points and promotes dendrite stabilization together with the Tricornered (Trc) kinase via effects on cell adhesion. Raw independently influences terminal dendrite elongation through a mechanism that involves modulation of the cytoskeleton, and this pathway is likely to involve the RNA-binding protein Argonaute 1 (AGO1), as raw and AGO1 genetically interact to promote terminal dendrite growth but not adhesion. Thus, Raw defines a potential point of convergence in distinct pathways shaping terminal dendrite patterning. PMID:25480915

  4. Cortical Dendritic Spine Heads Are Not Electrically Isolated by the Spine Neck from Membrane Potential Signals in Parent Dendrites

    PubMed Central

    Popovic, Marko A.; Gao, Xin; Carnevale, Nicholas T.; Zecevic, Dejan

    2014-01-01

    The evidence for an important hypothesis that cortical spine morphology might participate in modifying synaptic efficacy that underlies plasticity and possibly learning and memory mechanisms is inconclusive. Both theory and experiments suggest that the transfer of excitatory postsynaptic potential signals from spines to parent dendrites depends on the spine neck morphology and resistance. Furthermore, modeling of signal transfer in the opposite direction predicts that synapses on spine heads are not electrically isolated from voltages in the parent dendrite. In sharp contrast to this theoretical prediction, one of a very few measurements of electrical signals from spines reported that slow hyperpolarizing membrane potential changes are attenuated considerably by the spine neck as they spread from dendrites to synapses on spine heads. This result challenges our understanding of the electrical behavior of spines at a fundamental level. To re-examine the specific question of the transfer of dendritic signals to synapses of spines, we took advantage of a high-sensitivity Vm-imaging technique and carried out optical measurements of electrical signals from 4 groups of spines with different neck length and simultaneously from parent dendrites. The results show that spine neck does not filter membrane potential signals as they spread from the dendrites into the spine heads. PMID:23054810

  5. DENDRIFT - CALCULATION OF DENDRITE SETTLING VELOCITIES 1.0

    NASA Technical Reports Server (NTRS)

    Degroh, H. C.

    1994-01-01

    The convective transport and gravitational settling of unattached equiaxed grains and dendrite fragments can cause macrosegregation and influence the structure of the equiaxed zone in a variety of solidification arrangements. An understanding of how the highly nonspherical geometry of the dendrite influences its settling and transport characteristics is needed to determine the motion of unattached dendrites and predict structure and segregation in castings. The empirical results of previous studies have been used to develop DENDRIFT, which calculates the settling velocity of various dendritic shapes and a number of other parameters of interest such as the volume and surface area of the dendrite. As input, the program requires the physical properties of the system and some geometric parameters of the dendrite being considered, such as the average radius of the primary arm. DENDRIFT uses the concept of an envelope around the dendrite to enable the calculation of an effective sphericity. The settling velocities predicted by the code have been compared to experiments and were on average within 5% of those measured for model dendrites, and were consistent and in good agreement with three other experimental investigations. Thus, the code's use of the empirical relationships among velocity, sphericity, and envelope permeability appear valid, as do the wall and inertial correction factors developed. At this time, DENDRIFT does not account for gradients in composition or density, particle-particle interactions, tertiary dendrite arms, or the possible influences of off axis (tilted) dendrite settling. This program can also be used to estimate the settling velocities of spheres and cylinders with hemispherical ends. The code can be useful as a subprogram in a comprehensive solidification/casting code. The concepts demonstrated in DENDRIFT may also have wide application in the chemical processing industry by helping to describe the settling, or floating, of precipitates and

  6. Isolation of Human Skin Dendritic Cell Subsets.

    PubMed

    Gunawan, Merry; Jardine, Laura; Haniffa, Muzlifah

    2016-01-01

    Dendritic cells (DCs) are specialized leukocytes with antigen-processing and antigen-presenting functions. DCs can be divided into distinct subsets by anatomical location, phenotype and function. In human, the two most accessible tissues to study leukocytes are peripheral blood and skin. DCs are rare in human peripheral blood (<1 % of mononuclear cells) and have a less mature phenotype than their tissue counterparts (MacDonald et al., Blood. 100:4512-4520, 2002; Haniffa et al., Immunity 37:60-73, 2012). In contrast, the skin covering an average total surface area of 1.8 m(2) has approximately tenfold more DCs than the average 5 L of total blood volume (Wang et al., J Invest Dermatol 134:965-974, 2014). DCs migrate spontaneously from skin explants cultured ex vivo, which provide an easy method of cell isolation (Larsen et al., J Exp Med 172:1483-1493, 1990; Lenz et al., J Clin Invest 92:2587-2596, 1993; Nestle et al., J Immunol 151:6535-6545, 1993). These factors led to the extensive use of skin DCs as the "prototype" migratory DCs in human studies. In this chapter, we detail the protocols to isolate DCs and resident macrophages from human skin. We also provide a multiparameter flow cytometry gating strategy to identify human skin DCs and to distinguish them from macrophages. PMID:27142012

  7. Follicular dendritic cells in health and disease

    PubMed Central

    El Shikh, Mohey Eldin M.; Pitzalis, Costantino

    2012-01-01

    Follicular dendritic cells (FDCs) are unique immune cells that contribute to the regulation of humoral immune responses. These cells are located in the B-cell follicles of secondary lymphoid tissues where they trap and retain antigens (Ags) in the form of highly immunogenic immune complexes (ICs) consisting of Ag plus specific antibody (Ab) and/or complement proteins. FDCs multimerize Ags and present them polyvalently to B-cells in periodically arranged arrays that extensively crosslink the B-cell receptors for Ag (BCRs). FDC-FcγRIIB mediates IC periodicity, and FDC-Ag presentation combined with other soluble and membrane bound signals contributed by FDCs, like FDC-BAFF, -IL-6, and -C4bBP, are essential for the induction of the germinal center (GC) reaction, the maintenance of serological memory, and the remarkable ability of FDC-Ags to induce specific Ab responses in the absence of cognate T-cell help. On the other hand, FDCs play a negative role in several disease conditions including chronic inflammatory diseases, autoimmune diseases, HIV/AIDS, prion diseases, and follicular lymphomas. Compared to other accessory immune cells, FDCs have received little attention, and their functions have not been fully elucidated. This review gives an overview of FDC structure, and recapitulates our current knowledge on the immunoregulatory functions of FDCs in health and disease. A better understanding of FDCs should permit better regulation of Ab responses to suit the therapeutic manipulation of regulated and dysregulated immune responses. PMID:23049531

  8. Transcriptional regulation of dendritic cell diversity.

    PubMed

    Chopin, Michaël; Allan, Rhys S; Belz, Gabrielle T

    2012-01-01

    Dendritic cells (DCs) are specialized antigen presenting cells that are exquisitely adapted to sense pathogens and induce the development of adaptive immune responses. They form a complex network of phenotypically and functionally distinct subsets. Within this network, individual DC subsets display highly specific roles in local immunosurveillance, migration, and antigen presentation. This division of labor amongst DCs offers great potential to tune the immune response by harnessing subset-specific attributes of DCs in the clinical setting. Until recently, our understanding of DC subsets has been limited and paralleled by poor clinical translation and efficacy. We have now begun to unravel how different DC subsets develop within a complex multilayered system. These findings open up exciting possibilities for targeted manipulation of DC subsets. Furthermore, ground-breaking developments overcoming a major translational obstacle - identification of similar DC populations in mouse and man - now sets the stage for significant advances in the field. Here we explore the determinants that underpin cellular and transcriptional heterogeneity within the DC network, how these influence DC distribution and localization at steady-state, and the capacity of DCs to present antigens via direct or cross-presentation during pathogen infection.

  9. Brain dendritic cells: biology and pathology

    PubMed Central

    D’Agostino, Paul M.; Gottfried-Blackmore, Andres; Anandasabapathy, Niroshana

    2013-01-01

    Dendritic cells (DC) are the professional antigen-presenting cells of the immune system. In their quiescent and mature form, the presentation of self-antigens by DC leads to tolerance; whereas, antigen presentation by mature DC, after stimulation by pathogen-associated molecular patterns, leads to the onset of antigen-specific immunity. DC have been found in many of the major organs in mammals (e.g. skin, heart, lungs, intestines and spleen), while the brain has long been considered devoid of DC in the absence of neuroinflammation. Consequently, microglia, the resident immune cell of the brain, have been charged with many functional attributes commonly ascribed to DC. Recent evidence has challenged the notion that DC are either absent or minimal players in brain immune surveillance. This review will discuss the recent literature examining DC involvement within both the young and aged steady-state brain. We will also examine DC contributions during various forms of neuroinflammation resulting from neurodegenerative autoimmune disease, injury, and CNS infections. This review also touches upon DC trafficking between the central nervous system and peripheral immune compartments during viral infections, the new molecular technologies that could be employed to enhance our current understanding of brain DC ontogeny, and some potential therapeutic uses of DC within the CNS. PMID:22825593

  10. Ontogeny of rat thymic dendritic cells.

    PubMed Central

    Vicente, A; Varas, A; Alonso, L; Gómez de Moral, M; Zapata, A G

    1994-01-01

    In the present study we have combined various in vivo and in vitro approaches to analyse the appearance and development throughout ontogeny and postnatal life of the dendritic cell (DC) populations of rat thymus. The in situ ultrastructural study demonstrated immature interdigitating cells (IDC)/DC in the thymus of 17-day-old embryonic rats, but thymic stromal cell cultures from 16-day-old fetal rats seemed to contain DC precursors which, after several days in culture, produced strongly class II major histocompatibility complex (MHC)-positive, mature DC. According to morphology and class II MHC expression we also defined three different DC populations in the late embryonic rat thymus; two of them, which remained in the adult rat thymus, could represent distinct developmental stages within the IDC/DC lineage. The third cell subset might be involved in a massive process of negative selection, presumably occurring at the end of fetal life in the rat thymus. In supporting the existence of thymic DC subpopulations, we also demonstrated a differential expression of various cell markers, including CD4, CD8, CD25, adhesion molecules and the antigen recognized by OX44 monoclonal antibody (mAb), on thymic DC during both embryonic and adult life. Their possible significance for the attributed functions to thymic DC are discussed extensively. Images Figure 1 Figures 3-5 Figures 6-9 PMID:7913915

  11. Mycobacterium avium subspecies impair dendritic cell maturation.

    PubMed

    Basler, Tina; Brumshagen, Christina; Beineke, Andreas; Goethe, Ralph; Bäumer, Wolfgang

    2013-10-01

    Mycobacterium avium ssp. paratuberculosis (MAP) causes Johne's disease, a chronic, granulomatous enteritis of ruminants. Dendritic cells (DC) of the gut are ideally placed to combat invading mycobacteria; however, little is known about their interaction with MAP. Here, we investigated the interaction of MAP and the closely related M. avium ssp. avium (MAA) with murine DC and the effect of infected macrophages on DC maturation. The infection of DC with MAP or MAA induced DC maturation, which differed to that of LPS as maturation was accompanied by higher production of IL-10 and lower production of IL-12. Treatment of maturing DC with supernatants from mycobacteria-infected macrophages resulted in impaired DC maturation, leading to a semi-mature, tolerogenic DC phenotype expressing low levels of MHCII, CD86 and TNF-α after LPS stimulation. Though the cells were not completely differentiated they responded with an increased IL-10 and a decreased IL-12 production. Using recombinant cytokines we provide evidence that the semi-mature DC phenotype results from a combination of secreted cytokines and released antigenic mycobacterial components of the infected macrophage. Our results indicate that MAP and MAA are able to subvert DC function directly by infecting and indirectly via the milieu created by infected macrophages.

  12. Harnessing Dendritic Cells to Generate Cancer Vaccines

    PubMed Central

    Palucka, Karolina; Ueno, Hideki; Fay, Joseph; Banchereau, Jacques

    2009-01-01

    Passive immunotherapy of cancer, i.e., transfer of T cells or antibodies, can lead to some objective clinical responses, thus demonstrating that the immune system can reject tumors. However, passive immunotherapy is not expected to yield memory T cells that might control tumor outgrowth. Active immunotherapy with dendritic cell (DCs) vaccines has the potential to induce tumor-specific effector and memory T cells. Clinical trials testing first generation DC vaccines pulsed with tumor antigens provided a proof-of-principle that therapeutic immunity can be elicited. Newer generation DC vaccines are build on the increased knowledge of the DC system including the existence of distinct DC subsets and their plasticity all leading to generation of distinct types of immunity. Rather than the quantity of IFN-γ secreting CD8+ T cells, we should aim at generating high quality high avidity poly-functional effector CD8+ T cells able to reject tumors and long-lived memory CD8+ T cells able to prevent relapse. PMID:19769741

  13. Role of dendritic cells in cardiovascular diseases

    PubMed Central

    Zhang, Yi; Zhang, Cuihua

    2010-01-01

    Dendritic cells (DCs) are potent antigen-presenting cells that bridge innate and adaptive immune responses. Recent work has elucidated the DC life cycle, including several important stages such as maturation, migration and homeostasis, as well as DC classification and subsets/locations, which provided etiological insights on the role of DCs in disease processes. DCs have a close relationship to endothelial cells and they interact with each other to maintain immunity. DCs are deposited in the atherosclerotic plaque and contribute to the pathogenesis of atherosclerosis. In addition, the necrotic cardiac cells induced by ischemia activate DCs by Toll-like receptors, which initiate innate and adaptive immune responses to renal, hepatic and cardiac ischemia reperfusion injury (IRI). Furthermore, DCs are involved in the acute/chronic rejection of solid organ transplantation and mediate transplant tolerance as well. Advancing our knowledge of the biology of DCs will aid development of new approaches to treat many cardiovascular diseases, including atherosclerosis, cardiac IRI and transplantation. PMID:21179302

  14. Nuclear Regulatory Commission Semiannual Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-20

    ... agenda on April 26, 2010 (75 FR 21960). For this edition of the NRC's regulatory agenda, the most... publication of the last NRC semiannual agenda on April 26, 2010 (75 FR 21960). Within each group, the rules... regulations to improve the control over the distribution of source material to exempt persons and to...

  15. A novel theoretical approach to the analysis of dendritic transients.

    PubMed Central

    Agmon-Snir, H

    1995-01-01

    A novel theoretical framework for analyzing dendritic transients is introduced. This approach, called the method of moments, is an extension of Rall's cable theory for dendrites. It provides analytic investigation of voltage attenuation, signal delay, and synchronization problems in passive dendritic trees. In this method, the various moments of a transient signal are used to characterize the properties of the transient. The strength of the signal is measured by the time integral of the signal, its characteristic time is determined by its centroid ("center of gravity"), and the width of the signal is determined by a measure similar to the standard deviation in probability theory. Using these signal properties, the method of moments provides theorems, expressions, and efficient algorithms for analyzing the voltage response in arbitrary passive trees. The method yields new insights into spatiotemporal integration, coincidence detection mechanisms, and the properties of local interactions between synaptic inputs in dendritic trees. The method can also be used for matching dendritic neuron models to experimental data and for the analysis of synaptic inputs recorded experimentally. Images FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 FIGURE 10 PMID:8580308

  16. A dendrite-suppressing composite ion conductor from aramid nanofibres

    NASA Astrophysics Data System (ADS)

    Tung, Siu-On; Ho, Szushen; Yang, Ming; Zhang, Ruilin; Kotov, Nicholas A.

    2015-01-01

    Dendrite growth threatens the safety of batteries by piercing the ion-transporting separators between the cathode and anode. Finding a dendrite-suppressing material that combines high modulus and high ionic conductance has long been considered a major technological and materials science challenge. Here we demonstrate that these properties can be attained in a composite made from Kevlar-derived aramid nanofibres assembled in a layer-by-layer manner with poly(ethylene oxide). Importantly, the porosity of the membranes is smaller than the growth area of the dendrites so that aramid nanofibres eliminate ‘weak links’ where the dendrites pierce the membranes. The aramid nanofibre network suppresses poly(ethylene oxide) crystallization detrimental for ion transport, giving a composite that exhibits high modulus, ionic conductivity, flexibility, ion flux rates and thermal stability. Successful suppression of hard copper dendrites by the composite ion conductor at extreme discharge conditions is demonstrated, thereby providing a new approach for the materials engineering of solid ion conductors.

  17. A dendrite-suppressing composite ion conductor from aramid nanofibres.

    PubMed

    Tung, Siu-On; Ho, Szushen; Yang, Ming; Zhang, Ruilin; Kotov, Nicholas A

    2015-01-27

    Dendrite growth threatens the safety of batteries by piercing the ion-transporting separators between the cathode and anode. Finding a dendrite-suppressing material that combines high modulus and high ionic conductance has long been considered a major technological and materials science challenge. Here we demonstrate that these properties can be attained in a composite made from Kevlar-derived aramid nanofibres assembled in a layer-by-layer manner with poly(ethylene oxide). Importantly, the porosity of the membranes is smaller than the growth area of the dendrites so that aramid nanofibres eliminate 'weak links' where the dendrites pierce the membranes. The aramid nanofibre network suppresses poly(ethylene oxide) crystallization detrimental for ion transport, giving a composite that exhibits high modulus, ionic conductivity, flexibility, ion flux rates and thermal stability. Successful suppression of hard copper dendrites by the composite ion conductor at extreme discharge conditions is demonstrated, thereby providing a new approach for the materials engineering of solid ion conductors.

  18. A dendrite-suppressing composite ion conductor from aramid nanofibres.

    PubMed

    Tung, Siu-On; Ho, Szushen; Yang, Ming; Zhang, Ruilin; Kotov, Nicholas A

    2015-01-01

    Dendrite growth threatens the safety of batteries by piercing the ion-transporting separators between the cathode and anode. Finding a dendrite-suppressing material that combines high modulus and high ionic conductance has long been considered a major technological and materials science challenge. Here we demonstrate that these properties can be attained in a composite made from Kevlar-derived aramid nanofibres assembled in a layer-by-layer manner with poly(ethylene oxide). Importantly, the porosity of the membranes is smaller than the growth area of the dendrites so that aramid nanofibres eliminate 'weak links' where the dendrites pierce the membranes. The aramid nanofibre network suppresses poly(ethylene oxide) crystallization detrimental for ion transport, giving a composite that exhibits high modulus, ionic conductivity, flexibility, ion flux rates and thermal stability. Successful suppression of hard copper dendrites by the composite ion conductor at extreme discharge conditions is demonstrated, thereby providing a new approach for the materials engineering of solid ion conductors. PMID:25626170

  19. Tropomodulin isoforms utilize specific binding functions to modulate dendrite development.

    PubMed

    Gray, Kevin T; Suchowerska, Alexandra K; Bland, Tyler; Colpan, Mert; Wayman, Gary; Fath, Thomas; Kostyukova, Alla S

    2016-06-01

    Tropomodulins (Tmods) cap F-actin pointed ends and have altered expression in the brain in neurological diseases. The function of Tmods in neurons has been poorly studied and their role in neurological diseases is entirely unknown. In this article, we show that Tmod1 and Tmod2, but not Tmod3, are positive regulators of dendritic complexity and dendritic spine morphology. Tmod1 increases dendritic branching distal from the cell body and the number of filopodia/thin spines. Tmod2 increases dendritic branching proximal to the cell body and the number of mature dendritic spines. Tmods utilize two actin-binding sites and two tropomyosin (Tpm)-binding sites to cap F-actin. Overexpression of Tmods with disrupted Tpm-binding sites indicates that Tmod1 and Tmod2 differentially utilize their Tpm- and actin-binding sites to affect morphology. Disruption of Tmod1's Tpm-binding sites abolished the overexpression phenotype. In contrast, overexpression of the mutated Tmod2 caused the same phenotype as wild type overexpression. Proximity ligation assays indicate that the mutated Tmods are shuttled similarly to wild type Tmods. Our data begins to uncover the roles of Tmods in neural development and the mechanism by which Tmods alter neural morphology. These observations in combination with altered Tmod expression found in several neurological diseases also suggest that dysregulation of Tmod expression may be involved in the pathology of these diseases. © 2016 Wiley Periodicals, Inc. PMID:27126680

  20. Location-Dependent Excitatory Synaptic Interactions in Pyramidal Neuron Dendrites

    PubMed Central

    Behabadi, Bardia F.; Polsky, Alon; Jadi, Monika; Schiller, Jackie; Mel, Bartlett W.

    2012-01-01

    Neocortical pyramidal neurons (PNs) receive thousands of excitatory synaptic contacts on their basal dendrites. Some act as classical driver inputs while others are thought to modulate PN responses based on sensory or behavioral context, but the biophysical mechanisms that mediate classical-contextual interactions in these dendrites remain poorly understood. We hypothesized that if two excitatory pathways bias their synaptic projections towards proximal vs. distal ends of the basal branches, the very different local spike thresholds and attenuation factors for inputs near and far from the soma might provide the basis for a classical-contextual functional asymmetry. Supporting this possibility, we found both in compartmental models and electrophysiological recordings in brain slices that the responses of basal dendrites to spatially separated inputs are indeed strongly asymmetric. Distal excitation lowers the local spike threshold for more proximal inputs, while having little effect on peak responses at the soma. In contrast, proximal excitation lowers the threshold, but also substantially increases the gain of distally-driven responses. Our findings support the view that PN basal dendrites possess significant analog computing capabilities, and suggest that the diverse forms of nonlinear response modulation seen in the neocortex, including uni-modal, cross-modal, and attentional effects, could depend in part on pathway-specific biases in the spatial distribution of excitatory synaptic contacts onto PN basal dendritic arbors. PMID:22829759

  1. Homophilic Protocadherin Cell-Cell Interactions Promote Dendrite Complexity.

    PubMed

    Molumby, Michael J; Keeler, Austin B; Weiner, Joshua A

    2016-05-01

    Growth of a properly complex dendrite arbor is a key step in neuronal differentiation and a prerequisite for neural circuit formation. Diverse cell surface molecules, such as the clustered protocadherins (Pcdhs), have long been proposed to regulate circuit formation through specific cell-cell interactions. Here, using transgenic and conditional knockout mice to manipulate γ-Pcdh repertoire in the cerebral cortex, we show that the complexity of a neuron's dendritic arbor is determined by homophilic interactions with other cells. Neurons expressing only one of the 22 γ-Pcdhs can exhibit either exuberant or minimal dendrite complexity, depending only on whether surrounding cells express the same isoform. Furthermore, loss of astrocytic γ-Pcdhs, or disruption of astrocyte-neuron homophilic matching, reduces dendrite complexity cell non-autonomously. Our data indicate that γ-Pcdhs act locally to promote dendrite arborization via homophilic matching, and they confirm that connectivity in vivo depends on molecular interactions between neurons and between neurons and astrocytes.

  2. Dendrite growth under forced convection: analysis methods and experimental tests

    NASA Astrophysics Data System (ADS)

    Alexandrov, D. V.; Galenko, P. K.

    2014-08-01

    An analysis is given of the nonisothermal growth of a dendrite crystal under forced fluid flow in a binary system. The theoretical model utilized employs a free moving crystal-liquid interface and makes use of the Oseen approximation for the equations of motion of the liquid. A criterion for the stable growth of two-dimensional and three-dimensional parabolic dendrites is derived under the assumption of an anisotropic surface tension at the crystal-liquid interface, which generalizes the previous known results for the stable growth of a dendrite with convection in a one-component fluid and for the growth of a dendrite in a two-component system at rest. The criterion obtained within the Oseen hydrodynamic approximation is extended to arbitrary Peclet numbers and dendrite growth with convection in a nonisothermal multicomponent system. Model predictions are compared with experimental data on crystal growth kinetics in droplets processed in electromagnetic and electrostatic levitation facilities. Theoretical and simulation methods currently being developed are applied to crystallization processes under earthly and reduced gravity conditions.

  3. Dendritic Cells: A Spot on Sialic Acid

    PubMed Central

    Crespo, Hélio J.; Lau, Joseph T. Y.; Videira, Paula A.

    2013-01-01

    Glycans decorating cell surface and secreted proteins and lipids occupy the juncture where critical host–host and host-pathogen interactions occur. The role of glycan epitopes in cell–cell and cell-pathogen adhesive events is already well-established, and cell surface glycan structures change rapidly in response to stimulus and inflammatory cues. Despite the wide acceptance that glycans are centrally implicated in immunity, exactly how glycans and their changes contribute to the overall immune response remains poorly defined. Sialic acids are unique sugars that usually occupy the terminal position of the glycan chains and may be modified by external factors, such as pathogens, or upon specific physiological cellular events. At cell surface, sialic acid-modified structures form the key fundamental determinants for a number of receptors with known involvement in cellular adhesiveness and cell trafficking, such as the Selectins and the Siglec families of carbohydrate recognizing receptors. Dendritic cells (DCs) preside over the transition from innate to the adaptive immune repertoires, and no other cell has such relevant role in antigen screening, uptake, and its presentation to lymphocytes, ultimately triggering the adaptive immune response. Interestingly, sialic acid-modified structures are involved in all DC functions, such as antigen uptake, DC migration, and capacity to prime T cell responses. Sialic acid content changes along DC differentiation and activation and, while, not yet fully understood, these changes have important implications in DC functions. This review focuses on the developmental regulation of DC surface sialic acids and how manipulation of DC surface sialic acids can affect immune-critical DC functions by altering antigen endocytosis, pathogen and tumor cell recognition, cell recruitment, and capacity for T cell priming. The existing evidence points to a potential of DC surface sialylation as a therapeutic target to improve and diversify DC

  4. Regulatory guidance document

    SciTech Connect

    1994-05-01

    The Office of Civilian Radioactive Waste Management (OCRWM) Program Management System Manual requires preparation of the OCRWM Regulatory Guidance Document (RGD) that addresses licensing, environmental compliance, and safety and health compliance. The document provides: regulatory compliance policy; guidance to OCRWM organizational elements to ensure a consistent approach when complying with regulatory requirements; strategies to achieve policy objectives; organizational responsibilities for regulatory compliance; guidance with regard to Program compliance oversight; and guidance on the contents of a project-level Regulatory Compliance Plan. The scope of the RGD includes site suitability evaluation, licensing, environmental compliance, and safety and health compliance, in accordance with the direction provided by Section 4.6.3 of the PMS Manual. Site suitability evaluation and regulatory compliance during site characterization are significant activities, particularly with regard to the YW MSA. OCRWM`s evaluation of whether the Yucca Mountain site is suitable for repository development must precede its submittal of a license application to the Nuclear Regulatory Commission (NRC). Accordingly, site suitability evaluation is discussed in Chapter 4, and the general statements of policy regarding site suitability evaluation are discussed in Section 2.1. Although much of the data and analyses may initially be similar, the licensing process is discussed separately in Chapter 5. Environmental compliance is discussed in Chapter 6. Safety and Health compliance is discussed in Chapter 7.

  5. Native cellulose nanofibrills induce immune tolerance in vitro by acting on dendritic cells

    PubMed Central

    Tomić, Sergej; Kokol, Vanja; Mihajlović, Dušan; Mirčić, Aleksandar; Čolić, Miodrag

    2016-01-01

    Cellulose nanofibrills (CNFs) are attractive biocompatible, natural nanomaterials for wide biomedical applications. However, the immunological mechanisms of CNFs have been poorly investigated. Considering that dendritic cells (DCs) are the key immune regulatory cells in response to nanomaterials, our aim was to investigate the immunological mechanisms of CNFs in a model of DC-mediated immune response. We found that non-toxic concentrations of CNFs impaired the differentiation, and subsequent maturation of human monocyte-derived (mo)-DCs. In a co-culture with CD4+T cells, CNF-treated mo-DCs possessed a weaker allostimulatory and T helper (Th)1 and Th17 polarizing capacity, but a stronger capacity to induce Th2 cells and CD4+CD25hiFoxP3hi regulatory T cells. This correlated with an increased immunoglobulin-like transcript-4 and indolamine dioxygenase-1 expression by CNF-treated mo-DCs, following the partial internalization of CNFs and the accumulation of CD209 and actin bundles at the place of contacts with CNFs. Cumulatively, we showed that CNFs are able to induce an active immune tolerance by inducing tolerogenic DCs, which could be beneficial for the application of CNFs in wound healing and chronic inflammation therapies. PMID:27558765

  6. Modulation of Dendritic-Epithelial Cell Responses against Sphingomonas Paucimobilis by Dietary Fibers.

    PubMed

    Bermudez-Brito, Miriam; Faas, Marijke M; de Vos, Paul

    2016-01-01

    Non-fermenting Gram-negative bacilli, such as Sphingomonas paucimobilis (S.paucimobilis), are among the most widespread causes of nosocomial infections. Up to now, no definitive guidelines exist for antimicrobial therapy for S. paucimobilis infections. As we have shown that some dietary fibers exhibit pronounced immune-regulatory properties, we hypothesized that specific immune active dietary fibers might modulate the responses against S. paucimobilis. We studied the immunomodulatory effects of dietary fibers against S. paucimobilis on cytokine release and maturation of human dendritic cells (DCs) in co-cultures of DCs and intestinal epithelial cells (IECs). S. paucimobilis infection resulted in increased release of pro-inflammatory cytokines and chemokines by DCs/IECs; these effects were strongly attenuated by specific dietary fibers. Chicory inulin, sugar beet pectin, and both starches had the strongest regulatory effects. IL-12 and TNF-α were drastically diminished upon exposure to chicory inulin and sugar beet pectin, or both starches. High-maize 260, was more effective in the reduction of chemokine release than the others fibers tested. In summary, chicory inulin, sugar beet pectin, High-maize 260, and Novelose 330 attenuate S. paucimobilis-induced cytokines. These results demonstrate that dietary fibers with a specific chemical composition can be used to manage immune responses against pathogens such as S. paucimobilis. PMID:27452116

  7. Modulation of Dendritic-Epithelial Cell Responses against Sphingomonas Paucimobilis by Dietary Fibers

    PubMed Central

    Bermudez-Brito, Miriam; Faas, Marijke M; de Vos, Paul

    2016-01-01

    Non-fermenting Gram-negative bacilli, such as Sphingomonas paucimobilis (S.paucimobilis), are among the most widespread causes of nosocomial infections. Up to now, no definitive guidelines exist for antimicrobial therapy for S. paucimobilis infections. As we have shown that some dietary fibers exhibit pronounced immune-regulatory properties, we hypothesized that specific immune active dietary fibers might modulate the responses against S. paucimobilis. We studied the immunomodulatory effects of dietary fibers against S. paucimobilis on cytokine release and maturation of human dendritic cells (DCs) in co-cultures of DCs and intestinal epithelial cells (IECs). S. paucimobilis infection resulted in increased release of pro-inflammatory cytokines and chemokines by DCs/IECs; these effects were strongly attenuated by specific dietary fibers. Chicory inulin, sugar beet pectin, and both starches had the strongest regulatory effects. IL-12 and TNF-α were drastically diminished upon exposure to chicory inulin and sugar beet pectin, or both starches. High-maize 260, was more effective in the reduction of chemokine release than the others fibers tested. In summary, chicory inulin, sugar beet pectin, High-maize 260, and Novelose 330 attenuate S. paucimobilis-induced cytokines. These results demonstrate that dietary fibers with a specific chemical composition can be used to manage immune responses against pathogens such as S. paucimobilis. PMID:27452116

  8. Native cellulose nanofibrills induce immune tolerance in vitro by acting on dendritic cells

    NASA Astrophysics Data System (ADS)

    Tomić, Sergej; Kokol, Vanja; Mihajlović, Dušan; Mirčić, Aleksandar; Čolić, Miodrag

    2016-08-01

    Cellulose nanofibrills (CNFs) are attractive biocompatible, natural nanomaterials for wide biomedical applications. However, the immunological mechanisms of CNFs have been poorly investigated. Considering that dendritic cells (DCs) are the key immune regulatory cells in response to nanomaterials, our aim was to investigate the immunological mechanisms of CNFs in a model of DC-mediated immune response. We found that non-toxic concentrations of CNFs impaired the differentiation, and subsequent maturation of human monocyte-derived (mo)-DCs. In a co-culture with CD4+T cells, CNF-treated mo-DCs possessed a weaker allostimulatory and T helper (Th)1 and Th17 polarizing capacity, but a stronger capacity to induce Th2 cells and CD4+CD25hiFoxP3hi regulatory T cells. This correlated with an increased immunoglobulin-like transcript-4 and indolamine dioxygenase-1 expression by CNF-treated mo-DCs, following the partial internalization of CNFs and the accumulation of CD209 and actin bundles at the place of contacts with CNFs. Cumulatively, we showed that CNFs are able to induce an active immune tolerance by inducing tolerogenic DCs, which could be beneficial for the application of CNFs in wound healing and chronic inflammation therapies.

  9. Dendritic Cells Regulate GPR34 through Mitogenic Signals and Undergo Apoptosis in Its Absence.

    PubMed

    Jäger, Elisabeth; Schulz, Angela; Lede, Vera; Lin, Chen-Ching; Schöneberg, Torsten; Le Duc, Diana

    2016-03-15

    Dendritic cells (DCs) are specifically equipped with the G protein-coupled receptor 34 (GPR34). Tight regulation of GPR34 gene expression seems highly important for proper immunological functions, because the absence of this receptor leads to an alteration of the immune response, whereas overexpression was reported to be involved in neuroinflammation. However, the regulatory mechanism of GPR34 expression has not yet been investigated. Whole-transcriptome RNA sequencing analysis from spleens and DCs of GPR34 knockout and wild-type mice, combined with protein-protein interaction data, revealed functional modules affected by the absence of this receptor. Among these, NF-κB, MAPK, and apoptosis-signaling pathways showed high significance. Using murine DCs we experimentally show that NF-κB and MAPK pathways are involved in the downregulation of GPR34. DCs lacking GPR34 have a higher caspase-3/7 activity and increased apoptosis levels. Our study reveals a novel role of GPR34 in the fate of DCs and identifies a regulatory mechanism that could be relevant for treatment of GPR34-overexpressing pathologies, such as neuroinflammatory or cancer conditions. PMID:26851221

  10. Modulation of Dendritic-Epithelial Cell Responses against Sphingomonas Paucimobilis by Dietary Fibers.

    PubMed

    Bermudez-Brito, Miriam; Faas, Marijke M; de Vos, Paul

    2016-07-25

    Non-fermenting Gram-negative bacilli, such as Sphingomonas paucimobilis (S.paucimobilis), are among the most widespread causes of nosocomial infections. Up to now, no definitive guidelines exist for antimicrobial therapy for S. paucimobilis infections. As we have shown that some dietary fibers exhibit pronounced immune-regulatory properties, we hypothesized that specific immune active dietary fibers might modulate the responses against S. paucimobilis. We studied the immunomodulatory effects of dietary fibers against S. paucimobilis on cytokine release and maturation of human dendritic cells (DCs) in co-cultures of DCs and intestinal epithelial cells (IECs). S. paucimobilis infection resulted in increased release of pro-inflammatory cytokines and chemokines by DCs/IECs; these effects were strongly attenuated by specific dietary fibers. Chicory inulin, sugar beet pectin, and both starches had the strongest regulatory effects. IL-12 and TNF-α were drastically diminished upon exposure to chicory inulin and sugar beet pectin, or both starches. High-maize 260, was more effective in the reduction of chemokine release than the others fibers tested. In summary, chicory inulin, sugar beet pectin, High-maize 260, and Novelose 330 attenuate S. paucimobilis-induced cytokines. These results demonstrate that dietary fibers with a specific chemical composition can be used to manage immune responses against pathogens such as S. paucimobilis.

  11. Cysticerci Drive Dendritic Cells to Promote In Vitro and In Vivo Tregs Differentiation

    PubMed Central

    Adalid-Peralta, Laura; Arce-Sillas, Asiel; Fragoso, Gladis; Cárdenas, Graciela; Rosetti, Marcos; Casanova-Hernández, Didier; Rangel-Escareño, Claudia; Uribe-Figueroa, Laura; Fleury, Agnes; Sciutto, Edda

    2013-01-01

    Regulatory T cells (Tregs) play a crucial role in immune homeostasis. Treg induction is a strategy that parasites have evolved to modulate the host's inflammatory environment, facilitating their establishment and permanence. In human Taenia solium neurocysticercosis (NC), the concurrence of increased peripheral and central Treg levels and their capacity to inhibit T cell activation and proliferation support their role in controlling neuroinflammation. This study is aimed at identifing possible mechanisms of Treg induction in human NC. Monocyte-derived dendritic cells (DC) from healthy human donors, cocultivated with autologous CD4+ naïve cells either in the presence or absence of cysticerci, promoted CD25highFoxp3+ Treg differentiation. An increased Treg induction was observed when cysticerci were present. Moreover, an augmentation of suppressive-related molecules (SLAMF1, B7-H1, and CD205) was found in parasite-induced DC differentiation. Increased Tregs and a higher in vivo DC expression of the regulatory molecules SLAMF1 and CD205 in NC patients were also found. SLAMF1 gene was downregulated in NC patients with extraparenchymal cysticerci, exhibiting higher inflammation levels than patients with parenchymal parasites. Our findings suggest that cysticerci may modulate DC to favor a suppressive environment, which may help parasite establishment, minimizing the excessive inflammation, which may lead to tissue damage. PMID:23762101

  12. Targeting Antigens to Dec-205 on Dendritic Cells Induces Immune Protection in Experimental Colitis in Mice

    PubMed Central

    Wadwa, Munisch; Klopfleisch, Robert; Buer, Jan; Westendorf, Astrid M.

    2016-01-01

    The endocytotic c-type lectin receptor DEC-205 is highly expressed on immature dendritic cells. In previous studies, it was shown that antigen-targeting to DEC-205 is a useful tool for the induction of antigen-specific Foxp3+ regulatory T cells and thereby can prevent inflammatory processes. However, whether this approach is sufficient to mediate tolerance in mucosal tissues like the gut is unknown. In this study, we established a new mouse model in which the adoptive transfer of naive hemagglutinin (HA)-specific CD4+Foxp3– T cells into VILLIN-HA transgenic mice leads to severe colitis. To analyze if antigen-targeting to DEC-205 could protect against inflammation of the gut, VILLIN-HA transgenic mice were injected with an antibody–antigen complex consisting of the immunogenic HA110–120 peptide coupled to an α-DEC-205 antibody (DEC-HA) before adoptive T cell transfer. DEC-HA-treated mice showed significantly less signs of intestinal inflammation as was demonstrated by reduced loss of body weight and histopathology in the gut. Strikingly, abrogated intestinal inflammation was mediated via the conversion of naive HA-specific CD4+Foxp3– T cells into HA-specific CD4+Foxp3+ regulatory T cells. In this study, we provide evidence that antigen-targeting to DEC-205 can be utilized for the induction of tolerance in mucosal organs that are confronted with large numbers of exogenous antigens. PMID:27141310

  13. Native cellulose nanofibrills induce immune tolerance in vitro by acting on dendritic cells.

    PubMed

    Tomić, Sergej; Kokol, Vanja; Mihajlović, Dušan; Mirčić, Aleksandar; Čolić, Miodrag

    2016-01-01

    Cellulose nanofibrills (CNFs) are attractive biocompatible, natural nanomaterials for wide biomedical applications. However, the immunological mechanisms of CNFs have been poorly investigated. Considering that dendritic cells (DCs) are the key immune regulatory cells in response to nanomaterials, our aim was to investigate the immunological mechanisms of CNFs in a model of DC-mediated immune response. We found that non-toxic concentrations of CNFs impaired the differentiation, and subsequent maturation of human monocyte-derived (mo)-DCs. In a co-culture with CD4(+)T cells, CNF-treated mo-DCs possessed a weaker allostimulatory and T helper (Th)1 and Th17 polarizing capacity, but a stronger capacity to induce Th2 cells and CD4(+)CD25(hi)FoxP3(hi) regulatory T cells. This correlated with an increased immunoglobulin-like transcript-4 and indolamine dioxygenase-1 expression by CNF-treated mo-DCs, following the partial internalization of CNFs and the accumulation of CD209 and actin bundles at the place of contacts with CNFs. Cumulatively, we showed that CNFs are able to induce an active immune tolerance by inducing tolerogenic DCs, which could be beneficial for the application of CNFs in wound healing and chronic inflammation therapies. PMID:27558765

  14. Expansion of a BDCA1+CD14+ Myeloid Cell Population in Melanoma Patients May Attenuate the Efficacy of Dendritic Cell Vaccines.

    PubMed

    Bakdash, Ghaith; Buschow, Sonja I; Gorris, Mark A J; Halilovic, Altuna; Hato, Stanleyson V; Sköld, Annette E; Schreibelt, Gerty; Sittig, Simone P; Torensma, Ruurd; Duiveman-de Boer, Tjitske; Schröder, Christoph; Smits, Evelien L; Figdor, Carl G; de Vries, I Jolanda M

    2016-08-01

    The tumor microenvironment is characterized by regulatory T cells, type II macrophages, myeloid-derived suppressor cells, and other immunosuppressive cells that promote malignant progression. Here we report the identification of a novel BDCA1(+)CD14(+) population of immunosuppressive myeloid cells that are expanded in melanoma patients and are present in dendritic cell-based vaccines, where they suppress CD4(+) T cells in an antigen-specific manner. Mechanistic investigations showed that BDCA1(+)CD14(+) cells expressed high levels of the immune checkpoint molecule PD-L1 to hinder T-cell proliferation. While this BDCA1(+)CD14(+) cell population expressed markers of both BDCA1(+) dendritic cells and monocytes, analyses of function, transcriptome, and proteome established their unique nature as exploited by tumors for immune escape. We propose that targeting these cells may improve the efficacy of cancer immunotherapy. Cancer Res; 76(15); 4332-46. ©2016 AACR. PMID:27325645

  15. Regulatory sequence analysis tools.

    PubMed

    van Helden, Jacques

    2003-07-01

    The web resource Regulatory Sequence Analysis Tools (RSAT) (http://rsat.ulb.ac.be/rsat) offers a collection of software tools dedicated to the prediction of regulatory sites in non-coding DNA sequences. These tools include sequence retrieval, pattern discovery, pattern matching, genome-scale pattern matching, feature-map drawing, random sequence generation and other utilities. Alternative formats are supported for the representation of regulatory motifs (strings or position-specific scoring matrices) and several algorithms are proposed for pattern discovery. RSAT currently holds >100 fully sequenced genomes and these data are regularly updated from GenBank.

  16. Epidermal cells are the primary phagocytes in the fragmentation and clearance of degenerating dendrites in Drosophila

    PubMed Central

    Xiao, Hui; Wang, Denan; Franc, Nathalie C.; Jan, Lily Yeh; Jan, Yuh-Nung

    2014-01-01

    SUMMARY During developmental remodeling, neurites destined for pruning often degenerate on-site. Physical injury also induces degeneration of neurites distal to the injury site. Prompt clearance of degenerating neurites is important for maintaining tissue homeostasis and preventing inflammatory responses. Here we show that in both dendrite pruning and dendrite injury of Drosophila sensory neurons, epidermal cells rather than hemocytes are the primary phagocytes in clearing degenerating dendrites. Epidermal cells act via Draper-mediated recognition to facilitate dendrite degeneration and to engulf and degrade degenerating dendrites. Using multiple dendritic membrane markers to trace phagocytosis, we show that two members of the CD36 family, croquemort (crq) and debris buster (dsb), act at distinct stages of phagosome maturation for dendrite clearance. Our finding reveals the physiological importance of coordination between neurons and their surrounding epidermis, for both dendrite fragmentation and clearance. PMID:24412417

  17. Dendrite characteristics in directionally solidified Pb-8 pct Au and Pb-3 pct Pd alloys

    NASA Technical Reports Server (NTRS)

    Tewari, S. N.

    1986-01-01

    The dendritic microstructure and solute compression profiles for Pb-8 pct Au and Pb-3 pct Pd alloy samples are examined. Two groups of models, the minimum undercooled dendrite tip model of Burden and Hunt (1974) and Laxmanan (1974, 1984) and marginal stability at the dendrite tip models of Trivedi (1980) and Laxmanan (1974) are used to predict growth behavior of the alloy samples. The experimentally observed dendrite tip radius, primary arm spacing, and liquid composition at the dendrite tip are compared with theoretical predictions. It is observed that the modified minimum undercooling dendrite tip model and both of the marginal stability models accurately predict dendritic behavior. It is concluded that quantitative comparison of the primary arm spacing measurements can not form the basis for distinguishing among the various dendrite growth models in a positive temperature gradient.

  18. Electrical behaviour of dendritic spines as revealed by voltage imaging

    PubMed Central

    Popovic, Marko A.; Carnevale, Nicholas; Rozsa, Balazs; Zecevic, Dejan

    2015-01-01

    Thousands of dendritic spines on individual neurons process information and mediate plasticity by generating electrical input signals using a sophisticated assembly of transmitter receptors and voltage-sensitive ion channel molecules. Our understanding, however, of the electrical behaviour of spines is limited because it has not been possible to record input signals from these structures with adequate sensitivity and spatiotemporal resolution. Current interpretation of indirect data and speculations based on theoretical considerations are inconclusive. Here we use an electrochromic voltage-sensitive dye which acts as a transmembrane optical voltmeter with a linear scale to directly monitor electrical signals from individual spines on thin basal dendrites. The results show that synapses on these spines are not electrically isolated by the spine neck to a significant extent. Electrically, they behave as if they are located directly on dendrites. PMID:26436431

  19. A Dendritic Golgi Satellite between ERGIC and Retromer.

    PubMed

    Mikhaylova, Marina; Bera, Sujoy; Kobler, Oliver; Frischknecht, Renato; Kreutz, Michael R

    2016-01-12

    The local synthesis of transmembrane proteins underlies functional specialization of dendritic microdomains in neuronal plasticity. It is unclear whether these proteins have access to the complete machinery of the secretory pathway following local synthesis. In this study, we describe a probe called pGolt that allows visualization of Golgi-related organelles for live imaging in neurons. We show that pGolt labels a widespread microsecretory Golgi satellite (GS) system that is, in contrast to Golgi outposts, present throughout basal and apical dendrites of all pyramidal neurons. The GS system contains glycosylation machinery and is localized between ERGIC and retromer. Synaptic activity restrains lateral movement of ERGIC, GS, and retromer close to one another, allowing confined processing of secretory cargo. Several synaptic transmembrane proteins pass through and recycle back to the GS system. Thus, the presence of an ER-ERGIC-GS-retromer microsecretory system in all neuronal dendrites enables autonomous local control of transmembrane protein synthesis and processing. PMID:26748700

  20. MicroRNA-9 controls dendritic development by targeting REST

    PubMed Central

    Giusti, Sebastian A; Vogl, Annette M; Brockmann, Marisa M; Vercelli, Claudia A; Rein, Martin L; Trümbach, Dietrich; Wurst, Wolfgang; Cazalla, Demian; Stein, Valentin; Deussing, Jan M; Refojo, Damian

    2014-01-01

    MicroRNAs (miRNAs) are conserved noncoding RNAs that function as posttranscriptional regulators of gene expression. miR-9 is one of the most abundant miRNAs in the brain. Although the function of miR-9 has been well characterized in neural progenitors, its role in dendritic and synaptic development remains largely unknown. In order to target miR-9 in vivo, we developed a transgenic miRNA sponge mouse line allowing conditional inactivation of the miR-9 family in a spatio-temporal-controlled manner. Using this novel approach, we found that miR-9 controls dendritic growth and synaptic transmission in vivo. Furthermore, we demonstrate that miR-9-mediated downregulation of the transcriptional repressor REST is essential for proper dendritic growth. DOI: http://dx.doi.org/10.7554/eLife.02755.001 PMID:25406064

  1. Regulation of neuronal input transformations by tunable dendritic inhibition.

    PubMed

    Lovett-Barron, Matthew; Turi, Gergely F; Kaifosh, Patrick; Lee, Peter H; Bolze, Frédéric; Sun, Xiao-Hua; Nicoud, Jean-François; Zemelman, Boris V; Sternson, Scott M; Losonczy, Attila

    2012-03-01

    Transforming synaptic input into action potential output is a fundamental function of neurons. The pattern of action potential output from principal cells of the mammalian hippocampus encodes spatial and nonspatial information, but the cellular and circuit mechanisms by which neurons transform their synaptic input into a given output are unknown. Using a combination of optical activation and cell type-specific pharmacogenetic silencing in vitro, we found that dendritic inhibition is the primary regulator of input-output transformations in mouse hippocampal CA1 pyramidal cells, and acts by gating the dendritic electrogenesis driving burst spiking. Dendrite-targeting interneurons are themselves modulated by interneurons targeting pyramidal cell somata, providing a synaptic substrate for tuning pyramidal cell output through interactions in the local inhibitory network. These results provide evidence for a division of labor in cortical circuits, where distinct computational functions are implemented by subtypes of local inhibitory neurons. PMID:22246433

  2. Ternary dendritic nanowires as highly active and stable multifunctional electrocatalysts.

    PubMed

    Yang, Yoojin; Jin, Haneul; Kim, Ho Young; Yoon, Jisun; Park, Jongsik; Baik, Hionsuck; Joo, Sang Hoon; Lee, Kwangyeol

    2016-08-18

    Multimetallic nanocatalysts with a controlled structure can provide enhanced catalytic activity and durability by exploiting electronic, geometric, and strain effects. Herein, we report the synthesis of a novel ternary nanocatalyst based on Mo doped PtNi dendritic nanowires (Mo-PtNi DNW) and its bifunctional application in the methanol oxidation reaction (MOR) at the anode and the oxygen reduction reaction (ORR) at the cathode for direct methanol fuel cells. An unprecedented Mo-PtNi DNW structure can combine multiple structural attributes of the 1D nanowire morphology and dendritic surfaces. In the MOR, Mo-PtNi DNW exhibits superior activity to Pt/C and Mo doped Pt dendritic nanowires (Mo-Pt DNW), and excellent durability. Furthermore, Mo-PtNi DNW demonstrates excellent activity and durability for the ORR. This work highlights the important role of compositional and structural control in nanocatalysts for boosting catalytic performances. PMID:27507777

  3. Dendritic growth of undercooled nickel-tin. I, II

    NASA Technical Reports Server (NTRS)

    Wu, Y.; Piccone, T. J.; Shiohara, Y.; Flemings, M. C.

    1987-01-01

    A comparison is made between high speed cinematography and optical temperature measurements of the solidification of an undercooled Ni-25 wt pct Sn alloy. The first part of this study notes that solidification during the recalescence period at all undercoolings studied occurred in the form of a dendritelike front moving across the sample surface, and that the growth velocities observed agree with calculation results for the dendrite growth model of Lipton et al. (1986); it is concluded that the coarse structure observed comprises an array of much finer, solute-controlled dendrites. In the second part, attention is given to the solidification of levitated metal samples within a transparent glass medium for the cases of two undercooled Ni-Sn alloys, one of which is eutectic and another hypoeutectic. The data obtained suggest a solidification model involving dendrites of very fine structure growing into the melt at temperatures near the bulk undercooling temperature.

  4. Estimation of primary dendrite arm spacings in continuous casting products

    SciTech Connect

    Cicutti, C.; Bilmes, P.; Boeri, R.

    1997-09-01

    The proportion of steels produced by continuous casting has grown drastically during the last two decades, increasing to such an extent that in some countries, several grades of steel are exclusively made by this process. Many investigations recognized the significant influence of the solidification structure on the quality of cast products, and pointed out the importance of the development of appropriate tools to predict the microstructure as a function of thermal and physical parameters. The estimation of secondary dendrite arm spacings in continuously cast steel products has received some attention. However, very little effort has been focused on the prediction of primary dendrite arm spacings, to the best of the authors` knowledge. The main objective of this study is to develop simple expressions to estimate the variation of primary dendrite arm spacings through the section of continuous casting steel products.

  5. Shape Parameter for a Non-Axisymmetric Isothermal Dendrite

    NASA Technical Reports Server (NTRS)

    McFadden, G. B.; Coriell, S. R.; Sekerka, R. F.

    1999-01-01

    In previous work, we found approximate solutions for paraboloids having perturbations with four-fold axial symmetry in order to model dendritic growth in cubic materials. These solutions provide self-consistent corrections through second order in a shape parameter e to the Peclet number-supercooling relation of the Ivantsov solution. The parameter e is proportional to the amplitude of the four-fold correction to the dendrite shape, as measured from the Ivantsov paraboloid of revolution. We calculate e by comparing the dendrite tip shape to the portion of the equilibrium shape near the growth direction, (001), for anisotropic surface free energy, where the ni are components of the unit normal of the crystal surface. This comparison results in epsilon = -2(epsilon 4), independent of the Peclet number. From the experimental value of epsilon 4, we find epsilon approximately 0.011, in good agreement with the measured value epsilon approximately 0.008 of LaCombe et al.

  6. Regulation of Dendritic Cell Function by Vitamin D

    PubMed Central

    Barragan, Myriam; Good, Misty; Kolls, Jay K.

    2015-01-01

    Studies over the last two decades have revealed profound immunomodulatory aspects of vitamin D on various aspects of the immune system. This review will provide an overview of Vitamin D metabolism, a description of dendritic cell subsets, and highlight recent advances on the effects of vitamin D on dendritic cell function, maturation, cytokine production and antigen presentation. The active form of vitamin D, 1,25(OH)2D3, has important immunoregulatory and anti-inflammatory effects. Specifically, the 1,25(OH)2D3-Vitamin D3 complex can affect the maturation and migration of many dendritic cell subsets, conferring a special immunoregulatory role as well as tolerogenic properties affecting cytokine and chemokine production. Furthermore, there have been many recent studies demonstrating the effects of Vitamin D on allergic disease and autoimmunity. A clear understanding of the effects of the various forms of Vitamin D will provide new opportunities to improve human health. PMID:26402698

  7. Robust Type-specific Hemisynapses Induced by Artificial Dendrites

    NASA Astrophysics Data System (ADS)

    Kim, Eun Joong; Jeon, Chang Su; Lee, Soo Youn; Hwang, Inseong; Chung, Taek Dong

    2016-04-01

    Type-specificity of synapses, excitatory and inhibitory, regulates information process in neural networks via chemical neurotransmitters. To lay a foundation of synapse-based neural interfaces, artificial dendrites are generated by covering abiotic substrata with ectodomains of type-specific synaptogenic proteins that are C-terminally tagged with biotinylated fluorescent proteins. The excitatory artificial synapses displaying engineered ectodomains of postsynaptic neuroligin-1 (NL1) induce the formation of excitatory presynapses with mixed culture of neurons in various developmental stages, while the inhibitory artificial dendrites displaying engineered NL2 and Slitrk3 induce inhibitory presynapses only with mature neurons. By contrast, if the artificial dendrites are applied to the axonal components of micropatterned neurons, correctly-matched synaptic specificity emerges regardless of the neuronal developmental stages. The hemisynapses retain their initially established type-specificity during neuronal development and maintain their synaptic strength provided live neurons, implying the possibility of durable synapse-based biointerfaces.

  8. Robust Type-specific Hemisynapses Induced by Artificial Dendrites

    PubMed Central

    Kim, Eun Joong; Jeon, Chang Su; Lee, Soo Youn; Hwang, Inseong; Chung, Taek Dong

    2016-01-01

    Type-specificity of synapses, excitatory and inhibitory, regulates information process in neural networks via chemical neurotransmitters. To lay a foundation of synapse-based neural interfaces, artificial dendrites are generated by covering abiotic substrata with ectodomains of type-specific synaptogenic proteins that are C-terminally tagged with biotinylated fluorescent proteins. The excitatory artificial synapses displaying engineered ectodomains of postsynaptic neuroligin-1 (NL1) induce the formation of excitatory presynapses with mixed culture of neurons in various developmental stages, while the inhibitory artificial dendrites displaying engineered NL2 and Slitrk3 induce inhibitory presynapses only with mature neurons. By contrast, if the artificial dendrites are applied to the axonal components of micropatterned neurons, correctly-matched synaptic specificity emerges regardless of the neuronal developmental stages. The hemisynapses retain their initially established type-specificity during neuronal development and maintain their synaptic strength provided live neurons, implying the possibility of durable synapse-based biointerfaces. PMID:27072994

  9. Involvement of dendritic cells in autoimmune diseases in children

    PubMed Central

    López de Padilla, Consuelo M; Reed, Ann M

    2007-01-01

    Dendritic cells (DCs) are professional antigen-presenting cells that are specialized in the uptake of antigens and their transport from peripheral tissues to the lymphoid organs. Over the last decades, the properties of DCs have been intensely studied and much knowledge has been gained about the role of DCs in various diseases and health conditions where the immune system is involved, particularly in cancer and autoimmune disorders. Emerging clues in autoimmune diseases, suggest that dendritic cell dysregulation might be involved in the development of various autoimmune disorders in both adults and children. However, studies investigating a possible contribution of DCs in autoimmune diseases in the pediatric population alone are scanty. The purpose of this review is to give a general overview of the current literature on the relevance of dendritic cells in the most common autoimmune conditions of childhood. PMID:17625003

  10. Dendritic connectivity controls biodiversity patterns in experimental metacommunities

    PubMed Central

    Carrara, Francesco; Altermatt, Florian; Rodriguez-Iturbe, Ignacio; Rinaldo, Andrea

    2012-01-01

    Biological communities often occur in spatially structured habitats where connectivity directly affects dispersal and metacommunity processes. Recent theoretical work suggests that dispersal constrained by the connectivity of specific habitat structures, such as dendrites like river networks, can explain observed features of biodiversity, but direct evidence is still lacking. We experimentally show that connectivity per se shapes diversity patterns in microcosm metacommunities at different levels. Local dispersal in isotropic lattice landscapes homogenizes local species richness and leads to pronounced spatial persistence. On the contrary, dispersal along dendritic landscapes leads to higher variability in local diversity and among-community composition. Although headwaters exhibit relatively lower species richness, they are crucial for the maintenance of regional biodiversity. Our results establish that spatially constrained dendritic connectivity is a key factor for community composition and population persistence. PMID:22460788

  11. The morphoelectrotonic transform: a graphical approach to dendritic function.

    PubMed

    Zador, A M; Agmon-Snir, H; Segev, I

    1995-03-01

    Electrotonic structure of dendrites plays a critical role in neuronal computation and plasticity. In this article we develop two novel measures of electrotonic structure that describe intraneuronal signaling in dendrites of arbitrary geometry. The log-attenuation Lij measures the efficacy, and the propagation delay Pij the speed, of signal transfer between any two points i and j. These measures are additive, in the sense that if j lies between i and k, the total distance Lik is just the sum of the partial distances: Lik = Lij + Ljk, and similarly Pik = Pij + Pjk. This property serves as the basis for the morphoelectrotonic transform (MET), a graphical mapping from morphological into electrotonic space. In a MET, either Pij or Lij replace anatomical distance as the fundamental unit and so provide direct functional measures of intraneuronal signaling. The analysis holds for arbitrary transient signals, even those generated by nonlinear conductance changes underlying both synaptic and action potentials. Depending on input location and the measure of interest, a single neuron admits many METs, each emphasizing different functional consequences of the dendritic electrotonic structure. Using a single layer 5 cortical pyramidal neuron, we illustrate a collection of METs that lead to a deeper understanding of the electrical behavior of its dendritic tree. We then compare this cortical cell to representative neurons from other brain regions (cortical layer 2/3 pyramidal, region CA1 hippocampal pyramidal, and cerebellar Purkinje). Finally, we apply the MET to electrical signaling in dendritic spines, and extend this analysis to calcium signaling within spines. Our results demonstrate that the MET provides a powerful tool for obtaining a rapid and intuitive grasp of the functional properties of dendritic trees.

  12. Maladaptive dendritic spine remodeling contributes to diabetic neuropathic pain.

    PubMed

    Tan, Andrew M; Samad, Omar A; Fischer, Tanya Z; Zhao, Peng; Persson, Anna-Karin; Waxman, Stephen G

    2012-05-16

    Diabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic neuropathic pain is generally refractory to available clinical treatments. A structure-function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in CNS and PNS injury models of neuropathic pain. Here, we reasoned that if dendritic spine remodeling contributes to diabetic neuropathic pain, then (1) the presence of malformed spines should coincide with the development of pain, and (2) disrupting maladaptive spine structure should reduce chronic pain. To determine whether dendritic spine remodeling contributes to neuropathic pain in streptozotocin (STZ)-induced diabetic rats, we analyzed dendritic spine morphology and electrophysiological and behavioral signs of neuropathic pain. Our results show changes in dendritic spine shape, distribution, and shape on wide-dynamic-range (WDR) neurons within lamina IV-V of the dorsal horn in diabetes. These diabetes-induced changes were accompanied by WDR neuron hyperexcitability and decreased pain thresholds at 4 weeks. Treatment with NSC23766 (N(6)-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride), a Rac1-specific inhibitor known to interfere with spine plasticity, decreased the presence of malformed spines in diabetes, attenuated neuronal hyperresponsiveness to peripheral stimuli, reduced spontaneous firing activity from WDR neurons, and improved nociceptive mechanical pain thresholds. At 1 week after STZ injection, animals with hyperglycemia with no evidence of pain had few or no changes in spine morphology. These results demonstrate that diabetes-induced maladaptive dendritic spine remodeling has a mechanistic role in neuropathic pain. Molecular pathways that control spine morphogenesis and plasticity may be promising future targets for treatment.

  13. Formation and growth of lithium metal dendrites through solid block copolymer membranes

    NASA Astrophysics Data System (ADS)

    Harry, Katherine; Higa, Kenneth; Balsara, Nitash

    Dendrite growth from lithium metal in electrochemical systems is the primary problem that precludes the wide use of lithium metal as an anode material. While polystyrene-block-poly(ethylene oxide) copolymer electrolytes extend cell life by suppressing dendrite growth, dendrites eventually do grow and the batteries fail by a short-circuit. In situ hard X-ray microtomography experiments coupled with stress simulations shed light on the formation and growth of dendritic structures through stiff solid polymer electrolyte membranes.

  14. 3 CFR - Regulatory Review

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... been learned since that time. Far more is now known about regulation—not only about when it is... interests of future generations; identify methods of ensuring that regulatory review does not produce...

  15. Characterization of murine lung dendritic cells: similarities to Langerhans cells and thymic dendritic cells

    PubMed Central

    1990-01-01

    Dendritic cells (DC) are potent accessory cells (AC) for the initiation of primary immune responses. Although murine lymphoid DC and Langerhans cells have been extensively characterized, DC from murine lung have been incompletely described. We isolated cells from enzyme-digested murine lungs and bronchoalveolar lavages that were potent stimulators of a primary mixed lymphocyte response (MLR). The AC had a low buoyant density, were loosely adherent and nonphagocytic. AC function was unaffected by depletion of cells expressing the splenic DC marker, 33D1. In addition, antibody and complement depletion of cells bearing the macrophage marker F4/80, or removal of phagocytic cells with silica also failed to decrease AC activity. In contrast, AC function was decreased by depletion of cells expressing the markers J11d and the low affinity interleukin 2 receptor (IL-2R), both present on thymic and skin DC. AC function was approximately equal in FcR+ and FcR- subpopulations, indicating there was heterogeneity within the AC population. Consistent with the functional data, a combined two-color immunofluorescence and latex bead uptake technique revealed that lung cells high in AC activity were enriched in brightly Ia+ dendritic- shaped cells that (a) were nonphagocytic, (b) lacked specific T and B lymphocyte markers and the macrophage marker F4/80, but (c) frequently expressed C3biR, low affinity IL-2R, FcRII, and the markers NLDC-145 and J11d. Taken together, the functional and phenotypic data suggest the lung cells that stimulate resting T cells in an MLR and that might be important in local pulmonary immune responses are DC that bear functional and phenotypic similarity to other tissues DC, such as Langerhans cells and thymic DC. PMID:2162904

  16. Assessing the regulatory picture

    SciTech Connect

    Not Available

    1994-02-01

    This article addresses the safety of the nation's drinking water supply and discusses compliance of the Clean Water Act. Right now, the shape of the regulatory future is uncertain. The results of the D-DBP regulatory negotiation are imminent. Congress is ready to begin debating reauthorization of the Safe Drinking Water Act, and utilities are trying to comply with the regulations while trying not to price water out of the reach of some of their customers.

  17. NRC regulatory initiatives

    SciTech Connect

    Johnson, T.C.

    1989-11-01

    The US Nuclear Regulatory Commission (NRC) is addressing several low-level waste disposal issues that will be important to waste generators and to States and Compacts developing new disposal capacity. These issues include Greater-Than-Class C (GTCC) waste, mixed waste, below regulatory concern (BRC) waste, and the low-level waste data base. This paper discusses these issues and their current status.

  18. Electrical and Structural Characterization of Web Dendrite Crystals

    NASA Technical Reports Server (NTRS)

    Schwuttke, G. H.; Koliwad, K.; Dumas, K. A.

    1985-01-01

    Minority carrier lifetime distributions in silicon web dendrites are measured. Emphasis is placed on measuring areal homogeneity of lifetime, show its dependency on structural defects, and its unique change during hot processing. The internal gettering action of defect layers present in web crystals and their relation to minority carrier lifetime distributions is discussed. Minority carrier lifetime maps of web dendrites obtained before and after high temperature heat treatment are compared to similar maps obtained from 100 mm diameter Czochralski silicon wafers. Such maps indicate similar or superior areal homogeneity of minority carrier lifetime in webs.

  19. Modulation of dendrite growth of cuprous oxide by electrodeposition

    NASA Astrophysics Data System (ADS)

    Wan, Lijuan; Wang, Zhiqiang; Yang, Zaisan; Luo, Wenjun; Li, Zhaosheng; Zou, Zhigang

    2010-10-01

    Cuprous oxides with different dendrite morphologies were formed on F-doped tin oxide (FTO) covered glass substrates by potentiostatic deposition of cupric acetate. The effects of pH value (varied from 5.00 to 5.80) of electrolytes on the crystal morphologies of cuprous oxide were studied. Different crystal morphologies of cuprous oxides were obtained by the change of velocity of vertical growth and lateral growth through varying the pH value of electrolyte. The processes of Cu 2O dendrite crystal growth were analyzed through SEM images at different deposition times. Photoelectrochemical properties of the Cu 2O thin films prepared in the system are also studied.

  20. How a silver dendritic mesocrystal converts to a single crystal

    SciTech Connect

    Fang, J.; Ding, B.; Song, X.; Han, Y.

    2008-05-02

    In this paper, we demonstrate how a silver dendrite transforms from mesocrystal into single crystal and the stability for a dendritic silver mesocrystal within a Sn/AgNO3 galvanic replacement reaction. Our findings provide the direct evidence and visible picture of the transformation from mesocrystal to single crystalline structure and further confirm the particle-mediated crystallization mechanism. At the initial stage of the transformation, there is a crystallographic fusion process, dominated by oriented attachment mechanism. Ostwald ripening also plays an important role in forming smooth surface and regular shape of the final nanocrystal.

  1. Cell-penetrating and neurotargeting dendritic siRNA nanostructures.

    PubMed

    Brunner, Korbinian; Harder, Johannes; Halbach, Tobias; Willibald, Julian; Spada, Fabio; Gnerlich, Felix; Sparrer, Konstantin; Beil, Andreas; Möckl, Leonhard; Bräuchle, Christoph; Conzelmann, Karl-Klaus; Carell, Thomas

    2015-02-01

    We report the development of dendritic siRNA nanostructures that are able to penetrate even difficult to transfect cells such as neurons with the help of a special receptor ligand. The nanoparticles elicit strong siRNA responses, despite the dendritic structure. An siRNA dendrimer directed against the crucial rabies virus (RABV) nucleoprotein (N protein) and phosphoprotein (P protein) allowed the suppression of the virus titer in neurons below the detection limit. The cell-penetrating siRNA dendrimers, which were assembled using click chemistry, open up new avenues toward finding novel molecules able to cure this deadly disease.

  2. Electrical and Structural Characterization of Web Dendrite Crystals

    NASA Technical Reports Server (NTRS)

    Schwuttke, G. H.

    1984-01-01

    Minority carrier lifetime distributions in silicon web dendrites are measured. Emphasis is placed on measuring areal homogeneity of lifetime, show its dependancy on structural defects, and its unique change during hot processing. The internal gettering action of defect layers present in web crystals and their relation to minority carrier lifetime distributions is discussed. Minority carrier lifetime maps of web dendrites obtained before and after high temperature heat treatment are compared to similar maps obtained from 100 mm diameter Czochralski silicon wafers. Such maps indicate similar or superior areal homogeneity of minority carrier lifetime in webs.

  3. Primary Cilia and Dendritic Spines: Different but Similar Signaling Compartments

    PubMed Central

    Nechipurenko, Inna V.; Doroquez, David B.; Sengupta, Piali

    2013-01-01

    Primary non-motile cilia and dendritic spines are cellular compartments that are specialized to sense and transduce environmental cues and presynaptic signals, respectively. Despite their unique cellular roles, both compartments exhibit remarkable parallels in the general principles, as well as molecular mechanisms, by which their protein composition, membrane domain architecture, cellular interactions, and structural and functional plasticity are regulated. We compare and contrast the pathways required for the generation and function of cilia and dendritic spines, and suggest that insights from the study of one may inform investigations into the other of these critically important signaling structures. PMID:24048681

  4. Macrophages as APC and the dendritic cell myth.

    PubMed

    Hume, David A

    2008-11-01

    Dendritic cells have been considered an immune cell type that is specialized for the presentation of Ag to naive T cells. Considerable effort has been applied to separate their lineage, pathways of differentiation, and effectiveness in Ag presentation from those of macrophages. This review summarizes evidence that dendritic cells are a part of the mononuclear phagocyte system and are derived from a common precursor, responsive to the same growth factors (including CSF-1), express the same surface markers (including CD11c), and have no unique adaptation for Ag presentation that is not shared by other macrophages.

  5. Impairments in dendrite morphogenesis as etiology for neurodevelopmental disorders and implications for therapeutic treatments.

    PubMed

    Copf, Tijana

    2016-09-01

    Dendrite morphology is pivotal for neural circuitry functioning. While the causative relationship between small-scale dendrite morphological abnormalities (shape, density of dendritic spines) and neurodevelopmental disorders is well established, such relationship remains elusive for larger-scale dendrite morphological impairments (size, shape, branching pattern of dendritic trees). Here, we summarize published data on dendrite morphological irregularities in human patients and animal models for neurodevelopmental disorders, with focus on autism and schizophrenia. We next discuss high-risk genes for these disorders and their role in dendrite morphogenesis. We finally overview recent developments in therapeutic attempts and we discuss how they relate to dendrite morphology. We find that both autism and schizophrenia are accompanied by dendritic arbor morphological irregularities, and that majority of their high-risk genes regulate dendrite morphogenesis. Thus, we present a compelling argument that, along with smaller-scale morphological impairments in dendrites (spines and synapse), irregularities in larger-scale dendrite morphology (arbor shape, size) may be an important part of neurodevelopmental disorders' etiology. We suggest that this should not be ignored when developing future therapeutic treatments. PMID:27143622

  6. A general principle governs vision-dependent dendritic patterning of retinal ganglion cells.

    PubMed

    Xu, Hong-Ping; Sun, Jin Hao; Tian, Ning

    2014-10-15

    Dendritic arbors of retinal ganglion cells (RGCs) collect information over a certain area of the visual scene. The coverage territory and the arbor density of dendrites determine what fraction of the visual field is sampled by a single cell and at what resolution. However, it is not clear whether visual stimulation is required for the establishment of branching patterns of RGCs, and whether a general principle directs the dendritic patterning of diverse RGCs. By analyzing the geometric structures of RGC dendrites, we found that dendritic arbors of RGCs underwent a substantial spatial rearrangement after eye-opening. Light deprivation blocked both the dendritic growth and the branch patterning, suggesting that visual stimulation is required for the acquisition of specific branching patterns of RGCs. We further showed that vision-dependent dendritic growth and arbor refinement occurred mainly in the middle portion of the dendritic tree. This nonproportional growth and selective refinement suggest that the late-stage dendritic development of RGCs is not a passive stretching with the growth of eyes, but rather an active process of selective growth/elimination of dendritic arbors of RGCs driven by visual activity. Finally, our data showed that there was a power law relationship between the coverage territory and dendritic arbor density of RGCs on a cell-by-cell basis. RGCs were systematically less dense when they cover larger territories regardless of their cell type, retinal location, or developmental stage. These results suggest that a general structural design principle directs the vision-dependent patterning of RGC dendrites.

  7. Liquid metal feeding through dendritic region in Ni-Hard white iron

    SciTech Connect

    Oryshchyn, Danylo B.; Dogan, Omer N.

    2005-01-01

    Liquid permeability in the dendritic regions is one of the factors that determine porosity formation and macro segregation in castings. Permeability in the dendritic structure of Ni-Hard white iron was measured as a function of temperature. Effect of microstructural coarsening on the permeability was also investigated. Permeability increased with coarsening dendritic structure in Ni-Hard white iron.

  8. Adrenomedullin, a neuropeptide with immunoregulatory properties induces semi-mature tolerogenic dendritic cells

    PubMed Central

    Rullé, Sandrine; Kioon, Marie-Dominique Ah; Asensio, Carine; Mussard, Julie; Ea, Hang-Korng; Boissier, Marie-Christophe; Lioté, Frédéric; Falgarone, Géraldine

    2012-01-01

    Dendritic cells (DC) play a pivotal role in tolerance. Adrenomedullin (AM), a neuropeptide with anti-apoptotic and anti-inflammatory effects, may decrease T helper type 1 effector cells and induce regulatory T (Treg) cells. The aim of this study was to evaluate AM effects on murine dendritic cell (DC) maturation and functions. Bone marrow-derived DC were produced and stimulated with CpG motifs, lipopolysaccharide or AM for 24 hr. Then, DC maturation and expression of AM and AM receptors were evaluated. Compared with lipopolysaccharide-stimulated or CpG-stimulated DC, AM-stimulated DC had lower levels of co-stimulatory molecule expression and pro-inflammatory cytokine release. The AM induced high levels of interferon-γ but not of interleukin-10. Importantly, AM inhibited lipopolysaccharide-induced maturation of DC. However, allogeneic T-cell stimulation and endocytic capacity of AM-stimulated DC were comparable to those of semi-mature and mature DC. Moreover, DC expressed AM and its receptors at a basal level, and AM receptor expression increased with DC maturation. The AM stimulation induced indoleamine 2,3-dioxygenase (IDO) expression, promoting Treg cell expansion. For the first time, we describe the DC maturation phenotype by a neuropeptide (AM). We have demonstrated that AM and its receptors are expressed in DC and that exogenous AM can modify the DC phenotype and functions and can induce a semi-mature DC phenotype with IDO expression. These results indicate close interactions among immune system regulation mechanisms and calcitonin-like peptides. PMID:22348691

  9. Spi-B is critical for plasmacytoid dendritic cell function and development.

    PubMed

    Sasaki, Izumi; Hoshino, Katsuaki; Sugiyama, Takahiro; Yamazaki, Chihiro; Yano, Takahiro; Iizuka, Akihiko; Hemmi, Hiroaki; Tanaka, Takashi; Saito, Masuyoshi; Sugiyama, Masanaka; Fukuda, Yuri; Ohta, Tomokazu; Sato, Katsuaki; Ainai, Akira; Suzuki, Tadaki; Hasegawa, Hideki; Toyama-Sorimachi, Noriko; Kohara, Hiroshi; Nagasawa, Takashi; Kaisho, Tsuneyasu

    2012-12-01

    Plasmacytoid dendritic cells (pDCs), originating from hematopoietic progenitor cells in the BM, are a unique dendritic cell subset that can produce large amounts of type I IFNs by signaling through the nucleic acid-sensing TLR7 and TLR9 (TLR7/9). The molecular mechanisms for pDC function and development remain largely unknown. In the present study, we focused on an Ets family transcription factor, Spi-B, that is highly expressed in pDCs. Spi-B could transactivate the type I IFN promoters in synergy with IFN regulatory factor 7 (IRF-7), which is an essential transcription factor for TLR7/9-induced type I IFN production in pDCs. Spi-B-deficient pDCs and mice showed defects in TLR7/9-induced type I IFN production. Furthermore, in Spi-B-deficient mice, BM pDCs were decreased and showed attenuated expression of a set of pDC-specific genes whereas peripheral pDCs were increased; this uneven distribution was likely because of defective retainment of mature nondividing pDCs in the BM. The expression pattern of cell-surface molecules in Spi-B-deficient mice indicated the involvement of Spi-B in pDC development. The developmental defects of pDCs in Spi-B-deficient mice were more prominent in the BM than in the peripheral lymphoid organs and were intrinsic to pDCs. We conclude that Spi-B plays critical roles in pDC function and development.

  10. Tolerogen-induced interferon-producing killer dendritic cells (IKDCs) protect against EAE

    PubMed Central

    Huarte, Eduardo; Rynda-Apple, Agnieszka; Riccardi, Carol; Skyberg, Jerod A.; Golden, Sarah; Rollins, MaryClare F.; Ramstead, Andrew; Jackiw, Larissa O.; Maddaloni, Massimo; Pascual, David W.

    2011-01-01

    Natural killer (NK) cells and dendritic cells (DCs) have been shown to link the innate and adaptive immune systems. Likewise, a new innate cell subset, interferon-producing killer DCs (IKDCs), shares phenotypic and functional characteristics with both DCs and NK cells. Here, we show IKDCs play an essential role in the resolution of experimental autoimmune encephalomyelitis (EAE) upon treatment with the tolerizing agent, myelin oligodendrocyte glycoprotein (MOG), genetically fused to reovirus protein σ1 (termed MOG-pσ1). Activated IKDCs were recruited subsequent MOG-pσ1 treatment of EAE, and disease resolution was abated upon NK1.1 cell depletion. These IKDCs were able to kill activated CD4+ T cells and mature dendritic DCs, thus, contributing to EAE remission. In addition, IKDCs were responsible for MOG-pσ1-mediated MOG-specific regulatory T cell recruitment to the CNS. The IKDCs induced by MOG-pσ1 expressed elevated levels of HVEM for interactions with cognate ligand-positive cells: LIGHT+ NK and Teff cells and BTLA+ B cells. Further characterization revealed these activated IKDCs being MHC class IIhigh, and upon their adoptive transfer (CD11c+NK1.1+MHC class IIhigh), IKDCs, but not CD11c+NK1.1+MHC class IIintermediate/low (unactivated) cells, conferred protection against EAE. These activated IKDCs showed enhanced CD107a, PD-L1, and granzyme B expression and could present OVA, unlike unactivated IKDCs. Thus, these results demonstrate the interventional potency induced HVEM+ IKDCs to resolve autoimmune disease. PMID:22018711

  11. Suppression of Th1-mediated autoimmunity by embryonic stem cell-derived dendritic cells.

    PubMed

    Ikeda, Tokunori; Hirata, Shinya; Takamatsu, Koutaro; Haruta, Miwa; Tsukamoto, Hirotake; Ito, Takaaki; Uchino, Makoto; Ando, Yukio; Nagafuchi, Seiho; Nishimura, Yasuharu; Senju, Satoru

    2014-01-01

    We herein demonstrate the immune-regulatory effect of embryonic stem cell-derived dendritic cells (ES-DCs) using two models of autoimmune disease, namely non-obese diabetic (NOD) mice and experimental autoimmune encephalomyelitis (EAE). Treatment of pre-diabetic NOD mice with ES-DCs exerted almost complete suppression of diabetes development during the observation period for more than 40 weeks. The prevention of diabetes by ES-DCs was accompanied with significant reduction of insulitis and decreased number of Th1 and Th17 cells in the spleen. Development of EAE was also inhibited by the treatment with ES-DCs, and the therapeutic effect was obtained even if ES-DCs were administrated after the onset of clinical symptoms. Treatment of EAE-induced mice with ES-DCs reduced the infiltration of inflammatory cells into the spinal cord and suppressed the T cell response to the myelin antigen. Importantly, the ES-DC treatment did not affect T cell response to an exogenous antigen. As the mechanisms underlying the reduction of the number of infiltrating Th1 cells, we observed the inhibition of differentiation and proliferation of Th1 cells by ES-DCs. Furthermore, the expression of VLA-4α on Th1 cells was significantly inhibited by ES-DCs. Considering the recent advances in human induced pluripotent stem cell-related technologies, these results suggest a clinical application for pluripotent stem cell-derived dendritic cells as a therapy for T cell-mediated autoimmune diseases. PMID:25522369

  12. Immune-modifying properties of topical vitamin D: Focus on dendritic cells and T cells.

    PubMed

    Gorman, Shelley; Judge, Melinda A; Hart, Prue H

    2010-07-01

    Topical creams containing the active form of vitamin D (1,25-dihydroxyvitamin D3; 1,25(OH)2D3) or analogues of this compound are currently used with some success to treat skin conditions including psoriasis and vitiligo. As well as targeting inflammatory processes in the skin, topical application of 1,25(OH)2D3 also affects the function of immune cells in the skin and draining lymph nodes. Topically applied 1,25(OH)2D3 reduces the number of dendritic cells in the skin, resulting in suppressed immunity and in particular reduced contact hypersensitivity (CHS) responses. Topical 1,25(OH)2D3 may also promote the migration of dendritic cells from the skin to the draining lymph nodes. Skin application of 1,25(OH)2D3 prevented the inflammatory effects of UVB irradiation on lymph node hypertrophy, when cell numbers were examined 4 days after skin treatment. In contrast, when 1,25(OH)2D3 was applied to UVB irradiated skin, there was no reversal in the suppression of CHS responses caused by UVB irradiation. Instead, 1,25(OH)2D3 had an additive effect with UVB to suppress CHS responses to a greater degree than UVB alone. In these studies, 1,25(OH)2D3 was applied to the treated skin of BALB/c mice immediately following UVB irradiation. Finally, topical 1,25(OH)2D3 also enhanced the number and suppressive activity of CD4+CD25+ regulatory T cells in the lymphatic tissue draining skin.

  13. Methods of analysis of dendritic cell-derived exosome-shuttle microRNA and its horizontal propagation between dendritic cells.

    PubMed

    Montecalvo, Angela; Larregina, Adriana T; Morelli, Adrian E

    2013-01-01

    Exosomes are extremely small (<100 nm) membrane vesicles, generated in the endocytic compartment that are released to the extracellular milieu by living cells. Although the biological function of exosomes in vivo remains unclear, they seem to function as mechanisms of cell-to-cell communication for horizontal transfer of proteins, antigens, prions, morphogens, mRNA, and noncoding regulatory RNAs, including microRNAs (miRNAs) (also known as exosome-shuttle miRNAs). Dendritic cells (DCs), the most potent professional antigen-presenting leukocytes of the immune system, release relatively high levels of exosomes and also interact with free exosomes present in the extracellular space. Therefore, DCs constitute a good model for the analysis of exosome-shuttle miRNAs and their horizontal propagation between cells. This chapter provides basic protocols for purification of exosomes released by mouse bone marrow-derived DCs, analysis of their miRNA content, and assessment of the function of exosome-shuttle miRNAs, once they are transferred to target/acceptor DCs.

  14. Methods of analysis of dendritic cell-derived exosome-shuttle microRNA and its horizontal propagation between dendritic cells.

    PubMed

    Montecalvo, Angela; Larregina, Adriana T; Morelli, Adrian E

    2013-01-01

    Exosomes are extremely small (<100 nm) membrane vesicles, generated in the endocytic compartment that are released to the extracellular milieu by living cells. Although the biological function of exosomes in vivo remains unclear, they seem to function as mechanisms of cell-to-cell communication for horizontal transfer of proteins, antigens, prions, morphogens, mRNA, and noncoding regulatory RNAs, including microRNAs (miRNAs) (also known as exosome-shuttle miRNAs). Dendritic cells (DCs), the most potent professional antigen-presenting leukocytes of the immune system, release relatively high levels of exosomes and also interact with free exosomes present in the extracellular space. Therefore, DCs constitute a good model for the analysis of exosome-shuttle miRNAs and their horizontal propagation between cells. This chapter provides basic protocols for purification of exosomes released by mouse bone marrow-derived DCs, analysis of their miRNA content, and assessment of the function of exosome-shuttle miRNAs, once they are transferred to target/acceptor DCs. PMID:23719940

  15. Cellular source-specific effects of apolipoprotein (apo) E4 on dendrite arborization and dendritic spine development.

    PubMed

    Jain, Sachi; Yoon, Seo Yeon; Leung, Laura; Knoferle, Johanna; Huang, Yadong

    2013-01-01

    Apolipoprotein (apo) E4 is the leading genetic risk factor for Alzheimer's disease (AD), and it has a gene dose-dependent effect on the risk and age of onset of AD. Although apoE4 is primarily produced by astrocytes in the brain, neurons can also produce apoE4 under stress conditions. ApoE4 is known to inhibit neurite outgrowth and spine development in vitro and in vivo, but the potential influence of apoE4's cellular source on dendritic arborization and spine development has not yet been investigated. In this study, we report impairments in dendritic arborization and a loss of spines, especially thin (learning) and mushroom (memory) spines, in the hippocampus and entorhinal cortex of 19-21-month-old female neuron-specific-enolase (NSE)-apoE4 and apoE4-knockin (KI) mice compared to their respective apoE3-expressing counterparts. In general, NSE-apoE4 mice had more severe and widespread deficits in dendritic arborization as well as spine density and morphology than apoE4-KI mice. The loss of dendritic spines, especially mushroom spines, occurred in NSE-apoE4 mice as early as 7-8 months of age. In contrast, glial fibrillary acidic protein (GFAP)-apoE4 mice, which express apoE4 solely in astrocytes, did not have impairments in their dendrite arborization or spine density and morphology compared to GFAP-apoE3 mice at both ages. These results indicate that the effects of apoE4 on dendrite arborization, spine density, and spine morphology depend critically on its cellular source, with neuronal apoE4 having more detrimental effects than astrocytic apoE4.

  16. Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions

    PubMed Central

    Boor, P P C; Metselaar, H J; Mancham, S; van der Laan, L J W; Kwekkeboom, J

    2013-01-01

    Plasmacytoid dendritic cells (PDC) are involved in innate immunity by interferon (IFN)-α production, and in adaptive immunity by stimulating T cells and inducing generation of regulatory T cells (Treg). In this study we studied the effects of mammalian target of rapamycin (mTOR) inhibition by rapamycin, a commonly used immunosuppressive and anti-cancer drug, on innate and adaptive immune functions of human PDC. A clinically relevant concentration of rapamycin inhibited Toll-like receptor (TLR)-7-induced IFN-α secretion potently (−64%) but TLR-9-induced IFN-α secretion only slightly (−20%), while the same concentration suppressed proinflammatory cytokine production by TLR-7-activated and TLR-9-activated PDC with similar efficacy. Rapamycin inhibited the ability of both TLR-7-activated and TLR-9-activated PDC to stimulate production of IFN-γ and interleukin (IL)-10 by allogeneic T cells. Surprisingly, mTOR-inhibition enhanced the capacity of TLR-7-activated PDC to stimulate naive and memory T helper cell proliferation, which was caused by rapamycin-induced up-regulation of CD80 expression on PDC. Finally, rapamycin treatment of TLR-7-activated PDC enhanced their capacity to induce CD4+forkhead box protein 3 (FoxP3)+ regulatory T cells, but did not affect the generation of suppressive CD8+CD38+lymphocyte activation gene (LAG)-3+ Treg. In general, rapamycin inhibits innate and adaptive immune functions of TLR-stimulated human PDC, but enhances the ability of TLR-7-stimulated PDC to stimulate CD4+ T cell proliferation and induce CD4+FoxP3+ regulatory T cell generation. PMID:23968562

  17. Nectin-1 spots as a novel adhesion apparatus that tethers mitral cell lateral dendrites in a dendritic meshwork structure of the developing mouse olfactory bulb.

    PubMed

    Inoue, Takahito; Fujiwara, Takeshi; Rikitake, Yoshiyuki; Maruo, Tomohiko; Mandai, Kenji; Kimura, Kazushi; Kayahara, Tetsuro; Wang, Shujie; Itoh, Yu; Sai, Kousyoku; Mori, Masahiro; Mori, Kensaku; Mizoguchi, Akira; Takai, Yoshimi

    2015-08-15

    Mitral cells project lateral dendrites that contact the lateral and primary dendrites of other mitral cells and granule cell dendrites in the external plexiform layer (EPL) of the olfactory bulb. These dendritic structures are critical for odor information processing, but it remains unknown how they are formed. In immunofluorescence microscopy, the immunofluorescence signal for the cell adhesion molecule nectin-1 was concentrated on mitral cell lateral dendrites in the EPL of the developing mouse olfactory bulb. In electron microscopy, the immunogold particles for nectin-1 were symmetrically localized on the plasma membranes at the contacts between mitral cell lateral dendrites, which showed bilateral darkening without dense cytoskeletal undercoats characteristic of puncta adherentia junctions. We named the contacts where the immunogold particles for nectin-1 were symmetrically accumulated "nectin-1 spots." The nectin-1 spots were 0.21 μm in length on average and the distance between the plasma membranes was 20.8 nm on average. In 3D reconstruction of serial sections, clusters of the nectin-1 spots formed a disc-like structure. In the mitral cell lateral dendrites of nectin-1-knockout mice, the immunogold particles for nectin-1 were undetectable and the plasma membrane darkening was electron-microscopically normalized, but the plasma membranes were partly separated from each other. The nectin-1 spots were further identified between mitral cell lateral and primary dendrites and between mitral cell lateral dendrites and granule cell dendritic spine necks. These results indicate that the nectin-1 spots constitute a novel adhesion apparatus that tethers mitral cell dendrites in a dendritic meshwork structure of the developing mouse olfactory bulb.

  18. Some properties of dendritic macrophages from peripheral lymph.

    PubMed Central

    Barfoot, R; Denham, S; Gyure, L A; Hall, J G; Hobbs, S M; Jackson, L E; Robertson, D

    1989-01-01

    Peripheral lymph was collected from the skin and liver of sheep, and from the intestine of rats. The dendritic macrophages contained in it were isolated by centrifuging the lymph over a layer of 'Nycodenz'. Similar cells were produced by culturing mononuclear cells from venous blood, but the yields were very small. The numbers of dendritic cells in the lymph from the legs of sheep increased five-fold after xylene had been applied to the skin. Dendritic macrophages displayed abundant class II histocompatibility antigens on their surfaces, as well as immunoglobulins. Although the latter were probably acquired passively, they remained present for several days on cells cultured in vitro. When in vitro, dendritic cells could be shown to phagocytose marker particles, such as latex beads, but their performance was unimpressive compared to macrophages from the peritoneal cavities of rats. In contrast, their ability to phagocytose rapidly T4 phage or influenza viruses unequivocal and striking. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:2807381

  19. Lithium dendrite growth through solid polymer electrolyte membranes

    NASA Astrophysics Data System (ADS)

    Harry, Katherine; Schauser, Nicole; Balsara, Nitash

    2015-03-01

    Replacing the graphite-based anode in current batteries with a lithium foil will result in a qualitative increase in the energy density of lithium batteries. The primary reason for not adopting lithium-foil anodes is the formation of dendrites during cell charging. In this study, stop-motion X-ray microtomography experiments were used to directly monitor the growth of lithium dendrites during electrochemical cycling of symmetric lithium-lithium cells with a block copolymer electrolyte. In an attempt to understand the relationship between viscoelastic properties of the electrolyte on dendrite formation, a series of complementary experiments including cell cycling, tomography, ac impedance, and rheology, were conducted above and below the glass transition temperature of the non-conducting poly(styrene) block; the conducting phase is a mixture of rubbery poly(ethylene oxide) and a lithium salt. The tomography experiments enable quantification of the evolution of strain in the block copolymer electrolyte. Our work provides fundamental insight into the dynamics of electrochemical deposition of metallic films in contact with high modulus polymer electrolytes. Rational approaches for slowing down and, perhaps, eliminating dendrite growth are proposed.

  20. Dendritic brushes under good solvent conditions: a simulation study.

    PubMed

    Gergidis, Leonidas N; Kalogirou, Andreas; Vlahos, Costas

    2012-12-11

    The structural properties of polymer brushes, formed by dendron polymers up to the third generation, were studied by means of Brownian dynamics simulations for the macroscopic state of good solvent. The distributions of polymer units, of the free ends, of the dendrons centers of mass, and of the units of every dendritic generation and the radii of gyration necessary for the understanding of the internal stratification of brushes were calculated. Previous self-consistent field theory numerical simulations of first-generation dendritic brushes suggested that at high grafting densities two kinds of populations are evident, one of short dendrons having weakly extended spacers and another with tall dendrons having strongly stretched spacers. These Brownian dynamics calculations provided a more complicated picture of dendritic brushes, revealing different populations of short, tall, and in some cases intermediate height dendrons, depending on the dendron generation and spacer length. The scaling dependence of the height and the span of the dendritic brush on the grafting density and other parameters were found to be in good agreement with existing theoretical results for good solvents. PMID:23134236

  1. Thermodynamic-kinetic simulation of constrained dendrite growth in steels

    SciTech Connect

    Miettinen, J.

    2000-04-01

    A model of constrained dendritic growth for steels, based on thermodynamic and kinetic theory, is presented. The model links thermodynamic chemical potential-equality equations to an existing, approximate treatment of constrained dendritic growth in multicomponent steels, taking into account the deviation from the local thermodynamic equilibrium of the phase interface caused by interface friction, capillarity, and solute trapping. Due to the thermodynamic approach, with a thermodynamic model and recently assessed data, the present treatment yields a more accurate determination of phase stabilities than the earlier methods. Depending on the steel composition and the growth conditions (growth rate and temperature gradient), the model determines the dendrite tip undercooling, the primary solid phase (ferrite or austenite), the stability of that phase, certain dimensions of the microstructure, and the solute accumulation ahead of the dendrite tip. A special optional calculations is that of the equally probable formation of ferrite and austenite in stainless steels. Calculations for testing the model and for validation it with experimental data are presented.

  2. Synaptic integration in dendrites: exceptional need for speed.

    PubMed

    Golding, Nace L; Oertel, Donata

    2012-11-15

    Some neurons in the mammalian auditory system are able to detect and report the coincident firing of inputs with remarkable temporal precision. A strong, low-voltage-activated potassium conductance (g(KL)) at the cell body and dendrites gives these neurons sensitivity to the rate of depolarization by EPSPs, allowing neurons to assess the coincidence of the rising slopes of unitary EPSPs. Two groups of neurons in the brain stem, octopus cells in the posteroventral cochlear nucleus and principal cells of the medial superior olive (MSO), extract acoustic information by assessing coincident firing of their inputs over a submillisecond timescale and convey that information at rates of up to 1000 spikes s(-1). Octopus cells detect the coincident activation of groups of auditory nerve fibres by broadband transient sounds, compensating for the travelling wave delay by dendritic filtering, while MSO neurons detect coincident activation of similarly tuned neurons from each of the two ears through separate dendritic tufts. Each makes use of filtering that is introduced by the spatial distribution of inputs on dendrites. PMID:22930273

  3. Protocadherins branch out: Multiple roles in dendrite development

    PubMed Central

    Keeler, Austin B; Molumby, Michael J; Weiner, Joshua A

    2015-01-01

    The proper formation of dendritic arbors is a critical step in neural circuit formation, and as such defects in arborization are associated with a variety of neurodevelopmental disorders. Among the best gene candidates are those encoding cell adhesion molecules, including members of the diverse cadherin superfamily characterized by distinctive, repeated adhesive domains in their extracellular regions. Protocadherins (Pcdhs) make up the largest group within this superfamily, encompassing over 80 genes, including the ∼60 genes of the α-, β-, and γ-Pcdh gene clusters and the non-clustered δ-Pcdh genes. An additional group includes the atypical cadherin genes encoding the giant Fat and Dachsous proteins and the 7-transmembrane cadherins. In this review we highlight the many roles that Pcdhs and atypical cadherins have been demonstrated to play in dendritogenesis, dendrite arborization, and dendritic spine regulation. Together, the published studies we discuss implicate these members of the cadherin superfamily as key regulators of dendrite development and function, and as potential therapeutic targets for future interventions in neurodevelopmental disorders. PMID:25869446

  4. Avian dendritic cells: Phenotype and ontogeny in lymphoid organs.

    PubMed

    Nagy, Nándor; Bódi, Ildikó; Oláh, Imre

    2016-05-01

    Dendritic cells (DC) are critically important accessory cells in the innate and adaptive immune systems. Avian DCs were originally identified in primary and secondary lymphoid organs by their typical morphology, displaying long cell processes with cytoplasmic granules. Several subtypes are known. Bursal secretory dendritic cells (BSDC) are elongated cells which express vimentin intermediate filaments, MHC II molecules, macrophage colony-stimulating factor 1 receptor (CSF1R), and produce 74.3+ secretory granules. Avian follicular dendritic cells (FDC) highly resemble BSDC, express the CD83, 74.3 and CSF1R molecules, and present antigen in germinal centers. Thymic dendritic cells (TDC), which express 74.3 and CD83, are concentrated in thymic medulla while interdigitating DC are found in T cell-rich areas of secondary lymphoid organs. Avian Langerhans cells are a specialized 74.3-/MHC II+ cell population found in stratified squamous epithelium and are capable of differentiating into 74.3+ migratory DCs. During organogenesis hematopoietic precursors of DC colonize the developing lymphoid organ primordia prior to immigration of lymphoid precursor cells. This review summarizes our current understanding of the ontogeny, cytoarchitecture, and immunophenotype of avian DC, and offers an antibody panel for the in vitro and in vivo identification of these heterogeneous cell types.

  5. Search for a solute-drag effect in dendritic solidification

    SciTech Connect

    Eckler, K.; Herlach, D.M. ); Aziz, M.J. . Div. of Applied Sciences)

    1994-03-01

    The authors report the results of an indirect experimental test for the solute-drag effect in alloy solidification by fitting the data of Eckler et.al. for Ni-B dendrite tip velocities vs undercooling to models in several ways. The unknown equilibrium partition coefficient, k[sub e], was varied as a fitting parameter. When they combine the dendrite growth model of Boettinger et al. with the Continuous Growth Model (CGM) of Aziz and Kaplan with solute drag, they cannot fit the data for any value of k[sub e]. When they combine dendrite growth theory with the CGM without solute drag, they obtain a reasonable fit to the data for k[sub e] = 4 [times] 10[sup [minus]6]. When they combine dendrite growth theory with a new partial-solute-drag interpolation between the with-solute-drag and the without-solute-drag versions of the CGM, they obtain a still better fit to the data for k[sub e] = 2.8 [times] 10[sup [minus

  6. Dendritic and Axonal Wiring Optimization of Cortical GABAergic Interneurons.

    PubMed

    Anton-Sanchez, Laura; Bielza, Concha; Benavides-Piccione, Ruth; DeFelipe, Javier; Larrañaga, Pedro

    2016-10-01

    The way in which a neuronal tree expands plays an important role in its functional and computational characteristics. We aimed to study the existence of an optimal neuronal design for different types of cortical GABAergic neurons. To do this, we hypothesized that both the axonal and dendritic trees of individual neurons optimize brain connectivity in terms of wiring length. We took the branching points of real three-dimensional neuronal reconstructions of the axonal and dendritic trees of different types of cortical interneurons and searched for the minimal wiring arborization structure that respects the branching points. We compared the minimal wiring arborization with real axonal and dendritic trees. We tested this optimization problem using a new approach based on graph theory and evolutionary computation techniques. We concluded that neuronal wiring is near-optimal in most of the tested neurons, although the wiring length of dendritic trees is generally nearer to the optimum. Therefore, wiring economy is related to the way in which neuronal arborizations grow irrespective of the marked differences in the morphology of the examined interneurons.

  7. Variation of dorsal horn cell dendritic spread with map scale.

    PubMed

    Brown, P B; Millecchia, R; Culberson, J L; Gladfelter, W; Covalt-Dunning, D

    1996-10-21

    Cells in laminae III, IV, and V of cat dorsal horn were injected with horseradish peroxidase or neurobiotin. Dorsal views of the dendritic domains were constructed in order to measure their lengths, widths, areas, and length/width ratios in the horizontal plane (the plane of the somatotopic map). Dendritic domain width and area in the horizontal plane were negatively correlated with fractional distance between the medial and lateral edges of the dorsal horn. These results are consistent with the hypothesis that dendritic domain width varies with map scale, which is maximal in the medial dorsal horn. This is similar to the variation in widths of primary afferent bouton distributions. The parallel variation of dorsal horn cell dendritic domain width and primary afferent bouton distribution width with map scale suggests that there is a causal relation between morphology and map scale in the dorsal horn representation of the hindlimb. This variation of adult morphology with map scale must reflect mechanisms responsible for the assembly of receptive fields. PMID:8906504

  8. Dendritic and Axonal Wiring Optimization of Cortical GABAergic Interneurons.

    PubMed

    Anton-Sanchez, Laura; Bielza, Concha; Benavides-Piccione, Ruth; DeFelipe, Javier; Larrañaga, Pedro

    2016-10-01

    The way in which a neuronal tree expands plays an important role in its functional and computational characteristics. We aimed to study the existence of an optimal neuronal design for different types of cortical GABAergic neurons. To do this, we hypothesized that both the axonal and dendritic trees of individual neurons optimize brain connectivity in terms of wiring length. We took the branching points of real three-dimensional neuronal reconstructions of the axonal and dendritic trees of different types of cortical interneurons and searched for the minimal wiring arborization structure that respects the branching points. We compared the minimal wiring arborization with real axonal and dendritic trees. We tested this optimization problem using a new approach based on graph theory and evolutionary computation techniques. We concluded that neuronal wiring is near-optimal in most of the tested neurons, although the wiring length of dendritic trees is generally nearer to the optimum. Therefore, wiring economy is related to the way in which neuronal arborizations grow irrespective of the marked differences in the morphology of the examined interneurons. PMID:27345531

  9. Statistical analysis of dendritic spine distributions in rat hippocampal cultures

    PubMed Central

    2013-01-01

    Background Dendritic spines serve as key computational structures in brain plasticity. Much remains to be learned about their spatial and temporal distribution among neurons. Our aim in this study was to perform exploratory analyses based on the population distributions of dendritic spines with regard to their morphological characteristics and period of growth in dissociated hippocampal neurons. We fit a log-linear model to the contingency table of spine features such as spine type and distance from the soma to first determine which features were important in modeling the spines, as well as the relationships between such features. A multinomial logistic regression was then used to predict the spine types using the features suggested by the log-linear model, along with neighboring spine information. Finally, an important variant of Ripley’s K-function applicable to linear networks was used to study the spatial distribution of spines along dendrites. Results Our study indicated that in the culture system, (i) dendritic spine densities were "completely spatially random", (ii) spine type and distance from the soma were independent quantities, and most importantly, (iii) spines had a tendency to cluster with other spines of the same type. Conclusions Although these results may vary with other systems, our primary contribution is the set of statistical tools for morphological modeling of spines which can be used to assess neuronal cultures following gene manipulation such as RNAi, and to study induced pluripotent stem cells differentiated to neurons. PMID:24088199

  10. Dendritic Spines in Depression: What We Learned from Animal Models

    PubMed Central

    Qiao, Hui; Li, Ming-Xing; Xu, Chang; Chen, Hui-Bin; An, Shu-Cheng; Ma, Xin-Ming

    2016-01-01

    Depression, a severe psychiatric disorder, has been studied for decades, but the underlying mechanisms still remain largely unknown. Depression is closely associated with alterations in dendritic spine morphology and spine density. Therefore, understanding dendritic spines is vital for uncovering the mechanisms underlying depression. Several chronic stress models, including chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), have been used to recapitulate depression-like behaviors in rodents and study the underlying mechanisms. In comparison with CRS, CUMS overcomes the stress habituation and has been widely used to model depression-like behaviors. CSDS is one of the most frequently used models for depression, but it is limited to the study of male mice. Generally, chronic stress causes dendritic atrophy and spine loss in the neurons of the hippocampus and prefrontal cortex. Meanwhile, neurons of the amygdala and nucleus accumbens exhibit an increase in spine density. These alterations induced by chronic stress are often accompanied by depression-like behaviors. However, the underlying mechanisms are poorly understood. This review summarizes our current understanding of the chronic stress-induced remodeling of dendritic spines in the hippocampus, prefrontal cortex, orbitofrontal cortex, amygdala, and nucleus accumbens and also discusses the putative underlying mechanisms. PMID:26881133

  11. Conical Gradient Junctions of Dendritic Viologen Arrays on Electrodes

    PubMed Central

    Kawauchi, Takehiro; Oguchi, Yuki; Nagai, Keiji; Iyoda, Tomokazu

    2015-01-01

    The three-dimensional construction of arrays of functional molecules on an electrode surface, such as organic semiconductors and redox-active molecules, is a considerable challenge in the fabrication of sophisticated junctions for molecular devices. In particular, well-defined organic layers with precise molecular gradients are anticipated to function as novel metal/organic interfaces with specific electrical properties, such as a space charge layer at the metal/semiconductor interface. Here, we report a strategy for the construction of a three-dimensional molecular array with an electrical connection to a metal electrode by exploiting dendritic molecular architecture. Newly designed dendritic molecules consisting of viologens (1,1′-disubstituted-4,4′-bipyridilium salts) as the framework and mercapto groups as anchor units form unique self-assembled monolayers (SAMs) on a gold surface reflecting the molecular design. The dendritic molecules exhibit a conical shape and closely pack to form cone arrays on the substrate, whereas, in solution, they expand into more flexible conformations. Differences in the introduction position of the anchor units in the dendritic structure result in apical- and basal-type cone arrays in which the spatial concentration of the viologen units can be precisely configured in the cones. The concentration in apical-type SAMs increases away from the substrate, whereas the opposite is true in basal-type SAMs. PMID:26057120

  12. Dendritic spine geometry can localize GTPase signaling in neurons

    PubMed Central

    Ramirez, Samuel A.; Raghavachari, Sridhar; Lew, Daniel J.

    2015-01-01

    Dendritic spines are the postsynaptic terminals of most excitatory synapses in the mammalian brain. Learning and memory are associated with long-lasting structural remodeling of dendritic spines through an actin-mediated process regulated by the Rho-family GTPases RhoA, Rac, and Cdc42. These GTPases undergo sustained activation after synaptic stimulation, but whereas Rho activity can spread from the stimulated spine, Cdc42 activity remains localized to the stimulated spine. Because Cdc42 itself diffuses rapidly in and out of the spine, the basis for the retention of Cdc42 activity in the stimulated spine long after synaptic stimulation has ceased is unclear. Here we model the spread of Cdc42 activation at dendritic spines by means of reaction-diffusion equations solved on spine-like geometries. Excitable behavior arising from positive feedback in Cdc42 activation leads to spreading waves of Cdc42 activity. However, because of the very narrow neck of the dendritic spine, wave propagation is halted through a phenomenon we term geometrical wave-pinning. We show that this can account for the localization of Cdc42 activity in the stimulated spine, and, of interest, retention is enhanced by high diffusivity of Cdc42. Our findings are broadly applicable to other instances of signaling in extreme geometries, including filopodia and primary cilia. PMID:26337387

  13. Computational implications of cooperative plasticity induction at nearby dendritic sites.

    PubMed

    Morita, Kenji

    2009-01-01

    Recent studies have revealed that plasticity is not regulated independently at individual synapses but rather that there is cooperativity or associativity between nearby synapses in the dendritic tree of individual cortical pyramidal cells. Here, I summarize experimental results regarding such cooperative plasticity and its underlying mechanisms and consider their computational implications. PMID:19126862

  14. Amphiphilic dendritic peptides: Synthesis and behavior as an organogelator and liquid crystal.

    PubMed

    Gao, Baoxiang; Li, Hongxia; Xia, Defang; Sun, Sufang; Ba, Xinwu

    2011-02-11

    New amphiphilic dendritic peptides on dendritic polyaspartic acid were designed and synthesized. The organogel and liquid crystal properties of these amphiphilic dendritic peptides were fully studied by field-emission SEM, temperature dependent FT-IR, differential scanning calorimetry, polarization optical microscopy and X-ray diffraction experiments. Amphiphilic dendritic peptides G3 show good organogel properties with a minimum gelation concentration as low as 1 wt %. Furthermore, amphiphilic dendritic peptides G3 can form a hexagonal columnar liquid crystal assembly over a wide temperature range.

  15. Dendritic SNAREs add a new twist to the old neuron theory.

    PubMed

    Ovsepian, Saak V; Dolly, J Oliver

    2011-11-29

    Dendritic exocytosis underpins a broad range of integrative and homeostatic synaptic functions. Emerging data highlight the essential role of SNAREs in trafficking and fusion of secretory organelles with release of peptides and neurotransmitters from dendrites. This Perspective analyzes recent evidence inferring axo-dendritic polarization of vesicular release machinery and pinpoints progress made with existing challenges in this rapidly progressing field of dendritic research. Interpreting the relation of new molecular data to physiological results on secretion from dendrites would greatly advance our understanding of this facet of neuronal mechanisms.

  16. Preparation and SERS Study of Silver Microstructures with Dendritic Shape.

    PubMed

    Zhang, Xiao-tong; Zhao, Chun-liu; Zhou, Yu-meng; Dong, Qian-min; Lang, Ting-ting; Jin, Shang-zhong

    2015-10-01

    In the surface ehanced Raman scattering (SERS) technology, not only to improve the making process of SERS substrates, to be fast and easily, but also to enhance the SERS enhance factor, an easy replacement reaction between zinc and silver nitrate solution has been adopted to prepare silver micro-structures SERS-active substrate. The silver micro-substrates have many advantages. These substrates have good stability, well preservation, an easy making method and a fast making process. The surface profile of the silver microparticles is investigated by scanning electron microscope (SEM). The silver microstructures are dendritic shape in a symmetrical fashion with symmetrical distribution. When the time of the replace reaction is 40, 50 and 60 s, respectively, the average lengths of "trunks" in the silver dendritic microsubstractes are about 3, 5 and 10 μm, and the lengths of the "branches" are about 700 nm, 2 μm and 3 μm, respectively. The result shows that the longer time the replacement reaction takes, the longer lengths of the "trunks" and "branches" in the silver dendritic microsubstractes become. With the time of replace reaction increasing, the "trunk" and "branch" in the silver dendritic microsubstractes grow longer and a large amount of nano-level "leaves" grow out from the "branches" of the silver dendritic microsubstractes, so the silver micro size dendrates have nano level structure on surface. In order to investigate the SERS-active substrates application in SERS, a Fourier transform Raman spectrograph with a 1 064 nm laser wavelength is used to measure the SERS spectra. And good SERS spectra have been obtained by using dendritic silver microsubstrates on the silicon chip as a SERS substract, and Rhodamine 6G (R6G) as a molecule probe. It is found that the silver micro-substrates have good Raman characteristics. And comparing these SERS spectra, it gets the conclution that the spectra with best SERS enhance effect are obtained when R6G is obsorbed on the

  17. The tight relationship between asymmetric signaling and locational excitability in motoneuron dendrites.

    PubMed

    Kim, Hojeong; Heckman, C J

    2015-01-01

    Spinal motoneurons possess large, highly branching dendritic structures that contain thousands of synaptic contacts and various voltage-gated ion channels (VGICs). Research has indicated that dendritic arborization and cable properties provide the basis for foundational dendritic processing, which is characterized by direction-dependent signal propagation and location-dependent channel activation in dendritic arbors. Due to these arbors' complex structure, signals attenuate differentially depending on whether propagation occurs from the soma to the dendrite or in the opposite direction. In addition, current thresholds for the activation of dendritic ion channels differ depending on the location of these channels within dendrites. However, whether and how these foundational properties for dendritic signaling and excitability are related in motoneurons remains unclear. Based on our analyses of anatomically reconstructed motoneurons and novel reduced models, we propose that 1) directional signal propagation is similar across spinal motoneurons, regardless of cell type-specific structures; 2) reduced models that retain dendritic signaling asymmetry can accurately replicate anatomical dendritic excitability in both passive and active modes; and 3) asymmetric signal propagation and locational dendritic excitability are closely related, irrespective of motoneurons' arbor structures. PMID:27066175

  18. Signal transfer in passive dendrites with nonuniform membrane conductance.

    PubMed

    London, M; Meunier, C; Segev, I

    1999-10-01

    In recent years it became clear that dendrites possess a host of ion channels that may be distributed nonuniformly over their membrane surface. In cortical pyramids, for example, it was demonstrated that the resting membrane conductance G(m)(x) is higher (the membrane is "leakier") at distal dendritic regions than at more proximal sites. How does this spatial nonuniformity in G(m)(x) affect the input-output function of the neuron? The present study aims at providing basic insights into this question. To this end, we have analytically studied the fundamental effects of membrane non-uniformity in passive cable structures. Keeping the total membrane conductance over a given modeled structure fixed (i.e., a constant number of passive ion channels), the classical case of cables with uniform membrane conductance is contrasted with various nonuniform cases with the following general conclusions. (1) For cylindrical cables with "sealed ends," monotonic increase in G(m)(x) improves voltage transfer from the input location to the soma. The steeper the G(m)(x), the larger the improvement. (2) This effect is further enhanced when the stimulation is distal and consists of a synaptic input rather than a current source. (3) Any nonuniformity in G(m)(x) decreases the electrotonic length, L, of the cylinder. (4) The system time constant tau(0) is larger in the nonuniform case than in the corresponding uniform case. (5) When voltage transients relax with tau(0), the dendritic tree is not isopotential in the nonuniform case, at variance with the uniform case. The effect of membrane nonuniformity on signal transfer in reconstructed dendritic trees and on the I/f relation of the neuron is also considered, and experimental methods for assessing membrane nonuniformity in dendrites are discussed.

  19. Dendritic Organization of Olfactory Inputs to Medial Amygdala Neurons.

    PubMed

    Keshavarzi, Sepideh; Power, John M; Albers, Eva H H; Sullivan, Robert K S; Sah, Pankaj

    2015-09-23

    The medial amygdala (MeA) is a central hub in the olfactory neural network. It receives vomeronasal information directly from the accessory olfactory bulb (AOB) and main olfactory information largely via odor-processing regions such as the olfactory cortical amygdala (CoA). How these inputs are processed by MeA neurons is poorly understood. Using the GAD67-GFP mouse, we show that MeA principal neurons receive convergent AOB and CoA inputs. Somatically recorded AOB synaptic inputs had slower kinetics than CoA inputs, suggesting that they are electrotonically more distant. Field potential recording, pharmacological manipulation, and Ca(2+) imaging revealed that AOB synapses are confined to distal dendrites and segregated from the proximally located CoA synapses. Moreover, unsynchronized AOB inputs had significantly broader temporal summation that was dependent on the activation of NMDA receptors. These findings show that MeA principal neurons process main and accessory olfactory inputs differentially in distinct dendritic compartments. Significance statement: In most vertebrates, olfactory cues are processed by two largely segregated neural pathways, the main and accessory olfactory systems, which are specialized to detect odors and nonvolatile chemosignals, respectively. Information from these two pathways ultimately converges at higher brain regions, one of the major hubs being the medial amygdala. Little is known about how olfactory inputs are processed by medial amygdala neurons. This study shows that individual principal neurons in this region receive input from both pathways and that these synapses are spatially segregated on their dendritic tree. We provide evidence suggesting that this dendritic segregation leads to distinct input integration and impact on neuronal output; hence, dendritic mechanisms control olfactory processing in the amygdala. PMID:26400933

  20. Deterministic side-branching during thermal dendritic growth

    NASA Astrophysics Data System (ADS)

    Mullis, Andrew M.

    2015-06-01

    The accepted view on dendritic side-branching is that side-branches grow as the result of selective amplification of thermal noise and that in the absence of such noise dendrites would grow without the development of side-arms. However, recently there has been renewed speculation about dendrites displaying deterministic side-branching [see e.g. ME Glicksman, Metall. Mater. Trans A 43 (2012) 391]. Generally, numerical models of dendritic growth, such as phase-field simulation, have tended to display behaviour which is commensurate with the former view, in that simulated dendrites do not develop side-branches unless noise is introduced into the simulation. However, here we present simulations at high undercooling that show that under certain conditions deterministic side-branching may occur. We use a model formulated in the thin interface limit and a range of advanced numerical techniques to minimise the numerical noise introduced into the solution, including a multigrid solver. Not only are multigrid solvers one of the most efficient means of inverting the large, but sparse, system of equations that results from implicit time-stepping, they are also very effective at smoothing noise at all wavelengths. This is in contrast to most Jacobi or Gauss-Seidel iterative schemes which are effective at removing noise with wavelengths comparable to the mesh size but tend to leave noise at longer wavelengths largely undamped. From an analysis of the tangential thermal gradients on the solid-liquid interface the mechanism for side-branching appears to be consistent with the deterministic model proposed by Glicksman.

  1. Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury.

    PubMed

    Bandaru, Samira P; Liu, Shujun; Waxman, Stephen G; Tan, Andrew M

    2015-03-01

    Hyperreflexia and spasticity are chronic complications in spinal cord injury (SCI), with limited options for safe and effective treatment. A central mechanism in spasticity is hyperexcitability of the spinal stretch reflex, which presents symptomatically as a velocity-dependent increase in tonic stretch reflexes and exaggerated tendon jerks. In this study we tested the hypothesis that dendritic spine remodeling within motor reflex pathways in the spinal cord contributes to H-reflex dysfunction indicative of spasticity after contusion SCI. Six weeks after SCI in adult Sprague-Dawley rats, we observed changes in dendritic spine morphology on α-motor neurons below the level of injury, including increased density, altered spine shape, and redistribution along dendritic branches. These abnormal spine morphologies accompanied the loss of H-reflex rate-dependent depression (RDD) and increased ratio of H-reflex to M-wave responses (H/M ratio). Above the level of injury, spine density decreased compared with below-injury spine profiles and spine distributions were similar to those for uninjured controls. As expected, there was no H-reflex hyperexcitability above the level of injury in forelimb H-reflex testing. Treatment with NSC23766, a Rac1-specific inhibitor, decreased the presence of abnormal dendritic spine profiles below the level of injury, restored RDD of the H-reflex, and decreased H/M ratios in SCI animals. These findings provide evidence for a novel mechanistic relationship between abnormal dendritic spine remodeling in the spinal cord motor system and reflex dysfunction in SCI.

  2. The "conscious pilot"-dendritic synchrony moves through the brain to mediate consciousness.

    PubMed

    Hameroff, Stuart

    2010-01-01

    Cognitive brain functions including sensory processing and control of behavior are understood as "neurocomputation" in axonal-dendritic synaptic networks of "integrate-and-fire" neurons. Cognitive neurocomputation with consciousness is accompanied by 30- to 90-Hz gamma synchrony electroencephalography (EEG), and non-conscious neurocomputation is not. Gamma synchrony EEG derives largely from neuronal groups linked by dendritic-dendritic gap junctions, forming transient syncytia ("dendritic webs") in input/integration layers oriented sideways to axonal-dendritic neurocomputational flow. As gap junctions open and close, a gamma-synchronized dendritic web can rapidly change topology and move through the brain as a spatiotemporal envelope performing collective integration and volitional choices correlating with consciousness. The "conscious pilot" is a metaphorical description for a mobile gamma-synchronized dendritic web as vehicle for a conscious agent/pilot which experiences and assumes control of otherwise non-conscious auto-pilot neurocomputation. PMID:19669425

  3. Detection of subsurface structures underneath dendrites formed on cycled lithium metal electrodes.

    PubMed

    Harry, Katherine J; Hallinan, Daniel T; Parkinson, Dilworth Y; MacDowell, Alastair A; Balsara, Nitash P

    2014-01-01

    Failure caused by dendrite growth in high-energy-density, rechargeable batteries with lithium metal anodes has prevented their widespread use in applications ranging from consumer electronics to electric vehicles. Efforts to solve the lithium dendrite problem have focused on preventing the growth of protrusions from the anode surface. Synchrotron hard X-ray microtomography experiments on symmetric lithium-polymer-lithium cells cycled at 90 °C show that during the early stage of dendrite development, the bulk of the dendritic structure lies within the electrode, underneath the polymer/electrode interface. Furthermore, we observed crystalline impurities, present in the uncycled lithium anodes, at the base of the subsurface dendritic structures. The portion of the dendrite protruding into the electrolyte increases on cycling until it spans the electrolyte thickness, causing a short circuit. Contrary to conventional wisdom, it seems that preventing dendrite formation in polymer electrolytes depends on inhibiting the formation of subsurface structures in the lithium electrode.

  4. Receptor tyrosine phosphatase CLR-1 acts in skin cells to promote sensory dendrite outgrowth.

    PubMed

    Liu, Xianzhuang; Wang, Xiangming; Shen, Kang

    2016-05-01

    Sensory dendrite morphogenesis is directed by intrinsic and extrinsic factors. The extracellular environment plays instructive roles in patterning dendrite growth and branching. However, the molecular mechanism is not well understood. In Caenorhabditis elegans, the proprioceptive neuron PVD forms highly branched sensory dendrites adjacent to the hypodermis. We report that receptor tyrosine phosphatase CLR-1 functions in the hypodermis to pattern the PVD dendritic branches. Mutations in clr-1 lead to loss of quaternary branches, reduced secondary branches and increased ectopic branches. CLR-1 is necessary for the dendrite extension but not for the initial filopodia formation. Its role is dependent on the intracellular phosphatase domain but not the extracellular adhesion domain, indicating that it functions through dephosphorylating downstream factors but not through direct adhesion with neurons. Genetic analysis reveals that clr-1 also functions in parallel with SAX-7/DMA-1 pathway to control PVD primary dendrite development. We provide evidence of a new environmental factor for PVD dendrite morphogenesis. PMID:26968353

  5. Differential Dendritic Integration of Synaptic Potentials and Calcium in Cerebellar Interneurons.

    PubMed

    Tran-Van-Minh, Alexandra; Abrahamsson, Therése; Cathala, Laurence; DiGregorio, David A

    2016-08-17

    Dendritic voltage integration determines the transformation of synaptic inputs into output firing, while synaptic calcium integration drives plasticity mechanisms thought to underlie memory storage. Dendritic calcium integration has been shown to follow the same synaptic input-output relationship as dendritic voltage, but whether similar operations apply to neurons exhibiting sublinear voltage integration is unknown. We examined the properties and cellular mechanisms of these dendritic operations in cerebellar molecular layer interneurons using dendritic voltage and calcium imaging, in combination with synaptic stimulation or glutamate uncaging. We show that, while synaptic potentials summate sublinearly, concomitant dendritic calcium signals summate either linearly or supralinearly depending on the number of synapses activated. The supralinear dendritic calcium triggers a branch-specific, short-term suppression of neurotransmitter release that alters the pattern of synaptic activation. Thus, differential voltage and calcium integration permits dynamic regulation of neuronal input-output transformations without altering intrinsic nonlinear integration mechanisms. PMID:27537486

  6. Morphological analysis of dendrites and spines by hybridization of ridge detection with twin support vector machine.

    PubMed

    Wang, Shuihua; Chen, Mengmeng; Li, Yang; Shao, Ying; Zhang, Yudong; Du, Sidan; Wu, Jane

    2016-01-01

    Dendritic spines are described as neuronal protrusions. The morphology of dendritic spines and dendrites has a strong relationship to its function, as well as playing an important role in understanding brain function. Quantitative analysis of dendrites and dendritic spines is essential to an understanding of the formation and function of the nervous system. However, highly efficient tools for the quantitative analysis of dendrites and dendritic spines are currently undeveloped. In this paper we propose a novel three-step cascaded algorithm-RTSVM- which is composed of ridge detection as the curvature structure identifier for backbone extraction, boundary location based on differences in density, the Hu moment as features and Twin Support Vector Machine (TSVM) classifiers for spine classification. Our data demonstrates that this newly developed algorithm has performed better than other available techniques used to detect accuracy and false alarm rates. This algorithm will be used effectively in neuroscience research. PMID:27547530

  7. Morphological analysis of dendrites and spines by hybridization of ridge detection with twin support vector machine

    PubMed Central

    Wang, Shuihua; Chen, Mengmeng; Li, Yang; Shao, Ying; Zhang, Yudong

    2016-01-01

    Dendritic spines are described as neuronal protrusions. The morphology of dendritic spines and dendrites has a strong relationship to its function, as well as playing an important role in understanding brain function. Quantitative analysis of dendrites and dendritic spines is essential to an understanding of the formation and function of the nervous system. However, highly efficient tools for the quantitative analysis of dendrites and dendritic spines are currently undeveloped. In this paper we propose a novel three-step cascaded algorithm–RTSVM— which is composed of ridge detection as the curvature structure identifier for backbone extraction, boundary location based on differences in density, the Hu moment as features and Twin Support Vector Machine (TSVM) classifiers for spine classification. Our data demonstrates that this newly developed algorithm has performed better than other available techniques used to detect accuracy and false alarm rates. This algorithm will be used effectively in neuroscience research. PMID:27547530

  8. Dendritic gold nanowire growth observed in liquid with transmission electron microscopy.

    PubMed

    Kraus, Tobias; de Jonge, Niels

    2013-07-01

    The growth of nanoscale gold dendrites was studied in situ in a thin liquid film with transmission electron microscopy (TEM) using a liquid cell with silicon nitride (SiN) windows. Gold nanoparticle seeds were covered by a thin liquid layer containing precursor solution. Dendrite nucleation was induced by the electron beam leading to an initial burst of growth. The growth then settled at tip velocities between 0.1 and 2.0 nm/s for different dendrites. Tip velocities fluctuated as different dendrite geometries grew from the tips. Those dendrites showing granularities in their structure experienced the largest growth speed. Comparison of the observed velocities with diffusion-limited growth rates suggests that dendrite growth in thin films at this scale is limited by diffusion. The described method may find application in research on the mechanisms behind dendrite growth and also to study other types of anisotropic growth of nanomaterials driven by crystal and twin geometries.

  9. Differential Dendritic Integration of Synaptic Potentials and Calcium in Cerebellar Interneurons.

    PubMed

    Tran-Van-Minh, Alexandra; Abrahamsson, Therése; Cathala, Laurence; DiGregorio, David A

    2016-08-17

    Dendritic voltage integration determines the transformation of synaptic inputs into output firing, while synaptic calcium integration drives plasticity mechanisms thought to underlie memory storage. Dendritic calcium integration has been shown to follow the same synaptic input-output relationship as dendritic voltage, but whether similar operations apply to neurons exhibiting sublinear voltage integration is unknown. We examined the properties and cellular mechanisms of these dendritic operations in cerebellar molecular layer interneurons using dendritic voltage and calcium imaging, in combination with synaptic stimulation or glutamate uncaging. We show that, while synaptic potentials summate sublinearly, concomitant dendritic calcium signals summate either linearly or supralinearly depending on the number of synapses activated. The supralinear dendritic calcium triggers a branch-specific, short-term suppression of neurotransmitter release that alters the pattern of synaptic activation. Thus, differential voltage and calcium integration permits dynamic regulation of neuronal input-output transformations without altering intrinsic nonlinear integration mechanisms.

  10. Conditional self-discrimination enhances dendritic spine number and dendritic length at prefrontal cortex and hippocampal neurons of rats.

    PubMed

    Penagos-Corzo, Julio C; Bonilla, Andrea; Rodríguez-Moreno, Antonio; Flores, Gonzalo; Negrete-Díaz, José V

    2015-11-01

    We studied conditional self-discrimination (CSD) in rats and compared the neuronal cytoarchitecture of untrained animals and rats that were trained in self-discrimination. For this purpose, we used thirty 10-week-old male rats were randomized into three groups: one control group and two conditioning groups: a comparison group (associative learning) and an experimental group (self-discrimination). At the end of the conditioning process, the experimental group managed to discriminate their own state of thirst. After the conditioning process, dendritic morphological changes in the pyramidal neurons of the prefrontal cortex and CA1 region of the dorsal hippocampus were evaluated using Golgi-Cox stain method and then analyzed by the Sholl method. Differences were found in total dendritic length and spine density. Animals trained in self-discrimination showed an increase in the dendritic length and the number of dendritic spines of neurons of the prefrontal cortex and CA1 region of the dorsal hippocampus. Our data suggest that conditional self-discrimination improves the connectivity of the prefrontal cortex and dorsal CA1, which has implications for memory and learning processes.

  11. A Comparison between Growth Morphology of "Eutectic" Cells/Dendrites and Single-Phase Cells/Dendrites

    NASA Technical Reports Server (NTRS)

    Tewari, S. N.; Raj, S. V.; Locci, I. E.

    2003-01-01

    Directionally solidified (DS) intermetallic and ceramic-based eutectic alloys with an in-situ composite microstructure containing finely distributed, long aspect ratio, fiber, or plate reinforcements are being seriously examined for several advanced aero-propulsion applications. In designing these alloys, additional solutes need to be added to the base eutectic composition in order to improve heir high-temperature strength, and provide for adequate toughness and resistance to environmental degradation. Solute addition, however, promotes instability at the planar liquid-solid interface resulting in the formation of two-phase eutectic "colonies." Because morphology of eutectic colonies is very similar to the single-phase cells and dendrites, the stability analysis of Mullins and Sekerka has been extended to describe their formation. Onset of their formation shows a good agreement with this approach; however, unlike the single-phase cells and dendrites, there is limited examination of their growth speed dependence of spacing, morphology, and spatial distribution. The purpose of this study is to compare the growth speed dependence of the morphology, spacing, and spatial distribution of eutectic cells and dendrites with that for the single-phase cells and dendrites.

  12. Viral complement regulatory proteins.

    PubMed

    Rosengard, A M; Ahearn, J M

    1999-05-01

    The inactivation of complement provides cells and tissues critical protection from complement-mediated attack and decreases the associated recruitment of other inflammatory mediators. In an attempt to evade the host immune response, viruses have evolved two mechanisms to acquire complement regulatory proteins. They can directly seize the host cell complement regulators onto their outer envelope and/or they can produce their own proteins which are either secreted into the neighboring intercellular space or expressed as membrane-bound proteins on the infected host cell. The following review will concentrate on the viral homologues of the mammalian complement regulatory proteins, specifically those containing complement control protein (CCP) repeats. PMID:10408371

  13. Rationales for regulatory activity

    SciTech Connect

    Perhac, R.M.

    1997-02-01

    The author provides an outline which touches on the types of concerns about risk evaluation which are addressed in the process of establishing regulatory guides. Broadly he says regulatory activity serves three broad constituents: (1) Paternalism (private risk); (2) Promotion of social welfare (public risks); (3) Protection of individual rights (public risks). He then discusses some of the major issues encountered in reaching a decision on what is an acceptable level of risk within each of these areas, and how one establishes such a level.

  14. Effect of the environment on the dendritic morphology of the rat auditory cortex

    PubMed Central

    Bose, Mitali; Muñoz-Llancao, Pablo; Roychowdhury, Swagata; Nichols, Justin A.; Jakkamsetti, Vikram; Porter, Benjamin; Byrapureddy, Rajasekhar; Salgado, Humberto; Kilgard, Michael P.; Aboitiz, Francisco; Dagnino-Subiabre, Alexies; Atzori, Marco

    2010-01-01

    The present study aimed to identify morphological correlates of environment-induced changes at excitatory synapses of the primary auditory cortex (A1). We used the Golgi-Cox stain technique to compare pyramidal cells dendritic properties of Sprague-Dawley rats exposed to different environmental manipulations. Sholl analysis, dendritic length measures, and spine density counts were used to monitor the effects of sensory deafness and an auditory version of environmental enrichment (EE). We found that deafness decreased apical dendritic length leaving basal dendritic length unchanged, whereas EE selectively increased basal dendritic length without changing apical dendritic length. On the contrary, deafness decreased while EE increased spine density in both basal and apical dendrites of A1 layer 2/3 (LII/III) neurons. To determine whether stress contributed to the observed morphological changes in A1, we studied neural morphology in a restraint-induced model that lacked behaviorally relevant acoustic cues. We found that stress selectively decreased apical dendritic length in the auditory but not in the visual primary cortex. Similar to the acoustic manipulation, stress-induced changes in dendritic length possessed a layer specific pattern displaying LII/III neurons from stressed animals with normal apical dendrites but shorter basal dendrites, while infragranular neurons (layers V and VI) displayed shorter apical dendrites but normal basal dendrites. The same treatment did not induce similar changes in the visual cortex, demonstrating that the auditory cortex is an exquisitely sensitive target of neocortical plasticity, and that prolonged exposure to different acoustic as well as emotional environmental manipulation may produce specific changes in dendritic shape and spine density. PMID:19771593

  15. Passive Dendrites Enable Single Neurons to Compute Linearly Non-separable Functions

    PubMed Central

    Cazé, Romain Daniel; Humphries, Mark; Gutkin, Boris

    2013-01-01

    Local supra-linear summation of excitatory inputs occurring in pyramidal cell dendrites, the so-called dendritic spikes, results in independent spiking dendritic sub-units, which turn pyramidal neurons into two-layer neural networks capable of computing linearly non-separable functions, such as the exclusive OR. Other neuron classes, such as interneurons, may possess only a few independent dendritic sub-units, or only passive dendrites where input summation is purely sub-linear, and where dendritic sub-units are only saturating. To determine if such neurons can also compute linearly non-separable functions, we enumerate, for a given parameter range, the Boolean functions implementable by a binary neuron model with a linear sub-unit and either a single spiking or a saturating dendritic sub-unit. We then analytically generalize these numerical results to an arbitrary number of non-linear sub-units. First, we show that a single non-linear dendritic sub-unit, in addition to the somatic non-linearity, is sufficient to compute linearly non-separable functions. Second, we analytically prove that, with a sufficient number of saturating dendritic sub-units, a neuron can compute all functions computable with purely excitatory inputs. Third, we show that these linearly non-separable functions can be implemented with at least two strategies: one where a dendritic sub-unit is sufficient to trigger a somatic spike; another where somatic spiking requires the cooperation of multiple dendritic sub-units. We formally prove that implementing the latter architecture is possible with both types of dendritic sub-units whereas the former is only possible with spiking dendrites. Finally, we show how linearly non-separable functions can be computed by a generic two-compartment biophysical model and a realistic neuron model of the cerebellar stellate cell interneuron. Taken together our results demonstrate that passive dendrites are sufficient to enable neurons to compute linearly non

  16. Interaction of dendritic cells and T lymphocytes for the therapeutic effect of Dangguiliuhuang decoction to autoimmune diabetes

    PubMed Central

    Liu, Tingting; Cao, Hui; Ji, Yachun; Pei, Yufeng; Yu, Zhihong; Quan, Yihong; Xiang, Ming

    2015-01-01

    In traditional Chinese medicine (TCM), Dangguiliuhuang decoction (DGLHD) is an effective treatment of autoimmune diabetes. Here, we studied potential anti-diabetic mechanisms of DGLHD in a non-obese diabetic (NOD) mouse model. In vitro, DGLHD and individual active ingredients enhanced glucose uptake in HepG2 cells, inhibited T lymphocyte proliferation, and suppressed dendritic cells (DCs) function. In vivo, DGLHD significantly inhibited insulitis, delayed the onset and development of diabetes, promoted insulin secretion and sensitivity, and balanced partially normalized Th1 and Th2 cytokines in NOD mice. In addition, DGLHD increased α1-antitrypsin (AAT-1), Bcl-2, and CyclinD1, and decreased Bax levels in pancreas, spleen, thymus, DCs, and a NIT-1 cell line, all consistent with protecting and repairing islet β cell. More detailed studies indicated that DGLHD regulated the maturation and function of DCs, decreased the percentage of merocytic dendritic cells (mcDCs) subset, and increased programmed death ligand-1 (PD-L1) expression in DCs. DGLHD also impeded T lymphocyte proliferation and promoted regulatory T cells (Tregs) differentiation in vivo. A JAK2-STAT3-dependent pathway was involved in the suppression by DGLHD of interactions between DCs and T lymphocyte. The experiments implicated five active ingredients in specific anti-diabetic actions of DGLHD. The results demonstrated the reasonable composition of the formula. PMID:26358493

  17. IRF8 Transcription Factor Controls Survival and Function of Terminally Differentiated Conventional and Plasmacytoid Dendritic Cells, Respectively.

    PubMed

    Sichien, Dorine; Scott, Charlotte L; Martens, Liesbet; Vanderkerken, Matthias; Van Gassen, Sofie; Plantinga, Maud; Joeris, Thorsten; De Prijck, Sofie; Vanhoutte, Leen; Vanheerswynghels, Manon; Van Isterdael, Gert; Toussaint, Wendy; Madeira, Filipe Branco; Vergote, Karl; Agace, William W; Clausen, Björn E; Hammad, Hamida; Dalod, Marc; Saeys, Yvan; Lambrecht, Bart N; Guilliams, Martin

    2016-09-20

    Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated "terminal selectors." Using BM chimeras, conditional Irf8(fl/fl) mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs. PMID:27637148

  18. State-dependent diffusion of actin-depolymerizing factor/cofilin underlies the enlargement and shrinkage of dendritic spines

    PubMed Central

    Noguchi, Jun; Hayama, Tatsuya; Watanabe, Satoshi; Ucar, Hasan; Yagishita, Sho; Takahashi, Noriko; Kasai, Haruo

    2016-01-01

    Dendritic spines are the postsynaptic sites of most excitatory synapses in the brain, and spine enlargement and shrinkage give rise to long-term potentiation and depression of synapses, respectively. Because spine structural plasticity is accompanied by remodeling of actin scaffolds, we hypothesized that the filamentous actin regulatory protein cofilin plays a crucial role in this process. Here we investigated the diffusional properties of cofilin, the actin-severing and depolymerizing actions of which are activated by dephosphorylation. Cofilin diffusion was measured using fluorescently labeled cofilin fusion proteins and two-photon imaging. We show that cofilins are highly diffusible along dendrites in the resting state. However, during spine enlargement, wild-type cofilin and a phosphomimetic cofilin mutant remain confined to the stimulated spine, whereas a nonphosphorylatable mutant does not. Moreover, inhibition of cofilin phosphorylation with a competitive peptide disables spine enlargement, suggesting that phosphorylated-cofilin accumulation is a key regulator of enlargement, which is localized to individual spines. Conversely, spine shrinkage spreads to neighboring spines, even though triggered by weaker stimuli than enlargement. Diffusion of exogenous cofilin injected into a pyramidal neuron soma causes spine shrinkage and reduced PSD95 in spines, suggesting that diffusion of dephosphorylated endogenous cofilin underlies the spreading of spine shrinkage and long-term depression. PMID:27595610

  19. Human monocytes undergo functional re-programming during differentiation to dendritic cell mediated by human extravillous trophoblasts.

    PubMed

    Zhao, Lei; Shao, Qianqian; Zhang, Yun; Zhang, Lin; He, Ying; Wang, Lijie; Kong, Beihua; Qu, Xun

    2016-01-01

    Maternal immune adaptation is required for a successful pregnancy to avoid rejection of the fetal-placental unit. Dendritic cells within the decidual microenvironment lock in a tolerogenic profile. However, how these tolerogenic DCs are induced and the underlying mechanisms are largely unknown. In this study, we show that human extravillous trophoblasts redirect the monocyte-to-DC transition and induce regulatory dendritic cells. DCs differentiated from blood monocytes in the presence of human extravillous trophoblast cell line HTR-8/SVneo displayed a DC-SIGN(+)CD14(+)CD1a(-) phenotype, similar with decidual DCs. HTR8-conditioned DCs were unable to develop a fully mature phenotype in response to LPS, and altered the cytokine secretory profile significantly. Functionally, conditioned DCs poorly induced the proliferation and activation of allogeneic T cells, whereas promoted CD4(+)CD25(+)Foxp3(+) Treg cells generation. Furthermore, the supernatant from DC and HTR-8/SVneo coculture system contained significant high amount of M-CSF and MCP-1. Using neutralizing antibodies, we discussed the role of M-CSF and MCP-1 during monocyte-to-DCs differentiation mediated by extravillous trophoblasts. Our data indicate that human extravillous trophoblasts play an important role in modulating the monocyte-to-DC differentiation through M-CSF and MCP-1, which facilitate the establishment of a tolerogenic microenvironment at the maternal-fetal interface. PMID:26857012

  20. Human monocytes undergo functional re-programming during differentiation to dendritic cell mediated by human extravillous trophoblasts

    PubMed Central

    Zhao, Lei; Shao, Qianqian; Zhang, Yun; Zhang, Lin; He, Ying; Wang, Lijie; Kong, Beihua; Qu, Xun

    2016-01-01

    Maternal immune adaptation is required for a successful pregnancy to avoid rejection of the fetal–placental unit. Dendritic cells within the decidual microenvironment lock in a tolerogenic profile. However, how these tolerogenic DCs are induced and the underlying mechanisms are largely unknown. In this study, we show that human extravillous trophoblasts redirect the monocyte-to-DC transition and induce regulatory dendritic cells. DCs differentiated from blood monocytes in the presence of human extravillous trophoblast cell line HTR-8/SVneo displayed a DC-SIGN+CD14+CD1a− phenotype, similar with decidual DCs. HTR8-conditioned DCs were unable to develop a fully mature phenotype in response to LPS, and altered the cytokine secretory profile significantly. Functionally, conditioned DCs poorly induced the proliferation and activation of allogeneic T cells, whereas promoted CD4+CD25+Foxp3+ Treg cells generation. Furthermore, the supernatant from DC and HTR-8/SVneo coculture system contained significant high amount of M-CSF and MCP-1. Using neutralizing antibodies, we discussed the role of M-CSF and MCP-1 during monocyte-to-DCs differentiation mediated by extravillous trophoblasts. Our data indicate that human extravillous trophoblasts play an important role in modulating the monocyte-to-DC differentiation through M-CSF and MCP-1, which facilitate the establishment of a tolerogenic microenvironment at the maternal–fetal interface. PMID:26857012

  1. State-dependent diffusion of actin-depolymerizing factor/cofilin underlies the enlargement and shrinkage of dendritic spines.

    PubMed

    Noguchi, Jun; Hayama, Tatsuya; Watanabe, Satoshi; Ucar, Hasan; Yagishita, Sho; Takahashi, Noriko; Kasai, Haruo

    2016-01-01

    Dendritic spines are the postsynaptic sites of most excitatory synapses in the brain, and spine enlargement and shrinkage give rise to long-term potentiation and depression of synapses, respectively. Because spine structural plasticity is accompanied by remodeling of actin scaffolds, we hypothesized that the filamentous actin regulatory protein cofilin plays a crucial role in this process. Here we investigated the diffusional properties of cofilin, the actin-severing and depolymerizing actions of which are activated by dephosphorylation. Cofilin diffusion was measured using fluorescently labeled cofilin fusion proteins and two-photon imaging. We show that cofilins are highly diffusible along dendrites in the resting state. However, during spine enlargement, wild-type cofilin and a phosphomimetic cofilin mutant remain confined to the stimulated spine, whereas a nonphosphorylatable mutant does not. Moreover, inhibition of cofilin phosphorylation with a competitive peptide disables spine enlargement, suggesting that phosphorylated-cofilin accumulation is a key regulator of enlargement, which is localized to individual spines. Conversely, spine shrinkage spreads to neighboring spines, even though triggered by weaker stimuli than enlargement. Diffusion of exogenous cofilin injected into a pyramidal neuron soma causes spine shrinkage and reduced PSD95 in spines, suggesting that diffusion of dephosphorylated endogenous cofilin underlies the spreading of spine shrinkage and long-term depression. PMID:27595610

  2. MiR-130a regulates neurite outgrowth and dendritic spine density by targeting MeCP2.

    PubMed

    Zhang, Yunjia; Chen, Mengmeng; Qiu, Zilong; Hu, Keping; McGee, Warren; Chen, Xiaoping; Liu, Jianghong; Zhu, Li; Wu, Jane Y

    2016-07-01

    MicroRNAs (miRNAs) are critical for both development and function of the central nervous system. Significant evidence suggests that abnormal expression of miRNAs is associated with neurodevelopmental disorders. MeCP2 protein is an epigenetic regulator repressing or activating gene transcription by binding to methylated DNA. Both loss-of-function and gain-of-function mutations in the MECP2 gene lead to neurodevelopmental disorders such as Rett syndrome, autism and MECP2 duplication syndrome. In this study, we demonstrate that miR-130a inhibits neurite outgrowth and reduces dendritic spine density as well as dendritic complexity. Bioinformatics analyses, cell cultures and biochemical experiments indicate that miR-130a targets MECP2 and down-regulates MeCP2 protein expression. Furthermore, expression of the wild-type MeCP2, but not a loss-of-function mutant, rescues the miR-130a-induced phenotype. Our study uncovers the MECP2 gene as a previous unknown target for miR-130a, supporting that miR-130a may play a role in neurodevelopment by regulating MeCP2. Together with data from other groups, our work suggests that a feedback regulatory mechanism involving both miR-130a and MeCP2 may serve to ensure their appropriate expression and function in neural development. PMID:27245166

  3. Induction of Regulatory T Cells by Intravenous Immunoglobulin: A Bridge between Adaptive and Innate Immunity

    PubMed Central

    Kaufman, Gabriel N.; Massoud, Amir H.; Dembele, Marieme; Yona, Madelaine; Piccirillo, Ciriaco A.; Mazer, Bruce D.

    2015-01-01

    Intravenous immunoglobulin (IVIg) is a polyclonal immunoglobulin G preparation with potent immunomodulatory properties. The mode of action of IVIg has been investigated in multiple disease states, with various mechanisms described to account for its benefits. Recent data indicate that IVIg increases both the number and the suppressive capacity of regulatory T cells, a subpopulation of T cells that are essential for immune homeostasis. IVIg alters dendritic cell function, cytokine and chemokine networks, and T lymphocytes, leading to development of regulatory T cells. The ability of IVIg to influence Treg induction has been shown both in animal models and in human diseases. In this review, we discuss data on the potential mechanisms contributing to the interaction between IVIg and the regulatory T-cell compartment. PMID:26441974

  4. EPAct Transportation Regulatory Activities

    SciTech Connect

    2011-11-21

    The U.S. Department of Energy's (DOE) Vehicle Technologies Program manages several transportation regulatory activities established by the Energy Policy Act of 1992 (EPAct), as amended by the Energy Conservation Reauthorization Act of 1998, EPAct 2005, and the Energy Independence and Security Act of 2007 (EISA).

  5. The regulatory horizon

    NASA Technical Reports Server (NTRS)

    Cook, ED

    1987-01-01

    The author briefly discusses the FAA's position as it relates to cockpit resource management. For example, if Cockpit Resource Management (CRM) is a positive concept, why isn't everyone required to implement it? The regulatory practice of the FAA is discussed and questions and answers are presented.

  6. miR-9 and miR-124 synergistically affect regulation of dendritic branching via the AKT/GSK3β pathway by targeting Rap2a

    PubMed Central

    Xue, Qian; Yu, Caiyong; Wang, Yan; Liu, Ling; Zhang, Kun; Fang, Chao; Liu, Fangfang; Bian, Ganlan; Song, Bing; Yang, Angang; Ju, Gong; Wang, Jian

    2016-01-01

    A single microRNA (miRNA) can regulate expression of multiple proteins, and expression of an individual protein may be controlled by numerous miRNAs. This regulatory pattern strongly suggests that synergistic effects of miRNAs play critical roles in regulating biological processes. miR-9 and miR-124, two of the most abundant miRNAs in the mammalian nervous system, have important functions in neuronal development. In this study, we identified the small GTP-binding protein Rap2a as a common target of both miR-9 and miR-124. miR-9 and miR-124 together, but neither miRNA alone, strongly suppressed Rap2a, thereby promoting neuronal differentiation of neural stem cells (NSCs) and dendritic branching of differentiated neurons. Rap2a also diminished the dendritic complexity of mature neurons by decreasing the levels of pAKT and pGSK3β. Our results reveal a novel pathway in which miR-9 and miR-124 synergistically repress expression of Rap2a to sustain homeostatic dendritic complexity during neuronal development and maturation. PMID:27221778

  7. A Ca(2+)-, Mg(2+)-, and Zn(2+)-Based Dendritic Contractile Nanodevice with Two pH-Dependent Motional Functions.

    PubMed

    Stadler, Adrian-Mihail; Karmazin, Lydia; Bailly, Corinne

    2015-11-23

    A contractile dendritic motional device is reported where metal ions with biological importance--Ca(2+) (the main regulatory and signaling species of the natural muscles), Mg(2+), and Zn(2+)--initiate two kinds of motional functions. The first motional function is the metal-ion-induced contraction of a linear strand into a Z-shaped dinuclear complex, and the second one is the change of the height of Z-shaped complexes via transmetalation. By means of the pH-dependent counterligand tren, the two motional features of the machine can depend on alternate additions of acid and base. An optical response is associated with the conversion of the linear form (which is yellow) into the metalated Z-shaped one (which is red).

  8. Stromal Cells from Human Decidua Exert a Strong Inhibitory Effect on NK Cell Function and Dendritic Cell Differentiation

    PubMed Central

    Canegallo, Francesca; Conte, Romana; Venturini, Pier Luigi; Moretta, Lorenzo; Mingari, Maria Cristina

    2014-01-01

    Stromal cells (SC) are an important component of decidual tissues where they are in strict proximity with both NK and CD14+ myelomonocytic cells that play a role in the maintenance of pregnancy. In this study we analyzed whether decidual SC (DSC) could exert a regulatory role on NK and CD14+ cells that migrate from peripheral blood (PB) to decidua during pregnancy. We show that DSCs inhibit the IL15-mediated up-regulation of major activating NK receptors in PB-derived NK cells. In addition, the IL15-induced NK cell proliferation, cytolytic activity and IFN-γ production were severely impaired. DSCs sharply inhibited dendritic cells differentiation and their ability to induce allogeneic T cell proliferation. Indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2) mediated the inhibitory effect of DSCs. Our results strongly suggest an important role of DSCs in preventing potentially dangerous immune response, thus contributing to maintenance of pregnancy. PMID:24586479

  9. Activation of toll-like receptor-2 by endogenous matrix metalloproteinase-2 modulates dendritic-cell-mediated inflammatory responses.

    PubMed

    Godefroy, Emmanuelle; Gallois, Anne; Idoyaga, Juliana; Merad, Miriam; Tung, Navpreet; Monu, Ngozi; Saenger, Yvonne; Fu, Yichun; Ravindran, Rajesh; Pulendran, Bali; Jotereau, Francine; Trombetta, Sergio; Bhardwaj, Nina

    2014-12-11

    Matrix metalloproteinase-2 (MMP-2) is involved in several physiological mechanisms, including wound healing and tumor progression. We show that MMP-2 directly stimulates dendritic cells (DCs) to both upregulate OX40L on the cell surface and secrete inflammatory cytokines. The mechanism underlying DC activation includes physical association with Toll-like receptor-2 (TLR2), leading to NF-κB activation, OX40L upregulation on DCs, and ensuing TH2 differentiation. Significantly, MMP-2 polarizes T cells toward type 2 responses in vivo, in a TLR2-dependent manner. MMP-2-dependent type 2 polarization may represent a key immune regulatory mechanism for protection against a broad array of disorders, such as inflammatory, infectious, and autoimmune diseases, which can be hijacked by tumors to evade immunity.

  10. Activation of Toll-like receptor-2 by endogenous matrix metalloproteinase-2 modulates dendritic cell-mediated inflammatory responses

    PubMed Central

    Godefroy, Emmanuelle; Gallois, Anne; Idoyaga, Juliana; Merad, Miriam; Tung, Navpreet; Monu, Ngozi; Saenger, Yvonne; Fu, Yichun; Nair, Rajesh; Pulendran, Bali; Jotereau, Francine; Trombetta, Sergio; Bhardwaj, Nina

    2015-01-01

    SUMMARY Matrix metalloproteinase-2 (MMP-2) is involved in several physiological mechanisms, including wound healing and tumor progression. We show that MMP-2 directly stimulates dendritic cells (DCs) to both up-regulate OX40L on the cell surface and secrete inflammatory cytokines. The mechanism underlying DC activation includes physical association with Toll-like receptor-2 (TLR2), leading to NF-κB activation, OX40L up-regulation on DCs and ensuing TH2 differentiation. Significantly, MMP-2 polarizes T cells towards type-2 responses in vivo, in a TLR2-dependent manner. MMP-2-dependent type-2 polarization may represent a key immune regulatory mechanism to protect against a broad array of disorders, such as inflammatory, infectious and autoimmune diseases, which can be hijacked by tumors to evade immunity. PMID:25466255

  11. Pathological Mobilization and Activities of Dendritic Cells in Tumor-Bearing Hosts: Challenges and Opportunities for Immunotherapy of Cancer

    PubMed Central

    Tesone, Amelia J.; Svoronos, Nikolaos; Allegrezza, Michael J.; Conejo-Garcia, Jose R.

    2013-01-01

    A common characteristic of solid tumors is the pathological recruitment of immunosuppressive myeloid cells, which in certain tumors includes dendritic cells (DCs). DCs are of particular interest in the field of cancer immunotherapy because they induce potent and highly specific anti-tumor immune responses, particularly in the early phase of tumorigenesis. However, as tumors progress, these cells can be transformed into regulatory cells that contribute to an immunosuppressive microenvironment favoring tumor growth. Therefore, controlling DC phenotype has the potential to elicit effective anti-tumor responses while simultaneously weakening the tumor’s ability to protect itself from immune attack. This review focuses on the dual nature of DCs in the tumor microenvironment, the regulation of DC phenotype, and the prospect of modifying DCs in situ as a novel immunotherapeutic approach. PMID:24339824

  12. Regulatory role of suppressive motifs from commensal DNA.

    PubMed

    Bouladoux, N; Hall, J A; Grainger, J R; dos Santos, L M; Kann, M G; Nagarajan, V; Verthelyi, D; Belkaid, Y

    2012-11-01

    The microbiota contributes to the induction of both effector and regulatory responses in the gastrointestinal (GI) tract. However, the mechanisms controlling these distinct properties remain poorly understood. We previously showed that commensal DNA promotes intestinal immunity. Here, we find that the capacity of bacterial DNA to stimulate immune responses is species specific and correlated with the frequency of motifs known to exert immunosuppressive function. In particular, we show that the DNA of Lactobacillus species, including various probiotics, is enriched in suppressive motifs able to inhibit lamina propria dendritic cell activation. In addition, immunosuppressive oligonucleotides sustain T(reg) cell conversion during inflammation and limit pathogen-induced immunopathology and colitis. Altogether, our findings identify DNA-suppressive motifs as a molecular ligand expressed by commensals and support the idea that a balance between stimulatory and regulatory DNA motifs contributes to the induction of controlled immune responses in the GI tract and gut immune homeostasis. Further, our findings suggest that the endogenous regulatory capacity of DNA motifs enriched in some commensal bacteria could be exploited for therapeutic purposes. PMID:22617839

  13. A gene regulatory network armature for T-lymphocyte specification

    SciTech Connect

    Fung, Elizabeth-sharon

    2008-01-01

    Choice of a T-lymphoid fate by hematopoietic progenitor cells depends on sustained Notch-Delta signaling combined with tightly-regulated activities of multiple transcription factors. To dissect the regulatory network connections that mediate this process, we have used high-resolution analysis of regulatory gene expression trajectories from the beginning to the end of specification; tests of the short-term Notchdependence of these gene expression changes; and perturbation analyses of the effects of overexpression of two essential transcription factors, namely PU.l and GATA-3. Quantitative expression measurements of >50 transcription factor and marker genes have been used to derive the principal components of regulatory change through which T-cell precursors progress from primitive multipotency to T-lineage commitment. Distinct parts of the path reveal separate contributions of Notch signaling, GATA-3 activity, and downregulation of PU.l. Using BioTapestry, the results have been assembled into a draft gene regulatory network for the specification of T-cell precursors and the choice of T as opposed to myeloid dendritic or mast-cell fates. This network also accommodates effects of E proteins and mutual repression circuits of Gfil against Egr-2 and of TCF-l against PU.l as proposed elsewhere, but requires additional functions that remain unidentified. Distinctive features of this network structure include the intense dose-dependence of GATA-3 effects; the gene-specific modulation of PU.l activity based on Notch activity; the lack of direct opposition between PU.l and GATA-3; and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression.

  14. Noncrystallographic calcite dendrites from hot-spring deposits at Lake Bogoria, Kenya

    SciTech Connect

    Jones, B.; Renaut, R.W.

    1995-01-02

    Complex calcite crystals are an integral component of precipitates that form around the orifices of the Loburu and Mawe Moto hot springs on the shores of Lake bogoria, Kenya. Two types of large (up to 4 cm long) noncrystallographic dendrites are important components of these deposits. Feather dendrites are characterized by multiple levels of branching with individual branches developed through crystal splitting and spherulitic growth. Scandulitic (from Latin meaning shingle) dendrites are formed of stacked calcite crystals and are generally more compact than feather dendrites. These developed through the incremental stacking of rectangular-shaped calcite crystals that initially grew as skeletal crystals. Feather and scandulitic dendrites precipitated from the same waters in the same springs. The difference in morphology is therefore related to microenvironments in which they grew. Feather dendrites grew in any direction in pools of free-standing water provided that they were in constant contact with the solute. Conversely, scandulitic dendrites grew on rims of dams where water flowed over the surface in concert with the pulses of spring water. Thus, each calcite crystal in these dendrites represents one episode of crystal growth. The orientation of the component crystals in scandulitic dendrites is controlled by the topography of the dam or surface, not crystallographic criteria. The noncrystallographic dendrites formed from spring waters with initial temperatures of 90--99 C. Surficial water cooling, loss of CO{sub 2}, and presence of other elements that can interfere with crystal growth contributed to the formation of these unusual crystals.

  15. Computational study of electro-convection effects on dendrite growth in batteries

    NASA Astrophysics Data System (ADS)

    Tan, Jinwang; Ryan, Emily M.

    2016-08-01

    Dendrite formation on the anode surface of a battery is closely related to the safety and capacity of high energy density batteries, thus suppressing dendrite growth will significantly improve the performance of batteries. Many experimental reports reveal that convection near the dendrite nucleation site can change the local mass transport, and ultimately affect dendrite growth. Investigation of the convection effect in batteries will guide the development of strategies to suppress dendrite growth in a convective electrolyte. Most of the existing electro-convection computational models for dendrite growth studies are based on Eulerian frameworks. These methods have difficulty modeling the moving boundaries associated with dendrite growth and are less computationally efficient in simulating convective fluid motion. In this paper we adopt a mesh-free particle based Lagrangian method to address the challenges of previous grid based Eulerian electro-convection models. The developed model is verified by comparison to analytical solutions, including verification of ion migration and the electric potential. Simulation results show that the predicted dendrite growth and electro-convective flow patterns compare well with experimental results during early dendrite growth stages. Parametric studies reveal that low viscosity electrolytes suppress the dendrite growth by increasing the mass transport of ions near the anode/electrolyte interface.

  16. NMDA receptor blockade alters stress-induced dendritic remodeling in medial prefrontal cortex.

    PubMed

    Martin, Kathryn P; Wellman, Cara L

    2011-10-01

    The development and relapse of many psychopathologies can be linked to both stress and prefrontal cortex dysfunction. Glucocorticoid stress hormones target medial prefrontal cortex (mPFC) and either chronic stress or chronic administration of glucocorticoids produces dendritic remodeling in prefrontal pyramidal neurons. Exposure to stress also causes an increase in the release of the excitatory amino acid glutamate, which binds to N-methyl-D-aspartate (NMDA) receptors, which are plentiful in mPFC. NMDA receptor activation is crucial for producing hippocampal dendritic remodeling due to stress and for dendritic reorganization in frontal cortex after cholinergic deafferentation. Thus, NMDA receptors could mediate stress-induced dendritic retraction in mPFC. To test this hypothesis, dendritic morphology of pyramidal cells in mPFC was assessed after blocking NMDA receptors with the competitive NMDA antagonist ±3-(2-carboxypiperazin-4yl)propyl-1-phosphonic acid (CPP) during restraint stress. Administration of CPP prevented stress-induced dendritic atrophy. Instead, CPP-injected stressed rats showed hypertrophy of apical dendrites compared with controls. These results suggest that NMDA activation is crucial for stress-induced dendritic atrophy in mPFC. Furthermore, NMDA receptor blockade uncovers a new pattern of stress-induced dendritic changes, suggesting that other neurohormonal changes in concert with NMDA receptor activation underlie the net dendritic retraction seen after chronic stress.

  17. Investigating the Effects of Anisotropic Mass Transport on Dendrite Growth in High Energy Density Lithium Batteries

    SciTech Connect

    Tan, Jinwang; Tartakovsky, Alexandre M.; Ferris, Kim F.; Ryan, Emily M.

    2016-01-01

    Dendrite formation on the electrode surface of high energy density lithium (Li) batteries causes safety problems and limits their applications. Suppressing dendrite growth could significantly improve Li battery performance. Dendrite growth and morphology is a function of the mixing in the electrolyte near the anode interface. Most research into dendrites in batteries focuses on dendrite formation in isotropic electrolytes (i.e., electrolytes with isotropic diffusion coefficient). In this work, an anisotropic diffusion reaction model is developed to study the anisotropic mixing effect on dendrite growth in Li batteries. The model uses a Lagrangian particle-based method to model dendrite growth in an anisotropic electrolyte solution. The model is verified by comparing the numerical simulation results with analytical solutions, and its accuracy is shown to be better than previous particle-based anisotropic diffusion models. Several parametric studies of dendrite growth in an anisotropic electrolyte are performed and the results demonstrate the effects of anisotropic transport on dendrite growth and morphology, and show the possible advantages of anisotropic electrolytes for dendrite suppression.

  18. Spatiotemporal profile of dendritic outgrowth from newly born granule cells in the adult rat dentate gyrus.

    PubMed

    Shapiro, Lee A; Upadhyaya, Pooja; Ribak, Charles E

    2007-05-29

    Neurogenesis in the adult dentate gyrus occurs in the subgranular zone where newborn neurons (NNs) migrate a short distance into the granule cell layer and extend their rudimentary apical dendritic processes upon a radial glial scaffold. Using doublecortin (DCX) immunocytochemistry, these growing dendrites can be visualized because dendritic growth cones, including filipodia and lamellipodia, are labeled in both light and electron microscopic preparations. To study the rate of dendritic outgrowth of newborn dentate granule cells, single injections of 5-bromo-2-deoxyuridine (BrdU) with different survival times were combined with double immunolabeling for BrdU and DCX. At the earliest time points (4 and 12 h after BrdU injections), a rudimentary process can be observed to emanate from BrdU/DCX double-labeled cells. By 48 h the dendrites first appeared in the molecular layer. By 96 h after BrdU injection, these apical dendrites extended into the middle of the molecular layer where they ramified. The calculated rate of dendritic growth for NNs was about 15 microm per day for the first 3 days, and then a doubling in length occurred at 4 and 5 days that coincided with a retraction of the basal dendrite. In addition, electron microscopy of DCX-labeled apical dendrites showed that they were much thinner (1/4 to 1/3 the size) in diameter than unlabeled, mature apical dendrites and that they had developing synapses on them in the molecular layer.

  19. Mapping of dendritic lesions in patients with herpes simplex keratitis using in vivo confocal microscopy

    PubMed Central

    Yokogawa, Hideaki; Kobayashi, Akira; Mori, Natsuko; Sugiyama, Kazuhisa

    2015-01-01

    Purpose To produce a two-dimensional reconstruction map of dendritic lesions in patients with herpes simplex keratitis (HSK) using in vivo confocal microscopy. Methods Four eyes of four patients (mean 65.8 years) with HSK presenting with a dendritic lesion were enrolled. Slit-lamp biomicroscopy and in vivo laser confocal microscopy were performed. Acquired confocal images at the level of the epithelium were arranged and mapped into subconfluent montages. Changes in the shape and degree of light reflection of abnormal cells and deposits around dendritic lesions as well as other corneal layers were qualitatively evaluated. Results Mapping of dendritic lesion was successful in all cases, and the subconfluent montages clearly showed the larger image of dendritic lesion. In all cases, the dendritic lesion consisted of hyperreflective irregular epithelial cells, and was surrounded by distorted and elongated epithelial cells. In three cases, hyperreflective deposits were noted at the midline of the lesion. The corneal stroma showed a hyperreflective honeycomb pattern. In two cases, inflammatory cells were observed at the level of endothelial cell layer. Conclusion Mapping of dendritic lesions in patients with HSK was successful in all patients using in vivo confocal microscopy. Cellular level observation of dendritic lesion at a relatively larger magnification may help understand the in vivo morphological change of HSK. Further study in more patients with HSK and nonherpetic dendritic lesion is needed to utilize confocal microscopy images in differential diagnosis and follow-up of the epithelial lesions with dendrite. PMID:26445524

  20. High Fat Diet Inhibits Dendritic Cell and T Cell Response to Allergens but Does Not Impair Inhalational Respiratory Tolerance.

    PubMed

    Pizzolla, Angela; Oh, Ding Yuan; Luong, Suzanne; Prickett, Sara R; Henstridge, Darren C; Febbraio, Mark A; O'Hehir, Robyn E; Rolland, Jennifer M; Hardy, Charles L

    2016-01-01

    The incidence of obesity has risen to epidemic proportions in recent decades, most commonly attributed to an increasingly sedentary lifestyle, and a 'western' diet high in fat and low in fibre. Although non-allergic asthma is a well-established co-morbidity of obesity, the influence of obesity on allergic asthma is still under debate. Allergic asthma is thought to result from impaired tolerance to airborne antigens, so-called respiratory tolerance. We sought to investigate whether a diet high in fats affects the development of respiratory tolerance. Mice fed a high fat diet (HFD) for 8 weeks showed weight gain, metabolic disease, and alteration in gut microbiota, metabolites and glucose metabolism compared to age-matched mice fed normal chow diet (ND). Respiratory tolerance was induced by repeated intranasal (i.n.) administration of ovalbumin (OVA), prior to induction of allergic airway inflammation (AAI) by sensitization with OVA in alum i.p. and subsequent i.n. OVA challenge. Surprisingly, respiratory tolerance was induced equally well in HFD and ND mice, as evidenced by decreased lung eosinophilia and serum OVA-specific IgE production. However, in a pilot study, HFD mice showed a tendency for impaired activation of airway dendritic cells and regulatory T cells compared with ND mice after induction of respiratory tolerance. Moreover, the capacity of lymph node cells to produce IL-5 and IL-13 after AAI was drastically diminished in HFD mice compared to ND mice. These results indicate that HFD does not affect the inflammatory or B cell response to an allergen, but inhibits priming of Th2 cells and possibly dendritic cell and regulatory T cell activation. PMID:27483441

  1. High Fat Diet Inhibits Dendritic Cell and T Cell Response to Allergens but Does Not Impair Inhalational Respiratory Tolerance

    PubMed Central

    Pizzolla, Angela; Oh, Ding Yuan; Luong, Suzanne; Prickett, Sara R.; Henstridge, Darren C.; Febbraio, Mark A.; O’Hehir, Robyn E.; Rolland, Jennifer M.; Hardy, Charles L.

    2016-01-01

    The incidence of obesity has risen to epidemic proportions in recent decades, most commonly attributed to an increasingly sedentary lifestyle, and a ‘western’ diet high in fat and low in fibre. Although non-allergic asthma is a well-established co-morbidity of obesity, the influence of obesity on allergic asthma is still under debate. Allergic asthma is thought to result from impaired tolerance to airborne antigens, so-called respiratory tolerance. We sought to investigate whether a diet high in fats affects the development of respiratory tolerance. Mice fed a high fat diet (HFD) for 8 weeks showed weight gain, metabolic disease, and alteration in gut microbiota, metabolites and glucose metabolism compared to age-matched mice fed normal chow diet (ND). Respiratory tolerance was induced by repeated intranasal (i.n.) administration of ovalbumin (OVA), prior to induction of allergic airway inflammation (AAI) by sensitization with OVA in alum i.p. and subsequent i.n. OVA challenge. Surprisingly, respiratory tolerance was induced equally well in HFD and ND mice, as evidenced by decreased lung eosinophilia and serum OVA-specific IgE production. However, in a pilot study, HFD mice showed a tendency for impaired activation of airway dendritic cells and regulatory T cells compared with ND mice after induction of respiratory tolerance. Moreover, the capacity of lymph node cells to produce IL-5 and IL-13 after AAI was drastically diminished in HFD mice compared to ND mice. These results indicate that HFD does not affect the inflammatory or B cell response to an allergen, but inhibits priming of Th2 cells and possibly dendritic cell and regulatory T cell activation. PMID:27483441

  2. Spiny neurons of amygdala, striatum, and cortex use dendritic plateau potentials to detect network UP states

    PubMed Central

    Oikonomou, Katerina D.; Singh, Mandakini B.; Sterjanaj, Enas V.; Antic, Srdjan D.

    2014-01-01

    Spiny neurons of amygdala, striatum, and cerebral cortex share four interesting features: (1) they are the most abundant cell type within their respective brain area, (2) covered by thousands of thorny protrusions (dendritic spines), (3) possess high levels of dendritic NMDA conductances, and (4) experience sustained somatic depolarizations in vivo and in vitro (UP states). In all spiny neurons of the forebrain, adequate glutamatergic inputs generate dendritic plateau potentials (“dendritic UP states”) characterized by (i) fast rise, (ii) plateau phase lasting several hundred milliseconds, and (iii) abrupt decline at the end of the plateau phase. The dendritic plateau potential propagates toward the cell body decrementally to induce a long-lasting (longer than 100 ms, most often 200–800 ms) steady depolarization (∼20 mV amplitude), which resembles a neuronal UP state. Based on voltage-sensitive dye imaging, the plateau depolarization in the soma is precisely time-locked to the regenerative plateau potential taking place in the dendrite. The somatic plateau rises after the onset of the dendritic voltage transient and collapses with the breakdown of the dendritic plateau depolarization. We hypothesize that neuronal UP states in vivo reflect the occurrence of dendritic plateau potentials (dendritic UP states). We propose that the somatic voltage waveform during a neuronal UP state is determined by dendritic plateau potentials. A mammalian spiny neuron uses dendritic plateau potentials to detect and transform coherent network activity into a ubiquitous neuronal UP state. The biophysical properties of dendritic plateau potentials allow neurons to quickly attune to the ongoing network activity, as well as secure the stable amplitudes of successive UP states. PMID:25278841

  3. Toxicogenomics and the Regulatory Framework

    EPA Science Inventory

    Toxicogenomics presents regulatory agencies with the opportunity to revolutionize their analyses by enabling the collection of information on a broader range of responses than currently considered in traditional regulatory decision making. Analyses of genomic responses are expec...

  4. Establishment of Axon-Dendrite Polarity in Developing Neurons

    PubMed Central

    BARNES, Anthony P.; POLLEUX, Franck

    2011-01-01

    Neurons are among the most highly polarized cell type in the body and the polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. Significant progress has been made in the identification of the cellular and molecular mechanisms underlying the establishment of neuronal polarity using primarily in vitro approaches such as dissociated culture of rodent hippocampal and cortical neurons. This model has led to the predominant view suggesting that neuronal polarization is largely specified by stochastic, asymmetric activation of intracellular signaling pathways. Recent evidence shows that extracellular cues can play an instructive role during neuronal polarization in vitro and in vivo. In this review, we synthesize the recent data supporting an integrative model whereby extracellular cues orchestrate the intracellular signaling underlying the initial break of neuronal symmetry leading to axon-dendrite polarization. PMID:19400726

  5. Phase-field model of dendritic sidebranching with thermal noise.

    PubMed

    Karma, A; Rappel, W J

    1999-10-01

    We investigate dendritic sidebranching during crystal growth in an undercooled melt by simulation of a phase-field model which incorporates thermal noise of microscopic origin. As a nontrivial quantitative test of this model, we first show that the simulated fluctuation spectrum of a one-dimensional interface in thermal equilibrium agrees with the exact sharp-interface spectrum up to an irrelevant short-wavelength cutoff comparable to the interface thickness. Simulations of dendritic growth are then carried out in two dimensions to compute sidebranching characteristics (root-mean-square amplitude and sidebranch spacing) as a function of distance behind the tip. These quantities are compared quantitatively to the predictions of the existing linear WKB theory of noise amplification. The extension of this study to three dimensions remains needed to determine the origin of noise in experiments.

  6. Infection-mimicking materials to program dendritic cells in situ

    NASA Astrophysics Data System (ADS)

    Ali, Omar A.; Huebsch, Nathaniel; Cao, Lan; Dranoff, Glenn; Mooney, David J.

    2009-02-01

    Cancer vaccines typically depend on cumbersome and expensive manipulation of cells in the laboratory, and subsequent cell transplantation leads to poor lymph-node homing and limited efficacy. We propose that materials mimicking key aspects of bacterial infection may instead be used to directly control immune-cell trafficking and activation in the body. It is demonstrated that polymers can be designed to first release a cytokine to recruit and house host dendritic cells, and subsequently present cancer antigens and danger signals to activate the resident dendritic cells and markedly enhance their homing to lymph nodes. Specific and protective anti-tumour immunity was generated with these materials, as 90% survival was achieved in animals that otherwise die from cancer within 25days. These materials show promise as cancer vaccines, and more broadly suggest that polymers may be designed to program and control the trafficking of a variety of cell types in the body.

  7. The dendritic spine story: an intriguing process of discovery

    PubMed Central

    DeFelipe, Javier

    2015-01-01

    Dendritic spines are key components of a variety of microcircuits and they represent the majority of postsynaptic targets of glutamatergic axon terminals in the brain. The present article will focus on the discovery of dendritic spines, which was possible thanks to the application of the Golgi technique to the study of the nervous system, and will also explore the early interpretation of these elements. This discovery represents an interesting chapter in the history of neuroscience as it shows us that progress in the study of the structure of the nervous system is based not only on the emergence of new techniques but also on our ability to exploit the methods already available and correctly interpret their microscopic images. PMID:25798090

  8. Dendrite and Axon Specific Geometrical Transformation in Neurite Development

    PubMed Central

    Mironov, Vasily I.; Semyanov, Alexey V.; Kazantsev, Victor B.

    2016-01-01

    We propose a model of neurite growth to explain the differences in dendrite and axon specific neurite development. The model implements basic molecular kinetics, e.g., building protein synthesis and transport to the growth cone, and includes explicit dependence of the building kinetics on the geometry of the neurite. The basic assumption was that the radius of the neurite decreases with length. We found that the neurite dynamics crucially depended on the relationship between the rate of active transport and the rate of morphological changes. If these rates were in the balance, then the neurite displayed axon specific development with a constant elongation speed. For dendrite specific growth, the maximal length was rapidly saturated by degradation of building protein structures or limited by proximal part expansion reaching the characteristic cell size. PMID:26858635

  9. Targeting human dendritic cells in situ to improve vaccines

    PubMed Central

    Sehgal, Kartik; Dhodapkar, Kavita M.; Dhodapkar, Madhav V.

    2014-01-01

    Dendritic cells (DCs) provide a critical link between innate and adaptive immunity. The potent antigen presenting properties of DCs makes them a valuable target for the delivery of immunogenic cargo. Recent clinical studies describing in situ DC targeting with antibodymediated targeting of DC receptor through DEC-205 provide new opportunities for the clinical application of DC-targeted vaccines. Further advances with nanoparticle vectors which can encapsulate antigens and adjuvants within the same compartment and be targeted against diverse DC subsets also represent an attractive strategy for targeting DCs. This review provides a brief summary of the rationale behind targeting dendritic cells in situ, the existing pre-clinical and clinical data on these vaccines and challenges faced by the next generation DC-targeted vaccines. PMID:25072116

  10. Dendritic Cell Regulation by Cannabinoid-Based Drugs

    PubMed Central

    Svensson, Mattias; Chen, Puran; Hammarfjord, Oscar

    2010-01-01

    Cannabinoid pharmacology has made important advances in recent years after the cannabinoid system was discovered. Studies in experimental models and in humans have produced promising results using cannabinoid-based drugs for the treatment of obesity and cancer, as well as neuroinflammatory and chronic inflammatory diseases. Moreover, as we discuss here, additional studies also indicates that these drugs have immunosuppressive and anti-inflammatory properties including modulation of immune cell function. Thus, manipulation of the endocannabinoid system in vivo may provide novel therapeutic strategies against inflammatory disorders. At least two types of cannabinoid receptors, cannabinoid 1 and cannabinoid 2 receptors are expressed on immune cells such as dendritic cells (DC). Dendritic cells are recognized for their critical role in initiating and maintaining immune responses. Therefore, DC are potential targets for cannabinoid-mediated modulation. Here, we review the effects of cannabinoids on DC and provide some perspective concerning the therapeutic potential of cannabinoids for the treatment of human diseases involving aberrant inflammatory processes.

  11. Analytical and numerical predictions of dendritic grain envelopes

    SciTech Connect

    Gandin, C.A.; Rappaz, M.; Schaefer, R.J.

    1996-08-01

    An analytical model is developed for the prediction of the shape of dendritic grain envelopes during solidification of a metallic alloy in a Bridgman configuration (i.e., constant thermal gradient and cooling rate). The assumptions built into the model allow a direct comparison of the results with those obtained from a previously developed cellular automation-finite element (CAFE) model. After this comparison, the CAFE model is applied to the study of the extension of a single grain into an open region of liquid after passing a re-entrant corner. The simulation results are compared with experimental observations made on a directionally solidified succinonitrile-acetone alloy. Good agreement is found for the shape of the grain envelopes when varying the orientation of the primary dendrites with respect to the thermal gradient direction, the velocity of the isotherms or the thermal gradient.

  12. Dendritic Cell Apoptosis and the Pathogenesis of Dengue

    PubMed Central

    Martins, Sharon de T.; Silveira, Guilherme F.; Alves, Lysangela R.; dos Santos, Claudia Nunes Duarte; Bordignon, Juliano

    2012-01-01

    Dengue viruses and other members of the Flaviviridae family are emerging human pathogens. Dengue is transmitted to humans by Aedes aegypti female mosquitoes. Following infection through the bite, cells of the hematopoietic lineage, like dendritic cells, are the first targets of dengue virus infection. Dendritic cells (DCs) are key antigen presenting cells, sensing pathogens, processing and presenting the antigens to T lymphocytes, and triggering an adaptive immune response. Infection of DCs by dengue virus may induce apoptosis, impairing their ability to present antigens to T cells, and thereby contributing to dengue pathogenesis. This review focuses on general mechanisms by which dengue virus triggers apoptosis, and possible influence of DC-apoptosis on dengue disease severity. PMID:23202502

  13. Synaptic clustering within dendrites: an emerging theory of memory formation.

    PubMed

    Kastellakis, George; Cai, Denise J; Mednick, Sara C; Silva, Alcino J; Poirazi, Panayiota

    2015-03-01

    It is generally accepted that complex memories are stored in distributed representations throughout the brain, however the mechanisms underlying these representations are not understood. Here, we review recent findings regarding the subcellular mechanisms implicated in memory formation, which provide evidence for a dendrite-centered theory of memory. Plasticity-related phenomena which affect synaptic properties, such as synaptic tagging and capture, synaptic clustering, branch strength potentiation and spinogenesis provide the foundation for a model of memory storage that relies heavily on processes operating at the dendrite level. The emerging picture suggests that clusters of functionally related synapses may serve as key computational and memory storage units in the brain. We discuss both experimental evidence and theoretical models that support this hypothesis and explore its advantages for neuronal function.

  14. Synaptic clustering within dendrites: an emerging theory of memory formation

    PubMed Central

    Kastellakis, George; Cai, Denise J.; Mednick, Sara C.; Silva, Alcino J.; Poirazi, Panayiota

    2015-01-01

    It is generally accepted that complex memories are stored in distributed representations throughout the brain, however the mechanisms underlying these representations are not understood. Here, we review recent findings regarding the subcellular mechanisms implicated in memory formation, which provide evidence for a dendrite-centered theory of memory. Plasticity-related phenomena which affect synaptic properties, such as synaptic tagging and capture, synaptic clustering, branch strength potentiation and spinogenesis provide the foundation for a model of memory storage that relies heavily on processes operating at the dendrite level. The emerging picture suggests that clusters of functionally related synapses may serve as key computational and memory storage units in the brain. We discuss both experimental evidence and theoretical models that support this hypothesis and explore its advantages for neuronal function. PMID:25576663

  15. Large-area sheet task advanced dendritic web growth development

    NASA Technical Reports Server (NTRS)

    Duncan, C. S.; Seidensticker, R. G.; Mchugh, J. P.

    1984-01-01

    The thermal models used for analyzing dendritic web growth and calculating the thermal stress were reexamined to establish the validity limits imposed by the assumptions of the models. Also, the effects of thermal conduction through the gas phase were evaluated and found to be small. New growth designs, both static and dynamic, were generated using the modeling results. Residual stress effects in dendritic web were examined. In the laboratory, new techniques for the control of temperature distributions in three dimensions were developed. A new maximum undeformed web width of 5.8 cm was achieved. A 58% increase in growth velocity of 150 micrometers thickness was achieved with dynamic hardware. The area throughput goals for transient growth of 30 and 35 sq cm/min were exceeded.

  16. Computer Tomography Imaging Findings of Abdominal Follicular Dendritic Cell Sarcoma

    PubMed Central

    Li, Jing; Geng, Zhi-Jun; Xie, Chuan-Miao; Zhang, Xin-Ke; Chen, Rui-Ying; Cai, Pei-Qiang; Lv, Xiao-Fei

    2016-01-01

    Abstract Follicular dendritic cell sarcoma (FDCS) is a neoplasm that arises from follicular dendritic cells. FDCSs originating in the abdomen are extremely rare. Clinically, they often mimic a wide variety of other abdominal tumors, and correct preoperative diagnosis is often a challenging task. To date, only scattered cases of abdominal FDCS have been reported and few data are available on their radiological features. Here we present the computer tomography imaging findings of 5 patients with surgically and pathologically demonstrated abdominal FDCS. An abdominal FDCS should be included in the differential diagnosis when single or multiple masses with relatively large size, well- or ill-defined borders, complex internal architecture with marked internal necrosis and/or focal calcification, and heterogeneous enhancement with “rapid wash-in and slow wash-out” or “progressive enhancement” enhancement patterns in the solid component are seen. PMID:26735543

  17. Mnemonic Functions for Nonlinear Dendritic Integration in Hippocampal Pyramidal Circuits.

    PubMed

    Kaifosh, Patrick; Losonczy, Attila

    2016-05-01

    We present a model for neural circuit mechanisms underlying hippocampal memory. Central to this model are nonlinear interactions between anatomically and functionally segregated inputs onto dendrites of pyramidal cells in hippocampal areas CA3 and CA1. We study the consequences of such interactions using model neurons in which somatic burst-firing and synaptic plasticity are controlled by conjunctive processing of these separately integrated input pathways. We find that nonlinear dendritic input processing enhances the model's capacity to store and retrieve large numbers of similar memories. During memory encoding, CA3 stores heavily decorrelated engrams to prevent interference between similar memories, while CA1 pairs these engrams with information-rich memory representations that will later provide meaningful output signals during memory recall. While maintaining mathematical tractability, this model brings theoretical study of memory operations closer to the hippocampal circuit's anatomical and physiological properties, thus providing a framework for future experimental and theoretical study of hippocampal function. PMID:27146266

  18. Balancing Structure and Function at Hippocampal Dendritic Spines

    PubMed Central

    Bourne, Jennifer N.; Harris, Kristen M.

    2008-01-01

    Dendritic spines are the primary recipients of excitatory input in the central nervous system. They provide biochemical compartments that control locally the mechanisms of signaling at individual synapses. Hippocampal spines show structural plasticity as the basis for physiological changes in synaptic efficacy that underlie learning and memory. Spine structure is regulated by molecular mechanisms that are fine-tuned and adjusted according to developmental age, level and direction of synaptic activity, specific brain region, and exact behavioral or experimental conditions. Reciprocal changes between the structure and function of spines impact both local and global integration of signals within dendrites. Advances in imaging and computing technologies may provide the resources needed to reconstruct entire neural circuits. Key to this endeavor is having sufficient resolution to determine the extrinsic factors (such as perisynaptic astroglia) and the intrinsic factors (such as core subcellular organelles) that are required to build and maintain synapses. PMID:18284372

  19. Human tolerogenic dendritic cells produce IL-35 in the absence of other IL-12 family members.

    PubMed

    Dixon, Karen O; van der Kooij, Sandra W; Vignali, Dario A A; van Kooten, Cees

    2015-06-01

    IL-35 is a cytokine of the IL-12 family, existing as a heterodimer of IL-12p35 and Ebi3. IL-35 has anti-inflammatory properties and is produced by regulatory T cells in humans and mice, where it is required for optimal suppression of immune responses. Distinct from other IL-12 cytokines, the expression of IL-35 has not been described in antigen-presenting cells. In view of the immune-regulatory properties of IL-35, we investigated the expression, regulation, and function of IL-12p35 and Ebi3 in human monocyte-derived dendritic cells and tolerogenic DCs (tolDCs). These tolDCs do not produce IL-12p70 or the homodimer IL-12p40. We demonstrate that tolDCs completely lack transcriptional expression of IL-12p40. However, tolDCs maintain mRNA expression of IL-12p35 and Ebi3. Using intracellular flow cytometry and Western blot analysis, we show that tolDCs produce Ebi3 and IL-12p35, and both can be enhanced upon stimulation with IFN-γ, LPS, or CD40L. tolDCs supernatants have the capacity to suppress T-cell activation. Using IL12A silencing, we demonstrate that IL-12p35 is required for tolDCs to reach their full suppressive potential. Taken together, our results indicate that tolDCs produce IL-35, providing an additional novel mechanism by which tolDCs elicit their tolerogenic potential.

  20. Application of dendritic cells stimulated with Trichinella spiralis excretory-secretory antigens alleviates experimental autoimmune encephalomyelitis.

    PubMed

    Sofronic-Milosavljevic, L J; Radovic, I; Ilic, N; Majstorovic, I; Cvetkovic, J; Gruden-Movsesijan, A

    2013-06-01

    The parasitic nematode, Trichinella spiralis (T. spiralis), exerts an immunomodulatory effect on the host immune response through excretory-secretory products (ES L1) released from encysted muscle larvae. Our model of combined T. spiralis infection and experimental autoimmune encephalomyelitis (EAE) in Dark Agouti (DA) rats demonstrated a significant reduction in EAE severity in infected animals. Recently, we have created an immune status characteristic for the live infection by in vivo application of dendritic cells (DCs) stimulated with ES L1 products of T. spiralis muscle larvae. Moreover, these cells were able to ameliorate EAE when applied 7 days before EAE induction. ES L1-stimulated DCs increased production of IL-4, IL-10 and TGF-β, and decreased production of IFN-γ and IL-17, both at the systemic level and in target organs. A significant increase in the proportion of CD4+CD25+Foxp3+ T cells was found among spleen cells, and CNS infiltrates from DA rats treated with ES L1-stimulated DCs before EAE induction, compared to controls injected with unstimulated DCs. Regulatory T cells, together with elevated levels of IL-10 and TGF-β, are most likely involved in restraining the production of Th1 and Th17 cytokines responsible for autoimmunity and thus are responsible for the beneficial effect of ES L1-educated DCs on the course of EAE. Our results show that ES L1 antigen-stimulated DCs are able not only to provoke, but also to sustain anti-inflammatory and regulatory responses regardless of EAE induction, with subsequent amelioration of EAE, or even protection from the disease.

  1. Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation

    PubMed Central

    2012-01-01

    In efforts to minimize the chronic administration of immunosuppression (IS) drugs in transplantation and autoimmune disease, various cell-based tolerogenic therapies, including the use of regulatory or tolerogenic dendritic cells (tolDC) have been developed. These DC-based therapies aim to harness the inherent immunoregulatory potential of these professional antigen-presenting cells. In this short review, we describe both the demonstrated tolerogenic properties, and current limitations of rapamycin-conditioned DC (RAPA-DC). RAPA-DC are generated through inhibition of the integrative kinase mammalian target of rapamycin (mTOR) by the immunosuppressive macrolide rapamycin during propagation of monocyte-derived DC. Consistent with the characteristics of tolDC, murine RAPA-DC display resistance to phenotypic maturation induced by pro-inflammatory stimuli; exhibit the ability to migrate to secondary lymphoid tissue (important for ‘cross-presentation’ of antigen to T cells), and enrich for naturally-occurring CD4+ regulatory T cells. In rodent models, delivery of recipient-derived RAPA-DC pulsed with donor antigen prior to organ transplantation can prolong allogeneic heart-graft survival indefinitely, especially when combined with a short course of IS. These encouraging data support ongoing efforts to develop RAPA-DC for clinical testing. When compared to murine RAPA-DC however, human RAPA-DC have proven only partially resistant to maturation triggered by pro-inflammatory cytokines, and display heterogeneity in their impact on effector T-cell expansion and function. In total, the evidence suggests the need for more in-depth studies to better understand the mechanisms by which mTOR controls human DC function. These studies may facilitate the development of RAPA-DC therapy alone or together with agents that preserve/enhance their tolerogenic properties as clinical immunoregulatory vectors. PMID:23369601

  2. Progress on the development of human in vitro dendritic cell based assays for assessment of the sensitizing potential of a compound

    SciTech Connect

    Galvao dos Santos, G.; Reinders, J.; Ouwehand, K.; Rustemeyer, T.; Scheper, R.J.; Gibbs, S.

    2009-05-01

    Allergic contact dermatitis is the result of an adaptive immune response of the skin to direct exposure to an allergen. Since many chemicals are also allergens, European regulations require strict screening of all ingredients in consumer products. Until recently, identifying a potential allergen has completely relied on animal testing (e.g.: Local Lymph Node Assay). In addition to the ethical problems, both the 7th Amendment to the Cosmetics Directive and REACH have stimulated the development of alternative tests for the assessment of potential sensitizers. This review is aimed at summarising the progress on cell based assays, in particular dendritic cell based assays, being developed as animal alternatives. Primary cells (CD34{sup +} derived dendritic cells, monocyte derived dendritic cells) as well as dendritic cell-like cell lines (THP-1, U-937, MUTZ-3, KG-1, HL-60, and K562) are extensively described along with biomarkers such as cell surface markers, cytokines, chemokines and kinases. From this review, it can be concluded that no single cell based assay nor single marker is yet able to distinguish all sensitizers from non-sensitizers in a test panel of chemicals, nor is it possible to rank the sensitizing potential of the test chemicals. This suggests that sensitivity and specificity may be increased by a tiered assay approach. Only a limited number of genomic and proteomic studies have been completed until now. Such studies have the potential to identify novel biomarkers for inclusion in future assay development. Although progress is promising, this review suggests that it may be difficult to meet the up and coming European regulatory deadlines.

  3. α-Tocopherol supplementation of allergic female mice inhibits development of CD11c+CD11b+ dendritic cells in utero and allergic inflammation in neonates

    PubMed Central

    Abdala-Valencia, Hiam; Berdnikovs, Sergejs; Soveg, Frank W.

    2014-01-01

    α-Tocopherol blocks responses to allergen challenge in allergic adult mice, but it is not known whether α-tocopherol regulates the development of allergic disease. Development of allergic disease often occurs early in life. In clinical studies and animal models, offspring of allergic mothers have increased responsiveness to allergen challenge. Therefore, we determined whether α-tocopherol blocked development of allergic responses in offspring of allergic female mice. Allergic female mice were supplemented with α-tocopherol starting at mating. The pups from allergic mothers developed allergic lung responses, whereas pups from saline-treated mothers did not respond to the allergen challenge, and α-tocopherol supplementation of allergic female mice resulted in a dose-dependent reduction in eosinophils in the pup bronchoalveolar lavage and lungs after allergen challenge. There was also a reduction in pup lung CD11b+ dendritic cell subsets that are critical to development of allergic responses, but there was no change in several CD11b− dendritic cell subsets. Furthermore, maternal supplementation with α-tocopherol reduced the number of fetal liver CD11b+ dendritic cells in utero. In the pups, there was reduced allergen-induced lung mRNA expression of IL-4, IL-33, TSLP, CCL11, and CCL24. Cross-fostering pups at the time of birth demonstrated that α-tocopherol had a regulatory function in utero. In conclusion, maternal supplementation with α-tocopherol reduced fetal development of subsets of dendritic cells that are critical for allergic responses and reduced development of allergic responses in pups from allergic mothers. These results have implications for supplementation of allergic mothers with α-tocopherol. PMID:25015974

  4. Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway.

    PubMed

    Dai, Peihong; Wang, Weiyi; Cao, Hua; Avogadri, Francesca; Dai, Lianpan; Drexler, Ingo; Joyce, Johanna A; Li, Xiao-Dong; Chen, Zhijian; Merghoub, Taha; Shuman, Stewart; Deng, Liang

    2014-04-01

    Modified vaccinia virus Ankara (MVA) is an attenuated poxvirus that has been engineered as a vaccine against infectious agents and cancers. Our goal is to understand how MVA modulates innate immunity in dendritic cells (DCs), which can provide insights to vaccine design. In this study, using murine bone marrow-derived dendritic cells, we assessed type I interferon (IFN) gene induction and protein secretion in response to MVA infection. We report that MVA infection elicits the production of type I IFN in murine conventional dendritic cells (cDCs), but not in plasmacytoid dendritic cells (pDCs). Transcription factors IRF3 (IFN regulatory factor 3) and IRF7, and the positive feedback loop mediated by IFNAR1 (IFN alpha/beta receptor 1), are required for the induction. MVA induction of type I IFN is fully dependent on STING (stimulator of IFN genes) and the newly discovered cytosolic DNA sensor cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase). MVA infection of cDCs triggers phosphorylation of TBK1 (Tank-binding kinase 1) and IRF3, which is abolished in the absence of cGAS and STING. Furthermore, intravenous delivery of MVA induces type I IFN in wild-type mice, but not in mice lacking STING or IRF3. Treatment of cDCs with inhibitors of endosomal and lysosomal acidification or the lysosomal enzyme Cathepsin B attenuated MVA-induced type I IFN production, indicating that lysosomal enzymatic processing of virions is important for MVA sensing. Taken together, our results demonstrate a critical role of the cGAS/STING-mediated cytosolic DNA-sensing pathway for type I IFN induction in cDCs by MVA. We present evidence that vaccinia virulence factors E3 and N1 inhibit the activation of IRF3 and the induction of IFNB gene in MVA-infected cDCs.

  5. Receptor-Dependent Coronavirus Infection of Dendritic Cells

    PubMed Central

    Turner, Brian C.; Hemmila, Erin M.; Beauchemin, Nicole; Holmes, Kathryn V.

    2004-01-01

    In several mammalian species, including humans, coronavirus infection can modulate the host immune response. We show a potential role of dendritic cells (DC) in murine coronavirus-induced immune modulation and pathogenesis by demonstrating that the JAW SII DC line and primary DC from BALB/c mice and p/p mice with reduced expression of the murine coronavirus receptor, murine CEACAM1a, are susceptible to murine coronavirus infection by a receptor-dependent pathway. PMID:15113927

  6. Dendritic web-type solar cell mini-modules

    NASA Technical Reports Server (NTRS)

    Campbell, R. B.

    1985-01-01

    Twenty-five minimodules composed of dendritic web solar cells with nominal glass size of 12 by 40 cm were provided for study. The modules were identical with respect to design, materials, and manufacturing and assembly processes to full scale modules. The modules were also electrically functional. These minimodules were fabricated to provide test vehicle for environmental testing and to assess reliability of process and design procedures. The module design and performance are outlined.

  7. Modulatory effects on dendritic cells by human herpesvirus 6

    PubMed Central

    Gustafsson, Rasmus; Svensson, Mattias; Fogdell-Hahn, Anna

    2015-01-01

    Human herpesvirus 6A and 6B are β-herpesviruses approaching 100% seroprevalance worldwide. These viruses are involved in several clinical syndromes and have important immunomodulatory effects. Dendritic cells (DC) are key players in innate and adaptive immunity. Accordingly, DC are implicated in the pathogenesis of many human diseases, including infections. In this review the effects of HHV-6 infection on DC will be discussed. PMID:25983728

  8. Quantifying barcodes of dendritic spines using entropy-based metrics

    PubMed Central

    Viggiano, D.; Srivastava, D. P.; Speranza, L.; Perrone-Capano, C.; Bellenchi, G. C.; di Porzio, U.; Buckley, N. J.

    2015-01-01

    Spine motility analysis has become the mainstay for investigating synaptic plasticity but is limited in its versatility requiring complex, non automatized instrumentations. We describe an entropy-based method for determining the spatial distribution of dendritic spines that allows successful estimation of spine motility from still images. This method has the potential to extend the applicability of spine motility analysis to ex vivo preparations. PMID:26419702

  9. Role of plasmacytoid dendritic cells in breast cancer bone dissemination

    PubMed Central

    Sawant, Anandi; Ponnazhagan, Selvarangan

    2013-01-01

    Elevated levels of plasmacytoid dendritic cells (pDC) have been observed as breast cancer disseminates to the bone. The selective depletion of pDC in mice led to a total abrogation of bone metastasis as well as to an increase in TH1 antitumor response, suggesting that pDC may be considered as a potential therapeutic target for metastatic breast cancer. PMID:23526329

  10. Graphlocons: Large dendritic graphene crystals and their electronic properties

    SciTech Connect

    Massicotte, Mathieu; Yu, Victor; Whiteway, Eric; Hilke, Michael

    2013-12-04

    Submillimeter dendritic-shaped crystals were synthesized by low pressure vapor chemical vapor deposition inside a copper enclosure. With their sixfold symmetry and fractal-like shape, the resulting crystals resemble snowflakes. The electronic properties of the devices were investigated down to sub-Kelvin temperatures, showing mobilities over 5000 cm{sup 2}/Vs and the quantum Hall effect at 8T. The magnetoresistance also displayed a sharp peak at zero field which we attribute to weak localization.

  11. Measuring F-actin properties in dendritic spines

    PubMed Central

    Koskinen, Mikko; Hotulainen, Pirta

    2014-01-01

    During the last decade, numerous studies have demonstrated that the actin cytoskeleton plays a pivotal role in the control of dendritic spine shape. Synaptic stimulation rapidly changes the actin dynamics and many actin regulators have been shown to play roles in neuron functionality. Accordingly, defects in the regulation of the actin cytoskeleton in neurons have been implicated in memory disorders. Due to the small size of spines, it is difficult to detect changes in the actin structures in dendritic spines by conventional light microscopy imaging. Instead, to know how tightly actin filaments are bundled together, and how fast the filaments turnover, we need to use advanced microscopy techniques, such as fluorescence recovery after photobleaching (FRAP), photoactivatable green fluorescent protein (PAGFP) fluorescence decay and fluorescence anisotropy. Fluorescence anisotropy, which measures the Förster resonance energy transfer (FRET) between two GFP fluorophores, has been proposed as a method to measure the level of actin polymerization. Here, we propose a novel idea that fluorescence anisotropy could be more suitable to study the level of actin filament bundling instead of actin polymerization. We validate the method in U2OS cell line where the actin structures can be clearly distinguished and apply to analyze how actin filament organization in dendritic spines changes during neuronal maturation. In addition to fluorescence anisotropy validation, we take a critical look at the properties and limitations of FRAP and PAGFP fluorescence decay methods and offer our proposals for the analysis methods for these approaches. These three methods complement each other, each providing additional information about actin dynamics and organization in dendritic spines. PMID:25140131

  12. Glia selectively approach synapses on thin dendritic spines

    PubMed Central

    Medvedev, Nikolai; Popov, Victor; Henneberger, Christian; Kraev, Igor; Rusakov, Dmitri A.; Stewart, Michael G.

    2014-01-01

    This paper examines the relationship between the morphological modality of 189 dendritic spines and the surrounding astroglia using full three-dimensional reconstructions of neuropil fragments. An integrative measure of three-dimensional glial coverage confirms that thin spine postsynaptic densities are more tightly surrounded by glia. This distinction suggests that diffusion-dependent synapse–glia communication near ‘learning’ synapses (associated with thin spines) could be stronger than that near ‘memory’ synapses (associated with larger spines). PMID:25225105

  13. [Dendritic cells and interaction with other cell types. Immune tolerance].

    PubMed

    Guerder, S

    2001-07-01

    T cell tolerance to self antigen is mainly established in the thymus were self-reactive T cells are deleted. Interdigitating dendritic cells and medulary epithelial cells are directly involved in the deletion process. Some self-reactive T cells escape, however this thymic censorship and enter the peripheral pool of naive T cells. Multiple mechanisms are also at play in the periphery to control this potentially armfull T cells, this include deletion and immune deviation.

  14. Nuclear Regulatory Commission information digest

    SciTech Connect

    None,

    1990-03-01

    The Nuclear Regulatory Commission information digest provides summary information regarding the US Nuclear Regulatory Commission, its regulatory responsibilities, and areas licensed by the commission. This is an annual publication for the general use of the NRC Staff and is available to the public. The digest is divided into two parts: the first presents an overview of the US Nuclear Regulatory Commission and the second provides data on NRC commercial nuclear reactor licensees and commercial nuclear power reactors worldwide.

  15. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance.

    PubMed

    Steinman, Ralph Marvin; Nussenzweig, Michel C

    2002-01-01

    The immune system generally avoids horror autotoxicus or autoimmunity, an attack against the body's own constituents. This avoidance requires that self-reactive T cells be actively silenced or tolerized. We propose that dendritic cells (DCs) play a critical role in establishing tolerance, especially in the periphery, after functioning T cells have been produced in the thymus. In the steady state, meaning in the absence of acute infection and inflammation, DCs are in an immature state and not fully differentiated to carry out their known roles as inducers of immunity. Nevertheless, immature DCs continuously circulate through tissues and into lymphoid organs, capturing self antigens as well as innocuous environmental proteins. Recent experiments have provided direct evidence that antigen-loaded immature DCs silence T cells either by deleting them or by expanding regulatory T cells. This capacity of DCs to induce peripheral tolerance can work in two opposing ways in the context of infection. In acute infection, a beneficial effect should occur. The immune system would overcome the risk of developing autoimmunity and chronic inflammation if, before infection, tolerance were induced to innocuous environmental proteins as well as self antigens captured from dying infected cells. For chronic or persistent pathogens, a second but dire potential could take place. Continuous presentation of a pathogen by immature DCs, HIV-1 for example, may lead to tolerance and active evasion of protective immunity. The function of DCs in defining immunologic self provides a new focus for the study of autoimmunity and chronic immune-based diseases.

  16. Space exploration by dendritic cells requires maintenance of myosin II activity by IP3 receptor 1.

    PubMed

    Solanes, Paola; Heuzé, Mélina L; Maurin, Mathieu; Bretou, Marine; Lautenschlaeger, Franziska; Maiuri, Paolo; Terriac, Emmanuel; Thoulouze, Maria-Isabel; Launay, Pierre; Piel, Matthieu; Vargas, Pablo; Lennon-Duménil, Ana-Maria

    2015-03-12

    Dendritic cells (DCs) patrol the interstitial space of peripheral tissues. The mechanisms that regulate their migration in such constrained environment remain unknown. We here investigated the role of calcium in immature DCs migrating in confinement. We found that they displayed calcium oscillations that were independent of extracellular calcium and more frequently observed in DCs undergoing strong speed fluctuations. In these cells, calcium spikes were associated with fast motility phases. IP₃ receptors (IP₃Rs) channels, which allow calcium release from the endoplasmic reticulum, were identified as required for immature DCs to migrate at fast speed. The IP₃R1 isoform was further shown to specifically regulate the locomotion persistence of immature DCs, that is, their capacity to maintain directional migration. This function of IP₃R1 results from its ability to control the phosphorylation levels of myosin II regulatory light chain (MLC) and the back/front polarization of the motor protein. We propose that by upholding myosin II activity, constitutive calcium release from the ER through IP₃R1 maintains DC polarity during migration in confinement, facilitating the exploration of their environment.

  17. Tolerogenic IDO(+) Dendritic Cells Are Induced by PD-1-Expressing Mast Cells.

    PubMed

    Rodrigues, Cecilia Pessoa; Ferreira, Ana Carolina Franco; Pinho, Mariana Pereira; de Moraes, Cristiano Jacob; Bergami-Santos, Patrícia Cruz; Barbuto, José Alexandre Marzagão

    2016-01-01

    Mast cells (MCs) are tissue resident cells, rich in inflammatory mediators, involved in allergic reactions, and with an increasingly recognized role in immunomodulation. Dendritic cells (DCs), on the other hand, are central to the determination of immune response patterns, being highly efficient antigen-presenting cells that respond promptly to changes in their microenvironment. Here, we show that direct cell contact between immature monocyte-derived DCs (iDCs) and MC bends DCs toward tolerance induction. DCs that had direct contact with MC (MC-iDC) decreased HLA-DR but increased PD-L1 expression and stimulated regulatory T lymphocytes, which expresses FoxP3(+), secrete TGF-β and IL-10, and suppress the proliferation of mitogen-stimulated naïve T lymphocytes. Furthermore, MC-iDC expressed higher levels of indoleamine-2,3-deoxigenase (IDO), a phenomenon that was blocked by treatment of MC with anti-PD-1 or by the treatment of DCs with anti-PD-L1 or anti-PD-L2, but not by blocking of H1 and H2 histamine receptors on DCs. Contact with MC also increased phosphorylated STAT-3 levels in iDCs. When a STAT-3 inhibitor, JSI-124, was added to the DCs before contact with MC, the MC-iDC recovered their ability to induce allogeneic T cell proliferation and did not increase their IDO expression.

  18. Regulation of expression and function of IDO in human dendritic cells.

    PubMed

    Heitger, A

    2011-01-01

    In the human immune system, IDO expression and activity (IDO competence), are preferentially found in the antigenpresenting cell population, of which dendritic cells (DCs) represent an essential part. As will be comprehensively reviewed, IDO competence in human DCs, in general, is induced by molecules such as interferon-γ, which otherwise initiate immunity. IDO activity therefore, can be interpreted as a negative feedback pathway that limits uncontrolled immune responses. Because of its potent immunosuppressive effects (down-regulation of T cell responses or the expansion of T cell regulatory activity), IDO competence in human DCs is tightly regulated, at the transcriptional, translational and post-translational levels. I will critically discuss the experimental prerequisites and limits of attributing IDO competence to a mechanism of immunosuppression and examine, whether IDO competence itself can be viewed as mediating immunosuppression, or as representing one component among other immunosuppressive factors, involved in tolerogenic function of DCs. Finally, the newly emerging concepts of manipulating IDO competence as a therapy for either augmenting immune responses, such as in cancer, or down-regulating immune responses, such as in transplantation, will be summarized.

  19. CCR4 promotes medullary entry and thymocyte–dendritic cell interactions required for central tolerance

    PubMed Central

    Hu, Zicheng; Lancaster, Jessica N.; Sasiponganan, Chayanit

    2015-01-01

    Autoimmunity results from a breakdown in central or peripheral tolerance. To establish central tolerance, developing T cells must enter the thymic medulla, where they scan antigen-presenting cells (APCs) displaying a diverse array of autoantigens. If a thymocyte is activated by a self-antigen, the cell undergoes either deletion or diversion into the regulatory T cell (T reg) lineage, thus maintaining self-tolerance. Mechanisms promoting thymocyte medullary entry and interactions with APCs are incompletely understood. CCR4 is poised to contribute to central tolerance due to its expression by post-positive selection thymocytes, and expression of its ligands by medullary thymic dendritic cells (DCs). Here, we use two-photon time-lapse microscopy to demonstrate that CCR4 promotes medullary entry of the earliest post-positive selection thymocytes, as well as efficient interactions between medullary thymocytes and DCs. In keeping with the contribution of thymic DCs to central tolerance, CCR4 is involved in regulating negative selection of polyclonal and T cell receptor (TCR) transgenic thymocytes. In the absence of CCR4, autoreactive T cells accumulate in secondary lymphoid organs and autoimmunity ensues. These studies reveal a previously unappreciated role for CCR4 in the establishment of central tolerance. PMID:26417005

  20. Autologous Dendritic Cells Prolong Allograft Survival Through Tmem176b-Dependent Antigen Cross-Presentation

    PubMed Central

    Charnet, P.; Savina, A.; Tilly, G.; Gautreau, L.; Carretero-Iglesia, L.; Beriou, G.; Cebrian, I.; Cens, T.; Hepburn, L.; Chiffoleau, E.; Floto, R. A.; Anegon, I.; Amigorena, S.; Hill, M.; Cuturi, M. C.

    2015-01-01

    The administration of autologous (recipient-derived) tolerogenic dendritic cells (ATDCs) is under clinical evaluation. However, the molecular mechanisms by which these cells prolong graft survival in a donor-specific manner is unknown. Here, we tested mouse ATDCs for their therapeutic potential in a skin transplantation model. ATDC injection in combination with anti-CD3 treatment induced the accumulation of CD8+CD11c+ T cells and significantly prolonged allograft survival. TMEM176B is an intracellular protein expressed in ATDCs and initially identified in allograft tolerance. We show that Tmem176b−/− ATDCs completely failed to trigger both phenomena but recovered their effect when loaded with donor peptides before injection. These results strongly suggested that ATDCs require TMEM176B to cross-present antigens in a tolerogenic fashion. In agreement with this, Tmem176b−/− ATDCs specifically failed to cross-present male antigens or ovalbumin to CD8+ T cells. Finally, we observed that a Tmem176b-dependent cation current controls phagosomal pH, a critical parameter in cross-presentation. Thus, ATDCs require TMEM176B to cross-present donor antigens to induce donor-specific CD8+CD11c+ T cells with regulatory properties and prolong graft survival. PMID:24731243