Sample records for costimulatory molecules direct

  1. Expression of costimulatory molecules on peripheral blood lymphocytes of patients with systemic lupus erythematosus

    NARCIS (Netherlands)

    Bijl, M; Horst, G; Limburg, PC; Kallenberg, CGM

    Objective-In systemic lupus erythematosus (SLE) autoantibody production is T cell dependent. For a proper T and B cell interaction, signalling of costimulatory molecules on these cells is necessary. The expression of costimulatory molecules on peripheral blood lymphocytes in patients with SLE in

  2. T cell costimulatory molecules in anti-viral immunity: Potential role in immunotherapeutic vaccines. (United States)

    Watts, Tania H; Bertram, Edward M; Bukczynski, Jacob; Wen, Tao


    T lymphocyte activation is required to eliminate or control intracellular viruses. The activation of T cells requires both an antigen specific signal, involving the recognition of a peptide/major histocompatibility protein complex by the T cell receptor, as well as additional costimulatory signals. In chronic viral diseases, T cell responses, although present, are unable to eliminate the infection. By providing antigens and costimulatory molecules together, investigators may be able to increase and broaden the immune response, resulting in better immunological control or even elimination of the infection. Recent progress in understanding the function of costimulatory molecules suggests that different costimulatory molecules are involved in initial immune responses than are involved in recall responses. These new developments have important implications for therapeutic vaccine design. In this review the authors discuss the function of T cell costimulatory molecules in immune system activation and their potential for enhancing the efficacy of therapeutic vaccines.

  3. Localization in situ of costimulatory molecules and cytokines in B-cell non-Hodgkin's lymphoma

    NARCIS (Netherlands)

    Vyth-Dreese, F.A.; Boot, H.; Dellemijn, T.A.M.; Majoor, D.M.; Oomen, L.C.J.M.; Laman, J.D.; Meurs, M. van; Weger, R.A. de; Jong, D. de


    Costimulatory molecules are essential in cognate interactions between T and B lymphocytes. To study the prerequisites of functional interactions between malignant B cells and intermingled T cells in B-cell non-Hodgkin's lymphomas (B-NHL), we examined the expression of CD40, CD80 and CD86 and their

  4. Expression of major histocompatibility complex class II and costimulatory molecules in oral carcinomas in vitro. (United States)

    Villarroel-Dorrego, Mariana; Speight, Paul M; Barrett, A William


    Recognition in the 1980 s that keratinocytes can express class II molecules of the Major Histocompatibility Complex (MHC) first raised the possibility that these cells might have an immunological function, and may even act as antigen presenting cells (APC). For effective T lymphocyte activation, APC require, in addition to MHC II, appropriate costimulatory signals. The aim of this study was to determine the expression of MHC class II and the co-stimulatory molecules CD40, CD80 and CD86 in keratinocytes derived from healthy oral mucosa and oral carcinomas. Using flow cytometry, it was confirmed that oral keratinocytes, switch on, expression of MHC class II molecules after stimulation with IFNgamma in vitro. All keratinocyte lines expressed CD40 constitutively; by contrast, CD80 and CD86 were universally absent. Loss of CD80 and CD86 may be one means whereby tumours escape immunological surveillance.

  5. The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis. (United States)

    Tomiyama, Takashi; Yang, Guo-Xiang; Zhao, Ming; Zhang, Weici; Tanaka, Hajime; Wang, Jing; Leung, Patrick Sc; Okazaki, Kazuichi; He, Xiao-Song; Lu, Qianjin; Coppel, Ross L; Bowlus, Christopher L; Gershwin, M Eric


    Exosomes are nanoparticles of endocytic origin, secreted by a myriad of cell populations that are attracting increased attention by virtue of their ability to modulate cell-to-cell communications. They are also attracting attention in a variety of immunological issues, including autoimmunity and, in particular, their ability to regulate cytokine and chemokine activation. Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, which has a highly focused cytotoxic response against biliary epithelial cells. We have isolated exosomes from plasma from 29 patients with PBC and 30 healthy controls (HCs), and studied the effect of these exosomes on co-stimulatory molecule expression and cytokine production in mononuclear cell populations using an ex vivo system. We also identified the microRNA (miRNA) populations in PBC compared to HC exosomes. We report herein that although exosomes do not change cytokine production, they do significantly alter co-stimulatory molecule expression on antigen-presenting populations. Further, we demonstrated that CD86 up-regulated expression on CD14(+) monocytes, whereas CD40 up-regulated on CD11c(+) dendritic cells by exosomes from patients with PBC. In addition, there were differences of miRNA expression of circulating exosomes in patients with PBC. These data have significant importance based on observations that co-stimulatory molecules play a differential role in the regulation of T-cell activation. Our observation indicated that aberrant exosomes from PBC selectively induce expression of co-stimulatory molecules in different subset of antigen-presenting cells. These alterations may involve in pathogenesis of autoimmune liver disease.Cellular & Molecular Immunology advance online publication, 21 September 2015; doi:10.1038/cmi.2015.86.

  6. Costimulatory molecule programmed death-1 in the cytotoxic response during chronic hepatitis C (United States)

    Larrubia, Juan Ramón; Benito-Martínez, Selma; Miquel, Joaquín; Calvino, Miryam; Sanz-de-Villalobos, Eduardo; Parra-Cid, Trinidad


    Hepatitis C virus (HCV)-specific CD8+ T cells play an important role in the resolution of HCV infection. Nevertheless, during chronic hepatitis C these cells lack their effector functions and fail to control the virus. HCV has developed several mechanisms to escape immune control. One of these strategies is the up-regulation of negative co-stimulatory molecules such us programmed death-1 (PD-1). This molecule is up-regulated on intrahepatic and peripheral HCV-specific cytotoxic T cells during acute and chronic phases of the disease, whereas PD-1 expression is low in resolved infection. PD-1 expressing HCV-specific CD8+ T cells are exhausted with impairment of several effector mechanisms, such as: type-1 cytokine production, expansion ability after antigen encounter and cytotoxic ability. However, PD-1 associated exhaustion can be restored by blocking the interaction between PD-1 and its ligand (PD-L1). After this blockade, HCV-specific CD8+ T cells reacquire their functionality. Nevertheless, functional restoration depends on PD-1 expression level. High PD-1-expressing intrahepatic HCV-specific CD8+ T cells do not restore their effector abilities after PD-1/PD-L1 blockade. The mechanisms by which HCV is able to induce PD-1 up-regulation to escape immune control are unknown. Persistent TCR stimulation by a high level of HCV antigens could favour early PD-1 induction, but the interaction between HCV core protein and gC1q receptor could also participate in this process. The PD-1/PD-L1 pathway modulation could be a therapeutic strategy, in conjunction with the regulation of others co-stimulatory pathways, in order to restore immune response against HCV to succeed in clearing the infection. PMID:19891011

  7. Kinetics of expression of costimulatory molecules and their ligands in murine relapsing experimental autoimmune encephalomyelitis in vivo

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Navikas, V; Schaub, M


    We studied the kinetics of expression of costimulatory molecules and cytokines in the central nervous system (CNS) in murine relapsing experimental autoimmune encephalomyelitis (EAE). During the natural course of EAE, B7-2 expression in the CNS correlated with clinical signs, while B7-1 was exclu...

  8. CD40/CD154 blockade inhibits dendritic cell expression of inflammatory cytokines but not costimulatory molecules. (United States)

    Ferrer, Ivana R; Liu, Danya; Pinelli, David F; Koehn, Brent H; Stempora, Linda L; Ford, Mandy L


    Blockade of the CD40/CD154 pathway remains one of the most effective means of promoting graft survival following transplantation. However, the effects of CD40/CD154 antagonism on dendritic cell (DC) phenotype and functionality following transplantation remain incompletely understood. To dissect the effects of CD154/CD40 blockade on DC activation in vivo, we generated hematopoietic chimeras in mice that expressed a surrogate minor Ag (OVA). Adoptive transfer of OVA-specific CD4(+) and CD8(+) T cells led to chimerism rejection, which was inhibited by treatment with CD154 blockade. Surprisingly, CD154 antagonism did not alter the expression of MHC and costimulatory molecules on CD11c(+) DCs compared with untreated controls. However, DCs isolated from anti-CD154-treated animals exhibited a significant reduction in inflammatory cytokine secretion. Combined blockade of inflammatory cytokines IL-6 and IL-12p40 attenuated the expansion of Ag-specific CD4(+) and CD8(+) T cells and transiently inhibited the rejection of OVA-expressing cells. These results suggest that a major effect of CD154 antagonism in vivo is an impairment in the provision of signal three during donor-reactive T cell programming, as opposed to an impact on the provision of signal two. We conclude that therapies designed to target inflammatory cytokines during donor-reactive T cell activation may be beneficial in attenuating these responses and prolonging graft survival.

  9. Differential expression of the costimulatory molecules CD86, CD28, CD152 and PD-1 correlates with the host-parasite outcome in leprosy

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    Maria de Lourdes Palermo


    Full Text Available Leprosy is a spectral disease exhibiting two polar sides, namely, lepromatous leprosy (LL characterised by impaired T-cell responses and tuberculoid leprosy in which T-cell responses are strong. Proper T-cell activation requires signalling through costimulatory molecules expressed by antigen presenting cells and their ligands on T-cells. We studied the influence of costimulatory molecules on the immune responses of subjects along the leprosy spectrum. The expression of the costimulatory molecules was evaluated in in vitro-stimulated peripheral blood mononuclear cells of lepromatous and tuberculoid patients and healthy exposed individuals (contacts. We show that LL patients have defective monocyte CD86 expression, which likely contributes to the impairment of the antigen presentation process and to patients anergy. Accordingly, CD86 but not CD80 blockade inhibited the lymphoproliferative response to Mycobacterium leprae. Consistent with the LL anergy, there was reduced expression of the positive signalling costimulatory molecules CD28 and CD86 on the T-cells in these patients. In contrast, tuberculoid leprosy patients displayed increased expression of the negative signalling molecules CD152 and programmed death-1 (PD-1, which represents a probable means of modulating an exacerbated immune response and avoiding immunopathology. Notably, the contacts exhibited proper CD86 and CD28 expression but not exacerbated CD152 or PD-1 expression, suggesting that they tend to develop a balanced immunity without requiring immunosuppressive costimulatory signalling.

  10. Decreased Expression of T-Cell Costimulatory Molecule CD28 on CD4 and CD8 T Cells of Mexican Patients with Pulmonary Tuberculosis

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    German Bernal-Fernandez


    Full Text Available Patients with tuberculosis frequently develop anergy, a state of T-cell hyporesponsiveness in which defective T-cell costimulation could be a factor. To know if the expression of T-cell costimulatory molecules was altered in tuberculosis, we analyzed the peripheral blood T-cell phenotype of 23 Mexican patients with pulmonary tuberculosis. There was severe CD4 (P<.001 and CD8 (P<.01 lymphopenia and upregulation of costimulatory molecule CD30 on CD4 and CD8 T cells (P<.05; this increase was higher in relapsing tuberculosis. The main finding was severe downregulation of the major costimulatory molecule CD28 on both CD8 and CD4 T cells (P<.001. Depletion of the CD4/CD28 subset, a hitherto undescribed finding, is relevant because CD4 T cells constitute the main arm of the cell-mediated antimycobacterial immune response.

  11. Trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules through engagement of natural killer cells and stimulation of IFNγ secretion (United States)

    Chaganty, Bharat K. R.; Lu, Yang; Qiu, Songbo; Somanchi, Srinivas S.; Lee, Dean A.; Fan, Zhen


    ABSTRACT It is increasingly recognized that trastuzumab, an antibody approved for treating human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, exerts some of its antitumor effects through enhanced T cell responses. Full activation of CD8+ T cells requires both expression of major histocompatibility complex class I molecules (HLA-ABC) and expression of the T cell costimulatory molecule CD80 or CD86; however, the impact of trastuzumab treatment on the expression of HLA-ABC and CD80 and CD86 has not been investigated in HER2-overexpressing breast cancer cells. In this study, we found that, while there is no direct correlation between the expression of HER2 and HLA-ABC in breast cancer, knockdown of HER2 or inhibition of HER2 kinase by lapatinib downregulated HLA-ABC expression. Trastuzumab had no meaningful effects on HLA-ABC expression in HER2-overexpressing breast cancer cells in monoculture; however, treatment of such cells with trastuzumab in co-culture with human peripheral blood mononuclear cells (PBMC) significantly upregulated not only HLA-ABC expression but also CD86 expression. We showed that this upregulation was mediated by interferon gamma (IFNγ) secreted from the natural killer (NK) cells in PBMC as a result of engagement of NK cells by trastuzumab. We further confirmed this effect of trastuzumab in vivo using a mouse mammary tumor model transduced to overexpress human HER2. Together, our data provide evidence that trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules in HER2-overexpressing breast cancer cells in the presence of PBMC, which supports the view that T-cell-mediated immune responses are involved in trastuzumab-mediated antitumor effects. PMID:27141382

  12. [High Expression of co-stimulatory molecule CD40 in silicosis patients and intervention effect of yiqi huoxue decoction]. (United States)

    Wang, Shu-juan; Han, Jing-yin; Jia, Yang-min; Hu, Zu-ying


    To study whether co-stimulatory molecule CD40 of alveolar macrophage (AM) participated in the occurrence and development of silicosis, and to explore the intervention of Yiqi Huoxue Decoction (YHD) in the fibrosis of silicosis patients. Totally 46 silicosis inpatients and outpatients were recruited and randomly assigned to the Western treatment group (A) and the Chinese medicine (CM) treatment group (B), 23 in each group. Patients in Group A received routine symptomatic treatment such as anti-inflammation, phlegm resolving, anti-spasm, and asthma relief, and so on. Patients in Group B additionally took YHD, one dose daily for 14 successive days. Besides, another 18 patients with chronic cough and sense of laryngeal foreign bodies were recruited as the normal control group, who had no obvious lesion confirmed by bronchofi6roscope and clinical diagnosis of the lung. They were treated by symptomatic supporting treatment. The alveolar lavage fluid was collected from all patients and isolated, and AM cells were cultured. The level of CD40 mRNA was detected by RT-PCR. The expression of CD40 protein was detected by Western blot. Compared with the normal control group, expression levels of CD40 mRNA and CD40 protein significantly increased in Group A (P < 0.01). Compared with Group A, expression levels of CD40 mRNA and CD40 protein significantly decreased in Group B (P < 0.01). Highly expressed co-stimulatory molecule CD40 of AM might participate in pulmonary fibrosis. YHD could hinder its roles, inhibit the progression of fibrosis, thereby playing an interventional role of treatment.

  13. Organic dyes as small molecule protein-protein interaction inhibitors for the CD40-CD154 costimulatory interaction. (United States)

    Buchwald, Peter; Margolles-Clark, Emilio; Kenyon, Norma S; Ricordi, Camillo


    It is becoming increasingly clear that small molecules can often act as effective protein-protein interaction (PPI) inhibitors, an area of increasing interest for its many possible therapeutic applications. We have identified several organic dyes and related small molecules that (i) concentration-dependently inhibit the important CD40-CD154 costimulatory interaction with activities in the low micromolar (microM) range, (ii) show selectivity toward this particular PPI, (iii) seem to bind on the surface of CD154, and (iv) concentration-dependently inhibit the CD154-induced B cell proliferation. They were identified through an iterative activity screening/structural similarity search procedure starting with suramin as lead, and the best smaller compounds, the main focus of the present work, achieved an almost 3-fold increase in ligand efficiency (DeltaG(0)/nonhydrogen atom = 0.8 kJ/N(nHa)) approaching the average of known promising small-molecule PPI inhibitors (approximately 1.0 kJ/N(nHa)). Since CD154 is a member of the tumor necrosis factor (TNF) superfamily of cell surface interaction molecules, inhibitory activities on the TNF-R1-TNF-alpha interactions were also determined to test for specificity, and the compounds selected here all showed more than 30-fold selectivity toward the CD40-CD154 interaction. Because of their easy availability in various structural scaffolds and because of their good protein-binding ability, often explored for tissue-specific staining and other purposes, such organic dyes can provide a valuable addition to the chemical space searched to identify small molecule PPI inhibitors in general. (c) 2009 John Wiley & Sons, Ltd.

  14. MHC class II molecules deliver costimulatory signals in human T cells through a functional linkage with IL-2-receptors

    DEFF Research Database (Denmark)

    Odum, Niels; Kanner, S B; Ledbetter, J A


    a regulatory function in T cell activation. Here, we show that cross-linking HLA-DR and -DP but not -DQ molecules by immobilized mAb enhanced proliferative T cell responses to IL-2. In contrast, class II stimulation had no effect on IL-4-induced proliferation. The costimulatory effect was most pronounced...... at low concentrations of IL-2, was blocked by IL-2R mAb, and was at least partly mediated through an up-regulation of IL-2 high affinity receptors. As expected, activation of IL-2R by IL-2 induced tyrosine phosphorylation of several proteins including p56lck, and class II cross-linking by mAb induced...... tyrosine phosphorylation of specific substrates including PLC-gamma 1. Combined stimulation of IL-2R and class II molecules had an additive effect on tyrosine phosphorylation. Pretreatment of T cells with a protein tyrosine kinase inhibitor, herbimycin A, inhibited IL-2 and class II-induced proliferation...

  15. Interleukin 20 regulates dendritic cell migration and expression of co-stimulatory molecules

    DEFF Research Database (Denmark)

    Bech, Rikke; Jalilian, Babak; Agger, Ralf


    , but not the STAT3, pathway. IL-20 increased the migration of MDDCs in a biphasic response narrowly controlled by the interleukin concentration. A concomitant change in the shedding of CD18 integrins suggested that these adhesion molecules play a role in the migration of the MDDCs through the extracellular matrix...

  16. CD40/CD154 Blockade Inhibits Dendritic Cell Expression of Inflammatory Cytokines but not Costimulatory Molecules1 (United States)

    Ferrer, Ivana R.; Liu, Danya; Pinelli, David F.; Koehn, Brent H.; Stempora, Linda L.; Ford, Mandy L.


    Blockade of the CD40/CD154 pathway remains one of the most effective means of promoting graft survival following transplantation. However, the effects of CD40/CD154 antagonsim on dendritic cell (DC) phenotype and functionality following transplantation remain incompletely understood. To dissect the effects of CD154/CD40 blockade on DC activation in vivo, we generated hematopoietic chimeras in mice that expressed a surrogate minor antigen (OVA). Adoptive transfer of OVA-specific CD4+ and CD8+ T cells led to chimerism rejection, which was inhibited by treatment with CD154 blockade. Surprisingly, CD154 antagonism did not alter the expression of MHC and costimulatory molecules on CD11c+ DC compared to untreated controls. However, DCs isolated from anti-CD154 treated animals exhibited a significant reduction in inflammatory cytokine secretion. Combined blockade of inflammatory cytokines IL-6 and IL-12p40 attenuated the expansion of antigen-specific CD4+ and CD8+ T cells and transiently inhibited the rejection of OVA-expressing cells. These results suggest that a major effect of CD154 antagonism in vivo is an impairment in the provision of signal three during donor-reactive T cell programming, as opposed to an impact on the provision of signal two. We conclude that therapies designed to target inflammatory cytokines during donor-reactive T cell activation may be beneficial in attenuating these responses and prolonging graft survival. PMID:23002440

  17. Expression of costimulatory molecules in antigen-activated peritoneal macrophages treated with either ovalbumin or palmitoyl-ova conjugates

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    Flávia Márcia Oliveira


    Full Text Available One of the mechanisms by which adjuvants are believed to promote T-cell activation and prevent induction of oral tolerance is by up-regulating the expression of co-stimulatory molecules on antigen presenting cells. Mice treated orally with palmitoyl-ovalbumin conjugates become immunized, while those treated with native ovalbumin (Ova become tolerant. Cells from the peritoneal cavity of B6D2F1 mice were cultured in the presence of 0.01, or 0.1 mg/100ml of either Ova, or palmitoyl-Ova and tested for the presence of cell markers. PE-conjugated anti-mouse CD80, CD86, and CD11b antibodies as well as biotin-PE were used to stain the antigen-activated peritoneal cells. A significant increase in the expression of CD86 and CD80 was observed following in vitro stimulation with palmitoyl-Ova; additionally, both Ova and palmitoyl-Ova induced the basal expression of CD11b. These findings could be related with the strong T-cell proliferative response induced by palmitoyl-Ova.

  18. Endogenous expression of CD80 co-stimulatory molecule facilitates in vivo tumor regression of oral squamous carcinoma. (United States)

    Thomas, Giovana R; Wen, Judy


    Most tumor tissues, especially those of non-hematopoietic origin, do not express CD80 co-stimulatory molecules, possibly as a mechanism to evade immune surveillance. The objective of this study was to determine whether abundant endogenous CD80 expression on oral squamous cell carcinoma (SCC) early during tumor progression can facilitate immune elimination and reverse immune tolerance. The growth of regressor and progressor oral SCC lines with differing endogenous CD80 expression were examined in immune-competent and -deficient mice. Immune effectors were determined by T-cell depletion experiments and immunohistochemistry. Our studies show regression of early tumor growth when immunocompetent animals are inoculated with oral SCC progressor cell lines expressing abundant endogenous CD80. The CD80-induced antitumor response was due largely to induced T-cell responses. Our findings suggest that inadequate CD80 expression during early oral SCC formation may contribute to the escape of tumors from immune elimination. This information can be useful in the design of new approaches to generate more effective immunotherapy against this disease.

  19. Rhinovirus-induced alterations on peripheral blood mononuclear cell phenotype and costimulatory molecule expression in normal and atopic asthmatic subjects. (United States)

    Papadopoulos, N G; Stanciu, L A; Papi, A; Holgate, S T; Johnston, S L


    Rhinovirus (RV) infection is the commonest trigger of acute asthma exacerbations; however, the immune response to these viruses and any potential implications in the mechanisms leading to asthma exacerbations are not well understood. To assess the effects of in vitro RV infection on the phenotype and expression of costimulatory molecules on peripheral blood mononuclear cells (PBMC) from normal and atopic asthmatic subjects, as a model for RV antigen presentation. PBMC from seven normal and seven asthmatic subjects were exposed to one infectious unit/cell of RV16 for 48 h. Surface expression of CD25, CD28, CD40, CD54, CD80, CD86 and CTLA-4 was evaluated on CD3, CD4, CD8, CD14 and CD19 PBMC subpopulations by three-colour flow cytometry. No changes in the percentage of CD3, CD4, CD8 or CD19 were observed. CD14 was significantly reduced by the infection and this was more pronounced in normal subjects. On Th cells CTLA-4 was increased after RV infection only in the asthmatic group. Levels of CD80 and CD86 in the control cultures were lower in the asthmatic group. RV infection induced a significant increase of CD80 on monocytes and of CD86 on B cells, which occurred in both groups but were less marked in atopic asthmatic subjects. Exposure of PBMC to RV is able to activate the antigen presentation machinery. Differences between normal and atopic asthmatic individuals are compatible with the hypothesis that an aberrant immune response to RV may be involved in the development of acute exacerbations in atopic asthmatic subjects.

  20. Characterization and expression analysis of grouper (Epinephelus coioides) co-stimulatory molecules CD83 and CD80/86 post Cryptocaryon irritans infection. (United States)

    Mo, Ze-Quan; Wang, Jiu-Le; Yang, Man; Ni, Lu-Yun; Wang, Hai-Qing; Lao, Guo-Feng; Li, Yan-Wei; Li, An-Xing; Luo, Xiao-Chun; Dan, Xue-Ming


    Co-stimulatory molecules (CD83, CD80 and CD86), belong to immunoglobulin superfamily, are type I membrane glycoprotein, which express on antigen presenting cells and provide the second signal for the activation of T lymphocytes. In the present study, we cloned the grouper's CD83 (675 bp) and CD80/86 (876 bp). Homology analysis showed that both EcCD83 and EcCD80/86 shares the highest amino acid similarity (51% and 47%) for the overall sequence with puffer fish (Takifugu rubripes). Some conserved features and important functional residues in mammalian CD83, CD80 and CD86 were also identified from these molecules of teleosts including grouper, suggesting the function of both molecules may be conserved among vertebrates. In transfected HEK293T cells, both molecules localized on the membrane surface. Tissue distribution analysis showed both EcCD83 and EcCD80/86 mRNAs were mainly expressed in immune organs, and EcCD80/86 was extremely higher expressed in mucosal immune tissues including skin and gill than systematic immune organs, which indicates these co-stimulatory molecules may prime T cell activation in local mucosal tissues. In Cryptocaryon irritans infected groupers, the expression level of EcCD83 and EcCD80/86 were both seen significant up-regulation in the skin at most tested time points. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Heterologous expression of human costimulatory molecule B7-2 and construction of B7-2 immobilized polyhydroxyalkanoate nanoparticles for use as an immune activation agent

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    Li Ming-Chuan


    Full Text Available Abstract Background Costimulation of T cells via costimulatory molecules such as B7 is important for eliciting cell-mediated antitumor immunity. Presenting costimulation molecules by immobilizing recombinant B7 on the surface of nanovectors is a novel strategy for complementary therapy. Polyhydroxyalkanoates (PHAs are a family of biodegradable, non-toxic, biocompatible polyesters, which can be used as a nonspecific immobilizing matrix for protein presentation. Recombinant protein fusion with PHA granule binding protein phasin (PhaP can be easily immobilized on the surface of PHA nanoparticles through hydrophobic interactions between PhaP and PHA, and therefore provides a low-cost protein presenting strategy. Results In this study, the extracellular domain of the B7-2 molecule (also named as CD86 was fused with PhaP at its N-terminal and heterogeneously expressed in recombinant Escherichia coli strain BL21 (DE3. The purified B7-2-PhaP protein was immobilized on the surface of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate (PHBHHx-based nanoparticles. Loading of 240 μg (3.2 pMol of B7-2-PhaP protein per mg nanoparticles was achieved. Immobilized B7-2-PhaP on PHBHHx nanoparticles induced T cell activation and proliferation in vitro. Conclusions A PHA nanoparticle-based B7-2 costimulation molecule-presenting system was constructed. The PHA-based B7 presenting nanosystem provided costimulation signals to induce T cell activation and expansion in vitro. The B7-2-PhaP immobilized PHA nanosystem is a novel strategy for costimulation molecule presentation and may be used for costimulatory molecule complementary therapy.

  2. Suppressive effects of anti-allergic agent suplatast tosilate (IPD-1151T on the expression of co-stimulatory molecules on mouse splenocytes in vivo

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    Masatsugu Kurokawa


    Full Text Available The effects of IPD-1151T on the expression of costimulatory molecules, CD40, CD80 and CD86, were investigated in vivo using mice with allergic disorders. BALB/c mice were immunized intraperitoneally with two doses of dinitrophenylated ovalbumin (DNP-OVA at 1-week intervals. These mice then were treated intraperitoneally with 100μg/kg of IPD1151T once a day for 14 days, starting 7 days after the first immunization. On day 21, some mice were challenged intraperitoneally with DNP-OVA and the other mice were not challenged. All mice were autopsied on day 22 and assayed for immunoglobulin E, interleuken (IL-4 and IL-5 productions following DNP-OVA immunization. The intraperitoneal treatment with IPD-1151T strongly suppressed immunoglobulin E contents in serum, which were enhanced by DNA-OVA immunization. IPD-1151T also caused a decrease in both IL-4 and IL-5 levels in splenic lymphocytes. We next examined the influence of IPD1151T on co-stimulatory molecule expression on splenic lymphocytes. IPD-1151T caused suppression of CD40 and CD86 expression; however, the treatments did not affect CD80 expression.

  3. Expression of co-stimulatory and adhesion molecules and chemokine or apoptosis receptors on acute myeloid leukaemia : high CD40 and CD11a expression correlates with poor prognosis

    NARCIS (Netherlands)

    Brouwer, RE; Hoefnagel, J; van der Burg, BB; Jedema, [No Value; Zwinderman, KH; Starrenburg, ICW; Kluin-Nelemans, HC; Barge, RMY; Willemze, R; Falkenburg, JHF


    The expression of adhesion and co-stimulatory molecules. and chemokine and death receptors such as tumour necrosis factor (TNF) and FAS on acute myeloid leukaemia (AML) may influence the biology of the disease and response to chemotherapy and immunotherapy. In this study, we analysed the expression

  4. CD80 and CD86 Costimulatory Molecules Differentially Regulate OT-II CD4+ T Lymphocyte Proliferation and Cytokine Response in Cocultures with Antigen-Presenting Cells Derived from Pregnant and Pseudopregnant Mice

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    Tomasz Maj


    Full Text Available Immune phenomena during the preimplantation period of pregnancy are poorly understood. The aim of our study was to assess the capacity for antigen presentation of splenic antigen-presenting cells (APCs derived from pregnant and pseudopregnant mice in in vitro conditions. Therefore, sorted CD11c+ dendritic cells and macrophages F4/80+ and CD11b+ presenting ovalbumin (OVA were cocultured with CD4+ T cells derived from OT-II mice’s (C57BL6/J-Tg(TcraTcrb1100Mjb/J spleen. After 132 hours of cell culture, proliferation of lymphocytes (ELISA-BrdU, activation of these cells (flow cytometry, cytokine profile (ELISA, and influence of costimulatory molecules blocking on these parameters were measured. We did not detect any differences in regulation of Th1/Th2 cytokine balance. CD86 seems to be the main costimulatory molecule involved in the proliferation response but CD80 is the main costimulatory molecule influencing cytokine secretion in pregnant mice. In conclusion, this study showed that CD80 and CD86 costimulatory molecules regulate OT-II CD4+ T lymphocyte proliferation and cytokine response in cocultures with antigen-presenting cells derived from pregnant and pseudopregnant mice. The implications of these changes still remain unclear.

  5. Exploratory computational assessment of possible binding modes for small molecule inhibitors of the CD40-CD154 co-stimulatory interaction. (United States)

    Ganesan, L; Vidović, D; Schürer, S C; Buchwald, P


    Protein-protein interactions (PPI) tend to involve extensive, flat, and featureless interfaces that are difficult to disrupt by small molecule binding. However, recently, PPIs are being recognized as increasingly valuable 'druggable' targets. We have identified several small molecule inhibitors of the immunologically relevant CD40-CD154 co-stimulatory interaction that bind to the homotrimeric CD154, a member of the tumor necrosis factor superfamily (TNFSF). Recently, on the basis of the co-crystal structure of CD154 with another small molecule (BIO8898), it has been suggested that these PPIs could be particularly susceptible to small molecule blockade due to a subunit fracture mechanism resulting in a distortion of the trimeric structure. To investigate whether this mechanism can occur with our organic dye-related inhibitors, we performed exploratory computational docking experiments. Possible druggable pockets that can serve as binding sites for small molecule inhibitors were identified with the FFT map algorithm both along the CD154-CD40 binding interface (competitive, orthosteric model) and in the interior core of the CD154 trimer corresponding to the BIO8898 binding site (allosteric model). Docking experiments (using Glide) were performed at these sites using the PDB ID: 3QD6 (CD40-CD154) and 3LKJ (BIO8898-CD154) co-crystal structures, respectively. The docking algorithm was able to better discriminate binders from non-binders at the deeper allosteric site than at the competitive site. Accordingly, an allosteric inhibitory mechanism that involves intercalation between monomeric subunits seems feasible for our small molecules making the constitutively trimeric CD154 a likely druggable target.

  6. Effect of siRNA silencing of inducible co-stimulatory molecule on myocardial cell hypertrophy after cardiac infarction in rats. (United States)

    Wang, W M; Liu, Z; Chen, G


    As the most common cardiac disease, myocardial infarction is followed by hypertrophy of cardiac myocytes and reconstruction of ventricular structure. The up-regulation of a series of factors including metalloproteinases, inflammatory factors, and growth factors after primary infarction lead to the hypertrophy, apoptosis, necrosis, and fibroblast proliferation in cardiac muscle tissues. Recent studies have reported on the potency of small interfering RNA (siRNA) in treating cardiac diseases. We thus investigated the efficacy of inducible co-stimulatory molecule (ICOS)-specific siRNA silencing in myocardial hypertrophy in a cardiac infarction rat model. This cardiac infarction model was prepared by ligating the left anterior descending coronary artery. ICOS-siRNA treatment was administered in parallel with non-sense siRNA. After 18 days, the cross-sectional area of cardiac muscle tissues and the left ventricle weight index were measured, along with ICOS mRNA and protein expression levels, and pathological staining. Compared to those in the control groups, in myocardial infarcted rats, the application of ICOS-siRNA effectively decreased the left ventricle weight index, as well as the surface area of cardiac myocytes. Both mRNA and protein levels of ICOS were also significantly decreased. HE staining was consistent with these results. In conclusion, ICOS-targeted siRNA can effectively silence gene expression of ICOS, and provided satisfactory treatment efficacy for myocardial cell hypertrophy after infarction.

  7. Single-step antigen loading and maturation of dendritic cells through mRNA electroporation of a tumor-associated antigen and a TriMix of costimulatory molecules. (United States)

    Benteyn, Daphné; Van Nuffel, An M T; Wilgenhof, Sofie; Bonehill, Aude


    Dendritic cells (DC) are key players in several types of cancer vaccines. Large numbers of DC can easily be generated in closed systems from the monocyte fraction of the peripheral blood. They are the professional antigen-presenting cells, and electroporation of mRNA-encoding tumor antigens is a very efficient and a relatively simple way to load the DC with antigen. The co-electroporation of a tumor antigen of choice and the combination of 3 costimulatory molecules, including CD70, caTLR4, and CD40L (TriMix-DC), leads to fully potent antigen-presenting DC able to generate a broad immune response.Here we describe the in vitro transcription of the mRNA and the subsequent generation and electroporation of autologous DC used for the treatment of melanoma patients.

  8. ATVB Distinguished Scientist Award: How Costimulatory and Coinhibitory Pathways Shape Atherosclerosis. (United States)

    Ley, Klaus; Gerdes, Norbert; Winkels, Holger


    Immune cells play a critical role in atherosclerosis. Costimulatory and coinhibitory molecules of the tumor necrosis factor receptor and CD28 immunoglobulin superfamilies not only shape T-cell and B-cell responses but also have a major effect on antigen-presenting cells and nonimmune cells. Pharmacological inhibition or activation of costimulatory and coinhibitory molecules and genetic deletion demonstrated their involvement in atherosclerosis. This review highlights recent advances in understanding how costimulatory and coinhibitory pathways shape the immune response in atherosclerosis. Insights gained from costimulatory and coinhibitory molecule function in atherosclerosis may inform future therapeutic approaches. © 2017 American Heart Association, Inc.

  9. The proportion of CD40+ mucosal macrophages is increased in inflammatory bowel disease whereas CD40 ligand (CD154)+ T cells are relatively decreased, suggesting differential modulation of these costimulatory molecules in human gut lamina propria. (United States)

    Carlsen, Hege S; Yamanaka, Takeshi; Scott, Helge; Rugtveit, Jarle; Brandtzaeg, Per


    Signal transduction through binding of CD40 on antigen-presenting cells and CD40 ligand (CD154) on T cells appears to be crucial for mutual cellular activation. Antibodies aimed at blocking the CD40-CD154 costimulatory pathway dampen the severity of experimental colitis. To elucidate the microanatomical basis for signaling through this costimulatory pathway in human inflammatory bowel disease, we studied in situ the cellular distribution of these 2 molecules on lamina propria macrophages and T cells, respectively. Colonic specimens from 8 patients with ulcerative colitis and 8 with Crohn's disease, 8 small bowel specimens of Crohn's disease, and histologically normal control samples (6 from colon and 6 from small bowel) were included. Multicolor immunofluorescence in situ staining was performed to determine the percentage of subepithelial macrophages expressing CD40 and that of lamina propria T cells expressing CD154 while avoiding cells in lymphoid aggregates. The proportion of subepithelial CD40CD68 macrophages was significantly increased in normal colon compared with normal small bowel and showed further elevation in both colon and small bowel afflicted with inflammatory bowel disease. In addition, on a per-CD68-cell basis, CD40 expression was significantly increased in severely inflamed compared with moderately inflamed colonic specimens. Conversely, the proportion of CD154 T cells was similar in colon and small bowel, and interestingly, it was significantly reduced in colonic inflammatory bowel disease. Our findings suggested that modulation of CD40 expression by subepithelial macrophages and CD154 by lamina propria T cells is inversely modulated in the human gut.

  10. Monocyte derived dendritic cells have reduced expression of co-stimulatory molecules but are able to stimulate autologous T-cells in patients with MDS. (United States)

    Davison, Glenda M; Novitzky, Nicolas; Abdulla, Rygana


    Research has implied that the immune system plays a role in the pathogenesis of MDS and that T-cells are reacting to tumour antigen present on the surface of the malignant cells. This could imply that the immune system could be utilized to generate immune based therapy. The aim of this pilot study was to examine the feasibility of studying this further by analysing the interaction of dendritic cells with T-cells in a small cohort of MDS patients. Dendritic cells were generated in 6 MDS patients and 9 controls by culturing monocytes with GM-CSF and IL-4. After activation with LPS and TNFα, the dendritic cells were analyzed for expression of co-stimulatory and activation antigens. Thereafter, they were co-cultured with T-cells and the T-cell response was examined by measuring the % change in expression of the activation antigen CD69. MDS MoDC had reduced expression of HLA-DR (p=0.006), CD11c (p=0.0004), CD80 (p=0.03) and CD86 (p=0.003), while resting T-cells from MDS patients had higher expression of the activation antigen CD69 on all subsets. The % change in CD69 expression increased significantly for both the control and MDS T-cells after co-culture with allogeneic dendritic cells, however this change was lower in the MDS group. Despite the increased CD69 expression prior to culture, MDS MoDC significantly up-regulated CD69 expression on autologous T-cells to values that were statistically higher than control cells. This initial study suggests that the T-cells in MDS are able to respond to dendritic cells and are therefore probably not part of the malignant clone. It further implies that the dendritic cell population could be capable of presenting antigen and initiating an immune response and therefore further study is both feasible and warranted. Copyright © 2013 King Faisal Specialist Centre & Research Hospital. Published by Elsevier B.V. All rights reserved.

  11. Canine distemper virus infection leads to an inhibitory phenotype of monocyte-derived dendritic cells in vitro with reduced expression of co-stimulatory molecules and increased interleukin-10 transcription.

    Directory of Open Access Journals (Sweden)

    Visar Qeska

    Full Text Available Canine distemper virus (CDV exhibits a profound lymphotropism that causes immunosuppression and increased susceptibility of affected dogs to opportunistic infections. Similar to human measles virus, CDV is supposed to inhibit terminal differentiation of dendritic cells (DCs, responsible for disturbed repopulation of lymphoid tissues and diminished antigen presenting function in dogs. In order to testify the hypothesis that CDV-infection leads to an impairment of professional antigen presenting cells, canine DCs have been generated from peripheral blood monocytes in vitro and infected with CDV. Virus infection was confirmed and quantified by transmission electron microscopy, CDV-specific immunofluorescence, and virus titration. Flow cytometric analyses revealed a significant down-regulation of the major histocompatibility complex class II and co-stimulatory molecules CD80 and CD86 in CDV-infected DCs, indicative of disturbed antigen presenting capacity. Molecular analyses revealed an increased expression of the immune inhibitory cytokine interleukin-10 in DCs following infection. Results of the present study demonstrate that CDV causes phenotypical changes and altered cytokine expression of DCs, which represent potential mechanisms to evade host immune responses and might contribute to immune dysfunction and virus persistence in canine distemper.

  12. Increasing the repeating units of ethylene glycol-based dimethacrylates directed toward reduced oxidative stress and co-stimulatory factors expression in human monocytic cells. (United States)

    Tamura, Atsushi; Fukumoto, Izumi; Yui, Nobuhiko; Matsumura, Mitsuaki; Miura, Hiroyuki


    The ethylene glycol-based dimethacrylates are commonly used in biomaterials and dental restorative materials as a cross-linking agent. In this study, toxic effect of triethylene glycol dimethacrylate (TEGDMA) and poly(ethylene glycol) dimethacrylates (PEG-DMAs) with various ethylene glycol repeating units was investigated in terms of cytotoxicity, oxidative stress, and the expression of co-stimulatory factors in human leukemia cell line (THP-1 cells) to verify the effect of ethylene glycol repeating units. Note that the 1-octanol/water partition coefficient of PEG-based dimethacrylates decreased with increasing the ethylene glycol repeating units, indicating that the hydrophilicity of PEG-DMAs increased with ethylene glycol repeating units. The toxic effect of PEG-DMAs such as cytotoxicity, oxidative stress, and the expression of CD86 in treated THP-1 cells are reduced with increasing the ethylene glycol repeating units in PEG-DMAs. However, the expression of CD54 in treated THP-1 cells was not influenced with the ethylene glycol repeating units and the maximal expression level of CD54 was observed at the concentration range of 2-4 mM for all samples. Accordingly, hydrophilic character of PEG-DMAs with long ethylene glycol chains definitely alleviates the some toxic aspect of PEG-based DMAs. This finding would provide important insight into the design of new biomaterials and dental materials with superior biocompatibility. © 2014 Wiley Periodicals, Inc.

  13. T cell retargeting with MHC class I-restricted antibodies: the CD28 costimulatory domain enhances antigen-specific cytotoxicity and cytokine production

    NARCIS (Netherlands)

    R.A. Willemsen (Ralph); C. Ronteltap; P. Chames; J.E.M.A. Debets (Reno); R.L.H. Bolhuis (Reinder)


    textabstractT cells require both primary and costimulatory signals for optimal activation. The primary Ag-specific signal is delivered by engagement of the TCR. The second Ag-independent costimulatory signal is mediated by engagement of the T cell surface costimulatory molecule

  14. Sex-Associated Expression of Co-Stimulatory Molecules CD80, CD86, and Accessory Molecules, PDL-1, PDL-2 and MHC-II, in F480+ Macrophages during Murine Cysticercosis

    Directory of Open Access Journals (Sweden)

    Cristián Togno-Peirce


    Full Text Available Macrophages are critically involved in the interaction between T. crassiceps and the murine host immune system. Also, a strong gender-associated susceptibility to murine cysticercosis has been reported. Here, we examined the sex-associated expression of molecules MHC-II, CD80, CD86, PD-L1, and PD-L2 on peritoneal F4/80hi macrophages of BALB/c mice infected with Taenia crassiceps. Peritoneal macrophages from both sexes of mice were exposed to T. crassiceps total extract (TcEx. BALB/c Females mice recruit higher number of macrophages to the peritoneum. Macrophages from infected animals show increased expression of PDL2 and CD80 that was dependent from the sex of the host. These findings suggest that macrophage recruitment at early time points during T. crassiceps infection is a possible mechanism that underlies the differential sex-associated susceptibility displayed by the mouse gender.

  15. Direct cooling of polar molecules to sub-millikelvin temperatures

    CERN Document Server

    Prehn, Alexander; Glöckner, Rosa; Rempe, Gerhard; Zeppenfeld, Martin


    We demonstrate direct cooling of gaseous formaldehyde (H2CO) to the microkelvin regime. Our approach, optoelectrical Sisyphus cooling, provides a simple dissipative cooling method applicable to electrically trapped dipolar molecules. By reducing the temperature by three orders of magnitude and increasing the phase-space density by a factor of ~$10^4$ we generate an ensemble of $3\\cdot10^5$ molecules with a temperature of about 420\\mu K, populating a single rotational state with more than 80% purity.

  16. Direct photoassociation of halo molecules in ultracold 86 Sr (United States)

    Aman, J. A.; Hill, Joshua; Killian, T. C.


    We investigate the creation of 1S0 +1S0 halo molecules in strontium 86 through direct photoassociation in an optical dipole trap. We drive two photon Raman transitions near-resonance with a molecular level of the 1S0 +3P1 interatomic potential as the intermediate state. This provides large Frank-Condon factors and allows us to observe resonances for the creation of halo molecules through higher order Raman processes. The halo molecule is bound by EB 85 kHz at low excitation-laser intensity, but experiments show large AC Stark shifts of the molecular binding energy. These conditions suggest that STIRAP should be very effective for improving molecular conversion efficiency. Further experiments in a 3D lattice will explore molecular lifetimes and collision rates. Travel support provided by Shell Corporation.

  17. Antigen presenting cells costimulatory signaling during pre-implantation pregnancy 

    Directory of Open Access Journals (Sweden)

    Anna Sławek


    Full Text Available  Success of pregnancy depends on many factors. Three phenomena inducing immune tolerance against semi-allogeneic conceptus may play a crucial role in the pre-implantation period of pregnancy: influence of sex hormones in sex cycle, presence of oocyte or embryo and the presence of semen in the female reproductive tract. On the other hand dendritic cells are the most effective antigen-presenting cells in regulation of immune phenomena and also are considered as potent participants in inducing immune tolerance in the pregnancy. They communicate with T cells in cell contact-dependent manner or via cytokines. During cell-cell contacts, costimulatory molecules play a key role and their expression is often dependent on cytokines milieu. Both costimulatory molecules and cytokines influence generation of T regulatory cells. Interactions of these molecules are closely related. In this paper we would like to pay attention to the importance of antigen presenting cells costimulatory potency in immune regulation during a pre-implantation period of pregnancy.

  18. Direct spectroscopic observation of quantum jumps of a single molecule (United States)

    Basché, Th.; Kummer, S.; Bräuchle, C.


    BOHR'S notion of quantum jumps between electronic states of an excited atom has now been demonstrated experimentally for single ions confined in radio-frequency traps and interacting with a driving laser field1-3. In these experiments the fluorescence of a strongly allowed transition was shown to cease abruptly when the ion jumped into a metastable state which was coupled to the common electronic ground state by a weak radiative transition. But attempts to monitor quantum jumps of single molecules have been hampered by the fact that the lifetime of the metastable triplet state was too short in relation to the photon detection rate. By using a system with favourable photophysical parameters-terrylene doped into p-terphenyl crystals4-we have now been able to observe directly quantum jumps between electronic states of single terrylene molecules. In contrast to single atoms, here the quantum jumps occur as non-radiative transitions between states of different multiplicity, and are manifested as interruptions of the fluorescence signal. These results demonstrate how single-molecule spectros-copy can reveal truly quantum-mechanical effects in large polyatomic molecules.

  19. Interaction of T-cell and antigen presenting cell co-stimulatory genes in childhood IgE.

    NARCIS (Netherlands)

    Bottema, R.W.B.; Postma, D.S.; Reijmerink, N.E.; Thijs, C.; Stelma, F.F.; Smit, H.A.; van Schayck, C.P.; Brunekreef, B.; Koppelman, G.H.; Kerkhof, M.


    It is likely that multiple genes contribute to immunoglobulin (Ig)E production. Co-stimulatory molecules are crucial for the cross-talk between antigen presenting cells and T-lymphocytes which drives the IgE response. We evaluated gene-gene interactions of haplotype tagging polymorphisms in a

  20. Interaction of T-cell and antigen presenting cell co-stimulatory genes in childhood IgE

    NARCIS (Netherlands)

    Bottema, R. W. B.; Postma, D. S.; Reijmerink, N. E.; Thijs, C.; Stelma, F. F.; Simit, H. A.; van Schayck, C. P.; Brunekreef, B.; Koppelman, G. H.; Kerkhof, M.

    It is likely that multiple genes contribute to immunoglobulin (Ig)E production. Costimulatory molecules are crucial for the cross-talk between antigen presenting cells and T-lymphocytes which drives the IgE response. We evaluated gene-gene interactions of haplotype tagging polymorphisms in a pathway

  1. Monoclonal antibodies directed against surface molecules of multicell spheroids (United States)

    Martinez, Andrew O.


    The objective of this project is to generate a library of monoclonial antibodies (MAbs) directed against surface molecules of tumor and transformed cells grown as multicell spheroids (MCS). These MCS are highly organized, 3-dimensional multicellular structures which exhibit many characteristics of in vivo organized tissues which are not found in conventional monolayer or suspension culture. In brief, MCS combine the relevance or organized tissues with in vitro methodology making the MCS a good model system to study the interactions of mammalian cells, and thereby provide a functional assay for surface adhesion molecules. This project also involves investigations of cell-cell interactions in a gravity-based environment. It will provide an important base of scientific information for future comparative studies on the effects of hypergravity and simulated microgravity environments on cell-cell interactions. This project also has the potential to yield important materials (e.g. cellular products) which may be useful for the diagnosis and/or treatment of certain human diseases. Moreover, this project supports the training of one undergraduate and one graduate student; thus, it will also assist in developing a pool of future scientists with research experience in gravitational biology research.

  2. Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Schaub, M; Issazadeh-Navikas, Shohreh; Stadlbauer, T H


    Blockade of the CD28-B7 or CD40L-CD40 T cell costimulatory signals prevents induction of experimental autoimmune encephalomyelitis (EAE). However, the effect of simultaneous blockade of these signals in EAE is unknown. We show that administration of either MR1 (to block CD40L) or CTLA4Ig (to block...

  3. New Directions of Research in Molecules and Materials

    Indian Academy of Sciences (India)


    page 637–. 643) present a method to control the wetting behaviour of films grown at interfaces. Sur- factant molecules can act as both reducing and capping agents as shown by Kasture et al. (page 515–520) in the formation of silver nanoparticles.

  4. Costimulatory receptors in a teleost fish: Typical CD28, elusive CTLA4 (United States)

    Bernard, D.; Riteau, B.; Hansen, J.D.; Phillips, R.B.; Michel, F.; Boudinot, P.; Benmansour, A.


    T cell activation requires both specific recognition of the peptide-MHC complex by the TCR and additional signals delivered by costimulatory receptors. We have identified rainbow trout sequences similar to CD28 (rbtCD28) and CTLA4 (rbtCTLA4). rbtCD28 and rbtCTLA4 are composed of an extracellular Ig-superfamily V domain, a transmembrane region, and a cytoplasmic tail. The presence of a conserved ligand binding site within the V domain of both molecules suggests that these receptors likely recognize the fish homologues of the B7 family. The mRNA expression pattern of rbtCD28 and rbtCTLA4 in naive trout is reminiscent to that reported in humans and mice, because rbtCTLA4 expression within trout leukocytes was quickly up-regulated following PHA stimulation and virus infection. The cytoplasmic tail of rbtCD28 possesses a typical motif that is conserved in mammalian costimulatory receptors for signaling purposes. A chimeric receptor made of the extracellular domain of human CD28 fused to the cytoplasmic tail of rbtCD28 promoted TCR-induced IL-2 production in a human T cell line, indicating that rbtCD28 is indeed a positive costimulator. The cytoplasmic tail of rtrtCTLA4 lacked obvious signaling motifs and accordingly failed to signal when fused to the huCD28 extracellular domain. Interestingly, rbtCTLA4 and rbtCD28 are not positioned on the same chromosome and thus do not belong to a unique costimulatory cluster as in mammals. Finally, oar results raise questions about the origin and evolution of positive and negative costimulation in vertebrate immune systems. Copyright ?? 2006 by The American Association of Immunologists, Inc.

  5. Directly measuring single molecule heterogeneity using force spectroscopy

    CERN Document Server

    Hinczewski, Michael; Thirumalai, D


    One of the most intriguing results of single molecule experiments on proteins and nucleic acids is the discovery of functional heterogeneity: the observation that complex cellular machines exhibit multiple, biologically active conformations. The structural differences between these conformations may be subtle, but each distinct state can be remarkably long-lived, with random interconversions between states occurring only at macroscopic timescales, fractions of a second or longer. Though we now have proof of functional heterogeneity in a handful of systems---enzymes, motors, adhesion complexes---identifying and measuring it remains a formidable challenge. Here we show that evidence of this phenomenon is more widespread than previously known, encoded in data collected from some of the most well-established single molecule techniques: AFM or optical tweezer pulling experiments. We present a theoretical procedure for analyzing distributions of rupture/unfolding forces recorded at different pulling speeds. This re...

  6. Functional exhaustion of CD4+T cells induced by co-stimulatory signals from myeloid leukaemia cells. (United States)

    Ozkazanc, Didem; Yoyen-Ermis, Digdem; Tavukcuoglu, Ece; Buyukasik, Yahya; Esendagli, Gunes


    To cope with immune responses, tumour cells implement elaborate strategies such as adaptive resistance and induction of T-cell exhaustion. T-cell exhaustion has been identified as a state of hyporesponsiveness that arises under continuous antigenic stimulus. Nevertheless, contribution of co-stimulatory molecules to T-cell exhaustion in cancer remains to be better defined. This study explores the role of myeloid leukaemia-derived co-stimulatory signals on CD4 + T helper (Th) cell exhaustion, which may limit anti-tumour immunity. Here, CD86 and inducible T-cell co-stimulator ligand (ICOS-LG) co-stimulatory molecules that are found on myeloid leukaemia cells supported Th cell activation and proliferation. However, under continuous stimulation, T cells co-cultured with leukaemia cells, but not with peripheral blood monocytes, became functionally exhausted. These in vitro-generated exhausted Th cells were defined by up-regulation of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitory receptors. They were reluctant to proliferate upon re-stimulation and produced reduced amounts of interleukin-2 (IL-2), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Nonetheless, IL-2 supplementation restored the proliferation capacity of the exhausted Th cells. When the co-stimulation supplied by the myeloid leukaemia cells were blocked, the amount of exhausted Th cells was significantly decreased. Moreover, in the bone marrow aspirates from patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS), a subpopulation of Th cells expressing PD-1, TIM-3 and/or LAG3 was identified together with CD86 + and/or ICOS-LG + myeloid blasts. Collectively, co-stimulatory signals derived from myeloid leukaemia cells possess the capacity to facilitate functional exhaustion in Th cells. © 2016 John Wiley & Sons Ltd.

  7. Direct Identification of Protein-Protein Interactions by Single-Molecule Force Spectroscopy. (United States)

    Vera, Andrés M; Carrión-Vázquez, Mariano


    Single-molecule force spectroscopy based on atomic force microscopy (AFM-SMFS) has allowed the measurement of the intermolecular forces involved in protein-protein interactions at the molecular level. While intramolecular interactions are routinely identified directly by the use of polyprotein fingerprinting, there is a lack of a general method to directly identify single-molecule intermolecular unbinding events. Here, we have developed an internally controlled strategy to measure protein-protein interactions by AFM-SMFS that allows the direct identification of dissociation force peaks while ensuring single-molecule conditions. Single-molecule identification is assured by polyprotein fingerprinting while the intermolecular interaction is reported by a characteristic increase in contour length released after bond rupture. The latter is due to the exposure to force of a third protein that covalently connects the interacting pair. We demonstrate this strategy with a cohesin-dockerin interaction. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Exotic behavior of molecules in intense laser light fields. New research directions

    Energy Technology Data Exchange (ETDEWEB)

    Yamanouchi, Kaoru [Tokyo Univ., Department of Chemistry, Tokyo (Japan)


    The recent investigation of the dynamical behavior of molecules and clusters in intense laser fields has afforded us invaluable opportunities to understand fundamentals of the interaction between molecular species and light fields as well as to manipulate molecules and their dynamical pathways by taking advantage of characteristics of coherent ultrashort laser light fields. In the present report, new directions of this rapidly growing interdisciplinary research fields called molecular science in intense laser fields are discussed by referring to our recent studies. (author)

  9. Use of Direct Dynamics Simulations to Determine Unimolecular Reaction Paths and Arrhenius Parameters for Large Molecules. (United States)

    Yang, Li; Sun, Rui; Hase, William L


    In a previous study (J. Chem. Phys.2008, 129, 094701) it was shown that for a large molecule, with a total energy much greater than its barrier for decomposition and whose vibrational modes are harmonic oscillators, the expressions for the classical Rice-Ramsperger-Kassel-Marcus (RRKM) (i.e., RRK) and classical transition-state theory (TST) rate constants become equivalent. Using this relationship, a molecule's unimolecular rate constants versus temperature may be determined from chemical dynamics simulations of microcanonical ensembles for the molecule at different total energies. The simulation identifies the molecule's unimolecular pathways and their Arrhenius parameters. In the work presented here, this approach is used to study the thermal decomposition of CH3-NH-CH═CH-CH3, an important constituent in the polymer of cross-linked epoxy resins. Direct dynamics simulations, at the MP2/6-31+G* level of theory, were used to investigate the decomposition of microcanonical ensembles for this molecule. The Arrhenius A and Ea parameters determined from the direct dynamics simulation are in very good agreement with the TST Arrhenius parameters for the MP2/6-31+G* potential energy surface. The simulation method applied here may be particularly useful for large molecules with a multitude of decomposition pathways and whose transition states may be difficult to determine and have structures that are not readily obvious.

  10. Direct correlation functions of binary mixtures of hard Gaussian overlap molecules (United States)

    Moradi, M.; Khordad, R.


    We study the direct correlation function (DCF) of a classical fluid mixture of nonspherical molecules. The components of the mixture are two types of hard ellipsoidal molecules with different elongations, interacting through the hard Gaussian overlap (HGO) model. Two different approaches are used to calculate the DCFs of this fluid, and the results are compared. Here, the Pynn approximation [J. Chem. Phys. 60, 4579 (1974)] is extended to calculate the DCF of the binary mixtures of HGO molecules, then we use a formalism based on the weighted density functional theory introduced by Chamoux and Perera [J. Chem. Phys. 104, 1493 (1996)]. These results are fairly in agreement with each other. The pressure of this system is also calculated using the Fourier zero components of the DCF. The results are in agreement with the Monte Carlo molecular simulation.

  11. Efficient Isothermal Titration Calorimetry Technique Identifies Direct Interaction of Small Molecule Inhibitors with the Target Protein. (United States)

    Gal, Maayan; Bloch, Itai; Shechter, Nelia; Romanenko, Olga; Shir, Ofer M


    Protein-protein interactions (PPI) play a critical role in regulating many cellular processes. Finding novel PPI inhibitors that interfere with specific binding of two proteins is considered a great challenge, mainly due to the complexity involved in characterizing multi-molecular systems and limited understanding of the physical principles governing PPIs. Here we show that the combination of virtual screening techniques, which are capable of filtering a large library of potential small molecule inhibitors, and a unique secondary screening by isothermal titration calorimetry, a label-free method capable of observing direct interactions, is an efficient tool for finding such an inhibitor. In this study we applied this strategy in a search for a small molecule capable of interfering with the interaction of the tumor-suppressor p53 and the E3-ligase MDM2. We virtually screened a library of 15 million small molecules that were filtered to a final set of 80 virtual hits. Our in vitro experimental assay, designed to validate the activity of mixtures of compounds by isothermal titration calorimetry, was used to identify an active molecule against MDM2. At the end of the process the small molecule (4S,7R)-4-(4-chlorophenyl)-5-hydroxy-2,7-dimethyl-N-(6-methylpyridin-2-yl)-4,6,7,8 tetrahydrIoquinoline-3-carboxamide was found to bind MDM2 with a dissociation constant of ~2 µM. Following the identification of this single bioactive compound, spectroscopic measurements were used to further characterize the interaction of the small molecule with the target protein. 2D NMR spectroscopy was used to map the binding region of the small molecule, and fluorescence polarization measurement confirmed that it indeed competes with p53.

  12. Total, direct and dissociative electron impact ionization cross sections of the acetylene molecule

    Directory of Open Access Journals (Sweden)



    Full Text Available The total electron impact ionization cross sections of the acetylene molecule have been measured in the incident electron energy range from threshold to 1000 eV. These results are compared with other existing data, obtained by direct measurements of this molecular property or by indirect ones, via the partial ionization cross sections for the formation of different ions. Using three semiempirical equations, the total ionization cross sections were calculated and compared to available data, too. Direct and dissociative ionization cross sections were also calculated by a semiempirical equation and compared to existing data.

  13. Direct squencing from the minimal number of DNA molecules needed to fill a 454 picotiterplate.

    Directory of Open Access Journals (Sweden)

    Mária Džunková

    Full Text Available The large amount of DNA needed to prepare a library in next generation sequencing protocols hinders direct sequencing of small DNA samples. This limitation is usually overcome by the enrichment of such samples with whole genome amplification (WGA, mostly by multiple displacement amplification (MDA based on φ29 polymerase. However, this technique can be biased by the GC content of the sample and is prone to the development of chimeras as well as contamination during enrichment, which contributes to undesired noise during sequence data analysis, and also hampers the proper functional and/or taxonomic assignments. An alternative to MDA is direct DNA sequencing (DS, which represents the theoretical gold standard in genome sequencing. In this work, we explore the possibility of sequencing the genome of Escherichia coli fs 24 from the minimum number of DNA molecules required for pyrosequencing, according to the notion of one-bead-one-molecule. Using an optimized protocol for DS, we constructed a shotgun library containing the minimum number of DNA molecules needed to fill a selected region of a picotiterplate. We gathered most of the reference genome extension with uniform coverage. We compared the DS method with MDA applied to the same amount of starting DNA. As expected, MDA yielded a sparse and biased read distribution, with a very high amount of unassigned and unspecific DNA amplifications. The optimized DS protocol allows unbiased sequencing to be performed from samples with a very small amount of DNA.

  14. Immunotherapy of melanoma with the immune costimulatory monoclonal antibodies targeting CD137

    Directory of Open Access Journals (Sweden)

    Li SY


    Full Text Available Shi-Yan Li, Yizhen Liu Cancer Research Institute, Scott and White Healthcare, Temple, TX, USA Abstract: Knowledge of how the immune system recognizes and attempts to control cancer growth and development has improved dramatically. The advent of immunotherapies for cancer has resulted in robust clinical responses and confirmed that the immune system can significantly inhibit tumor progression. Until recently, metastatic melanoma was a disease with limited treatment options and a poor prognosis. CD137 (also known as 4-1BB a member of the tumor necrosis factor (TNF receptor superfamily, is an activation-induced T cell costimulator molecule. Growing evidence indicates that anti-CD137 monoclonal antibodies possess strong antitumor properties, the result of their powerful capability to activate CD8+ T cells, to produce interferon (IFN-γ, and to induce cytolytic markers. Combination therapy of anti-CD137 with other anticancer agents, such as radiation, has robust tumor-regressing abilities against nonimmunogenic or poorly immunogenic tumors. Of importance, targeting CD137 eliminates established tumors, and the fact that anti-CD137 therapy acts in concert with other anticancer agents and/or radiation therapy to eradicate nonimmunogenic and weakly immunogenic tumors is an additional benefit. Currently, BMS-663513, a humanized anti-CD137 antibody, is in clinical trials in patients with solid tumors, including melanoma, renal carcinoma, ovarian cancer, and B-cell malignancies. In this review, we discuss the basis of the therapeutic potential of targeting CD137 in cancer treatment, focusing in particular, on BMS-663513 as an immune costimulatory monoclonal antibody for melanoma immunotherapy. Keywords: anti-CD137 monoclonal antibodies, immune costimulator molecule, BMS-663513

  15. Direct Monte Carlo simulation of the sympathetic cooling of trapped molecules by ultracold argon atoms

    Energy Technology Data Exchange (ETDEWEB)

    Barletta, P; Tennyson, J; Barker, P F, E-mail: [Department of Physics and Astronomy, University College London, WC1E 6BT (United Kingdom)


    We demonstrate that cold molecules (H{sub 2} and benzene) can be created at temperatures below 1 mK by sympathetic cooling with laser-cooled rare gas atoms on timescales of seconds. The thermalization process is studied using the direct simulation Monte Carlo (DSMC) method, which allows a detailed analysis of the atomic and molecular spatial and energy distributions as a function of time. As part of this study, ultracold elastic cross sections for Ar-Ar and Ar-C{sub 6}H{sub 6} are also calculated.

  16. Semisynthetic bioluminescent sensor proteins for direct detection of antibodies and small molecules in solution. (United States)

    Arts, Remco; Ludwig, Susann Katrina Julie; van Gerven, Benice C B; Magdalena Estirado, Eva; Milroy, Lech-Gustav; Merkx, Maarten


    Single-step immunoassays that can be performed directly in solution are ideally suited for point-of-care diagnostics. Our group recently developed a new platform of bioluminescent sensor proteins (LUMABS; LUMinescent AntiBody Sensor) that allow antibody detection in blood plasma. Thus far, LUMABS has been limited to the detection of antibodies recognizing natural peptide epitopes. Here, we report the development of semisynthetic LUMABS sensors that recognize non-peptide epitopes. The non-natural amino acid para-azidophenylalanine was introduced at the position of the original antibody-recognition sites as a chemical handle to enable site-specific conjugation of synthetic epitope molecules coupled to a dibenzocylcooctyne moiety via strain-promoted click chemistry. The approach was successfully demonstrated by developing semisynthetic LUMABS sensors for antibodies targeting the small molecules dinitrophenol and creati-nine (DNP-LUMABS and CR-LUMABS) with affinities of 5.8 pM and 1.3 nM, respectively. An important application of these semisynthetic LUMABS is the detection of small molecules using a competition assay format, which is demonstrated here for the detection of creatinine. Using a preassembled complex of CR-LUMABS and an anti-creatinine antibody, the detection of high micromolar concentrations of creatinine was possible both in buffer and 1:1 diluted blood plasma. The use of semisynthetic LUMABS sensors significantly expands the range of antibody targets and enables the application of LUMABS sensors for the ratiometric bioluminescent detection of small molecules using a competitive immunoassay format.

  17. Supramolecular self-assembled molecules as organic directing agent for synthesis of zeolites. (United States)

    Corma, Avelino; Rey, Fernando; Rius, Jordi; Sabater, Maria J; Valencia, Susana


    Solid materials with uniform micropores, such as zeolites, can act as selective catalysts and adsorbents for molecular mixtures by separating those molecules small enough to enter their pores while leaving the larger molecules behind. Zeolite A is a microporous material with a high void volume. Despite its widespread industrial use in, for example, molecular separations and in detergency, its capability as a petroleum-refining material is limited owing to its poor acid-catalytic activity and hydrothermal stability, and its low hydrophobicity. These characteristics are ultimately a consequence of the low framework Si/Al ratio (normally around one) and the resulting high cationic fraction within the pores and cavities. Researchers have modified the properties of type-A zeolites by increasing the Si/Al compositions up to a ratio of three. Here we describe the synthesis of zeolite A structures exhibiting high Si/Al ratios up to infinity (pure silica). We synthesize these materials, named ITQ-29, using a supramolecular organic structure-directing agent obtained by the self-assembly, through pi-pi type interactions, of two identical organic cationic moieties. The highly hydrophobic pure-silica zeolite A can be used for hydrocarbon separations that avoid oligomerization reactions, whereas materials with high Si/Al ratios give excellent shape-selective cracking additives for increasing propylene yield in fluid catalytic cracking operations. We have also extended the use of our supramolecular structure-directing agents to the synthesis of a range of other zeolites.

  18. Overlooked Mechanisms in Type 1 Diabetes Etiology: How Unique Costimulatory Molecules Contribute to Diabetogenesis

    Directory of Open Access Journals (Sweden)

    David H. Wagner


    Full Text Available Type 1 Diabetes (T1D develops when immune cells invade the pancreatic islets resulting in loss of insulin production in beta cells. T cells have been proven to be central players in that process. What is surprising, however, is that classic mechanisms of tolerance cannot explain diabetogenesis; alternate mechanisms must now be considered. T cell receptor (TCR revision is the process whereby T cells in the periphery alter TCR expression, outside the safety-net of thymic selection pressures. This process results in an expanded T cell repertoire, capable of responding to a universe of pathogens, but limitations are that increased risk for autoimmune disease development occurs. Classic T cell costimulators including the CD28 family have long been thought to be the major drivers for full T cell activation. In actuality, CD28 and its family member counterparts, ICOS and CTLA-4, all drive regulatory responses. Inflammation is driven by CD40, not CD28. CD40 as a costimulus has been largely overlooked. When naïve T cells interact with antigen presenting cell CD154, the major ligand for CD40, is induced. This creates a milieu for T cell (CD40–T cell (CD154 interaction, leading to inflammation. Finally, defined pathogenic effector cells including TH40 (CD4+CD40+ cells can express FOXP3 but are not Tregs. The cells loose FOXP3 to become pathogenic effector cells. Each of these mechanisms creates novel options to better understand diabetogenesis and create new therapeutic targets for T1D.

  19. Expression of the Novel Costimulatory Molecule B7-H5 in Pancreatic Cancer. (United States)

    Byers, Joshua T; Paniccia, Alessandro; Kaplan, Jeffrey; Koenig, Michelle; Kahn, Nate; Wilson, Lora; Chen, Lieping; Schulick, Richard D; Edil, Barish H; Zhu, Yuwen


    This study investigated how the B7-H5 protein, a new member of the B7 family, is expressed in normal human pancreas tissues and examined its expression changes in pancreatic cancer. In this analysis, B7-H5 expression was examined by immunohistochemical staining of frozen specimens from patients undergoing pancreatic resection. Membranous B7-H5 protein was expressed on normal ductal epithelium within the pancreas. Other cell types from the normal pancreas, such as acinar cells and islet cells, did not express B7-H5. In adenocarcinoma, B7-H5 staining was decreased or absent. Interestingly, B7-H5 expression in intraductal papillary mucinous neoplasms varied with grade. No B7-H5 expression was found with other cancer types such as neuroendocrine tumors, but normal ducts adjacent to tumors were highly positive. The findings showed that B7-H5 expression was restricted to ductal cells in the normal pancreas and the expression was downregulated in pancreatic adenocarcinomas. In addition, the findings showed that B7-H5 expression changes within different stages of dysplasia. The study suggests that loss of the B7-H5 signal may contribute to immune evasion of pancreatic adenocarcinoma. However future studies are needed.

  20. Deposition of low sheet resistance indium tin oxide directly onto functional small molecules

    KAUST Repository

    Franklin, Joseph B.


    © 2014 Elsevier B.V. All rights reserved. We outline a methodology for depositing tin-doped indium oxide (ITO) directly onto semiconducting organic small molecule films for use as a transparent conducting oxide top-electrode. ITO films were grown using pulsed laser deposition onto copper(II)phthalocyanine (CuPc):buckminsterfullerene (C60) coated substrates. The ITO was deposited at a substrate temperature of 150 °C over a wide range of background oxygen pressures (Pd) (0.67-10 Pa). Deposition at 0.67 ≤ Pd ≤ 4.7 Pa led to delamination of the organic films owing to damage induced by the high energy ablated particles, at intermediate 4.7 ≤ Pd < 6.7 Pa pressures macroscopic cracking is observed in the ITO. Increasing Pd further, ≥ 6.7 Pa, supports the deposition of continuous, polycrystalline and highly transparent ITO films without damage to the CuPc:C60. The free carrier concentration of ITO is strongly influenced by Pd; hence growth at > 6.7 Pa induces a significant decrease in conductivity; with a minimum sheet resistance (Rs) of 145 /□ achieved for 300 nm thick ITO films. To reduce the Rs a multi-pressure deposition was implemented, resulting in the formation of polycrystalline, highly transparent ITO with an Rs of - 20/□ whilst maintaining the inherent functionality and integrity of the small molecule substrate.

  1. Legume receptors perceive the rhizobial lipochitin oligosaccharide signal molecules by direct binding. (United States)

    Broghammer, Angelique; Krusell, Lene; Blaise, Mickaël; Sauer, Jørgen; Sullivan, John T; Maolanon, Nicolai; Vinther, Maria; Lorentzen, Andrea; Madsen, Esben B; Jensen, Knud J; Roepstorff, Peter; Thirup, Søren; Ronson, Clive W; Thygesen, Mikkel B; Stougaard, Jens


    Lipochitin oligosaccharides called Nod factors function as primary rhizobial signal molecules triggering legumes to develop new plant organs: root nodules that host the bacteria as nitrogen-fixing bacteroids. Here, we show that the Lotus japonicus Nod factor receptor 5 (NFR5) and Nod factor receptor 1 (NFR1) bind Nod factor directly at high-affinity binding sites. Both receptor proteins were posttranslationally processed when expressed as fusion proteins and extracted from purified membrane fractions of Nicotiana benthamiana or Arabidopsis thaliana. The N-terminal signal peptides were cleaved, and NFR1 protein retained its in vitro kinase activity. Processing of NFR5 protein was characterized by determining the N-glycosylation patterns of the ectodomain. Two different glycan structures with identical composition, Man(3)XylFucGlcNAc(4), were identified by mass spectrometry and located at amino acid positions N68 and N198. Receptor-ligand interaction was measured by using ligands that were labeled or immobilized by application of chemoselective chemistry at the anomeric center. High-affinity ligand binding was demonstrated with both solid-phase and free solution techniques. The K(d) values obtained for Nod factor binding were in the nanomolar range and comparable to the concentration range sufficient for biological activity. Structure-dependent ligand specificity was shown by using chitin oligosaccharides. Taken together, our results suggest that ligand recognition through direct ligand binding is a key step in the receptor-mediated activation mechanism leading to root nodule development in legumes.

  2. A direct relativistic approach to ligand field theory calculations of spin-orbit components of diatomic molecules (United States)

    Bencheikh, M.; Schamps, J.


    The basic equations of a direct relativistic approach to ligand field theory are derived for the calculation of spin-orbit splittings of diatomic molecules. The decisive advantage of this direct method over the standard perturbational procedure, especially in case of strong spin-orbit effect, are pointed out and discussed.

  3. Directed evolution of an E. coli inner membrane transporter for improved efflux of biofuel molecules (United States)


    Background The depletion of fossil fuels and the rising need to meet global energy demands have led to a growing interest in microbial biofuel synthesis, particularly in Escherichia coli, due to its tractable characteristics. Besides engineering more efficient metabolic pathways for synthesizing biofuels, efforts to improve production yield by engineering efflux systems to overcome toxicity problems is also crucial. This study aims to enhance hydrocarbon efflux capability in E. coli by engineering a native inner membrane transporter, AcrB, using the directed evolution approach. Results We developed a selection platform based on competitive growth using a toxic substrate surrogate, which allowed rapid selection of AcrB variants showing enhanced efflux of linear and cyclic fuel molecule candidates, n-octane and α-pinene. Two mutants exhibiting increased efflux efficiency for n-octane and α-pinene by up to 47% and 400%, respectively, were isolated. Single-site mutants based on the mutations found in the isolated variants were synthesized and the amino acid substitutions N189H, T678S, Q737L and M844L were identified to have conferred improvement in efflux efficiency. The locations of beneficial mutations in AcrB suggest their contributions in widening the substrate channel, altering the dynamics of substrate efflux and promoting the assembly of AcrB with the outer membrane channel protein TolC for more efficient substrate export. It is interesting to note that three of the four beneficial mutations were located relatively distant from the known substrate channels, thus exemplifying the advantage of directed evolution over rational design. Conclusions Using directed evolution, we have isolated AcrB mutants with improved efflux efficiency for n-octane and α-pinene. The utilization of such optimized native efflux pumps will increase productivity of biofuels synthesis and alleviate toxicity and difficulties in production scale-up in current microbial platforms. PMID

  4. Costimulatory Pathways: Physiology and Potential Therapeutic Manipulation in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Nien Yee Kow


    Full Text Available System lupus erythematosus (SLE is an immune-complex-mediated autoimmune condition with protean immunological and clinical manifestation. While SLE has classically been advocated as a B-cell or T-cell disease, it is unlikely that a particular cell type is more pathologically predominant than the others. Indeed, SLE is characterized by an orchestrated interplay amongst different types of immunopathologically important cells participating in both innate and adaptive immunity including the dendritic cells, macrophages, neutrophils and lymphocytes, as well as traditional nonimmune cells such as endothelial, epithelial, and renal tubular cells. Amongst the antigen-presenting cells and lymphocytes, and between lymphocytes, the costimulatory pathways which involve mutual exchange of information and signalling play an essential role in initiating, perpetuating, and, eventually, attenuating the proinflammatory immune response. In this review, advances in the knowledge of established costimulatory pathways such as CD28/CTLA-4-CD80/86, ICOS-B7RP1, CD70-CD27, OX40-OX40L, and CD137-CD137L as well as their potential roles involved in the pathophysiology of SLE will be discussed. Attempts to target these costimulatory pathways therapeutically will pave more potential treatment avenues for patients with SLE. Preliminary laboratory and clinical evidence of the potential therapeutic value of manipulating these costimulatory pathways in SLE will also be discussed in this review.

  5. Efficient small molecule bulk heterojunction solar cells with high fill factors via pyrene-directed molecular self-assembly

    KAUST Repository

    Lee, Olivia P.


    Efficient organic photovoltaic (OPV) materials are constructed by attaching completely planar, symmetric end-groups to donor-acceptor electroactive small molecules. Appending C2-pyrene as the small molecule end-group to a diketopyrrolopyrrole core leads to materials with a tight, aligned crystal packing and favorable morphology dictated by π-π interactions, resulting in high power conversion efficiencies and high fill factors. The use of end-groups to direct molecular self-assembly is an effective strategy for designing high-performance small molecule OPV devices. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Energy and spectrum of BeO molecule under the electric field from different directions

    NARCIS (Netherlands)

    Jiang, M.; Guo, F. J.; Yan, A. Y.; Zhang, C. W.; Miao, F.


    Based on the density functional theory DFT/ B3LYP at 6-311g level, the ground states of BeO molecule are optimized. The effects of electric field on the bond length, the system energy, the charge distribution, the energy levels, the HOMO-LUMO gaps and the infrared spectrum of BeO molecule are

  7. Direct observation of hindered eccentric rotation of an individual molecule : Cu-phthalocyanine on C60

    NARCIS (Netherlands)

    Stöhr, Meike; Wagner, T; Gabriel, M; Weyers, B; Moller, R


    Individual Cu-phthalocyanine molecules have been investigated by scanning tunnel microscopy on a closed packed film of C-60 at various temperatures. The molecules are found to bind asymmetrically to one C-60. While they remain in one position at low temperature, they can hop between six equivalent

  8. Organized single-molecule magnets: direct observation of new Mn{sub 12} derivatives on gold

    Energy Technology Data Exchange (ETDEWEB)

    Cornia, A.; Fabretti, A.C.; Pacchioni, M.; Zobbi, L. E-mail:; Bonacchi, D.; Caneschi, A.; Gatteschi, D.; Biagi, R.; Del Pennino, U.; De Renzi, V.; Gurevich, L.; Zant, H.S.J. van der


    Gold adsorbates of the dodecamanganese(III,IV) single-molecule magnet (SMM) [Mn{sub 12}O{sub 12}(L){sub 16}(H{sub 2}O){sub 4}] where L=16-(acetylthio)hexadecanoate have been prepared and investigated by X-ray photoelectron spectroscopy and scanning tunneling microscopy (STM). The successful imaging of Mn{sub 12} molecules by STM represents a first step toward the magnetic addressing of individual SMMs and the development of molecule-based devices for magnetic information storage.

  9. Competitive direct vs. indirect photochromism dynamics of constrained inverse dithienylethene molecules. (United States)

    Lietard, Aude; Piani, Giovanni; Poisson, Lionel; Soep, Benoît; Mestdagh, Jean-Michel; Aloïse, Stéphane; Perrier, Aurélie; Jacquemin, Denis; Takeshita, Michinori


    State-of-the-art experimental and theoretical tools were used to investigate the gas-phase relaxation dynamics of various photoexcited photochromic dithienylethene molecules in situations where several relaxation channels are simultaneously at play. Unconstrained and constrained dynamics were addressed by considering unbridged and bridged molecules with a polyether bridge of various sizes (from 2 to 4 units). Time-resolved ultrafast ionization spectroscopy techniques were used to probe the dynamics. This revealed the existence of several relaxation pathways from the first excited state to the ground-state. Characteristic times were determined for each process. These channels compete at an early stage of the dynamics only when the initial wavepacket splits into two parts. A striking excited state wavepacket oscillation is observed in bridged molecules. A general reaction mechanism is proposed which rationalizes the carbon-carbon distance rule which is widely used as an empirical tool to predict the photoactivity of photochromic molecules in crystals.

  10. Direct observation of enzymes replicating DNA using a single-molecule DNA stretching assay

    NARCIS (Netherlands)

    Kulczyk, A.W.; Tanner, N.A.; Loparo, J.J.; Richardson, C.C.; Oijen, A.M. van


    We describe a method for observing real time replication of individual DNA molecules mediated by proteins of the bacteriophage replication system. Linearized lambda DNA is modified to have a biotin on the end of one strand, and a digoxigenin moiety on the other end of the same strand. The

  11. Legume receptors perceive the rhizobial lipochitin oligosaccharide signal molecules by direct binding

    DEFF Research Database (Denmark)

    Broghammer, Angelique; Krusell, Lene; Blaise, Mickaël


    Lipochitin oligosaccharides called Nod factors function as primary rhizobial signal molecules triggering legumes to develop new plant organs: root nodules that host the bacteria as nitrogen-fixing bacteroids. Here, we show that the Lotus japonicus Nod factor receptor 5 (NFR5) and Nod factor recep...

  12. Laser desorption/ionization mass spectrometry for direct profiling and imaging of small molecules from raw biological materials

    Energy Technology Data Exchange (ETDEWEB)

    Cha, Sangwon [Iowa State Univ., Ames, IA (United States)


    Matrix-assisted laser desorption/ionization(MALDI) mass spectrometry(MS) has been widely used for analysis of biological molecules, especially macromolecules such as proteins. However, MALDI MS has a problem in small molecule (less than 1 kDa) analysis because of the signal saturation by organic matrixes in the low mass region. In imaging MS (IMS), inhomogeneous surface formation due to the co-crystallization process by organic MALDI matrixes limits the spatial resolution of the mass spectral image. Therefore, to make laser desorption/ionization (LDI) MS more suitable for mass spectral profiling and imaging of small molecules directly from raw biological tissues, LDI MS protocols with various alternative assisting materials were developed and applied to many biological systems of interest. Colloidal graphite was used as a matrix for IMS of small molecules for the first time and methodologies for analyses of small metabolites in rat brain tissues, fruits, and plant tissues were developed. With rat brain tissues, the signal enhancement for cerebroside species by colloidal graphite was observed and images of cerebrosides were successfully generated by IMS. In addition, separation of isobaric lipid ions was performed by imaging tandem MS. Directly from Arabidopsis flowers, flavonoids were successfully profiled and heterogeneous distribution of flavonoids in petals was observed for the first time by graphite-assisted LDI(GALDI) IMS.

  13. Direct measurement and modulation of single-molecule coordinative bonding forces in a transition metal complex

    DEFF Research Database (Denmark)

    Hao, Xian; Zhu, Nan; Gschneidtner, Tina


    Coordination chemistry has been a consistently active branch of chemistry since Werner's seminal theory of coordination compounds inaugurated in 1893, with the central focus on transition metal complexes. However, control and measurement of metal-ligand interactions at the single-molecule level...... remain a daunting challenge. Here we demonstrate an interdisciplinary and systematic approach that enables measurement and modulation of the coordinative bonding forces in a transition metal complex. Terpyridine is derived with a thiol linker, facilitating covalent attachment of this ligand on both gold...... substrate surfaces and gold-coated atomic force microscopy tips. The coordination and bond breaking between terpyridine and osmium are followed in situ by electrochemically controlled atomic force microscopy at the single-molecule level. The redox state of the central metal atom is found to have...

  14. Direct quantification of single-molecules of microRNA by total internal reflection fluorescence microscopy. (United States)

    Chan, Ho-Man; Chan, Lai-Sheung; Wong, Ricky Ngok-Shun; Li, Hung-Wing


    MicroRNAs (miRNAs) express differently in normal and cancerous tissues and thus are regarded as potent cancer biomarkers for early diagnosis. However, the short length and low abundance of miRNAs have brought challenges to the established detection assay in terms of sensitivity and selectivity. In this work, we present a novel miRNA detection assay in single-molecule level with total internal reflection fluorescence microscopy (TIRFM). It is a solution-based hybridization detection system that does not require pretreatment steps such as sample enrichment or signal amplification. The hsa-miR-21 (miR-21) is chosen as target miRNA for its significant elevated content in a variety of cancers as reported previously. Herein, probes of complementary single-stranded oligonucleotide were hybridized in solution to miR-21 and labeled with fluorescent dye YOYO-1. The fluorescent hybrids were imaged by an electron-multiplying charge-coupled device (EMCCD) coupled TIRFM system and quantified by single-molecule counting. This single molecule detection (SMD) assay shows a good correlation between the number of molecules detected and the factual concentration of miRNA. The detection assay is applied to quantify the miR-21 in extracted total RNA samples of cancerous MCF-7 cells, HepG2 cells, and normal HUVEC cells, respectively. The results agreed very well with those from the prevalent real-time polymerase chain reaction (qRT-PCR) analysis. This assay is of high potential for applications in miRNA expression profiling and early cancer diagnosis.

  15. Direct and sustained intracellular delivery of exogenous molecules using acoustic-transfection with high frequency ultrasound (United States)

    Yoon, Sangpil; Kim, Min Gon; Chiu, Chi Tat; Hwang, Jae Youn; Kim, Hyung Ham; Wang, Yingxiao; Shung, K. Kirk


    Controlling cell functions for research and therapeutic purposes may open new strategies for the treatment of many diseases. An efficient and safe introduction of membrane impermeable molecules into target cells will provide versatile means to modulate cell fate. We introduce a new transfection technique that utilizes high frequency ultrasound without any contrast agents such as microbubbles, bringing a single-cell level targeting and size-dependent intracellular delivery of macromolecules. The transfection apparatus consists of an ultrasonic transducer with the center frequency of over 150 MHz and an epi-fluorescence microscope, entitled acoustic-transfection system. Acoustic pulses, emitted from an ultrasonic transducer, perturb the lipid bilayer of the cell membrane of a targeted single-cell to induce intracellular delivery of exogenous molecules. Simultaneous live cell imaging using HeLa cells to investigate the intracellular concentration of Ca2+ and propidium iodide (PI) and the delivery of 3 kDa dextran labeled with Alexa 488 were demonstrated. Cytosolic delivery of 3 kDa dextran induced via acoustic-transfection was manifested by diffused fluorescence throughout whole cells. Short-term (6 hr) cell viability test and long-term (40 hr) cell tracking confirmed that the proposed approach has low cell cytotoxicity.

  16. A directed approach for engineering conditional protein stability using biologically silent small molecules. (United States)

    Maynard-Smith, Lystranne A; Chen, Ling-Chun; Banaszynski, Laura A; Ooi, A G Lisa; Wandless, Thomas J


    The ability to regulate the function of specific proteins using cell-permeable molecules can be a powerful method for interrogating biological systems. To bring this type of "chemical genetic" control to a wide range of proteins, we recently developed an experimental system in which the stability of a small protein domain expressed in mammalian cells depends on the presence of a high affinity ligand. This ligand-dependent stability is conferred to any fused partner protein. The FK506- and rapamycin-binding protein (FKBP12) has been the subject of extensive biophysical analyses, including both kinetic and thermodynamic studies of the wild-type protein as well as dozens of mutants. The goal of this study was to determine if the thermodynamic stabilities (DeltaDeltaG(U-F)) of various amino acid substitutions within a given protein are predictive for engineering additional ligand-dependent destabilizing domains. We used FKBP12 as a model system and found that in vitro thermodynamic stability correlates weakly with intracellular degradation rates of the mutants and that the ability of a given mutation to destabilize the protein is context-dependent. We evaluated several new FKBP12 ligands for their ability to stabilize these mutants and found that a cell-permeable molecule called Shield-1 is the most effective stabilizing ligand. We then performed an unbiased microarray analysis of NIH3T3 cells treated with various concentrations of Shield-1. These studies show that Shield-1 does not elicit appreciable cellular responses.

  17. Organic molecules in protoplanetary disks: new insights and directions with ALMA (United States)

    Walsh, Catherine


    The current era of exoplanet detection and characterisation has revealed the ubiquity and diversity of (exo)planetary systems around stars in the solar neighbourhood. Protoplanetary disks around young stars contain the matter - dust, gas, and ice - which will go into forming new (exo)planetary systems. One open question regarding this planet-building material is the degree of chemical complexity inherited and/or attained in the protoplanetary disk prior to planet formation. Is it possible that our chemical origins lie as far back as the molecular cloud from which the sun formed? The superior sensitivity and resolution of ALMA, the Atacama Large Millimeter/submillimeter Array is allowing us, for the first time, to detect and resolve emission from complex organic molecules (> 5 atoms) in protoplanetary disks around nearby young stars. In this talk, I will review recent exciting detections of chemical complexity in disks with ALMA, and discuss the implications of these observations on our understanding of chemistry (in the gas and solid phase) in the planet- and comet-forming zones. I will also speculate on the potential for ALMA to observe molecules on higher 'rungs' on the 'ladder' of complexity in nearby planet-forming disks, and describe how such detections can provide insight on the importance of interstellar chemistry on our origins.

  18. Direct measurement of interaction forces between a platinum dichloride complex and DNA molecules. (United States)

    Muramatsu, Hiroshi; Shimada, Shogo; Okada, Tomoko


    The interaction forces between a platinum dichloride complex and DNA molecules have been studied using atomic force microscopy (AFM). The platinum dichloride complex, di-dimethylsulfoxide-dichloroplatinum (II) (Pt(DMSO) 2 Cl 2 ), was immobilized on an AFM probe by coordinating the platinum to two amino groups to form a complex similar to Pt(en)Cl 2 , which is structurally similar to cisplatin. The retraction forces were measured between the platinum complex and DNA molecules immobilized on mica plates using force curve measurements. The histogram of the retraction force for λ-DNA showed several peaks; the unit retraction force was estimated to be 130 pN for a pulling rate of 60 nm/s. The retraction forces were also measured separately for four single-base DNA oligomers (adenine, guanine, thymine, and cytosine). Retraction forces were frequently observed in the force curves for the DNA oligomers of guanine and adenine. For the guanine DNA oligomer, the most frequent retraction force was slightly lower than but very similar to the retraction force for λ-DNA. A higher retraction force was obtained for the adenine DNA oligomer than for the guanine oligomer. This result is consistent with a higher retraction activation energy of adenine with the Pt complex being than that of guanine because the kinetic rate constant for retraction correlates to exp(FΔx - ΔE) where ΔE is an activation energy, F is an applied force, and Δx is a displacement of distance.

  19. Direct and sustained intracellular delivery of exogenous molecules using acoustic-transfection with high frequency ultrasound. (United States)

    Yoon, Sangpil; Kim, Min Gon; Chiu, Chi Tat; Hwang, Jae Youn; Kim, Hyung Ham; Wang, Yingxiao; Shung, K Kirk


    Controlling cell functions for research and therapeutic purposes may open new strategies for the treatment of many diseases. An efficient and safe introduction of membrane impermeable molecules into target cells will provide versatile means to modulate cell fate. We introduce a new transfection technique that utilizes high frequency ultrasound without any contrast agents such as microbubbles, bringing a single-cell level targeting and size-dependent intracellular delivery of macromolecules. The transfection apparatus consists of an ultrasonic transducer with the center frequency of over 150 MHz and an epi-fluorescence microscope, entitled acoustic-transfection system. Acoustic pulses, emitted from an ultrasonic transducer, perturb the lipid bilayer of the cell membrane of a targeted single-cell to induce intracellular delivery of exogenous molecules. Simultaneous live cell imaging using HeLa cells to investigate the intracellular concentration of Ca(2+) and propidium iodide (PI) and the delivery of 3 kDa dextran labeled with Alexa 488 were demonstrated. Cytosolic delivery of 3 kDa dextran induced via acoustic-transfection was manifested by diffused fluorescence throughout whole cells. Short-term (6 hr) cell viability test and long-term (40 hr) cell tracking confirmed that the proposed approach has low cell cytotoxicity.

  20. Directional quantum-controlled chemistry: Generating aligned ultracold molecules via photoassociation (United States)

    Kallush, S.; Carini, J. L.; Gould, P. L.; Kosloff, R.


    Photoassociation of ultracold atoms with pulsed laser light is shown to lead to alignment of the product molecules along the excitation laser polarization axis. We theoretically investigate pulsed two-photon photoassociation of 87Rb atoms into a specific weakly bound level of the a 3Σu+ metastable electronic state and find both stationary and time-dependent field-free alignment. Although a transform-limited pulse yields significant alignment, a frequency-chirped pulse dramatically enhances the ultracold molecular formation rate at the cost of a slight decrease in the alignment. Employing multiple pulses synchronized with the vibrational and rotational periods leads to coherent enhancement of both population and alignment of the target state. Inclusion of the rotational degree of freedom in the model gives rise to processes with multiple quantum paths, which lead to quantum effects such as interference and coherence revivals.

  1. Electric Power Generation through the Direct Interaction of Pristine Graphene-Oxide with Water Molecules. (United States)

    Xu, Tong; Ding, Xiaoteng; Shao, Changxiang; Song, Long; Lin, Tengyu; Gao, Xue; Xue, Jiangli; Zhang, Zhipan; Qu, Liangti


    Converting ubiquitous environmental energy into electric power holds tremendous social and financial interests. Traditional energy harvesters and converters are limited by the specific materials and complex configuration of devices. Herein, it is presented that electric power can be directly produced from pristine graphene oxide (GO) without any pretreatment or additives once encountering the water vapor, which will generate an open-circuit-voltage of up to 0.4-0.7 V and a short-circuit-current-density of 2-25 µA cm -2 on a single piece of GO film. This phenomenon results from the directional movement of charged hydrogen ions through the GO film. The present work demonstrates and provides an extremely simple method for electric energy generation, which offers more applications of graphene-based materials in green energy converting field. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Potent host-directed small-molecule inhibitors of myxovirus RNA-dependent RNA-polymerases.

    Directory of Open Access Journals (Sweden)

    Stefanie A Krumm

    Full Text Available Therapeutic targeting of host cell factors required for virus replication rather than of pathogen components opens new perspectives to counteract virus infections. Anticipated advantages of this approach include a heightened barrier against the development of viral resistance and a broadened pathogen target spectrum. Myxoviruses are predominantly associated with acute disease and thus are particularly attractive for this approach since treatment time can be kept limited. To identify inhibitor candidates, we have analyzed hit compounds that emerged from a large-scale high-throughput screen for their ability to block replication of members of both the orthomyxovirus and paramyxovirus families. This has returned a compound class with broad anti-viral activity including potent inhibition of different influenza virus and paramyxovirus strains. After hit-to-lead chemistry, inhibitory concentrations are in the nanomolar range in the context of immortalized cell lines and human PBMCs. The compound shows high metabolic stability when exposed to human S-9 hepatocyte subcellular fractions. Antiviral activity is host-cell species specific and most pronounced in cells of higher mammalian origin, supporting a host-cell target. While the compound induces a temporary cell cycle arrest, host mRNA and protein biosynthesis are largely unaffected and treated cells maintain full metabolic activity. Viral replication is blocked at a post-entry step and resembles the inhibition profile of a known inhibitor of viral RNA-dependent RNA-polymerase (RdRp activity. Direct assessment of RdRp activity in the presence of the reagent reveals strong inhibition both in the context of viral infection and in reporter-based minireplicon assays. In toto, we have identified a compound class with broad viral target range that blocks host factors required for viral RdRp activity. Viral adaptation attempts did not induce resistance after prolonged exposure, in contrast to rapid

  3. Small Molecule-directed Immunotherapy against Recurrent Infection by Mycobacterium tuberculosis* (United States)

    Bhattacharya, Debapriya; Dwivedi, Ved Prakash; Maiga, Mamoudou; Maiga, Mariama; Van Kaer, Luc; Bishai, William R.; Das, Gobardhan


    Tuberculosis remains the biggest infectious threat to humanity with one-third of the population infected and 1.4 million deaths and 8.7 million new cases annually. Current tuberculosis therapy is lengthy and consists of multiple antimicrobials, which causes poor compliance and high treatment dropout, resulting in the development of drug-resistant variants of tuberculosis. Therefore, alternate methods to treat tuberculosis are urgently needed. Mycobacterium tuberculosis evades host immune responses by inducing T helper (Th)2 and regulatory T (Treg) cell responses, which diminish protective Th1 responses. Here, we show that animals (Stat-6−/−CD4-TGFβRIIDN mice) that are unable to generate both Th2 cells and Tregs are highly resistant to M. tuberculosis infection. Furthermore, simultaneous inhibition of these two subsets of Th cells by therapeutic compounds dramatically reduced bacterial burden in different organs. This treatment was associated with the generation of protective Th1 immune responses. As these therapeutic agents are not directed to the harbored organisms, they should avoid the risk of promoting the development of drug-resistant M. tuberculosis variants. PMID:24711459

  4. Direct inactivation of human immunodeficiency virus type 1 by a novel small-molecule entry inhibitor, DCM205. (United States)

    Duong, Yen T; Meadows, D Christopher; Srivastava, Indresh K; Gervay-Hague, Jacquelyn; North, Thomas W


    With more than 40 million people living with human immunodeficiency virus (HIV), there is an urgent need to develop drugs that can be used in the form of a topical microbicide to prevent infection through sexual transmission. DCM205 is a recently discovered small-molecule inhibitor of HIV type 1 (HIV-1) that is able to directly inactivate HIV-1 in the absence of a cellular target. DCM205 is active against CXCR4-, CCR5-, and dual-tropic laboratory-adapted and primary strains of HIV-1. DCM205 binds to the HIV-1 envelope glycoprotein, and competition studies map the DCM205 binding at or near the V3 loop of gp120. Binding to this site interferes with the soluble CD4 interaction. With its ability to disable the virus particle, DCM205 represents a promising new class of HIV entry inhibitor that can be used as a strategy in the prevention of HIV-1/AIDS.

  5. Antigen-presenting cells containing bacterial peptidoglycan in synovial tissues of rheumatoid arthritis patients coexpress costimulatory molecules and cytokines

    NARCIS (Netherlands)

    Schrijver, I. A.; Melief, M. J.; Tak, P. P.; Hazenberg, M. P.; Laman, J. D.


    Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by intimal lining hyperplasia and massive infiltration of the synovial sublining by antigen-presenting cells (APCs), lymphocytes, and plasma cells. Peptidoglycan (PG), a major cell wall component of gram-positive bacteria,

  6. Direct Determination of a Small-Molecule Drug, Valproic Acid, by an Electrically-Detected Microcantilever Biosensor for Personalized Diagnostics

    Directory of Open Access Journals (Sweden)

    Long-Sun Huang


    Full Text Available Direct, small-molecule determination of the antiepileptic drug, valproic acid, was investigated by a label-free, nanomechanical biosensor. Valproic acid has long been used as an antiepileptic medication, which is administered through therapeutic drug monitoring and has a narrow therapeutic dosage range of 50–100 μg·mL−1 in blood or serum. Unlike labeled and clinically-used measurement techniques, the label-free, electrical detection microcantilever biosensor can be miniaturized and simplified for use in portable or hand-held point-of-care platforms or personal diagnostic tools. A micromachined microcantilever sensor was packaged into the micro-channel of a fluidic system. The measurement of the antiepileptic drug, valproic acid, in phosphate-buffered saline and serum used a single free-standing, piezoresistive microcantilever biosensor in a thermally-controlled system. The measured surface stresses showed a profile over a concentration range of 50–500 μg·mL−1, which covered the clinically therapeutic range of 50–100 μg·mL−1. The estimated limit of detection (LOD was calculated to be 45 μg·mL−1, and the binding affinity between the drug and the antibody was measured at around 90 ± 21 μg·mL−1. Lastly, the results of the proposed device showed a similar profile in valproic acid drug detection with those of the clinically-used fluorescence polarization immunoassay.

  7. Epithelial cell-adhesion molecule-directed trifunctional antibody immunotherapy for symptom management of advanced ovarian cancer

    Directory of Open Access Journals (Sweden)

    Eskander RN


    Full Text Available Ramez N Eskander, Krishnansu S Tewari Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Irvine, CA, USA Abstract: Despite advances in cytotoxic chemotherapy and surgical cytoreduction, disease recurrence continues to be a troubling problem in patients with advanced-stage epithelial ovarian cancer (EOC. Malignant ascites affects approximately 10% of patients with recurrent EOC and is associated with troublesome symptoms, including abdominal pressure, distension, dyspnea, pelvic pain, and bowel/bladder dysfunction. To date, no effective therapy has been identified for the treatment of malignant ascites in patients with recurrent, advanced-stage ovarian cancer. Recently, immune modulation has gained attention as a novel approach to anti-cancer therapy. This review explores the role of epithelial cell-adhesion molecule (EpCAM-directed immunotherapy, with a specific focus on the mechanism of action of the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3. In addition, clinical trials exploring the use of catumaxomab in the treatment of malignant ascites in patients with ovarian cancer are reviewed. Keywords: ovarian cancer, immunotherapy, catumaxomab, CD3, EpCAM

  8. Co-stimulatory signals increase the reactivity of γδ T cells towards mycobacterial antigens (United States)

    González-Amaro, R; Portales-Pérez, D P; Baranda, L; Moncada, B; Toro, C; López-Briones, S; Espitia, C; Mancilla, R


    Although it has been shown that γδ T lymphocytes are able to react with different cell-associated or soluble antigens, the immune repertoire of these cells appears to be skewed to the recognition of mycobacterial antigens. We have studied the number and reactivity of γδ T cells towards several mycobacterial antigens in patients with tuberculosis and leprosy, as well as their healthy contacts and control individuals. We found an increased number of Vδ2+ cells in healthy contacts (PPD+ and lepromin+) and tuberculoid leprosy patients. The γδ T cells from lepromatous leprosy showed a decreased response to all antigens tested, but some of these patients exhibited a significant response to the 30-kD glycoprotein of Mycobacterium tuberculosis. Interestingly, the reactivity of γδ T cells against mycobacterial antigens was significantly increased by costimulatory signals generated through CD7, LFA-1, CD50 and CD69 in all groups. However, signalling through CD69 did not enhance the responsiveness of γδ lymphocytes from lepromatous patients. On the other hand, the in vitro blockade of IL-10 with a specific antibody enhanced the cell proliferation of γδ lymphocytes from lepromatous leprosy patients, whereas exogenous IL-10 had an opposite effect in most individuals studied. These results suggest the potential role of different cell membrane receptors in the regulation of γδ T cell proliferation induced by mycobacteria, as well as the possible involvement of IL-10 in this phenomenon. PMID:10844525

  9. Direct single-molecule observations of local denaturation of a DNA double helix under a negative supercoil state. (United States)

    Takahashi, Shunsuke; Motooka, Shinya; Usui, Tomohiro; Kawasaki, Shohei; Miyata, Hidefumi; Kurita, Hirofumi; Mizuno, Takeshi; Matsuura, Shun-ichi; Mizuno, Akira; Oshige, Masahiko; Katsura, Shinji


    Effects of a negative supercoil on the local denaturation of the DNA double helix were studied at the single-molecule level. The local denaturation in λDNA and λDNA containing the SV40 origin of DNA replication (SV40ori-λDNA) was directly observed by staining single-stranded DNA regions with a fusion protein comprising the ssDNA binding domain of a 70-kDa subunit of replication protein A and an enhanced yellow fluorescent protein (RPA-YFP) followed by staining the double-stranded DNA regions with YOYO-1. The local denaturation of λDNA and SV40ori-λDNA under a negative supercoil state was observed as single bright spots at the single-stranded regions. When negative supercoil densities were gradually increased to 0, -0.045, and -0.095 for λDNA and 0, -0.047, and -0.1 for SV40ori-λDNA, single bright spots at the single-stranded regions were frequently induced under higher negative supercoil densities of -0.095 for λDNA and -0.1 for SV40ori-λDNA. However, single bright spots of the single-stranded regions were rarely observed below a negative supercoil density of -0.045 and -0.047 for λDNA and SV40ori-λDNA, respectively. The probability of occurrence of the local denaturation increased with negative superhelicity for both λDNA and SV40ori-λDNA.

  10. Simultaneous delivery of hydrophobic small molecules and siRNA using Sterosomes to direct mesenchymal stem cell differentiation for bone repair. (United States)

    Cui, Zhong-Kai; Sun, Justin A; Baljon, Jessalyn J; Fan, Jiabing; Kim, Soyon; Wu, Benjamin M; Aghaloo, Tara; Lee, Min


    The use of small molecular drugs with gene manipulation offers synergistic therapeutic efficacy by targeting multiple signaling pathways for combined treatment. Stimulation of mesenchymal stem cells (MSCs) with osteoinductive small molecule phenamil combined with suppression of noggin is a promising therapeutic strategy that increases bone morphogenetic protein (BMP) signaling and bone repair. Our cationic Sterosome formulated with stearylamine (SA) and cholesterol (Chol) is an attractive co-delivery system that not only forms stable complexes with small interfering RNA (siRNA) molecules but also solubilizes hydrophobic small molecules in a single vehicle, for directing stem cell differentiation. Herein, we demonstrate the ability of SA/Chol Sterosomes to simultaneously deliver hydrophobic small molecule phenamil and noggin-directed siRNA to enhance osteogenic differentiation of MSCs both in in vitro two- and three-dimensional settings as well as in a mouse calvarial defect model. These results suggest a novel liposomal platform to simultaneously deliver therapeutic genes and small molecules for combined therapy. Application of phenamil, a small molecular bone morphogenetic protein (BMP) stimulator, combined with suppression of natural BMP antagonists such as noggin is a promising therapeutic strategy to enhance bone regeneration. Here, we present a novel strategy to co-deliver hydrophobic small molecule phenamil and noggin-targeted siRNA via cationic Sterosomes formed with stearylamine (SA) and high content of cholesterol (Chol) to enhance osteogenesis and bone repair. SA/Chol Sterosomes demonstrated high phenamil encapsulation efficiency, supported sustained release of encapsulated drugs, and significantly reduced drug dose requirements to induce osteogenic differentiation of mesenchymal stem cells (MSCs). Simultaneous deliver of phenamil and noggin siRNA in a single vehicle synergistically enhanced MSC osteogenesis and calvarial bone repair. This study suggests

  11. Direct comparison of {sup 111}In-labelled two-helix and three-helix Affibody molecules for in vivo molecular imaging

    Energy Technology Data Exchange (ETDEWEB)

    Rosik, Daniel; Karlstroem, Amelie Eriksson [KTH Royal Institute of Technology, Division of Molecular Biotechnology, School of Biotechnology, Stockholm (Sweden); Orlova, Anna; Malmberg, Jennie; Varasteh, Zohreh [Uppsala University, Preclinical PET Platform, Uppsala (Sweden); Altai, Mohamed; Tolmachev, Vladimir [Uppsala University, Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Sandstroem, Mattias [Uppsala University Hospital, Section of Medical Physics, Department of Oncology, Uppsala (Sweden)


    Radiolabelled Affibody molecules have demonstrated a potential for visualization of tumour-associated molecular targets. Affibody molecules (7 kDa) are composed of three alpha-helices. Recently, a smaller two-helix variant of Affibody molecules (5.1 kDa) was developed. The aim of this study was to compare two- and three-helix HER2-targeting Affibody molecules directly in vivo. The three-helix Affibody molecule ABY-002 and the two-helix Affibody molecule PEP09239 were labelled with {sup 111}In at the N-termini via DOTA chelator. Tumour-targeting properties were directly compared at 1 and 4 h after injection in mice bearing SKOV-3 xenografts with high HER2 expression and LS174T xenografts with low HER2 expression. The dissociation constants (K{sub D}) for HER2 binding were 78 pM for the three-helix Affibody molecule and 2.1 nM for the two-helix Affibody molecule. {sup 111}In-PEP09239 cleared more rapidly from the blood. In xenografts with high HER2 expression, the uptake of {sup 111}In-ABY-002 was significantly higher than that of {sup 111}In-PEP09239. The tumour-to-blood ratio was higher for {sup 111}In-PEP09239 at 4 h after injection, while there was no significant difference in other tumour-to-organ ratios. The tumour uptake of {sup 111}In-ABY-002 was eightfold higher than that of {sup 111}In-PEP09239 in xenografts with low expression. Tumour-to-blood ratios were equal in this case, but other tumour-to-organ ratios were appreciably higher for the three-helix variant. For tumours with high HER2 expression, two-helix HER2-targeting Affibody molecules can provide higher tumour-to-blood ratio at the cost of lower tumour uptake. In the case of low expression, both tumour uptake and tumour-to-organ ratios are appreciably higher for three-helix than for two-helix HER2-targeting Affibody molecules. (orig.)

  12. The human leucocyte-common (LC) molecule: dissection of leukaemias using monoclonal antibodies directed against framework and restricted antigenic determinants. (United States)

    Ritter, M A; Sauvage, C A; Pegram, S M; Myers, C D; Dalchau, R; Fabre, J W


    Monoclonal antibodies have previously been raised against two separate antigenic determinants on the human LC molecule. One, F10.89.4, recognizes a 'framework' epitope on all LC molecules; these are found on the majority of leucocytes. The other, F8.11.13, recognizes only a 'restricted' epitope present on a subset of these molecules; this subset is found on B lymphocytes and a subpopulation of T lymphocytes. LC molecules on myeloid cells do not carry the 'restricted' antigenic determinant. We have investigated the differential expression of these LC epitopes on human leukaemias, using immunofluorescence on fresh leukaemic blasts and established cell lines. Our study shows that, as on normal haemopoietic cells, LC molecules on B leukaemias bear both 'framework' and 'restricted' epitopes, while the majority of T leukaemias bear only the 'framework' determinant. The small proportion of T cells that are F8.11.13+ ('restricted' epitope) are relatively mature, being of either OKT4+ or OKT8+ phenotype, and may be in an activated state (HLA-DR+). However, in contrast to normal haemopoietic cells, some myeloid leukaemias carry both 'framework' and 'restricted' epitopes (30% AML and AMML samples are F10.89.4+, F8.11.13+), and it is within this group that all TdT+ AML and AMML cases lie. Thus, these monoclonal antibodies should be useful for studying haemopoiesis in man and for analyzing human haemopoietic malignancies.

  13. Design of a low-temperature plasma (LTP) probe with adjustable output temperature and variable beam diameter for the direct detection of organic molecules. (United States)

    Martínez-Jarquín, Sandra; Winkler, Robert


    The direct detection of organic molecules by mass spectrometry requires ionization methods which are compatible with ambient conditions. A relatively new strategy is the use of a free low-temperature plasma beam for ionization. The objective is to design a safe and adjustable plasma beam to enable optimal ionization and desorption parameters for specific molecules. A plasma probe based on a dielectric barrier discharge was designed, where the plasma is guided through an internal second tube. This setup permits different beam diameter settings and the control of the plasma temperature. The ionization and desorption of pure organic compounds, as well as their direct detection from roasted coffee beans, were tested. The presented plasma probe provides improved safety with respect to arcing, ozone generation and electric shock, compared with conventional designs. The functionality of previously reported devices is expanded. A defined plasma diameter can be set by choosing the appropriate insert, while the input voltage controls the plasma temperature. The variation of measurement parameters enables the optimized direct detection of target compounds from roasted coffee beans, such as caffeine, guaiacol and vanillin. The presented low-temperature plasma probe allows the fine-tuning of ionization and desorption parameters, according to the target molecules. Possible applications include: (1) The ambient ionization and desorption of organic compounds with different volatility and (2) The direct analysis of food products such as roasted coffee beans. Copyright © 2013 John Wiley & Sons, Ltd.

  14. Direct integration of micromachined pipettes in a flow channel for single DNA molecule study by optical tweezers

    NARCIS (Netherlands)

    Rusu, C.R.; van 't Oever, Ronny; de Boer, Meint J.; Jansen, Henricus V.; Berenschot, Johan W.; Bennink, Martin L.; Kanger, Johannes S.; de Grooth, B.G.; Elwenspoek, Michael Curt; Greve, Jan; Brugger, J.P.; van den Berg, Albert

    We have developed a micromachined flow cell consisting of a flow channel integrated with micropipettes. The flow cell is used in combination with an optical trap setup (optical tweezers) to study mechanical and structural properties of λ-DNA molecules. The flow cell was realized using silicon

  15. Direct binding of autoimmune disease related T cell epitopes to purified Lewis rat MHC class II molecules

    DEFF Research Database (Denmark)

    Joosten, I; Wauben, M H; Holewijn, M C


    characteristics of the Lewis rat MHC class II RT1.B1 molecule. We have now developed a biochemical binding assay which enables competition studies in which the relative MHC binding affinity of a set of non-labelled peptides can be assessed while employing detection of biotinylated marker peptides...

  16. Constitutive expression of a costimulatory ligand on antigen-presenting cells in the nervous system drives demyelinating disease

    DEFF Research Database (Denmark)

    Zehntner, Simone P; Brisebois, Marcel; Tran, Elise


    that transgenic mice constitutively expressing the costimulatory ligand B7.2/CD86 on microglia in the central nervous system (CNS) and on related cells in the proximal peripheral nervous tissue spontaneously develop autoimmune demyelinating disease. Disease-affected nervous tissue in transgenic mice showed...... recipients but not into non-transgenic recipients. These data provide evidence that B7/CD28 interactions within the nervous tissue are critical determinants of disease development. Our findings have important implications for understanding the etiology of nervous system autoimmune diseases such as multiple...

  17. Enhanced T-cell apoptosis in human septic shock is associated with alteration of the costimulatory pathway. (United States)

    Roger, P-M; Hyvernat, H; Breittmayer, J-P; Dunais, B; Dellamonica, J; Bernardin, G; Bernard, A


    T-cell apoptosis during septic shock (SS) has been associated with deleterious outcome, but the mechanisms of apoptosis are not well understood. As T-cells are not infected in bacterial infection, our hypothesis was that deleterious interactions between lymphocytes and monocytes could be involved. This is a cross-sectional study of 27 patients presenting with community-acquired SS, 23 infected patients without SS and 18 controls. Cytofluorometric techniques were used to study apoptosis, the costimulatory pathway and cytokine synthesis. Apoptosis was increased in SS compared to infected patients without SS and controls: the median values were 18, 2 and 3%, respectively, for CD4(+) T-cells (P < 0.001), and 12, 5 and 2%, respectively, for CD8(+) T-cells (P < 0.001). Patients with SS exhibited significant CD152 over-expression on T-cells, while CD86 expression was decreased on monocytes (P = 0.004). The synthesis of interleukin-2 was decreased in patients with SS compared to the other groups, while secretions of interferon-gamma and TNF-alpha were not altered. Ten surviving patients with SS showed a trend towards the normalisation of these parameters on day 7. In SS, T-cell apoptosis is related, at least in part, to the alteration of the costimulatory pathway, which, in turn, leads to significant modification of the cytokine network.

  18. A direct relativistic four-component multiconfiguration self-consistent-field method for molecules

    DEFF Research Database (Denmark)

    Thyssen, Jørn; Fleig, Timo; Jensen, Hans Jørgen Aagaard


    quaternion algebra for one-electron operators was extended to treat two-electron integrals and density matrices in an efficient and nonredundant way. The iterative procedure is direct with respect to both configurational and spinor variational parameters; this permits the use of large configuration...

  19. Direct reaction field force field : A consistent way to connect and combine quantum-chemical and classical descriptions of molecules

    NARCIS (Netherlands)

    Duijnen , van Piet Th.; de Vries, A.H.


    The direct reaction field (DRF) force field gives a classical description of intermolecular interactions based on ab initio quantum-chemical descriptions of matter. The parameters of the DRF force field model molecular electrostatic and response properties, which are represented by distributed

  20. Dissecting EB1-microtubule interactions from every direction: using single-molecule visualization and static and dynamic binding measurements (United States)

    Lopez, Benjamin


    EB1 is an important microtubule associating protein (MAP) that acts as a master coordinator of protein activity at the growing plus-end of the microtubule. We can recapitulate the plus-end binding behavior of EB1 along the entire length of a static microtubule using microtubules polymerized in the presence of the nonhydrolyzable GTP analogs GMPCPP and GTP γS instead of GTP. Through the use of single-molecule TIRF imaging we find that EB1 is highly dynamic (with a sub-second characteristic binding lifetime) and continuously diffusive while bound to the microtubule. We measure the diffusion coefficient, D, through linear fitting to mean-squared displacement of individually labeled proteins, and the binding lifetime, τ, by fitting a single exponential decay to the probability distribution of trajectory lifetimes. In agreement with measurements of other diffusive MAPs, we find that D increases and τ decreases with increasing ionic strength. We also find that D is sensitive to the choice of GTP analog: EB1 proteins bound to GTP γS polymerized microtubules have a D half of that found with GMPCPP polymerized microtubules. To compare these single-molecule measurements to the bulk binding behavior of EB1, we use TIRF imaging to measure the intensity of microtubules coated with EB1-GFP as a function of EB1 concentration. We find that EB1 binding is cooperative and both the quantity of EB1 bound and the dissociation constant are sensitive to GTP analog and ionic concentration. The correlation between binding affinity and D and the cooperative nature of EB1-microtubule binding leads to a decrease in D with increasing EB1 concentration. Interestingly, we also find an increase in τ at high EB1 concentrations, consistent with attractive EB1-microtubule interactions driving the cooperativity. To further understand the nature of the cooperativity we estimate the interaction energy by measuring the association and dissociation rates (kon and koff respectively) at different

  1. The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo

    DEFF Research Database (Denmark)

    Kishimoto, K; Dong, V M; Issazadeh-Navikas, Shohreh


    We used signal transducer and activator of transcription 4 (STAT4) and STAT6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allografts to study the role of T-cell costimulatory pathways in regulating allogeneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice hav...

  2. Costimulatory ligand CD70 allows induction of CD8+ T-cell immunity by immature dendritic cells in a vaccination setting

    NARCIS (Netherlands)

    Keller, Anna M.; Xiao, Yanling; Peperzak, Victor; Naik, Shalin H.; Borst, Jannie


    The use of dendritic cells (DCs) as anticancer vaccines holds promise for therapy but requires optimization. We have explored the potential of costimulatory ligand CD70 to boost the capacity of DCs to evoke effective CD8(+) T-cell immunity. We show that immature conventional DCs, when endowed with

  3. Direct Determination of Chitosan–Mucin Interactions Using a Single-Molecule Strategy: Comparison to Alginate–Mucin Interactions

    Directory of Open Access Journals (Sweden)

    Kristin E. Haugstad


    Full Text Available Aqueous chitosan possesses attractive interaction capacities with various molecular groups that can be involved in hydrogen bonds and electrostatic and hydrophobic interactions. In the present paper, we report on the direct determination of chitosan–mucin molecular pair interactions at various solvent conditions as compared to alginate–mucin interactions. Two chitosans of high molecular weight with different degrees of acetylation—thus possessing different solubility profiles in aqueous solution as a function of pH and two alginates with different fractions of α-guluronic acid were employed. The interaction properties were determined through a direct unbinding assay at the single-molecular pair level using an atomic force microscope. When probed against immobilized mucin, both chitosans and alginates revealed unbinding profiles characteristic of localized interactions along the polymers. The interaction capacities and estimated parameters of the energy landscapes of the pairwise chitosan–mucin and alginate–mucin interactions are discussed in view of possible contributions from various fundamental forces. Signatures arising both from an electrostatic mechanism and hydrophobic interaction are identified in the chitosan–mucin interaction properties. The molecular nature of the observed chitosan–mucin and alginate–mucin interactions indicates that force spectroscopy provides fundamental insights that can be useful in understanding the surface binding properties of other potentially mucoadhesive polymers.

  4. Direct measurement of dysprosium(III)˙˙˙dysprosium(III) interactions in a single-molecule magnet (United States)

    Moreno Pineda, Eufemio; Chilton, Nicholas F.; Marx, Raphael; Dörfel, María; Sells, Daniel O.; Neugebauer, Petr; Jiang, Shang-Da; Collison, David; van Slageren, Joris; McInnes, Eric J. L.; Winpenny, Richard E. P.


    Lanthanide compounds show much higher energy barriers to magnetic relaxation than 3d-block compounds, and this has led to speculation that they could be used in molecular spintronic devices. Prototype molecular spin valves and molecular transistors have been reported, with remarkable experiments showing the influence of nuclear hyperfine coupling on transport properties. Modelling magnetic data measured on lanthanides is always complicated due to the strong spin-orbit coupling and subtle crystal field effects observed for the 4f-ions; this problem becomes still more challenging when interactions between lanthanide ions are also important. Such interactions have been shown to hinder and enhance magnetic relaxation in different examples, hence understanding their nature is vital. Here we are able to measure directly the interaction between two dysprosium(III) ions through multi-frequency electron paramagnetic resonance spectroscopy and other techniques, and explain how this influences the dynamic magnetic behaviour of the system.

  5. Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design. (United States)

    Yu, Wenying; Xiao, Hui; Lin, Jiayuh; Li, Chenglong


    Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is responsible for both actions. A new fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study. A designed novel compound, 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5), was confirmed to bind to STAT3 SH2 by fluorescence polarization assay. In addition, four out of the five chosen compounds have IC50 values lower than 5 μM for the U2OS cancer cells. 8 (LY5) has an IC50 range in 0.5-1.4 μM in various cancer cell lines. 8 also suppresses tumor growth in an in vivo mouse model. This study has demonstrated the utility of this approach and could be used to other drug targets in general.

  6. Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites.

    Directory of Open Access Journals (Sweden)

    Fabrice Ango


    Full Text Available The geometric and subcellular organization of axon arbors distributes and regulates electrical signaling in neurons and networks, but the underlying mechanisms have remained elusive. In rodent cerebellar cortex, stellate interneurons elaborate characteristic axon arbors that selectively innervate Purkinje cell dendrites and likely regulate dendritic integration. We used GFP BAC transgenic reporter mice to examine the cellular processes and molecular mechanisms underlying the development of stellate cell axons and their innervation pattern. We show that stellate axons are organized and guided towards Purkinje cell dendrites by an intermediate scaffold of Bergmann glial (BG fibers. The L1 family immunoglobulin protein Close Homologue of L1 (CHL1 is localized to apical BG fibers and stellate cells during the development of stellate axon arbors. In the absence of CHL1, stellate axons deviate from BG fibers and show aberrant branching and orientation. Furthermore, synapse formation between aberrant stellate axons and Purkinje dendrites is reduced and cannot be maintained, leading to progressive atrophy of axon terminals. These results establish BG fibers as a guiding scaffold and CHL1 a molecular signal in the organization of stellate axon arbors and in directing their dendritic innervation.

  7. Partial identification by site-directed mutagenesis of a cell growth inhibitory site on the human galectin-1 molecule

    Directory of Open Access Journals (Sweden)

    Zhang Jialiang


    Full Text Available Abstract Background Previous work, by us and others, has shown that mammalian galectins-1 have a growth-inhibitory activity for mammalian cells which is apparently independent of their β-galactoside binding site. Results We have made recombinant human galectin-1 as a bacterial fusion protein with an N-terminal hexahistidine tag. This protein displays both haemagglutination and growth-inhibitory activities, even in the presence of the hexahistidine tag. Site-directed mutagenesis of this protein has confirmed the independent nature of the protein sites responsible for the two biological activities. Mutant proteins were created, which displayed each activity in the absence of the other. Conclusions Human galectin-1 possesses a growth-inhibitory site, which is not part of the β-galactoside binding site. A surface loop, comprising amino acid residues 25–30, and joining two internal β-strands, forms part of the growth-inhibitory site. This region is relatively close to the N-terminus of the protein, and N-terminal substitutions or extensions also affect growth-inhibitory activity. Further experiments will be necessary to fully define this site.

  8. Nonadiabatic laser-induced alignment of molecules: Reconstructing ⟨θ⟩ directly from ⟨θ2D⟩ by Fourier analysis. (United States)

    Søndergaard, Anders Aspegren; Shepperson, Benjamin; Stapelfeldt, Henrik


    We present an efficient, noise-robust method based on Fourier analysis for reconstructing the three-dimensional measure of the alignment degree, ⟨cos 2 θ⟩, directly from its two-dimensional counterpart, ⟨cos 2 θ 2D ⟩. The method applies to nonadiabatic alignment of linear molecules induced by a linearly polarized, nonresonant laser pulse. Our theoretical analysis shows that the Fourier transform of the time-dependent ⟨cos 2 θ 2D ⟩ trace over one molecular rotational period contains additional frequency components compared to the Fourier transform of ⟨cos 2 θ⟩. These additional frequency components can be identified and removed from the Fourier spectrum of ⟨cos 2 θ 2D ⟩. By rescaling of the remaining frequency components, the Fourier spectrum of ⟨cos 2 θ⟩ is obtained and, finally, ⟨cos 2 θ⟩ is reconstructed through inverse Fourier transformation. The method allows the reconstruction of the ⟨cos 2 θ⟩ trace from a measured ⟨cos 2 θ 2D ⟩ trace, which is the typical observable of many experiments, and thereby provides direct comparison to calculated ⟨cos 2 θ⟩ traces, which is the commonly used alignment metric in theoretical descriptions. We illustrate our method by applying it to the measurement of nonadiabatic alignment of I 2 molecules. In addition, we present an efficient algorithm for calculating the matrix elements of cos 2 θ 2D and any other observable in the symmetric top basis. These matrix elements are required in the rescaling step, and they allow for highly efficient numerical calculation of ⟨cos 2 θ 2D ⟩ and ⟨cos 2 θ⟩ in general.

  9. Engineered cells for costimulatory enhancement combined with IL-21 enhance the generation of PD-1-disrupted CTLs for adoptive immunotherapy. (United States)

    Shao, Jie; Xu, Qiuping; Su, Shu; Meng, Fanyan; Zou, Zhengyun; Chen, Fangjun; Du, Juan; Qian, Xiaoping; Liu, Baorui


    Blockade of the immune cell checkpoint inhibitors programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) has become a powerful tool in cancer treatment, which is effective across various solid cancer types and hematologic malignancies. Our previous studies showed that by reducing immune tolerance, clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) modified cytotoxic T lymphocytes (CTLs) rank highly in terms of immune responses and cytotoxicity. In this study, a genetically modified K562 cell line with surface expression of 4-1BBL was developed to expand PD-1-disrupted CTLs in vitro for further adoptive immunotherapy against cancer. Our findings demonstrate that after a long-term, up to 28days, engineered cells for costimulatory enhancement (ECCE) combined with IL-21 promote the expansion of PD-1-disrupted CTLs with a less differentiated "young" phenotype, enhanced immune response and superior cytotoxic effector characteristics. These new in vitro conditions represent a nimble and cost-effective approach to developing PD-1-disrupted CTLs with improved therapeutic potential. Copyright © 2017. Published by Elsevier Inc.

  10. [Influence of blocking B7/CD28 and CD40/CD154 co-stimulatory signals on immune function of sensitized mice]. (United States)

    Ye, Qi-Xiang; Xu, Lu-Hong; Xu, Wei; Fang, Jian-Pei


    This study was aimed to explore the effects of blocking B7/CD28 and CD40/CD154 co-stimulatory signals on immune function of sensitized mice', and provide the evidences of acquired immune tolerance for allogeneic bone marrow transplantation. The mice sensitized on 7 day before transplant were divided into 4 groups: (1)CTLA4Ig+ anti-CD154 isotype control IgG; (2)anti-CD154 +CTLA4Ig isotype control IgG; (3)CTLA4Ig and anti-CD154; (4)isotype control IgG of CTLA4Ig and anti-CD154. CTLA4Ig and anti-CD154 used in normal BALB/c mice as isotype control IgG. Each mouse in all groups received CTLA4Ig and anti-CD154 (or corresponding isotype control IgG) 500 µg respectively, and was injected via tail vein on 7 day before transplant. There were 5 mice in each group. The mice were sacrificed on day 0, then the number of CD19(+)CD69(+)B cells, CD44(high)/CD62L(high) and CD44(high)/CD62L(low)/- T cells were measured by flow cytometry. Changes of cytokines and sensitized antibody were tested by ELISA or flow cytometry. The results showed that the numbers of CD19(+)CD69(+)B cells were significantly increased in comparison with the normal group (P CD154 co-stimulatory signals (P CD154 co-stimulatory signals. Blocking these two signals together, displayed a synergistic effect (P CD154 treated groups significantly decreased as compared with sensitized group (P CD154 co-stimulatory signal can inhibit the cellular and humoral immune function, whereas blocking these two signals together displays a synergistic effect.

  11. Molecule nanoweaver (United States)

    Gerald, II; Rex, E [Brookfield, IL; Klingler, Robert J [Glenview, IL; Rathke, Jerome W [Homer Glen, IL; Diaz, Rocio [Chicago, IL; Vukovic, Lela [Westchester, IL


    A method, apparatus, and system for constructing uniform macroscopic films with tailored geometric assemblies of molecules on the nanometer scale. The method, apparatus, and system include providing starting molecules of selected character, applying one or more force fields to the molecules to cause them to order and condense with NMR spectra and images being used to monitor progress in creating the desired geometrical assembly and functionality of molecules that comprise the films.

  12. Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule.

    Directory of Open Access Journals (Sweden)

    Katiuscia Pagano

    Full Text Available Fibroblast growth factors (FGFs are recognized targets for the development of therapies against angiogenesis-driven diseases, including cancer. The formation of a ternary complex with the transmembrane tyrosine kinase receptors (FGFRs, and heparan sulphate proteoglycans (HSPGs is required for FGF2 pro-angiogenic activity. Here by using a combination of techniques including Nuclear Magnetic Resonance, Molecular Dynamics, Surface Plasmon Resonance and cell-based binding assays we clarify the molecular mechanism of inhibition of an angiostatic small molecule, sm27, mimicking the endogenous inhibitor of angiogenesis, thrombospondin-1. NMR and MD data demonstrate that sm27 engages the heparin-binding site of FGF2 and induces long-range dynamics perturbations along FGF2/FGFR1 interface regions. The functional consequence of the inhibitor binding is an impaired FGF2 interaction with both its receptors, as demonstrated by SPR and cell-based binding assays. We propose that sm27 antiangiogenic activity is based on a twofold-direct and allosteric-mechanism, inhibiting FGF2 binding to both its receptors.

  13. Molecule Matters

    Indian Academy of Sciences (India)

    Fluorescence usually originates from the lowest excited electronic state (singlet) irrespective of the excitation and hence, the fluorescence spectrum of a molecule is characterized by a single band. However, what makes DMABN a very special molecule is that it exhibits dual fluorescence (i.e. emission of. Molecule Matters.

  14. Origination of new immunological functions in the costimulatory molecule B7-H3: the role of exon duplication in evolution of the immune system.

    Directory of Open Access Journals (Sweden)

    Jing Sun

    Full Text Available B7-H3, a recently identified B7 family member, has different isoforms in human and mouse. Mouse B7-H3 gene has only one isoform (2IgB7-H3 with two Ig-like domains, whereas human B7-H3 has two isoforms (2IgB7-H3 and 4IgB7-H3. In this study a systematic genomic survey across various species from teleost fishes to mammals revealed that 4IgB7-H3 isoform also appeared in pigs, guinea pigs, cows, dogs, African elephants, pandas, megabats and higher primate animals, which resulted from tandem exon duplication. Further sequence analysis indicated that this duplication generated a new conserved region in the first IgC domain, which might disable 4IgB7-H3 from releasing soluble form, while 2IgB7-H3 presented both membrane and soluble forms. Through three-dimensional (3D structure modeling and fusion-protein binding assays, we discovered that the duplicated isoform had a different structure and might bind to another potential receptor on activated T cells. In T cell proliferation assay, human 2IgB7-H3 (h2IgB7-H3 and mouse B7-H3 (mB7-H3 both increased T cell proliferation and IL-2, IFN-γ production, whereas human 4IgB7-H3 (h4IgB7-H3 reduced cytokine production and T cell proliferation compared to control. Furthermore, both h2IgB7-H3 and mB7-H3 upregulated the function of lipopolysacharide (LPS-activated monocyte in vitro. Taken together, our data implied that during the evolution of vertebrates, B7-H3 exon duplication contributed to the generation of a new 4IgB7-H3 isoform in many mammalian species, which have carried out distinct functions in the immune responses.

  15. Molecule Matters

    Indian Academy of Sciences (India)

    is such an innocuous molecule that you might not think it worthy of special attention. We take this molecule for granted because it is abundantly available on earth. About 80 % of the earth's atmosphere, which means a total of 4×1018 kg, is dinitrogen![1] Secondly, it is ignored because it is quite un- reactive. Nitrogen is such ...

  16. Molecule Matters

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 14; Issue 4. Molecule Matters – van der Waals Molecules - History and Some Perspectives on Intermolecular Forces. E Arunan. Feature Article Volume 14 Issue 4 April 2009 pp 346-356 ...

  17. Carbohydrate-binding agents efficiently prevent dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-directed HIV-1 transmission to T lymphocytes. (United States)

    Balzarini, Jan; Van Herrewege, Yven; Vermeire, Kurt; Vanham, Guido; Schols, Dominique


    Exposure of HIV-1 to dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-expressing B-lymphoblast Raji cells (Raji/DC-SIGN) but not to wild-type Raji/0 cells results in the capture of HIV-1 particles to the cells as measured by the quantification of cell-associated p24 antigen. Cocultivation of HIV-1-captured Raji/DC-SIGN cells with uninfected CD4+ T lymphocyte C8166 cells results in abundant formation of syncytia within 36 h after cocultivation. Short preexposure of HIV-1 to carbohydrate-binding agents (CBA) dose dependently prevents the Raji/DC-SIGN cells from efficiently binding the virus particles, and no syncytia formation occurs upon subsequent cocultivation with C8166 cells. Thus, the mannose-specific [i.e., the plant lectins Hippeastrum hybrid agglutinin (HHA), Galanthus nivalis agglutinin (GNA), Narcissus pseudonarcissus agglutinin; and Cymbidium agglutinin (CA); the procaryotic cyanovirin-N (CV-N); and the monoclonal antibody 2G12) and N-acetylglucosamine-specific (i.e., the plant lectin Urtica dioica agglutinin) CBAs efficiently abrogate the DC-SIGN-directed HIV-1 capture and subsequent transmission to T lymphocytes. In this assay, the CD4-down-regulating cyclotriazodisulfonamide derivative, the CXCR4 and CCR5 coreceptor antagonists 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl] - 1,4,8,11 - tetrazacyclotetradecane (AMD3100) and maraviroc, the gp41-binding enfuvirtide, and the polyanionic substances dextran sulfate (M(r) 5000), sulfated polyvinyl alcohol, and the naphthalene sulfonate polymer PRO-2000 were markedly less efficient or even completely ineffective. Similar observations were made in primary monocyte-derived dendritic cell cultures that were infected with HIV-1 particles that had been shortly pre-exposed to the CBAs CV-N, CA, HHA, and GNA and the polyanions DS-5000 and PRO-2000. The potential of CBAs, but not polyanions and other structural/functional classes of entry inhibitors, to impair

  18. Atkins' molecules

    CERN Document Server

    Atkins, Peters


    Originally published in 2003, this is the second edition of a title that was called 'the most beautiful chemistry book ever written'. In it, we see the molecules responsible for the experiences of our everyday life - including fabrics, drugs, plastics, explosives, detergents, fragrances, tastes, and sex. With engaging prose Peter Atkins gives a non-technical account of an incredible range of aspects of the world around us, showing unexpected connections, and giving an insight into how this amazing world can be understood in terms of the atoms and molecules from which it is built. The second edition includes dozens of extra molecules, graphical presentation, and an even more accessible and enthralling account of the molecules themselves.

  19. Interstellar Molecules (United States)

    Solomon, Philip M.


    Radioastronomy reveals that clouds between the stars, once believed to consist of simple atoms, contain molecules as complex as seven atoms and may be the most massive objects in our Galaxy. (Author/DF)

  20. Enumerating molecules.

    Energy Technology Data Exchange (ETDEWEB)

    Visco, Donald Patrick, Jr. (, . Tennessee Technological University, Cookeville, TN); Faulon, Jean-Loup Michel; Roe, Diana C.


    This report is a comprehensive review of the field of molecular enumeration from early isomer counting theories to evolutionary algorithms that design molecules in silico. The core of the review is a detail account on how molecules are counted, enumerated, and sampled. The practical applications of molecular enumeration are also reviewed for chemical information, structure elucidation, molecular design, and combinatorial library design purposes. This review is to appear as a chapter in Reviews in Computational Chemistry volume 21 edited by Kenny B. Lipkowitz.

  1. Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization

    Directory of Open Access Journals (Sweden)

    Wenzhong Yan


    Full Text Available In this work, the relationship between cyclophilin A (CypA and HCV prompted us to screen a series of small molecule CypA inhibitors which were previously reported by our group. Among them, compound 1, discovered as a non-immunosuppressive anti-HCV agent with an EC50 value of 0.67 μM in a virus assay, was selected for further study. Subsequent chemical modification by O-acylation led to a novel class of molecules, among which compound 25 demonstrated the most potent anti-HCV activity in the virus assay (EC50 = 0.19 μM, but low cytotoxicity and hERG cardiac toxicity. The following studies (a solution stability assay and a simple pharmacokinetic test together with a CypA enzyme inhibition assay preliminarily indicated that 25 was a prodrug of 1. To the best of our knowledge, 25 is probably the most potent currently reported small molecule anti-HCV agent acting via the CypA inhibitory mechanism. Consequently, our study has provided a new potential small molecule for curing HCV infection.

  2. Direct visualization of individual DNA molecules by fluorescence microscopy: characterization of the factors affecting signal/background and optimization of imaging conditions using YOYO. (United States)

    Gurrieri, S; Wells, K S; Johnson, I D; Bustamante, C


    A new series of high-affinity cyanine dyes was tested for the visualization of the dynamics of single DNA molecules through a fluorescence microscope. In particular, YOYO-1 (1,1'-(4,4,7,7-tetramethyl-4,7-diazaundecamethylene)- bis-4-[3-methyl-2,3-dihydro-(benzo-1,3-oxazole)- 2-methylidene]-quinolinium tetraiodide) forms a very stable, highly fluorescent complex with double-stranded DNA and dramatically improves the quality of the images. We have characterized the factors affecting the signal/background in the imaging of single DNA molecules by fluorescence microscopy and compared the results obtained using YOYO-1 with those obtained using standard fluorescent dyes like ethidium bromide or acridine orange.

  3. Molecule Matters

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 9. Molecule Matters - A Chromium Compound with a Quintuple Bond. K C Kumara Swamy. Feature Article Volume 11 Issue 9 September 2006 pp 72-75. Fulltext. Click here to view fulltext PDF. Permanent link:

  4. Molecule Matters

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 13; Issue 5. Molecule Matters - N-Heterocyclic Carbenes - The Stable Form of R2 C: Anil J Elias. Feature Article Volume 13 Issue 5 May 2008 pp 456-467. Fulltext. Click here to view fulltext PDF. Permanent link:

  5. Molecule Matters

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 11. Molecule Matters - Carbon Dioxide: Molecular States and Beyond. T P Radhakrishnan. Feature Article Volume 11 Issue 11 November 2006 pp 88-92. Fulltext. Click here to view fulltext PDF. Permanent link:

  6. Carbohydrate-binding agents efficiently prevent dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-directed HIV-1 transmission to T lymphocytes


    Balzarini, Jan; Van Herrewege, Yven; Vermeire, Kurt; Vanham, Guido; Schols, Dominique


    Exposure of HIV-1 to dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-expressing B-lymphoblast Raji cells (Raji/DC-SIGN) but not to wild-type Raji/0 cells results in the capture of HIV-1 particles to the cells as measured by the quantification of cell-associated p24 antigen. Cocultivation of HIV-1-captured Raji/DC-SIGN cells with uninfected CD4+ T lymphocyte C8166 cells results in abundant formation of syncytia within 36 h after cocultivation. Short pre...

  7. Blockade of CD40-CD154 costimulatory pathway promotes long-term survival of full-thickness porcine corneal grafts in nonhuman primates: clinically applicable xenocorneal transplantation. (United States)

    Choi, H J; Lee, J J; Kim, D H; Kim, M K; Lee, H J; Ko, A Y; Kang, H J; Park, C; Wee, W R


    The porcine cornea may be a good solution for the shortage of human donor corneas because its size and refractive properties are comparable to those of the human cornea. However, antigenic differences need to be overcome to apply xenocorneal transplantation in actual clinical practice. We aimed to investigate the feasibility of full-thickness porcine corneas as human corneal substitutes using a CD40-CD154 costimulatory pathway blocking strategy in a clinically applicable pig-to-nonhuman primate corneal transplantation model. As a result, the mean survival time of the xenocorneal grafts in recipients who received anti-CD154 antibody-based immunosuppressants (POD318 (n = 4); >933, >243, 318 and >192) was significantly longer than that in controls (POD28 (n = 3); 21, 28 and 29; p = 0.010, log-rank test). Administration of anti-CD154 antibodies markedly reduced inflammatory cellular infiltrations (predominantly CD8 T cells and macrophages) into the xenocorneal grafts and almost completely blocked xenoantigen-triggered increases in Th1-associated cytokines, chemokines and C3a in the aqueous humor. Moreover, systemic expansion of memory T cells was effectively controlled and responses of anti-Gal/donor pig-specific antibodies were considerably diminished by programmed injection of anti-CD154 antibodies. Consequently, porcine corneas might be promising human corneal substitutes when the transplantation is accompanied by potent immunosuppression such as a CD40-CD154 costimulatory pathway blockade. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  8. A direct assay of carboxyl-containing small molecules by SALDI-MS on a AgNP/rGO-based nanoporous hybrid film. (United States)

    Hong, Min; Xu, Lidan; Wang, Fangli; Geng, Zhirong; Li, Haibo; Wang, Huaisheng; Li, Chen-Zhong


    Silver nanoparticles (AgNPs) and reduced graphene oxide (rGO) hybrid nanoporous structures fabricated by the layer-by-layer (LBL) electrostatic self-assembly have been applied as a simple platform for the rapid analysis of carboxyl-containing small molecules by surface-assisted laser desorption/ionization (D/I) mass spectrometry (SALDI-MS). By the simple one-step deposition of analytes onto the (AgNP/rGO)9 multilayer film, the MS measurements of various carboxyl-containing small molecules (including amino acids, fatty acids and organic dicarboxylic acids) can be done. In contrast to other energy transfer materials relative to AgNPs, the signal interferences of a Ag cluster (Agn(+) or Agn(-)) and a C cluster (Cn(+) or Cn(-)) have been effectively reduced or eliminated. The effects of various factors, such as the pore structure and composition of the substrates, on the efficiency of D/I have been investigated by comparing with the (AgNP)9 LBL nanoporous structure, (AgNP/rGO)9/(SiO2NP)6 LBL multilayer film and AgNP/prGO nanocomposites.

  9. Transcriptome Profiling Using Single-Molecule Direct RNA Sequencing Approach for In-depth Understanding of Genes in Secondary Metabolism Pathways of Camellia sinensis

    Directory of Open Access Journals (Sweden)

    Qingshan Xu


    Full Text Available Characteristic secondary metabolites, including flavonoids, theanine and caffeine, are important components of Camellia sinensis, and their biosynthesis has attracted widespread interest. Previous studies on the biosynthesis of these major secondary metabolites using next-generation sequencing technologies limited the accurately prediction of full-length (FL splice isoforms. Herein, we applied single-molecule sequencing to pooled tea plant tissues, to provide a more complete transcriptome of C. sinensis. Moreover, we identified 94 FL transcripts and four alternative splicing events for enzyme-coding genes involved in the biosynthesis of flavonoids, theanine and caffeine. According to the comparison between long-read isoforms and assemble transcripts, we improved the quality and accuracy of genes sequenced by short-read next-generation sequencing technology. The resulting FL transcripts, together with the improved assembled transcripts and identified alternative splicing events, enhance our understanding of genes involved in the biosynthesis of characteristic secondary metabolites in C. sinensis.

  10. Direct measurement of the translational mobility of deuterium hydride molecules confined in a model microporous material: AlPO4-5 zeolite (United States)

    Martin, C.; Coulomb, J. P.; Ferrand, M.


    We have measured by incoherent quasi-elastic neutron scattering the diffusion coefficient Dt of sorbed hydrogen (HD) molecules in the one-dimensional micropore network of AlPO4-5 zeolite. The confined hydrogen phase in such nano-scale cylindrical tubes (diameter phi = 7.3 Å) behaves as a quasi-(1d) fluid phase. At temperature T = 19.5 K, in the medium loading regime (Θ simeq 40%), the translational molecular mobility is quite large, Dt = 0.45·10-5 cm2 s-1. When increasing Θ, Dt strongly decreases down to 0.03·10-5 cm2 s-1 (Θ simeq 95%). At lower temperature T = 10.3 K, the HD molecular mobility is still important, Dt = 0.15·10-5 cm2 s-1 at Θ simeq 40%.

  11. Transcriptome Profiling Using Single-Molecule Direct RNA Sequencing Approach for In-depth Understanding of Genes in Secondary Metabolism Pathways of Camellia sinensis (United States)

    Xu, Qingshan; Zhu, Junyan; Zhao, Shiqi; Hou, Yan; Li, Fangdong; Tai, Yuling; Wan, Xiaochun; Wei, ChaoLing


    Characteristic secondary metabolites, including flavonoids, theanine and caffeine, are important components of Camellia sinensis, and their biosynthesis has attracted widespread interest. Previous studies on the biosynthesis of these major secondary metabolites using next-generation sequencing technologies limited the accurately prediction of full-length (FL) splice isoforms. Herein, we applied single-molecule sequencing to pooled tea plant tissues, to provide a more complete transcriptome of C. sinensis. Moreover, we identified 94 FL transcripts and four alternative splicing events for enzyme-coding genes involved in the biosynthesis of flavonoids, theanine and caffeine. According to the comparison between long-read isoforms and assemble transcripts, we improved the quality and accuracy of genes sequenced by short-read next-generation sequencing technology. The resulting FL transcripts, together with the improved assembled transcripts and identified alternative splicing events, enhance our understanding of genes involved in the biosynthesis of characteristic secondary metabolites in C. sinensis. PMID:28744294

  12. Mycobacterium tuberculosis lipoproteins directly regulate human memory CD4(+) T cell activation via Toll-like receptors 1 and 2. (United States)

    Lancioni, Christina L; Li, Qing; Thomas, Jeremy J; Ding, XueDong; Thiel, Bonnie; Drage, Michael G; Pecora, Nicole D; Ziady, Assem G; Shank, Samuel; Harding, Clifford V; Boom, W Henry; Rojas, Roxana E


    The success of Mycobacterium tuberculosis as a pathogen relies on its ability to regulate the host immune response. M. tuberculosis can manipulate adaptive T cell responses indirectly by modulating antigen-presenting cell (APC) function or by directly interacting with T cells. Little is known about the role of M. tuberculosis molecules in direct regulation of T cell function. Using a biochemical approach, we identified lipoproteins LprG and LpqH as major molecules in M. tuberculosis lysate responsible for costimulation of primary human CD4(+) T cells. In the absence of APCs, activation of memory CD4(+) T cells with LprG or LpqH in combination with anti-CD3 antibody induces Th1 cytokine secretion and cellular proliferation. Lipoprotein-induced T cell costimulation was inhibited by blocking antibodies to Toll-like receptor 2 (TLR2) and TLR1, indicating that human CD4(+) T cells can use TLR2/TLR1 heterodimers to directly respond to M. tuberculosis products. M. tuberculosis lipoproteins induced NF-κB activation in CD4(+) T cells in the absence of TCR co-engagement. Thus, TLR2/TLR1 engagement alone by M. tuberculosis lipoprotein triggered intracellular signaling, but upregulation of cytokine production and proliferation required co-engagement of the TCR. In conclusion, our results demonstrate that M. tuberculosis lipoproteins LprG and LpqH participate in the regulation of adaptive immunity not only by inducing cytokine secretion and costimulatory molecules in innate immune cells but also through directly regulating the activation of memory T lymphocytes.

  13. Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling

    Directory of Open Access Journals (Sweden)

    So-Young Hwang


    Full Text Available The Wnt/β-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of β-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic β-catenin pathway for cancer therapy, the development of specific inhibitors remains insufficient. Using a T cell factor (TCF-dependent luciferase-reporter system, we screened for small-molecule compounds that act against Wnt/β-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenylsulfonyl]amino}benzoate as a selective inhibitor of Wnt/β-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to β-catenin, promoting its degradation, and specifically downregulates Wnt/β-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/β-catenin signaling pathway.

  14. Direct Observation of the Reversible Two-State Unfolding and Refolding of an α/β Protein by Single-Molecule Atomic Force Microscopy. (United States)

    He, Chengzhi; Hu, Chunguang; Hu, Xiaodong; Hu, Xiaotang; Xiao, Adam; Perkins, Thomas T; Li, Hongbin


    Directly observing protein folding in real time using atomic force microscopy (AFM) is challenging. Here the use of AFM to directly monitor the folding of an α/β protein, NuG2, by using low-drift AFM cantilevers is demonstrated. At slow pulling speeds (forces, bringing the non-equilibrium unfolding-refolding reactions towards equilibrium. At very low pulling speeds (ca. 2 nm s(-1)), unfolding and refolding were observed to occur in near equilibrium. Based on the Crooks fluctuation theorem, we then measured the equilibrium free energy change between folded and unfolded states of NuG2. The improved long-term stability of AFM achieved using gold-free cantilevers allows folding-unfolding reactions of α/β proteins to be directly monitored near equilibrium, opening the avenue towards probing the folding reactions of other mechanically important α/β and all-β elastomeric proteins. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Antibody fragments directed against different portions of the human neural cell adhesion molecule L1 act as inhibitors or activators of L1 function.

    Directory of Open Access Journals (Sweden)

    Yan Wang

    Full Text Available The neural cell adhesion molecule L1 plays important roles in neuronal migration and survival, neuritogenesis and synaptogenesis. L1 has also been found in tumors of different origins, with levels of L1 expression correlating positively with the metastatic potential of tumors. To select antibodies targeting the varied functions of L1, we screened the Tomlinson library of recombinant human antibody fragments to identify antibodies binding to recombinant human L1 protein comprising the entire extracellular domain of human L1. We obtained four L1 binding single-chain variable fragment antibodies (scFvs, named I4, I6, I13, and I27 and showed by enzyme-linked immunosorbent assay (ELISA that scFvs I4 and I6 have high affinity to the immunoglobulin-like (Ig domains 1-4 of L1, while scFvs I13 and I27 bind strongly to the fibronectin type III homologous (Fn domains 1-3 of L1. Application of scFvs I4 and I6 to human SK-N-SH neuroblastoma cells reduced proliferation and transmigration of these cells. Treatment of SK-N-SH cells with scFvs I13 and I27 enhanced cell proliferation and migration, neurite outgrowth, and protected against the toxic effects of H(2O(2 by increasing the ratio of Bcl-2/Bax. In addition, scFvs I4 and I6 inhibited and scFvs I13 and I27 promoted phosphorylation of src and Erk. Our findings indicate that scFvs reacting with the immunoglobulin-like domains 1-4 inhibit L1 functions, whereas scFvs interacting with the fibronectin type III domains 1-3 trigger L1 functions of cultured neuroblastoma cells.

  16. Modulation of innate immune mechanisms to enhance vaccine induced immunity: Role of co-inhibitory molecules

    Directory of Open Access Journals (Sweden)

    Sreenivas eGannavaram


    Full Text Available No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several anti-leishmanial vaccine formulations have been tested in various animal models including genetically modified live attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells i.e., dendritic cells (DC and macrophages (M. Further, Leishmania parasites have evolved strategies to actively inhibit TH1 polarizing functions of DCs, and to condition the infected M towards anti-inflammatory/alternative/M2 phenotype. The altered phenotype of phagocytic cells is characterized by decreased production of anti-microbial reactive oxygen, nitrogen molecules and pro-inflammatory cytokines such as IFN-, IL-12 and TNF-α. These early events limit the activation of TH1 effector cells and set the stage for pathogenesis. Further, this early control of innate immunity by the virulent parasites results in substantial alteration in the adaptive immunity characterized by reduced proliferation of CD4+ and CD8+ T cells, and TH2 biased immunity that results in production of anti-inflammatory cytokines such as TGF-, and IL-10. More recent studies have also documented the induction of co-inhibitory ligands such as CTLA-4, PD-L1, CD200 and Tim-3 that induce exhaustion and/or non-proliferation in antigen experienced T cells. Most of these studies focus on viral infections in chronic phase thus limiting the direct application of these results from these studies to parasitic infections and much less to parasitic vaccines. However, these studies suggest that vaccine induced protective immunity can be modulated using strategies that enhance the co-stimulation that might reduce the threshold necessary for T cell activation and conversely by strategies that reduce or block inhibitory molecules such as PD-L1 and CD200. In this

  17. Modulation of Innate Immune Mechanisms to Enhance Leishmania Vaccine-Induced Immunity: Role of Coinhibitory Molecules. (United States)

    Gannavaram, Sreenivas; Bhattacharya, Parna; Ismail, Nevien; Kaul, Amit; Singh, Rakesh; Nakhasi, Hira L


    No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several antileishmanial vaccine formulations have been tested in various animal models, including genetically modified live-attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells, i.e., dendritic cells (DCs) and macrophages (MΦ). Furthermore, Leishmania parasites have evolved strategies to actively inhibit TH1 polarizing functions of DCs and to condition the infected MΦ toward anti-inflammatory/alternative/M2 phenotype. The altered phenotype of phagocytic cells is characterized by decreased production of antimicrobial reactive oxygen, nitrogen molecules, and pro-inflammatory cytokines, such as IFN-γ, IL-12, and TNF-α. These early events limit the activation of TH1-effector cells and set the stage for pathogenesis. Furthermore, this early control of innate immunity by the virulent parasites results in substantial alteration in the adaptive immunity characterized by reduced proliferation of CD4(+) and CD8(+) T cells and TH2-biased immunity that results in production of anti-inflammatory cytokines, such as TGF-β, and IL-10. More recent studies have also documented the induction of coinhibitory ligands, such as CTLA-4, PD-L1, CD200, and Tim-3, that induce exhaustion and/or non-proliferation in antigen-experienced T cells. Most of these studies focus on viral infections in chronic phase, thus limiting the direct application of these results to parasitic infections and much less to parasitic vaccines. However, these studies suggest that vaccine-induced protective immunity can be modulated using strategies that enhance the costimulation that might reduce the threshold necessary for T cell activation and conversely by strategies that reduce or block inhibitory molecules, such as PD-L1 and CD200. In this review, we will focus on

  18. Molecule Matters van der Waals Molecules

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 14; Issue 12. Molecule Matters van der Waals Molecules - Noble Gas Clusters are London Molecules! E Arunan. Feature Article Volume 14 Issue 12 December 2009 pp 1210-1222 ...

  19. Direction of Intercalation of a bis-Ru(II) Complex to DNA Probed by a Minor Groove Binding Molecule 4',6-Diamidino-2-phenylindole

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Yoon Jung; Kim, Raeyeong; Chitrapriya, Nataraj; Kim, Seog K.; Bae, Inho [Yeungnam Univ., Gyeongsan (Korea, Republic of)


    Direction of intercalation to DNA of the planar dipyrido[3,2-a:2',3'-c]phenazine ligands (dppz) of a bis-Ru(II) complex namely, [Ru(1,10-phenanthroline){sub 2}dipyrido[3,2-a:2',3'-c]phenazine]{sup 2+} linkered by a 1,3-bis(4-pyridyl)propane, was investigated by probing the behavior of 4',6-diamidino-2-phenylindole (DAPI) that bound deep in the minor groove. Bis-intercalation of DPPZ resulted in a little blue shift and hyperchromism in DAPI absorption band, and a large decrease in DAPI fluorescence intensity which accompanied by an increase in the dppz emission intensity. Diminishing the intensity of the positive induced circular dichroism (CD) and linear dichroism (LD) were also observed. These spectral changes indicated that insertion of dppz ligand caused the change of the binding mode of DAPI, which probably moved to the exterior of DNA from the minor groove and interacted with the phospghate groups of DNA by electrostatic interaction. At the surface of DNA, DAPI binds at the phosphate groups of DNA by electrostatic attraction. Consequently, this observation indicated that the dppz ligand intercalated from the minor groove.

  20. Development of an automated dual-mode supercritical fluid chromatography and reversed-phase liquid chromatography mass-directed purification system for small-molecule drug discovery. (United States)

    Hettiarachchi, Kanaka; Kong, May; Yun, Andersen; Jacobsen, John R; Xue, Qifeng


    We report the development of a dual-mode mass-directed supercritical fluid chromatography and reversed-phase liquid chromatography purification system. The addition of a third pump allows for flexible mobile phase control between the two techniques, and enables operation of either chromatography mode within minutes by activation of a set of switching valves on a single system. Software control, fluidic pathways, interface to the mass spectrometer, and fraction collection have been modified for compatibility between both separation methods. The conditioning solvent and tuning parameters for the mass spectrometer were adjusted to achieve an ideal signal trace in either mode with good linearity (r(2) > 0.970) over a range of concentrations and minimal noise for accurate peak detection and isolation. The registration success rate is 90% and overall sample recovery for either technique is 80-90%. Combining two orthogonal separation and purification modes in one single system has improved the purification throughput of complex mixtures and has been a valuable, cost-saving tool in our laboratory. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Quantifying protein-ligand interactions by direct electrospray ionization-MS analysis: evidence of nonuniform response factors induced by high molecular weight molecules and complexes. (United States)

    Lin, Hong; Kitova, Elena N; Klassen, John S


    The deleterious effects of high molecular weight (MW) solute (polymers and noncovalent assemblies) on protein-ligand (PL) affinity measurements carried out using the direct electrospray ionization mass spectrometry (ESI-MS) assay are described. The presence of high MW solute, that do not interact with the protein (P) or ligand (L) of interest, is shown to result in a decrease in the abundance (Ab) ratio (R) of ligand-bound to free protein ions (i.e., Ab(PL)/Ab(P)) measured for protein-carbohydrate complexes. This effect, which can reduce the apparent association constant by more than 60%, is found to be more pronounced as the differences in the surface properties of P and PL become more significant. It is proposed that the decrease in R reflects a reduction in the number of available surface sites in the ESI droplets upon introduction of large solute and increased competition between P and the more hydrophilic PL for these sites. That a similar decrease in R is observed upon introduction of surfactants to solution provides qualitative support for this hypothesis.

  2. Ion-Molecule Reaction Dynamics. (United States)

    Meyer, Jennifer; Wester, Roland


    We review the recent advances in the investigation of the dynamics of ion-molecule reactions. During the past decade, the combination of single-collision experiments in crossed ion and neutral beams with the velocity map ion imaging detection technique has enabled a wealth of studies on ion-molecule reactions. These methods, in combination with chemical dynamics simulations, have uncovered new and unexpected reaction mechanisms, such as the roundabout mechanism and the subtle influence of the leaving group in anion-molecule nucleophilic substitution reactions. For this important class of reactions, as well as for many fundamental cation-molecule reactions, the information obtained with crossed-beam imaging is discussed. The first steps toward understanding micro-solvation of ion-molecule reaction dynamics are presented. We conclude with the presentation of several interesting directions for future research.

  3. Gene immunotherapy of chronic lymphocytic leukemia: a phase I study of intranodally injected adenovirus expressing a chimeric CD154 molecule. (United States)

    Castro, Januario E; Melo-Cardenas, Johanna; Urquiza, Mauricio; Barajas-Gamboa, Juan S; Pakbaz, Ramin S; Kipps, Thomas J


    New therapies for chronic lymphocytic leukemia (CLL) are needed, particularly those that can eradicate residual disease and elicit anti-CLL immune responses. CD40 ligation on CLL cells, which can be achieved using adenovirus encoding chimeric CD154 (Ad-ISF35), enhances their ability to function as antigen-presenting cells and increases their sensitivity to clearance by immune-effector mechanisms. In this study, we report the results of a first-in-man phase I trial of intranodal direct injection (IDI) of Ad-ISF35 in patients with CLL to evaluate toxicity, safety, and tolerability. Fifteen patients received a single IDI of 1 × 10(10) to 33 × 10(10) Ad-ISF35 viral particles (vp), with a defined maximum tolerated dose as 1 × 10(11) vp. Although the most common adverse events were transient grade 1 to 2 pain at the injection site and flu-like symptoms following IDI, some patients receiving the highest dose had transient, asymptomatic grade 3 to 4 hypophosphatemia, neutropenia, or transaminitis. Increased expression of death receptor, immune costimulatory molecules, and Ad-ISF35 vector DNA was detected in circulating CLL cells. Notably, we also observed preliminary clinical responses, including reductions in leukemia cell counts, lymphadenopathy, and splenomegaly. Six patients did not require additional therapy for more than 6 months, and three achieved a partial remission. In conclusion, Ad-ISF35 IDI was safely delivered in patients with CLLs and induced systemic biologic and clinical responses. These results provide the rationale for phase II studies in CLLs, lymphomas, and CD40-expressing solid tumors.

  4. Photonic Molecule Lasers Revisited (United States)

    Gagnon, Denis; Dumont, Joey; Déziel, Jean-Luc; Dubé, Louis J.


    Photonic molecules (PMs) formed by coupling two or more optical resonators are ideal candidates for the fabrication of integrated microlasers, photonic molecule lasers. Whereas most calculations on PM lasers have been based on cold-cavity (passive) modes, i.e. quasi-bound states, a recently formulated steady-state ab initio laser theory (SALT) offers the possibility to take into account the spectral properties of the underlying gain transition, its position and linewidth, as well as incorporating an arbitrary pump profile. We will combine two theoretical approaches to characterize the lasing properties of PM lasers: for two-dimensional systems, the generalized Lorenz-Mie theory will obtain the resonant modes of the coupled molecules in an active medium described by SALT. Not only is then the theoretical description more complete, the use of an active medium provides additional parameters to control, engineer and harness the lasing properties of PM lasers for ultra-low threshold and directional single-mode emission. We will extend our recent study and present new results for a number of promising geometries. The authors acknowledge financial support from NSERC (Canada) and the CERC in Photonic Innovations of Y. Messaddeq.

  5. Molecule Matters van der Waals Molecules

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 15; Issue 7. Molecule Matters van der Waals Molecules - Rg•••HF Complexes are Debye Molecules! E Arunan. Feature Article Volume 15 Issue 7 July 2010 pp 667-674. Fulltext. Click here to view fulltext PDF. Permanent link:

  6. The co-stimulatory effects of MyD88-dependent Toll-like receptor signaling on activation of murine γδ T cells.

    Directory of Open Access Journals (Sweden)

    Jinping Zhang

    Full Text Available γδ T cells express several different toll-like receptor (TLRs. The role of MyD88- dependent TLR signaling in TCR activation of murine γδ T cells is incompletely defined. Here, we report that Pam3CSK4 (PAM, TLR2 agonist and CL097 (TLR7 agonist, but not lipopolysaccharide (TLR4 agonist, increased CD69 expression and Th1-type cytokine production upon anti-CD3 stimulation of γδ T cells from young adult mice (6-to 10-week-old. However, these agonists alone did not induce γδ T cell activation. Additionally, we noted that neither PAM nor CL097 synergized with anti-CD3 in inducing CD69 expression on γδ T cells of aged mice (21-to 22-month-old. Compared to young γδ T cells, PAM and CL097 increased Th-1 type cytokine production with a lower magnitude from anti-CD3- stimulated, aged γδ T cells. Vγ1+ and Vγ4+ cells are two subpopulations of splenic γδ T cells. PAM had similar effects in anti-CD3-activated control and Vγ4+ subset- depleted γδ T cells; whereas CL097 induced more IFN-γ production from Vγ4+ subset-depleted γδ T cells than from the control group. Finally, we studied the role of MyD88-dependent TLRs in γδ T cell activation during West Nile virus (WNV infection. γδ T cell, in particular, Vγ1+ subset expansion was significantly reduced in both MyD88- and TLR7- deficient mice. Treatment with TLR7 agonist induced more Vγ1+ cell expansion in wild-type mice during WNV infection. In summary, these results suggest that MyD88-dependent TLRs provide co-stimulatory signals during TCR activation of γδ T cells and these have differential effects on distinct subsets.

  7. Measuring an antibody affinity distribution molecule by molecule

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, Andrew M [Los Alamos National Laboratory; Werner, James H [Los Alamos National Laboratory; Temirov, Jamshid [INVITROGEN


    Single molecule fluorescence mIcroscopy was used to observe the binding and unbinding of hapten decorated quantum dots with individual surface immobilized antibodies. The fluorescence time history from an individual antibody site can be used to calculate its binding affinity. While quantum dot blinking occurs during these measurements, we describe a simple empirical method to correct the apparent/observed affinity to account for the blinking contribution. The combination of many single molecule affinity measurements from different antibodies yields not only the average affinity, it directly measures the full shape and character of the surface affinity distribution function.

  8. Lanthanide single molecule magnets

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Jinkui; Zhang, Peng [Chinese Academy of Sciences, Changchun (China). Changchun Inst. of Applied Chemistry


    This book begins by providing basic information on single-molecule magnets (SMMs), covering the magnetism of lanthanide, the characterization and relaxation dynamics of SMMs and advanced means of studying lanthanide SMMs. It then systematically introduces lanthanide SMMs ranging from mononuclear and dinuclear to polynuclear complexes, classifying them and highlighting those SMMs with high barrier and blocking temperatures - an approach that provides some very valuable indicators for the structural features needed to optimize the contribution of an Ising type spin to a molecular magnet. The final chapter presents some of the newest developments in the lanthanide SMM field, such as the design of multifunctional and stimuli-responsive magnetic materials as well as the anchoring and organization of the SMMs on surfaces. In addition, the crystal structure and magnetic data are clearly presented with a wealth of illustrations in each chapter, helping newcomers and experts alike to better grasp ongoing trends and explore new directions.

  9. Ultracold molecule assembly with photonic crystals (United States)

    Pérez-Ríos, Jesús; Kim, May E.; Hung, Chen-Lung


    Photoassociation (PA) is a powerful technique to synthesize molecules directly and continuously from cold and ultracold atoms into deeply bound molecular states. In freespace, however, PA efficiency is constrained by the number of spontaneous decay channels linking the initial excited molecular state to a sea of final (meta)stable rovibronic levels. Here, we propose a novel scheme based on molecules strongly coupled to a guided photonic mode in a photonic crystal waveguide that turns PA into a powerful tool for near deterministic formation of ultracold molecules in their ground rovibrational level. Our example shows a potential ground state molecule production efficiency > 90 % , and a saturation rate > {10}6 molecules per second. By combining state-of-the-art cold atomic and molecular physics with nanophotonic engineering, our scheme presents a novel experimental package for trapping, cooling, and optically manipulating ultracold molecules, thus opening up new possibilities in the direction of ultracold chemistry and quantum information.

  10. Bacterial invasion reconstructed molecule by molecule

    Energy Technology Data Exchange (ETDEWEB)

    Werner, James H [Los Alamos National Laboratory


    We propose to visualize the initial stages of bacterial infection of a human host cell with unmatched spatial and temporal resolution. This work will develop a new capability for the laboratory (super-resolution optical imaging), will test unresolved scientific hypotheses regarding host-pathogen interaction dynamics, and leverages state of the art 3D molecular tracking instrumentation developed recently by our group. There is much to be gained by applying new single molecule tools to the important and familiar problem of pathogen entry into a host cell. For example, conventional fluorescence microscopy has identified key host receptors, such as CD44 and {alpha}5{beta}1 integrin, that aggregate near the site of Salmonella typhimurium infection of human cells. However, due to the small size of the bacteria ({approx} 2 {micro}m) and the diffraction of the emitted light, one just sees a fluorescent 'blob' of host receptors that aggregate at the site of attachment, making it difficult to determine the exact number of receptors present or whether there is any particular spatial arrangement of the receptors that facilitates bacterial adhesion/entry. Using newly developed single molecule based super-resolution imaging methods, we will visualize how host receptors are directed to the site of pathogen adhesion and whether host receptors adopt a specific spatial arrangement for successful infection. Furthermore, we will employ our 3D molecular tracking methods to follow the injection of virulence proteins, or effectors, into the host cell by the pathogen Type III secretion system (TTSS). We expect these studies to provide mechanistic insights into the early events of pathogen infection that have here-to-fore been technically beyond our reach. Our Research Goals are: Goal 1--Construct a super-resolution fluorescence microscope and use this new capability to image the spatial distribution of different host receptors (e.g. CD44, as {alpha}5{beta}1 integrin) at the

  11. [Biophysics of single molecules]. (United States)

    Serdiuk, I N; Deriusheva, E I


    The modern methods of research of biological molecules whose application led to the development of a new field of science, biophysics of single molecules, are reviewed. The measurement of the characteristics of single molecules enables one to reveal their individual features, and it is just for this reason that much more information can be obtained from one molecule than from the entire ensample of molecules. The high sensitivity of the methods considered in detail makes it possible to come close to the solution of the basic problem of practical importance, namely, the determination of the nucleotide sequence of a single DNA molecule.

  12. CD molecules 2005: human cell differentiation molecules

    Czech Academy of Sciences Publication Activity Database

    Zola, H.; Swart, B.; Nicholson, I.; Aasted, B.; Bensussan, A.; Boumsell, L.; Buckley, C.; Clark, G.; Drbal, Karel; Engel, P.; Hart, D.; Hořejší, Václav; Isacke, C.; Macardle, P.; Malavasi, F.; Mason, D.; Olive, D.; Saalmüller, A.; Schlossman, S.F.; Schwartz-Albiez, R.; Simmons, P.; Tedder, T.F.; Uguccioni, M.; Warren, H.


    Roč. 106, č. 9 (2005), s. 3123-3126 ISSN 0006-4971 Institutional research plan: CEZ:AV0Z5052915 Keywords : CD molecules * leukocyte antigen Subject RIV: EC - Immunology Impact factor: 10.131, year: 2005

  13. The Role of Costimulatory Molecules in the Development of Memory and Effector T Helper 2 Cells During an in vivo Immune Response to the Murine Gastrointestinal Parasite Heligmosomoides polygyrus (United States)


    in serum IgG2a levels; this immune response is important for protection against intracellular pathogens such as viruses and bacteria . The Th2 immune...J. Noelle. 1993. In vivo CD40-gp39 interactions are essential for thymus -dependent immunity. II. Prolonged suppression of primary and secondary...J. G. Krueger, H. D. Ochs, S. L. Kelley, and S. Kang. 1999. CTLA4Ig- mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

  14. Stochastic Models of Molecule Formation on Dust (United States)

    Charnley, Steven; Wirstroem, Eva


    We will present new theoretical models for the formation of molecules on dust. The growth of ice mantles and their layered structure is accounted for and compared directly to observations through simulation of the expected ice absorption spectra

  15. Time Resolved Energy Transfer and Photodissociation of Vibrationally Excited Molecules

    National Research Council Canada - National Science Library

    Crim, F. F


    ...) in solution and in the gas phase. This second experiment is one of the few direct comparisons of intramolecular vibrational energy flow in a solvated molecule with that in the same molecule isolated in a gas...

  16. Formation of Ultracold Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Cote, Robin [Univ. of Connecticut, Storrs, CT (United States)


    Advances in our ability to slow down and cool atoms and molecules to ultracold temperatures have paved the way to a revolution in basic research on molecules. Ultracold molecules are sensitive of very weak interactions, even when separated by large distances, which allow studies of the effect of those interactions on the behavior of molecules. In this program, we have explored ways to form ultracold molecules starting from pairs of atoms that have already reached the ultracold regime. We devised methods that enhance the efficiency of ultracold molecule production, for example by tuning external magnetic fields and using appropriate laser excitations. We also investigates the properties of those ultracold molecules, especially their de-excitation into stable molecules. We studied the possibility of creating new classes of ultra-long range molecules, named macrodimers, thousand times more extended than regular molecules. Again, such objects are possible because ultra low temperatures prevent their breakup by collision. Finally, we carried out calculations on how chemical reactions are affected and modified at ultracold temperatures. Normally, reactions become less effective as the temperature decreases, but at ultracold temperatures, they can become very effective. We studied this counter-intuitive behavior for benchmark chemical reactions involving molecular hydrogen.

  17. Ultracold Polar Molecules (United States)


    formation of ultracold 87RbCs molecules in their rovibrational ground state by magnetoassociation followed by STIRAP, resulting in 14 papers acknowledging...produce at high densities. We revealed broad Feshbach resonances that we hope will allow production of higher-density 85Rb clouds. We are now...attempting to achieve the next step, formation of 85RbCs molecules. 15. SUBJECT TERMS EOARD, ultracold polar molecules, Feshbach resonance 16. SECURITY

  18. Research Directed at Developing a Classical Theory to Describe Isotope Separation of Polyatomic Molecules Illuminated by Intense Infrared Radiation. Final Report for period May 7, 1979 to September 30, 1979; Extension December 31, 1997 (United States)

    Lamb, W. E. Jr.


    This final report describes research on the theory of isotope separation produced by the illumination of polyatomic molecules by intense infrared laser radiation. This process is investigated by treating the molecule, sulfur hexafluoride, as a system of seven classical particles that obey the Newtonian equations of motion. A minicomputer is used to integrate these differential equations. The particles are acted on by interatomic forces, and by the time-dependent electric field of the laser. We have a very satisfactory expression for the interaction of the laser and the molecule which is compatible with infrared absorption and spectroscopic data. The interatomic potential is capable of improvement, and progress on this problem is still being made. We have made several computer runs of the dynamical behavior of the molecule using a reasonably good model for the interatomic force law. For the laser parameters chosen, we find that typically the molecule passes quickly through the resonance region into the quasi-continuum and even well into the real continuum before dissociation actually occurs. When viewed on a display terminal, the motions are exceedingly complex. As an aid to the visualization of the process, we have made a number of 16 mm movies depicting a three-dimensional representation of the motion of the seven particles. These show even more clearly the enormous complexity of the motions, and make clear the desirability of finding ways of characterizing the motion in simple ways without giving all of the numerical detail. One of the ways to do this is to introduce statistical parameters such as a temperature associated with the distribution of kinetic energies of the single particle. We have made such an analysis of our data runs, and have found favorable indications that such methods will prove useful in keeping track of the dynamical histories.

  19. Optical Characteristics of Biological Molecules in the Terahertz Gap

    National Research Council Canada - National Science Library

    Globus, Tatiana; Parthasarathy, Ramakrishnan; Khromova, Tatyana; Woolard, Dwight; Swami, Nathan; Gatesman, Andrew J; Waldman, Jerry


    .... In this work, we present results from parallel measurements of reflection and transmission spectra of biological molecules to enable detailed and direct calculation of refractive index and absorption...

  20. Molecule of the Month

    Indian Academy of Sciences (India)

    The most logical way to reduce the reactivity of a molecule of 1 would be to put a single molecule of 1 in an unreactive "cage". Chemistry Nobel winner Donald J. Cram (1987) has shown that it is indeed possible (Angew. Chem. Int. Ed. Engl., 30, 1028. 1991)!. Cram and co-workers synthesized a variety of spheroidal molecu-.

  1. Single-Molecule Spectroscopy

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 20; Issue 2. Single-Molecule Spectroscopy: Every Molecule is Different! Kankan Bhattacharyya. General Article Volume 20 Issue 2 February 2015 pp 151-164. Fulltext. Click here to view fulltext PDF. Permanent link:

  2. Algebraic theory of molecules

    CERN Document Server

    Iachello, F


    1. The Wave Mechanics of Diatomic Molecules. 2. Summary of Elements of Algebraic Theory. 3. Mechanics of Molecules. 4. Three-Body Algebraic Theory. 5. Four-Body Algebraic Theory. 6. Classical Limit and Coordinate Representation. 8. Prologue to the Future. Appendices. Properties of Lie Algebras; Coupling of Algebras; Hamiltonian Parameters


    NARCIS (Netherlands)


    In this paper, some results obtained on the formation of isolated molecules of composition SnOx in silver and SnFx in copper-are reviewed. Hyperfine interaction and ion beam interaction techniques were used for the identification of these molecules.

  4. Electrons in Molecules

    Indian Academy of Sciences (India)

    “What are electrons doing in molecules?” This is a deceptively simple question that scientists have been trying to answer for more than eighty years. With the advent of quantum mechanics in 1926, it became clear that we must understand the dynamics of electronic motion in atoms, molecules and solids in order to explain ...

  5. Molecule of the Month

    Indian Academy of Sciences (India)

    Atoms in a molecule generally prefer, particularly among the neighbouring ones, certain optimmn geometrical relationships. These are manifested in specific ranges of bond lengths, bond angles, torsion angles etc. As it always happens, chemists are interested in making molecules where these 'standard relationships' are ...

  6. Single molecule electronic devices. (United States)

    Song, Hyunwook; Reed, Mark A; Lee, Takhee


    Single molecule electronic devices in which individual molecules are utilized as active electronic components constitute a promising approach for the ultimate miniaturization and integration of electronic devices in nanotechnology through the bottom-up strategy. Thus, the ability to understand, control, and exploit charge transport at the level of single molecules has become a long-standing desire of scientists and engineers from different disciplines for various potential device applications. Indeed, a study on charge transport through single molecules attached to metallic electrodes is a very challenging task, but rapid advances have been made in recent years. This review article focuses on experimental aspects of electronic devices made with single molecules, with a primary focus on the characterization and manipulation of charge transport in this regime. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Single-molecule magnet engineering

    DEFF Research Database (Denmark)

    Pedersen, Kasper Steen; Bendix, Jesper; Clérac, Rodolphe


    Tailoring the specific magnetic properties of any material relies on the topological control of the constituent metal ion building blocks. Although this general approach does not seem to be easily applied to traditional inorganic bulk magnets, coordination chemistry offers a unique tool...... to delicately tune, for instance, the properties of molecules that behave as "magnets", the so-called single-molecule magnets (SMMs). Although many interesting SMMs have been prepared by a more or less serendipitous approach, the assembly of predesigned, isolatable molecular entities into higher nuclearity...... complexes constitutes an elegant and fascinating strategy. This Feature article focuses on the use of building blocks or modules (both terms being used indiscriminately) to direct the structure, and therefore also the magnetic properties, of metal ion complexes exhibiting SMM behaviour. This journal is...

  8. Synthetic small molecules as machines: a chemistry perspective

    Indian Academy of Sciences (India)



    Jul 1, 2017 ... 1953: Mechanical Bonds in Molecules. Mid-20th century: Chemists were trying to build molecular chains in which ring-shaped molecules were linked together. The dream: To create mechanical bonds, where molecules are interlocked without the atoms interacting directly with each other. Frisch, H. L. ...

  9. Visualizing Chemical Bonds in Synthetic Molecules (United States)

    Collins, Laura C.; Ruth, Anthony; Green, David B.; Janko, Boldizsar; Gomes, Kenjiro K.

    The use of synthetic quantum systems makes it possible to study phenomena that cannot be probed by conventional experiments. We created synthetic molecules using atomic manipulation and directly imaged the chemical bonds using tunneling spectroscopy. These synthetic systems allow us to probe the structure and electronic properties of chemical bonds in molecules, including those that would be unstable in nature, with unprecedented detail. The experimental images of electronic states in our synthetic molecules show a remarkable match to the charge distribution predicted by density functional theory calculations. The statistical analysis of the spectroscopy of these molecules can be adapted in the future to quantify aromaticity, which has been difficult to quantify universally thus far due to vague definitions. We can also study anti-aromatic molecules which are unstable naturally, to illuminate the electronic consequences of antiaromaticity.

  10. Single molecule logical devices. (United States)

    Renaud, Nicolas; Hliwa, Mohamed; Joachim, Christian


    After almost 40 years of development, molecular electronics has given birth to many exciting ideas that range from molecular wires to molecular qubit-based quantum computers. This chapter reviews our efforts to answer a simple question: how smart can a single molecule be? In our case a molecule able to perform a simple Boolean function is a child prodigy. Following the Aviram and Ratner approach, these molecules are inserted between several conducting electrodes. The electronic conduction of the resulting molecular junction is extremely sensitive to the chemical nature of the molecule. Therefore designing this latter correctly allows the implementation of a given function inside the molecular junction. Throughout the chapter different approaches are reviewed, from hybrid devices to quantum molecular logic gates. We particularly stress that one can implement an entire logic circuit in a single molecule, using either classical-like intramolecular connections, or a deformation of the molecular orbitals induced by a conformational change of the molecule. These approaches are radically different from the hybrid-device approach, where several molecules are connected together to build the circuit.

  11. Dynamics of Activated Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Mullin, Amy S. [Univ. of Maryland, College Park, MD (United States)


    Experimental studies have been performed to investigate the collisional energy transfer processes of gas-phase molecules that contain large amounts of internal energy. Such molecules are prototypes for molecules under high temperature conditions relevant in combustion and information about their energy transfer mechanisms is needed for a detailed understanding and modeling of the chemistry. We use high resolution transient IR absorption spectroscopy to measure the full, nascent product distributions for collisions of small bath molecules that relax highly vibrationally excited pyrazine molecules with E=38000 cm-1 of vibrational energy. To perform these studies, we developed new instrumentation based on modern IR light sources to expand our experimental capabilities to investigate new molecules as collision partners. This final report describes our research in four areas: the characterization of a new transient absorption spectrometer and the results of state-resolved collision studies of pyrazine(E) with HCl, methane and ammonia. Through this research we have gained fundamental new insights into the microscopic details of relatively large complex molecules at high energy as they undergo quenching collisions and redistribute their energy.

  12. Direct and Indirect Effects of Cytomegalovirus-induced gamma-delta T Cells after Kidney Transplantation

    Directory of Open Access Journals (Sweden)

    Lionel eCouzi


    Full Text Available Despite effective anti-viral therapies, cytomegalovirus (CMV is still associated with direct (CMV disease and indirect effects (rejection and poor graft survival in kidney transplant recipients. Recently, an unconventional T cell population (collectively designated as Vδ2neg γδ T cells has been characterized during the anti-CMV immune response in all solid-organ and bone-marrow transplant recipients, neonates, and healthy people. These CMV-induced γδ T cells undergo a dramatic and stable expansion after CMV infection, in a conventional ‘adaptive’ manner. Similarly as CMV-specific CD8+ αβ T cells, they exhibit an effector/memory TEMRA phenotype and cytotoxic effector functions. Activation of Vd2neg gd T cells by CMV-infected cells involves the TCR and still ill-defined co-stimulatory molecules such LFA-1. A multiple of Vd2neg gd TCR ligands are apparently recognized on CMV-infected cells, the first one identified being the MHC-related molecule endothelial protein C receptor (EPCR. A singularity of CMV-induced Vd2neg gd T cells is to acquire CD16 expression and to exert an antibody-dependent cell-mediated inhibition on CMV replication, which is controlled by a specific cytokine microenvironment. Beyond the well-demonstrated direct anti-CMV effect of Vδ2neg γδ T cells, unexpected indirect effects of these cells have been also observed in the context of kidney transplantation. CMV-induced Vδ2neg γδ T cells have been involved in surveillance of malignancy subsequent to long term immunosuppression. Moreover, CMV-induced CD16+ γδ T cells are cell effectors of antibody-mediated rejection of kidney transplants, and represent a new physiopathological contribution to the well-known association between CMV infection and poor graft survival. All these basic and clinical studies paved the road to the development of a future γδ T cell-based immunotherapy. In the meantime, γδ T cell monitoring should prove a valuable immunological

  13. Electron correlation in molecules

    CERN Document Server

    Wilson, S


    Electron correlation effects are of vital significance to the calculation of potential energy curves and surfaces, the study of molecular excitation processes, and in the theory of electron-molecule scattering. This text describes methods for addressing one of theoretical chemistry's central problems, the study of electron correlation effects in molecules.Although the energy associated with electron correlation is a small fraction of the total energy of an atom or molecule, it is of the same order of magnitude as most energies of chemical interest. If the solution of quantum mechanical equatio

  14. Heavy exotic molecules (United States)

    Liu, Yizhuang; Zahed, Ismail

    We briefly review the formation of pion-mediated heavy-light exotic molecules with both charm and bottom, under the general structures of chiral and heavy quark symmetries. The charm isosinglet exotic molecules with JPC = 1++ binds, which we identify as the reported neutral X(3872). The bottom isotriplet exotic with JPC = 1+1 binds, and is identified as a mixed state of the reported charged exotics Zb+(10610) and Zb-(10650). The bound bottom isosinglet molecule with JPC = 1++ is a possible neutral Xb(10532) to be observed.

  15. Single molecules and nanotechnology

    CERN Document Server

    Vogel, Horst


    This book focuses on recent advances in the rapidly evolving field of single molecule research. These advances are of importance for the investigation of biopolymers and cellular biochemical reactions, and are essential to the development of quantitative biology. Written by leading experts in the field, the articles cover a broad range of topics, including: quantum photonics of organic dyes and inorganic nanoparticles their use in detecting properties of single molecules the monitoring of single molecule (enzymatic) reactions single protein (un)folding in nanometer-sized confined volumes the dynamics of molecular interactions in biological cells The book is written for advanced students and scientists who wish to survey the concepts, techniques and results of single molecule research and assess them for their own scientific activities.

  16. Quantum dot molecules

    CERN Document Server

    Wu, Jiang


    This book reviews recent advances in the exciting and rapidly growing field of quantum dot molecules (QDMs). It offers state-of-the-art coverage of novel techniques and connects fundamental physical properties with device design.

  17. Electron-molecule collisions

    CERN Document Server

    Takayanagi, Kazuo


    Scattering phenomena play an important role in modern physics. Many significant discoveries have been made through collision experiments. Amongst diverse kinds of collision systems, this book sheds light on the collision of an electron with a molecule. The electron-molecule collision provides a basic scattering problem. It is scattering by a nonspherical, multicentered composite particle with its centers having degrees of freedom of motion. The molecule can even disintegrate, Le., dissociate or ionize into fragments, some or all of which may also be molecules. Although it is a difficult problem, the recent theoretical, experimental, and computational progress has been so significant as to warrant publication of a book that specializes in this field. The progress owes partly to technical develop­ ments in measurements and computations. No less important has been the great and continuing stimulus from such fields of application as astrophysics, the physics of the earth's upper atmosphere, laser physics, radiat...

  18. The plasma levels of soluble HLA-G molecules correlate directly with CD34+ cell concentration and HLA-G 14bp insertion/insertion polymorphism in cord blood donors. (United States)

    Capittini, Cristina; Bergamaschi, Paola; Sachetto, Sara; Truglio, Mariarosa; Viola, Monica; Marchesi, Andrea; Genovese, Valeria; Romano, Bina; Guarene, Marco; Poma, Rossella; Martinetti, Miryam; Tinelli, Carmine; Salvaneschi, Laura


    Cord blood provides haematopoietic stem cells for allogeneic transplantation and, thanks to the naivety of its immune system, has several advantages over other sources of stem cells. In the transplantation setting, the presence of immunosuppressive human leucocyte antigen (HLA)-G molecules has been advocated to prevent both rejection and Graft-versus-Host disease. HLA-G is physiologically expressed throughout pregnancy and is contained in cord blood at birth. Moreover, it has recently been reported that not only cord blood mesenchymal cells, but also CD34+ cell progenies produce soluble HLA-G (sHLA-G). We tried to identify the largest producer of sHLA-G among 85 healthy cord blood donors at Pavia Cord Blood Bank, correlating the sHLA-G concentration with the HLA-G 14bp insertion/deletion (INS/DEL) genotype and CD34+ cell concentration. We measured sHLA-G levels in 36 cord blood plasma stored at -20 °C for 2 months and 49 cord blood plasma stored at -196 °C for 4-6 years, by enzyme-linked immunosorbent assay. All cord blood donors were genotyped for the HLA-G 14bp INS/DEL polymorphism by polymerase chain reaction. For each cord blood unit, we measured the cell concentration by flow cytometry. We did not find differences in sHLA-G levels between cord blood plasma aliquots stored for 4-6 years at -196 °C and cord blood plasma aliquots stored for 2 months at -20 °C. We observed a higher sHLA-G concentration in cord blood plasma donors who carried the HLA-G 14bp INS/INS genotype and had higher CD34+ cell concentrations (P=0.006). This is the first report showing that the best cord blood stem cell donor is also the best sHLA-G producer, particularly if genetically characterized by the HLA-G 14bp INS/INS genotype. If the therapeutic role of sHLA-G molecules were to be finally established in the transplantation setting, our data suggest that cord blood plasma donors can provide a safe source of allogeneic sHLA-G immunosuppressive molecules ready for transfusion.


    Energy Technology Data Exchange (ETDEWEB)

    Loinard, Laurent; Menten, Karl M.; Guesten, Rolf [Max-Planck Institut fuer Radioastronomie, Auf dem Huegel 69, 53121 Bonn (Germany); Zapata, Luis A.; Rodriguez, Luis F. [Centro de Radioastronomia y Astrofisica, Universidad Nacional Autonoma de Mexico, Apartado Postal 3-72, 58090 Morelia, Michoacan (Mexico)


    We report the detection toward {eta} Carinae of six new molecules, CO, CN, HCO{sup +}, HCN, HNC, and N{sub 2}H{sup +}, and of two of their less abundant isotopic counterparts, {sup 13}CO and H{sup 13}CN. The line profiles are moderately broad ({approx}100 km s{sup -1}), indicating that the emission originates in the dense, possibly clumpy, central arcsecond of the Homunculus Nebula. Contrary to previous claims, CO and HCO{sup +} do not appear to be underabundant in {eta} Carinae. On the other hand, molecules containing nitrogen or the {sup 13}C isotope of carbon are overabundant by about one order of magnitude. This demonstrates that, together with the dust responsible for the dimming of {eta} Carinae following the Great Eruption, the molecules detected here must have formed in situ out of CNO-processed stellar material.

  20. The reaction dynamics of alkali dimer molecules and electronically excited alkali atoms with simple molecules

    Energy Technology Data Exchange (ETDEWEB)

    Hou, Hongtao [Univ. of California, Berkeley, CA (United States). Dept. of Chemistry


    This dissertation presents the results from the crossed molecular beam studies on the dynamics of bimolecular collisions in the gas phase. The primary subjects include the interactions of alkali dimer molecules with simple molecules, and the inelastic scattering of electronically excited alkali atoms with O2. The reaction of the sodium dimers with oxygen molecules is described in Chapter 2. Two reaction pathways were observed for this four-center molecule-molecule reaction, i.e. the formations of NaO2 + Na and NaO + NaO. NaO2 products exhibit a very anisotropic angular distribution, indicating a direct spectator stripping mechanism for this reaction channel. The NaO formation follows the bond breaking of O2, which is likely a result of a charge transfer from Na2 to the excited state orbital of O2-. The scattering of sodium dimers from ammonium and methanol produced novel molecules, NaNH3 and Na(CH3OH), respectively. These experimental observations, as well as the discussions on the reaction dynamics and the chemical bonding within these molecules, will be presented in Chapter 3. The lower limits for the bond dissociation energies of these molecules are also obtained. Finally, Chapter 4 describes the energy transfer between oxygen molecules and electronically excited sodium atoms.

  1. Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. (United States)

    Kean, Leslie S; Turka, Laurence A; Blazar, Bruce R


    In the past decade, the power of harnessing T-cell co-signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR-Ts) and second, re-animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re-ignite T-cell immunity, in order to eradicate tumors. In transplantation, there is also great interest in targeting T-cell co-signaling, but with the opposite goal: in this field, we seek the Yin to cancer immunotherapy's Yang, and focus on manipulating T-cell co-signaling to induce tolerance rather than activation. In this review, we discuss the major T-cell signaling pathways that are being investigated for tolerance induction, detailing preclinical studies and the path to the clinic for many of these molecules. These include blockade of co-stimulation pathways and agonism of coinhibitory pathways, in order to achieve the delicate state of balance that is transplant tolerance: a state which guarantees lifelong transplant acceptance without ongoing immunosuppression, and with preservation of protective immune responses. In the context of the clinical translation of immune tolerance strategies, we discuss the significant challenge that is embodied by the fact that targeted pathway modulators may have opposing effects on tolerance based on their impact on effector vs regulatory T-cell biology. Achieving this delicate balance holds the key to the major challenge of transplantation: lifelong control of alloreactivity while maintaining an otherwise intact immune system. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Nanodevices for generating power from molecules and batteryless sensing (United States)

    Wang, Yinmin; Wang, Xianying; Hamza, Alex V.


    A nanoconverter or nanosensor is disclosed capable of directly generating electricity through physisorption interactions with molecules that are dipole containing organic species in a molecule interaction zone. High surface-to-volume ratio semiconductor nanowires or nanotubes (such as ZnO, silicon, carbon, etc.) are grown either aligned or randomly-aligned on a substrate. Epoxy or other nonconductive polymers are used to seal portions of the nanowires or nanotubes to create molecule noninteraction zones. By correlating certain molecule species to voltages generated, a nanosensor may quickly identify which species is detected. Nanoconverters in a series parallel arrangement may be constructed in planar, stacked, or rolled arrays to supply power to nano- and micro-devices without use of external batteries. In some cases breath, from human or other life forms, contain sufficient molecules to power a nanoconverter. A membrane permeable to certain molecules around the molecule interaction zone increases specific molecule nanosensor selectivity response.

  3. Nanodevices for generating power from molecules and batteryless sensing

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yinmin; Wang, Xianying; Hamza, Alex V.


    A nanoconverter or nanosensor is disclosed capable of directly generating electricity through physisorption interactions with molecules that are dipole containing organic species in a molecule interaction zone. High surface-to-volume ratio semiconductor nanowires or nanotubes (such as ZnO, silicon, carbon, etc.) are grown either aligned or randomly-aligned on a substrate. Epoxy or other nonconductive polymers are used to seal portions of the nanowires or nanotubes to create molecule noninteraction zones. By correlating certain molecule species to voltages generated, a nanosensor may quickly identify which species is detected. Nanoconverters in a series parallel arrangement may be constructed in planar, stacked, or rolled arrays to supply power to nano- and micro-devices without use of external batteries. In some cases breath, from human or other life forms, contain sufficient molecules to power a nanoconverter. A membrane permeable to certain molecules around the molecule interaction zone increases specific molecule nanosensor selectivity response.

  4. Nanodevices for generating power from molecules and batteryless sensing (United States)

    Wang, Yinmin; Wang, Xianying; Hamza, Alex V.


    A nanoconverter or nanosensor is disclosed capable of directly generating electricity through physisorption interactions with molecules that are dipole containing organic species in a molecule interaction zone. High surface-to-volume ratio semiconductor nanowires or nanotubes (such as ZnO, silicon, carbon, etc.) are grown either aligned or randomly-aligned on a substrate. Epoxy or other nonconductive polymers are used to seal portions of the nanowires or nanotubes to create molecule noninteraction zones. By correlating certain molecule species to voltages generated, a nanosensor may quickly identify which species is detected. Nanoconverters in a series parallel arrangement may be constructed in planar, stacked, or rolled arrays to supply power to nano- and micro-devices without use of external batteries. In some cases breath, from human or other life forms, contain sufficient molecules to power a nanoconverter. A membrane permeable to certain molecules around the molecule interaction zone increases specific molecule nanosensor selectivity response.

  5. CD28: Direct and Critical Receptor for Superantigen Toxins

    Directory of Open Access Journals (Sweden)

    Ziv Rotfogel


    Full Text Available Every adaptive immune response requires costimulation through the B7/CD28 axis, with CD28 on T-cells functioning as principal costimulatory receptor. Staphylococcal and streptococcal superantigen toxins hyperstimulate the T-cell-mediated immune response by orders of magnitude, inducing a lethal cytokine storm. We show that to elicit an inflammatory cytokine storm and lethality, superantigens must bind directly to CD28. Blocking access of the superantigen to its CD28 receptor with peptides mimicking the contact domains in either toxin or CD28 suffices to protect mice effectively from lethal shock. Our finding that CD28 is a direct receptor of superantigen toxins broadens the scope of microbial pathogen recognition mechanisms.

  6. Molecule of the Month

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 1; Issue 2. Molecule of the Month Isomers of Benzene - Still Pursuing Dreams. J Chandrasekhar. Feature Article Volume 1 Issue 2 February 1996 pp 80-83. Fulltext. Click here to view fulltext PDF. Permanent link:

  7. Electrons in Molecules

    Indian Academy of Sciences (India)

    etc.) as well as explain the variations in bond lengths, bond angles, conformational angles, barriers to internal rotation! inversion, stretching!bending force constants, etc. However, when a molecule is quite large, with many occupied MOs, it is not advisable to bypass the actual computation of forces. As another application of ...

  8. Molecule-based magnets

    Indian Academy of Sciences (India)

    Keywords. Molecular lattices; spin–spin interaction; photo-induced magnetism; single molecule magnets. ... Since the first successful synthesis of molecular magnets in 1986, a large variety of them have been synthesized, which can be categorized on the basis of the chemical nature of the magnetic units involved: organic-, ...

  9. Atoms, Molecules, and Compounds

    CERN Document Server

    Manning, Phillip


    Explores the atoms that govern chemical processes. This book shows how the interactions between simple substances such as salt and water are crucial to life on Earth and how those interactions are predestined by the atoms that make up the molecules.

  10. Quantum Interference of Molecules

    Indian Academy of Sciences (India)

    IAS Admin

    GENERAL │ ARTICLE. Quantum Interference of Molecules. Probing the Wave Nature of Matter. Anu Venugopalan. Keywords. Matter waves, wave-particle du- ality, electron interference, decoherence. Anu Venugopalan is on the faculty of the School of. Basic and Applied. Sciences, GGS. Indraprastha University,. Delhi.

  11. On quark molecules

    CERN Document Server

    Dolgov, A D; Okun, Lev Borisovich


    A nonrelativistic quark model with three triplets and an octet of coloured gluons is considered. The interaction energy is calculated for some quark molecules. It is shown that states of the type qqqq and qqqqq are bounded more tightly than qq and qqq, respectively. This may indicate an existence of exotic particles in the nature or, perhaps, that the model is invalid. (11 refs).

  12. Atoms, Molecules and Radiation

    Indian Academy of Sciences (India)

    IAS Admin

    A Refresher Course in Applications of Quantum Mechanics to 'Atoms, Molecules and Radiation' will be held at the Indian Academy of Sciences, Bangalore from December 8 to 20. 2014. The Course is primarily aimed at teachers teaching quantum mechanics and/ or atomic and molecular physics at the UG / PG level.

  13. Molecule of the Month

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 16; Issue 12. Molecule of the Month - Molecular-Chameleon: Solvatochromism at its Iridescent Best! Photon Rao. Volume 16 Issue 12 December 2011 pp 1303-1306. Fulltext. Click here to view fulltext PDF. Permanent link:

  14. Molecule of the Month

    Indian Academy of Sciences (India)

    attempting to adapt the success of organic chemistry in the study of organosilicon compounds. Nevertheless chemists persisted with a sense of doggedness to try and mimic organic molecules with non- carbon elements. The year 1981 marks a watershed in the efforts to prepare and stabilise multiply-bonded compounds of ...

  15. Atoms, Molecules and Radiation

    Indian Academy of Sciences (India)

    IAS Admin


    Nov 10, 2015 ... Module 3: Interaction of electromagnetic radiation with matter: Quantum theory of radiation, spontaneous, stimulated emission and absorption probabilities, electric dipole selection rules, Einstein A and B coefficients, Rabi coefficients, Thomson Scattering, Jaynes-Cummings Model. Module 4: Molecules ...

  16. Molecule of the Month

    Indian Academy of Sciences (India)

    ethanol, blue in isopropyl alcohol, green in acetone and greenish-yellow in anisole. The electronic absorption spectrum of a molecule often depends on the solvent used. The change in position (and, sometimes, intensity) of the UVNis band accompanying a change in the polarity of the medium is called solvatochromism.

  17. Excitons: Molecules in flatland (United States)

    Yao, Wang


    Forming molecules from atoms is commonplace in dense atomic gases. But it now seems that some two-dimensional materials provide a suitable environment for creating complex molecular states from the hydrogen-like electron-hole pairs that form in semiconductors.

  18. Molecule of the Month

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 1; Issue 9. Molecule of the Month Adamantane - A Plastic Piece of Diamond. J Chandrasekhar. Feature Article Volume 1 Issue 9 September 1996 pp 66-71. Fulltext. Click here to view fulltext PDF. Permanent link:

  19. Single-Molecule Spectroscopy

    Indian Academy of Sciences (India)

    IAS Admin

    a heterogeneous medium the local environment of each molecule may be different. This gives rise to large vari- ations of those properties which depend on the medium. (e.g., local polarity or viscosity). For instance, in a bio- logical cell the local environment at the membrane may be drastically different from that in the ...

  20. Molecule of the Month

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 16; Issue 12. Molecule of the Month - Adamantane - A Plastic Piece of Diamond. J Chandrasekhar. Volume 16 Issue 12 December 2011 pp 1232-1237. Fulltext. Click here to view fulltext PDF. Permanent link:

  1. OMG: Open Molecule Generator

    Directory of Open Access Journals (Sweden)

    Peironcely Julio E


    Full Text Available Abstract Computer Assisted Structure Elucidation has been used for decades to discover the chemical structure of unknown compounds. In this work we introduce the first open source structure generator, Open Molecule Generator (OMG, which for a given elemental composition produces all non-isomorphic chemical structures that match that elemental composition. Furthermore, this structure generator can accept as additional input one or multiple non-overlapping prescribed substructures to drastically reduce the number of possible chemical structures. Being open source allows for customization and future extension of its functionality. OMG relies on a modified version of the Canonical Augmentation Path, which grows intermediate chemical structures by adding bonds and checks that at each step only unique molecules are produced. In order to benchmark the tool, we generated chemical structures for the elemental formulas and substructures of different metabolites and compared the results with a commercially available structure generator. The results obtained, i.e. the number of molecules generated, were identical for elemental compositions having only C, O and H. For elemental compositions containing C, O, H, N, P and S, OMG produces all the chemically valid molecules while the other generator produces more, yet chemically impossible, molecules. The chemical completeness of the OMG results comes at the expense of being slower than the commercial generator. In addition to being open source, OMG clearly showed the added value of constraining the solution space by using multiple prescribed substructures as input. We expect this structure generator to be useful in many fields, but to be especially of great importance for metabolomics, where identifying unknown metabolites is still a major bottleneck.

  2. Novel Applications of Buffer-gas Cooling to Cold Atoms, Diatomic Molecules, and Large Molecules (United States)

    Drayna, Garrett Korda

    Cold gases of atoms and molecules provide a system for the exploration of a diverse set of physical phenomena. For example, cold gasses of magnetically and electrically polar atoms and molecules are ideal systems for quantum simulation and quantum computation experiments, and cold gasses of large polar molecules allow for novel spectroscopic techniques. Buffer-gas cooling is a robust and widely applicable method for cooling atoms and molecules to temperatures of approximately 1 Kelvin. In this thesis, I present novel applications of buffer-gas cooling to obtaining gases of trapped, ultracold atoms and diatomic molecules, as well as the study of the cooling of large organic molecules. In the first experiment of this thesis, a buffer-gas beam source of atoms is used to directly load a magneto-optical trap. Due to the versatility of the buffer-gas beam source, we obtain trapped, sub-milliKelvin gases of four different lanthanide species using the same experimental apparatus. In the second experiment of this thesis, a buffer-gas beam is used as the initial stage of an experiment to directly laser cool and magneto-optically trap the diatomic molecule CaF. In the third experiment of this thesis, buffer-gas cooling is used to study the cooling of the conformational state of large organic molecules. We directly observe conformational relaxation of gas-phase 1,2-propanediol due to cold collisions with helium gas. Lastly, I present preliminary results on a variety of novel applications of buffer-gas cooling, such as mixture analysis, separation of chiral mixtures, the measurement of parity-violation in chiral molecules, and the cooling and spectroscopy of highly unstable reaction intermediates.

  3. Annual review of cold atoms and molecules

    CERN Document Server

    Bongs, Kai; Carr, Lincoln D; Rey, Ana Maria; Zhai, Hui


    The aim of this book is to present review articles describing the latest theoretical and experimental developments in the field of cold atoms and molecules. Our hope is that this series will promote research by both highlighting recent breakthroughs and by outlining some of the most promising research directions in the field.

  4. Molecules on si: electronics with chemistry. (United States)

    Vilan, Ayelet; Yaffe, Omer; Biller, Ariel; Salomon, Adi; Kahn, Antoine; Cahen, David


    Basic scientific interest in using a semiconducting electrode in molecule-based electronics arises from the rich electrostatic landscape presented by semiconductor interfaces. Technological interest rests on the promise that combining existing semiconductor (primarily Si) electronics with (mostly organic) molecules will result in a whole that is larger than the sum of its parts. Such a hybrid approach appears presently particularly relevant for sensors and photovoltaics. Semiconductors, especially Si, present an important experimental test-bed for assessing electronic transport behavior of molecules, because they allow varying the critical interface energetics without, to a first approximation, altering the interfacial chemistry. To investigate semiconductor-molecule electronics we need reproducible, high-yield preparations of samples that allow reliable and reproducible data collection. Only in that way can we explore how the molecule/electrode interfaces affect or even dictate charge transport, which may then provide a basis for models with predictive power.To consider these issues and questions we will, in this Progress Report, review junctions based on direct bonding of molecules to oxide-free Si.describe the possible charge transport mechanisms across such interfaces and evaluate in how far they can be quantified.investigate to what extent imperfections in the monolayer are important for transport across the monolayer.revisit the concept of energy levels in such hybrid systems.

  5. Atoms, molecules & elements

    CERN Document Server

    Graybill, George


    Young scientists will be thrilled to explore the invisible world of atoms, molecules and elements. Our resource provides ready-to-use information and activities for remedial students using simplified language and vocabulary. Students will label each part of the atom, learn what compounds are, and explore the patterns in the periodic table of elements to find calcium (Ca), chlorine (Cl), and helium (He) through hands-on activities.

  6. Photonic Molecules and Spectral Engineering (United States)

    Boriskina, Svetlana V.

    This chapter reviews the fundamental optical properties and applications of photonic molecules (PMs) - photonic structures formed by electromagnetic coupling of two or more optical microcavities (photonic atoms). Controllable interaction between light and matter in photonic atoms can be further modified and enhanced by the manipulation of their mutual coupling. Mechanical and optical tunability of PMs not only adds new functionalities to microcavity-based optical components but also paves the way for their use as testbeds for the exploration of novel physical regimes in atomic physics and quantum optics. Theoretical studies carried on for over a decade yielded novel PM designs that make possible lowering thresholds of semiconductor microlasers, producing directional light emission, achieving optically induced transparency, and enhancing sensitivity of microcavity-based bio-, stress-, and rotation sensors. Recent advances in material science and nano-fabrication techniques make possible the realization of optimally tuned PMs for cavity quantum electrodynamic experiments, classical and quantum information processing, and sensing.

  7. Hadronic molecules with hidden charm and bottom

    Directory of Open Access Journals (Sweden)

    Guo Feng-Kun


    Full Text Available Many of the new structures observed since 2003 in experiments in the heavy quarkonium mass region, such as the X(3872 and Zc (3900, are rather close to certain thresholds, and thus can be good candidates of hadronic molecules, which are loose bound systems of hadrons. We will discuss the consequences of heavy quark symmetry for hadronic molecules with heavy quarks. We will also emphasize that the hadronic molecular component of a given structure can be directly probed in long-distance processes, while the short-distance processes are not sensitive to it.

  8. Single molecule insights on conformational selection and induced fit mechanism

    DEFF Research Database (Denmark)

    Hatzakis, Nikos


    of unsynchronized molecules, often masking intrinsic dynamic behavior of proteins and biologically significant transient intermediates. Single molecule measurements are emerging as a powerful tool for characterizing protein function. They offer the direct observation and quantification of the activity, abundance...... and lifetime of multiple states and transient intermediates in the energy landscape, that are typically averaged out in non-synchronized ensemble measurements. Here we survey new insights from single molecule studies that advance our understanding of the molecular mechanisms underlying biomolecular recognition....

  9. Soluble Co-Signaling Molecules Predict Long-Term Graft Outcome in Kidney-Transplanted Patients (United States)

    Melendreras, Susana G.; Martínez-Camblor, Pablo; Menéndez, Aurora; Bravo-Mendoza, Cristina; González-Vidal, Ana; Coto, Eliecer; Díaz-Corte, Carmen; Ruiz-Ortega, Marta; López-Larrea, Carlos; Suárez-Álvarez, Beatriz


    Co-signaling molecules are responsible for full T-cell activation after solid organ transplantation. Their increased expression can lead to the release of a soluble form that can modulate the immune response post-transplantation. We analyzed the presence of co-signaling molecules (sCD30, sCD40, sCD137, sCTLA-4, sCD80, sCD28, sCD40L, sPD-1, and sPD-L1) in serum from kidney-transplanted patients (n = 59) obtained at different times (before transplantation, and 15 days, 3 months and 1 year post-transplantation) and their contribution to graft outcome was evaluated using principal component analysis. Before transplantation, high levels of soluble co-signaling molecules (mainly sCD30, sCD137 and sCD40) were detected in all patients. These molecules were modulated soon after receiving an allograft but never attained similar levels to those of healthy controls. A signature based on the determination of six soluble co-stimulatory (sCD30, sCD40, sCD137 and sCD40L) and co-inhibitory (sPD-1 and sPD-L1) molecules at 3 months post-transplantation allowed a group of patients to be identified (27.12%) with a worse long-term graft outcome. Patients with high levels of soluble molecules showed a progressive and gradual deterioration of kidney function (increased creatinine and proteinuria levels and decreased estimated glomerular filtration rate) over time and a higher risk of graft loss at 6 years post-transplantation than patients with low levels of these molecules (62.55% versus 5.14%, psoluble co-signaling molecules in kidney-transplanted patients whose quantification at 3 months post-transplantation might be a useful biomarker of immune status and help to predict long-term graft evolution. PMID:25478957

  10. Augmented CD3(+)CD8(+) and CD3(+)CD56(-) cells in cytokine-induced killer cells cultured with engineered cells for costimulatory enhancement from heavily pretreated patients with solid tumor. (United States)

    Wang, Lili; Yi, Yongxiang; Yin, Dandan; Zhou, Zhenxian; Fan, Jing; Ye, Wei; Zhao, Wei


    Cytokine-induced killer cells (CIKs) were shown to be a promising tool in the quest for new therapeutic approaches in the setting of metastatic solid tumors refractory to standard treatments. However, there is a practical clinical problem of different expansion rates and cell function as individual variability exists. Stimulatory molecular 4-1BB could promote division and survival of T cells and enhance effector activity including cytokine production. This study aimed to invest the contribution of co-stimulation signal to CIKs production for exploring new strategies, which increase the expansion and reliability of CIKs generation to improve access to CIKs therapy. We studied the larger-scale expansion of CIKs cultured with engineered cells for costimulatory enhancement (ECCE) consisting of K562 cells that expressed 4-1BBL in heavily pretreated patients with solid tumor. The proliferation and cytotoxic capacity of CIKs were evaluated. Phenotypes of CIKs were analyzed using flow cytometry. Cytokine levels of interferon (IFN)-γ and tumor necrosis factor (TNF)-α were detected using enzyme-linked immunosorbent assay (ELISA). The proliferation and cytotoxic activity of CIKs were significantly up-regulated by ECCE. The percentages of CD3(+)CD8(+) and CD3(+)CD56(-) CIKs were significantly increased while the percentage of CD3(+)CD56(+) CIKs was decreased. In addition, the secretion of IFN-γ and TNF-α by CIKs could also be enhanced significantly when ECCE were added into the culture system. This study suggests that ECCE may improve the efficacy of CIKs therapy and make CIKs therapy possible for the patients whose CIKs would be hard to be cultured using conventional methods. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  11. Properties of Complex Molecules at Metal Surfaces (United States)

    Rosei, Federico


    The adsorption of complex molecules on surfaces has recently been the subject of intensive investigation, both because of the molecules intrinsic properties, and for prospective applications (e.g. in molecular electronics) [1,2]. In general, molecular ordering on a surface is controlled by a delicate balance between intermolecular forces and molecule-substrate interactions. Under suitable conditions, these interactions can be tuned by the appropriate choice of substrate material and symmetry. Several studies have indicated that, upon molecular adsorption, surfaces do not always behave as static templates, but may rearrange dramatically to accommodate different molecular species [3,4]. By means of high-resolution, fast-scanning scanning tunneling microscopy (STM) unprecedented new insight was recently achieved into a number of fundamental processes related to the interaction of largish molecules with surfaces such as molecular diffusion [5], bonding of adsorbates on surfaces and molecular self-assembly [5,6]. In addition to the normal imaging mode, the STM tip can also be employed to manipulate single atoms and molecules in a bottom-up fashion, collectively or one at a time. In this way, molecule-induced surface restructuring processes can be revealed directly and nanostructures can be engineered with atomic precision to study surface quantum phenomena of fundamental interest. Here I will present a short review of recent work, in which several features of the complex interaction between large organic molecules and metal surfaces were revealed. The focus is on experiments performed using STM and other complementary surface-sensitive techniques. 1. F. Rosei et al., Properties of large organic molecules on metal surfaces, Prog. Surf. Science 71, 95 (2003). 2. F. Rosei, R. Rosei, Atomic description of elementary surface processes: diffusion and dynamics, Surf. Science 500, 395 (2002) 3. F. Rosei et al., Organic Molecules Acting as Templates on Metal Surfaces, Science

  12. Watching single molecules dance (United States)

    Mehta, Amit Dinesh

    Molecular motors convert chemical energy, from ATP hydrolysis or ion flow, into mechanical motion. A variety of increasingly precise mechanical probes have been developed to monitor and perturb these motors at the single molecule level. Several outstanding questions can be best approached at the single molecule level. These include: how far does a motor progress per energy quanta consumed? how does its reaction cycle respond to load? how many productive catalytic cycles can it undergo per diffusional encounter with its track? and what is the mechanical stiffness of a single molecule connection? A dual beam optical trap, in conjunction with in vitro ensemble motility assays, has been used to characterize two members of the myosin superfamily: muscle myosin II and chick brain myosin V. Both move the helical polymer actin, but myosin II acts in large ensembles to drive muscle contraction or cytokinesis, while myosin V acts in small numbers to transport vesicles. An optical trapping apparatus was rendered sufficiently precise to identify a myosin working stroke with 1nm or so, barring systematic errors such as those perhaps due to random protein orientations. This and other light microscopic motility assays were used to characterize myosin V: unlike myosin II this vesicle transport protein moves through many increments of travel while remaining strongly bound to a single actin filament. The step size, stall force, and travel distance of myosin V reveal a remarkably efficient motor capable of moving along a helical track for over a micrometer without significantly spiraling around it. Such properties are fully consistent with the putative role of an organelle transport motor, present in small numbers to maintain movement over long ranges relative to cellular size scales. The contrast between myosin II and myosin V resembles that between a human running on the moon and one walking on earth, where the former allows for faster motion when in larger ensembles but for less

  13. Passing Current through Touching Molecules

    DEFF Research Database (Denmark)

    Schull, G.; Frederiksen, Thomas; Brandbyge, Mads


    The charge flow from a single C-60 molecule to another one has been probed. The conformation and electronic states of both molecules on the contacting electrodes have been characterized using a cryogenic scanning tunneling microscope. While the contact conductance of a single molecule between two...


    African Journals Online (AJOL)


    The color of substances results from the absorption of selected components of white light by the collection of molecules constituting a visible sample of the substance. The molecules are however not coloured. Indicator molecules change their structure and composition when exposed to acids or bases, because they react ...

  15. Nitric Oxide: The Wonder Molecule

    Indian Academy of Sciences (India)

    (heart attack) and hypertension. Nitric oxide (NO), an inorganic molecule formed by vascular endothelial cells is now thought to be a messenger molecule that is believed to playa crucial role in various biological processes of both physiological and pathological importance. Nitric oxide is a simple heterodiatomic molecule ...

  16. Small Molecule Immunosensing Using Surface Plasmon Resonance

    Directory of Open Access Journals (Sweden)

    John Mitchell


    Full Text Available Surface plasmon resonance (SPR biosensors utilize refractive index changes to sensitively detect mass changes at noble metal sensor surface interfaces. As such, they have been extensively applied to immunoassays of large molecules, where their high mass and use of sandwich immunoassay formats can result in excellent sensitivity. Small molecule immunosensing using SPR is more challenging. It requires antibodies or high-mass or noble metal labels to provide the required signal for ultrasensitive assays. Also, it can suffer from steric hindrance between the small antigen and large antibodies. However, new studies are increasingly meeting these and other challenges to offer highly sensitive small molecule immunosensor technologies through careful consideration of sensor interface design and signal enhancement. This review examines the application of SPR transduction technologies to small molecule immunoassays directed to different classes of small molecule antigens, including the steroid hormones, toxins, drugs and explosives residues. Also considered are the matrix effects resulting from measurement in chemically complex samples, the construction of stable sensor surfaces and the development of multiplexed assays capable of detecting several compounds at once. Assay design approaches are discussed and related to the sensitivities obtained.

  17. Lanthanide single molecule magnets

    CERN Document Server

    Tang, Jinkui


    This book begins by providing basic information on single-molecule magnets (SMMs), covering the magnetism of lanthanide, the characterization and relaxation dynamics of SMMs, and advanced means of studying lanthanide SMMs. It then systematically introduces lanthanide SMMs ranging from mononuclear and dinuclear to polynuclear complexes, classifying them and highlighting those SMMs with high barrier and blocking temperatures – an approach that provides some very valuable indicators for the structural features needed to optimize the contribution of an Ising type spin to a molecular magnet. The final chapter presents some of the newest developments in the lanthanide SMM field, such as the design of multifunctional and stimuli-responsive magnetic materials as well as the anchoring and organization of the SMMs on surfaces. In addition, the crystal structure and magnetic data are clearly presented with a wealth of illustrations in each chapter, helping newcomers and experts alike to better grasp ongoing trends and...

  18. [Adhesion molecules and cancer]. (United States)

    Pierres, A; Benoliel, A M; Bongrand, P


    This review was aimed at summarizing recent advances in the understanding of cell adhesion in order to discuss the possible relevance of new knowledge to the exploration of cancer patients and elaboration of therapeutic strategies. During the last 10 years, many adhesion molecules were identified, thus allowing to determine their tissue distribution and functional regulation. The concept of adhesiveness was refined. It is now well known that adhesive rate (i.e., the minimal contact time required for bond formation) and binding strength (i.e., the minimal force required to detach bound cells) are distinct parameters. They may be regulated independently, and influence the cell behavior in different ways. It is now possible to achieve accurate control of tumor cell adhesiveness, either by inhibiting an adhesive mechanism (through monoclonal antibodies, competitive ligands, or inhibition of receptor expression with antisense strategy or gene knock-out) or by promoting a binding mechanism (with receptor transfection or pro-inflammatory stimulation). Recent progress opens new possibilities for diagnosis and treatment. First, the interpretation of experimental data may be improved. Cell adhesive behavior is not entirely accounted for by the density of membrane adhesion receptors. Indeed, adhesion is influenced by receptor connection to the cytoskeleton and structure of the cell coat. An adhesion receptor may be anti-metastatic through an increase in tumor cohesion and cell differentiation, or pro-metastatic, through facilitation of cell migration towards a target tissue. New therapeutic strategies may include anti-adhesive procedure aimed at preventing metastasis formation. The potential importance of a better control of inflammatory processes is also emphasized in view of the influence of these processes on the expression of adhesion molecules.

  19. Single molecule electronics and devices. (United States)

    Tsutsui, Makusu; Taniguchi, Masateru


    The manufacture of integrated circuits with single-molecule building blocks is a goal of molecular electronics. While research in the past has been limited to bulk experiments on self-assembled monolayers, advances in technology have now enabled us to fabricate single-molecule junctions. This has led to significant progress in understanding electron transport in molecular systems at the single-molecule level and the concomitant emergence of new device concepts. Here, we review recent developments in this field. We summarize the methods currently used to form metal-molecule-metal structures and some single-molecule techniques essential for characterizing molecular junctions such as inelastic electron tunnelling spectroscopy. We then highlight several important achievements, including demonstration of single-molecule diodes, transistors, and switches that make use of electrical, photo, and mechanical stimulation to control the electron transport. We also discuss intriguing issues to be addressed further in the future such as heat and thermoelectric transport in an individual molecule.

  20. Circular Intensity Differential Scattering of chiral molecules

    Energy Technology Data Exchange (ETDEWEB)

    Bustamante, C.J.


    In this thesis a theory of the Circular Intensity Differential Scattering (CIDS) of chiral molecules as modelled by a helix oriented with respect to the direction of incidence of light is presented. It is shown that a necessary condition for the existence of CIDS is the presence of an asymmetric polarizability in the scatterer. The polarizability of the scatterer is assumed generally complex, so that both refractive and absorptive phenomena are taken into account.

  1. Giant Faraday Rotation in Mesogenic Organic Molecules


    Vandendriessche, Stefaan; Cleuvenbergen, Stijn,; Willot, Pieter; Hennrich, Gunther; Srebro, Monika; V. K. Valev, Ventsislav; Koeckelberghs, Guy; Clays, Koen; Autschbach, Jochen; Verbiest, Thierry


    Faraday rotation, the rotation of the polarization of light due to a magnetic field in the direction of propagation of the light, is used in applications ranging from quantum memory to the detection of biomagnetic fields. For these applications large Faraday rotation is necessary, but absorption of light is detrimental. In search of these properties, we have characterized the Verdet constant of a so far unexplored class of mesogenic organic molecules. We report their spectra and provide an in...

  2. Single-Molecule Plasmon Sensing: Current Status and Future Prospects. (United States)

    Taylor, Adam B; Zijlstra, Peter


    Single-molecule detection has long relied on fluorescent labeling with high quantum-yield fluorophores. Plasmon-enhanced detection circumvents the need for labeling by allowing direct optical detection of weakly emitting and completely nonfluorescent species. This review focuses on recent advances in single molecule detection using plasmonic metal nanostructures as a sensing platform, particularly using a single particle-single molecule approach. In the past decade two mechanisms for plasmon-enhanced single-molecule detection have been demonstrated: (1) by plasmonically enhancing the emission of weakly fluorescent biomolecules, or (2) by monitoring shifts of the plasmon resonance induced by single-molecule interactions. We begin with a motivation regarding the importance of single molecule detection, and advantages plasmonic detection offers. We describe both detection mechanisms and discuss challenges and potential solutions. We finalize by highlighting the exciting possibilities in analytical chemistry and medical diagnostics.

  3. Electron-excited molecule interactions

    Energy Technology Data Exchange (ETDEWEB)

    Christophorou, L.G. (Oak Ridge National Lab., TN (USA) Tennessee Univ., Knoxville, TN (USA). Dept. of Physics)


    In this paper the limited but significant knowledge to date on electron scattering from vibrationally/rotationally excited molecules and electron scattering from and electron impact ionization of electronically excited molecules is briefly summarized and discussed. The profound effects of the internal energy content of a molecule on its electron attachment properties are highlighted focusing in particular on electron attachment to vibrationally/rotationally and to electronically excited molecules. The limited knowledge to date on electron-excited molecule interactions clearly shows that the cross sections for certain electron-molecule collision processes can be very different from those involving ground state molecules. For example, optically enhanced electron attachment studies have shown that electron attachment to electronically excited molecules can occur with cross sections 10{sup 6} to 10{sup 7} times larger compared to ground state molecules. The study of electron-excited molecule interactions offers many experimental and theoretical challenges and opportunities and is both of fundamental and technological significance. 54 refs., 15 figs.

  4. Single-molecule sorting of DNA helicases. (United States)

    Bain, Fletcher E; Wu, Colin G; Spies, Maria


    DNA helicases participate in virtually all aspects of cellular DNA metabolism by using ATP-fueled directional translocation along the DNA molecule to unwind DNA duplexes, dismantle nucleoprotein complexes, and remove non-canonical DNA structures. Post-translational modifications and helicase interacting partners are often viewed as determining factors in controlling the switch between bona fide helicase activity and other functions of the enzyme that do not involve duplex separation. The bottleneck in developing a mechanistic understanding of human helicases and their control by post-translational modifications is obtaining sufficient quantities of the modified helicase for traditional structure-functional analyses and biochemical reconstitutions. This limitation can be overcome by single-molecule analysis, where several hundred surface-tethered molecules are sufficient to obtain a complete kinetic and thermodynamic description of the helicase-mediated substrate binding and rearrangement. Synthetic oligonucleotides site-specifically labeled with Cy3 and Cy5 fluorophores can be used to create a variety of DNA substrates that can be used to characterize DNA binding, as well as helicase translocation and duplex unwinding activities. This chapter describes "single-molecule sorting", a robust experimental approach to simultaneously quantify, and distinguish the activities of helicases carrying their native post-translational modifications. Using this technique, a DNA helicase of interest can be produced and biotinylated in human cells to enable surface-tethering for the single-molecule studies by total internal reflection fluorescence microscopy. The pool of helicases extracted from the cells is expected to contain a mixture of post-translationally modified and unmodified enzymes, and the contributions from either population can be monitored separately, but in the same experiment providing a direct route to evaluating the effect of a given modification. Copyright

  5. Single molecule tracking (United States)

    Shera, E. Brooks


    A detection system is provided for identifying individual particles or molecules having characteristic emission in a flow train of the particles in a flow cell. A position sensitive sensor is located adjacent the flow cell in a position effective to detect the emissions from the particles within the flow cell and to assign spatial and temporal coordinates for the detected emissions. A computer is then enabled to predict spatial and temporal coordinates for the particle in the flow train as a function of a first detected emission. Comparison hardware or software then compares subsequent detected spatial and temporal coordinates with the predicted spatial and temporal coordinates to determine whether subsequently detected emissions originate from a particle in the train of particles. In one embodiment, the particles include fluorescent dyes which are excited to fluoresce a spectrum characteristic of the particular particle. Photones are emitted adjacent at least one microchannel plate sensor to enable spatial and temporal coordinates to be assigned. The effect of comparing detected coordinates with predicted coordinates is to define a moving sample volume which effectively precludes the effects of background emissions.

  6. Organic Molecules in Meteorites (United States)

    Martins, Zita


    Carbonaceous meteorites are primitive samples from the asteroid belt, containing 3-5wt% organic carbon. The exogenous delivery of organic matter by carbonaceous meteorites may have contributed to the organic inventory of the early Earth. The majority (>70%) of the meteoritic organic material consist of insoluble organic matter (IOM) [1]. The remaining meteoritic organic material (Haber-Bosch type gas-grain reactions after the meteorite parent body cooled to lower temperatures [13, 14].The analysis of the abundances and distribution of the organic molecules present in meteorites helps to determine the physical and chemical conditions of the early solar system, and the prebiotic organic compounds available on the early Earth.[1] Cody and Alexander (2005) GCA 69, 1085. [2] Cronin and Chang (1993) in: The Chemistry of Life’s Origin. pp. 209-258. [3] Martins and Sephton (2009) in: Amino acids, peptides and proteins in organic chemistry. pp. 1-42. [4] Martins (2011) Elements 7, 35. [5] Botta et al. (2007) MAPS 42, 81. [6] Martins et al. (2015) MAPS, in press. [7] Cooper and Cronin (1995) GCA 59, 1003. [8] Glavin et al. (2006) MAPS. 41, 889. [9] Glavin et al. (2011) MAPS 45, 1948. [10] Elsila et al. (2005) GCA 5, 1349. [11] Glavin and Dworkin (2009) PNAS 106, 5487. [12] Pizzarello et al. (2003) GCA 67, 1589. [13] Chan et al. (2012) MAPS. 47, 1502. [14] Burton et al. (2011) MAPS 46, 1703.

  7. Theoretical Investigations Regarding Single Molecules

    DEFF Research Database (Denmark)

    Pedersen, Kim Georg Lind

    Neoclassical Valence Bond Theory, Quantum Transport, Quantum Interference, Kondo Effect, and Electron Pumping. Trap a single organic molecule between two electrodes and apply a bias voltage across this "molecular junction". When electrons pass through the molecule, the different electron paths can...... interfere destructively or constructively. Destructive interference effects in electron transport could potentially improve thermo-electrics, organic logic circuits and energy harvesting. We have investigated destructive interference in off-resonant transport through organic molecules, and have found a set...

  8. Molecules Best Paper Award 2012

    Directory of Open Access Journals (Sweden)

    Derek J. McPhee


    Full Text Available Molecules starts to institute the “Best Paper” award to recognize these outstanding papers in the area of natural products, medicinal chemistry and molecular diversity published in Molecules. We are pleased to announce the first “Molecules Best Paper Award” for 2012. Nominations were selected by the editor-in-chief and selected editorial board members from all the papers published in 2008. [...

  9. Molecules Best Paper Award 2013

    Directory of Open Access Journals (Sweden)

    Derek J. McPhee


    Full Text Available Molecules has started to institute a "Best Paper" award to recognize the most outstanding papers in the area of natural products, medicinal chemistry and molecular diversity published in Molecules. We are pleased to announce the second "Molecules Best Paper Award" for 2013. Candidates were chosen by the Editor-in-Chief and selected editorial board members from among all the papers published in 2009.

  10. Molecules Best Paper Award 2014

    Directory of Open Access Journals (Sweden)

    Derek J. McPhee


    Full Text Available Molecules instituted some years ago a “Best Paper” award to recognize the most outstanding papers in the area of natural products, medicinal chemistry and molecular diversity published each year in Molecules. We are pleased to announce the third “Molecules Best Paper Award” for 2014. The winners were chosen by the Editor-in-Chief and selected editorial board members from among all the papers published in 2010. Reviews and research papers were evaluated separately.

  11. Biofuels: from microbes to molecules

    National Research Council Canada - National Science Library

    Lu, Xuefeng


    .... The production of different biofuel molecules including hydrogen, methane, ethanol, butanol, higher chain alcohols, isoprenoids and fatty acid derivatives, from genetically engineered microbes...

  12. Molecules Best Paper Award 2015

    Directory of Open Access Journals (Sweden)

    Derek J. McPhee


    Full Text Available Molecules instituted some years ago a “Best Paper” award to recognize the most outstanding papers in the area of organic synthesis, natural products, medicinal chemistry and molecular diversity published each year in Molecules. We are pleased to announce the third “Molecules Best Paper Award” for 2015. The winners were chosen by the Editor-in-Chief and selected editorial board members from among all the papers published in 2011. Reviews and research papers were evaluated separately. We are pleased to announce that the following eight papers have won the Molecules Best Paper Award for 2015:[...

  13. Single-molecule analysis using DNA origami. (United States)

    Rajendran, Arivazhagan; Endo, Masayuki; Sugiyama, Hiroshi


    During the last two decades, scientists have developed various methods that allow the detection and manipulation of single molecules, which have also been called "in singulo" approaches. Fundamental understanding of biochemical reactions, folding of biomolecules, and the screening of drugs were achieved by using these methods. Single-molecule analysis was also performed in the field of DNA nanotechnology, mainly by using atomic force microscopy. However, until recently, the approaches used commonly in nanotechnology adopted structures with a dimension of 10-20 nm, which is not suitable for many applications. The recent development of scaffolded DNA origami by Rothemund made it possible for the construction of larger defined assemblies. One of the most salient features of the origami method is the precise addressability of the structures formed: Each staple can serve as an attachment point for different kinds of nanoobjects. Thus, the method is suitable for the precise positioning of various functionalities and for the single-molecule analysis of many chemical and biochemical processes. Here we summarize recent progress in the area of single-molecule analysis using DNA origami and discuss the future directions of this research. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Mapping the Small Molecule Interactome by Mass Spectrometry. (United States)

    Flaxman, Hope A; Woo, Christina M


    Mapping small molecule interactions throughout the proteome provides the critical structural basis for functional analysis of their impact on biochemistry. However, translation of mass spectrometry-based proteomics methods to directly profile the interaction between a small molecule and the whole proteome is challenging because of the substoichiometric nature of many interactions, the diversity of covalent and noncovalent interactions involved, and the subsequent computational complexity associated with their spectral assignment. Recent advances in chemical proteomics have begun fill this gap to provide a structural basis for the breadth of small molecule-protein interactions in the whole proteome. Innovations enabling direct characterization of the small molecule interactome include faster, more sensitive instrumentation coupled to chemical conjugation, enrichment, and labeling methods that facilitate detection and assignment. These methods have started to measure molecular interaction hotspots due to inherent differences in local amino acid reactivity and binding affinity throughout the proteome. Measurement of the small molecule interactome is producing structural insights and methods for probing and engineering protein biochemistry. Direct structural characterization of the small molecule interactome is a rapidly emerging area pushing new frontiers in biochemistry at the interface of small molecules and the proteome.

  15. Quantum transport through single molecules

    NARCIS (Netherlands)

    Osorio Oliveros, E.A.


    This thesis describes three-terminal transport measurements through single molecules. The interest in this field stems from the dream that single molecules will form the building blocks for future nanoscale electronic devices. The advantages are their small size -nanometers-, and their synthetic

  16. Cold molecules, collisions and reactions (United States)

    Hecker Denschlag, Johannes


    I will report on recent experiments of my group where we have been studying the formation of ultracold diatomic molecules and their subsequent inelastic/reactive collisions. For example, in one of these experiments we investigate collisions of triplet Rb2 molecules in the rovibrational ground state. We observe fast molecular loss and compare the measured loss rates to predictions based on universality. In another set of experiments we investigate the formation of (BaRb)+ molecules after three-body recombination of a single Ba+ ion with two Rb atoms in an ultracold gas of Rb atoms. Our investigations indicate that the formed (BaRb)+ molecules are weakly bound and that several secondary processes take place ranging from photodissociation of the (BaRb)+ molecule to reactive collisions with Rb atoms. I will explain how we can experimentally distinguish these processes and what the typical reaction rates are. Support from the German Research foundation DFG and the European Community is acknowledged.

  17. Vibrational coupling in plasmonic molecules. (United States)

    Yi, Chongyue; Dongare, Pratiksha D; Su, Man-Nung; Wang, Wenxiao; Chakraborty, Debadi; Wen, Fangfang; Chang, Wei-Shun; Sader, John E; Nordlander, Peter; Halas, Naomi J; Link, Stephan


    Plasmon hybridization theory, inspired by molecular orbital theory, has been extremely successful in describing the near-field coupling in clusters of plasmonic nanoparticles, also known as plasmonic molecules. However, the vibrational modes of plasmonic molecules have been virtually unexplored. By designing precisely configured plasmonic molecules of varying complexity and probing them at the individual plasmonic molecule level, intramolecular coupling of acoustic modes, mediated by the underlying substrate, is observed. The strength of this coupling can be manipulated through the configuration of the plasmonic molecules. Surprisingly, classical continuum elastic theory fails to account for the experimental trends, which are well described by a simple coupled oscillator picture that assumes the vibrational coupling is mediated by coherent phonons with low energies. These findings provide a route to the systematic optical control of the gigahertz response of metallic nanostructures, opening the door to new optomechanical device strategies. Published under the PNAS license.

  18. An optical conveyor for molecules. (United States)

    Weinert, Franz M; Braun, Dieter


    Trapping single ions under vacuum allows for precise spectroscopy in atomic physics. The confinement of biological molecules in bulk water is hindered by the lack of comparably strong forces. Molecules have been immobilized to surfaces, however often with detrimental effects on their function. Here, we optically trap molecules by creating the microscale analogue of a conveyor belt: a bidirectional flow is combined with a perpendicular thermophoretic molecule drift. Arranged in a toroidal geometry, the conveyor accumulates a hundredfold excess of 5-base DNA within seconds. The concentrations of the trapped DNA scale exponentially with length, reaching trapping potential depths of 14 kT for 50 bases. The mechanism does not require microfluidics, electrodes, or surface modifications. As a result, the trap can be dynamically relocated. The optical conveyor can be used to enhance diffusion-limited surface reactions, redirect cellular signaling, observe individual biomolecules over a prolonged time, or approach single-molecule chemistry in bulk water.

  19. Clinical implications of co-inhibitory molecule expression in the tumor microenvironment for DC vaccination: a game of stop and go

    Directory of Open Access Journals (Sweden)

    Angela eVasaturo


    Full Text Available The aim of therapeutic dendritic cell (DC vaccines in cancer immunotherapy is to activate cytotoxic T cells to recognize and attack the tumor. T cell activation requires the interaction of the T cell receptor with a cognate major histocompatibility complex (MHC-peptide complex. Although initiated by antigen engagement, it is the complex balance between co-stimulatory and co-inhibitory signals on DCs that results in T cell activation or tolerance. Even when already activated, tumor-specific T cells can be neutralized by the expression of co-inhibitory molecules on tumor cells. These and other immunosuppressive cues in the tumor microenvironment are major factors currently hampering the application of DC vaccination. In this review, we discuss recent data regarding the essential and complex role of co-inhibitory molecules in regulating the immune response within the tumor microenvironment. In particular, possible therapeutic intervention strategies aimed at reversing or neutralizing suppressive networks within the tumor microenvironment will be emphasized. Importantly, blocking co-inhibitory molecule signaling, often referred to as immune checkpoint blockade, does not necessarily lead to an effective activation of tumor-specific T cells. Therefore, combination of checkpoint blockade with other immune potentiating therapeutic strategies, such as DC vaccination, might serve as a synergistic combination, capable of reversing effector T cells immunosuppression while at the same time increasing the efficacy of T cell-mediated immunotherapies. This will ultimately result in long-term anti-tumor immunity.

  20. Quantitative single-molecule imaging by confocal laser scanning microscopy. (United States)

    Vukojevic, Vladana; Heidkamp, Marcus; Ming, Yu; Johansson, Björn; Terenius, Lars; Rigler, Rudolf


    A new approach to quantitative single-molecule imaging by confocal laser scanning microscopy (CLSM) is presented. It relies on fluorescence intensity distribution to analyze the molecular occurrence statistics captured by digital imaging and enables direct determination of the number of fluorescent molecules and their diffusion rates without resorting to temporal or spatial autocorrelation analyses. Digital images of fluorescent molecules were recorded by using fast scanning and avalanche photodiode detectors. In this way the signal-to-background ratio was significantly improved, enabling direct quantitative imaging by CLSM. The potential of the proposed approach is demonstrated by using standard solutions of fluorescent dyes, fluorescently labeled DNA molecules, quantum dots, and the Enhanced Green Fluorescent Protein in solution and in live cells. The method was verified by using fluorescence correlation spectroscopy. The relevance for biological applications, in particular, for live cell imaging, is discussed.

  1. Single Molecule Electronics and Devices (United States)

    Tsutsui, Makusu; Taniguchi, Masateru


    The manufacture of integrated circuits with single-molecule building blocks is a goal of molecular electronics. While research in the past has been limited to bulk experiments on self-assembled monolayers, advances in technology have now enabled us to fabricate single-molecule junctions. This has led to significant progress in understanding electron transport in molecular systems at the single-molecule level and the concomitant emergence of new device concepts. Here, we review recent developments in this field. We summarize the methods currently used to form metal-molecule-metal structures and some single-molecule techniques essential for characterizing molecular junctions such as inelastic electron tunnelling spectroscopy. We then highlight several important achievements, including demonstration of single-molecule diodes, transistors, and switches that make use of electrical, photo, and mechanical stimulation to control the electron transport. We also discuss intriguing issues to be addressed further in the future such as heat and thermoelectric transport in an individual molecule. PMID:22969345

  2. Self-assembly patterning of organic molecules on a surface (United States)

    Pan, Minghu; Fuentes-Cabrera, Miguel; Maksymovych, Petro; Sumpter, Bobby G.; Li, Qing


    The embodiments disclosed herein include all-electron control over a chemical attachment and the subsequent self-assembly of an organic molecule into a well-ordered three-dimensional monolayer on a metal surface. The ordering or assembly of the organic molecule may be through electron excitation. Hot-electron and hot-hole excitation enables tethering of the organic molecule to a metal substrate, such as an alkyne group to a gold surface. All-electron reactions may allow a direct control over the size and shape of the self-assembly, defect structures and the reverse process of molecular disassembly from single molecular level to mesoscopic scale.

  3. Targeting the Human T-Cell Inducible COStimulator Molecule with a Monoclonal Antibody Prevents Graft-vs-Host Disease and Preserves Graft vs Leukemia in a Xenograft Murine Model

    Directory of Open Access Journals (Sweden)

    Aude Burlion


    Full Text Available BackgroundGraft-vs-host disease (GVHD is a major complication of allogenic bone marrow transplantation (BMT. Targeting costimulatory molecules with antagonist antibodies could dampen the excessive immune response that occurs, while preserving the beneficial graft vs leukemia (GVL of the allogeneic response. Previous studies using a mouse model of GVHD have shown that targeting the T-cell Inducible COStimulator (ICOS, CD278 molecule is beneficial, but it is unclear whether the same applies to human cells.MethodsHere, we assessed whether a monoclonal antibody (mAb to human ICOS was able to antagonize the costimulatory signal delivered in vivo to human T cells. To test this hypothesis, we used a xenogeneic model of GVHD where human peripheral blood mononuclear cells were adoptively transferred in immunocompromised NOD.SCID.gc-null mice (NSG.ResultsIn this model, control mice invariably lost weight and died by day 50. In contrast, 65% of the mice receiving a single injection of the anti-hICOS mAb survived beyond 100 days. Moreover, a significant improvement in survival was obtained in a curative xeno-GVHD setting. Mechanistically, administration of the anti-hICOS mAb was associated with a strong reduction in perivascular infiltrates in liver and lungs and reduction in frequencies and numbers of human T cells in the spleen. In addition, the mAb prevented T-cell expansion in the blood during xeno-GVHD. Importantly, GVHD-protected mice retained the ability to control the P815 mastocytoma cell line, mimicking GVL in humans.ConclusionA mAb-targeting human ICOS alleviated GVHD without impairing GVL in a xenograft murine model. Thus, ICOS represents a promising target in the management of BMT, preventing GVHD while preserving GVL.

  4. A Single-Molecule Diode

    National Research Council Canada - National Science Library

    Mark Elbing; Rolf Ochs; Max Koentopp; Matthias Fischer; Carsten von Hänisch; Florian Weigend; Ferdinand Evers; Heiko B. Weber; Marcel Mayor; Mark A. Ratner


    ...-systems with mutually shifted energy levels. The asymmetry thus implied manifests itself in a current-voltage characteristic with pronounced dependence on the sign of the bias voltage, which makes the molecule a prototype for a molecular diode...

  5. Fluorescence Microscopy of Single Molecules (United States)

    Zimmermann, Jan; van Dorp, Arthur; Renn, Alois


    The investigation of photochemistry and photophysics of individual quantum systems is described with the help of a wide-field fluorescence microscopy approach. The fluorescence single molecules are observed in real time.

  6. Triacylglycerol: nourishing molecule in endurance

    Indian Academy of Sciences (India)

    rich molecules as an energy sourceobtained from host cell debris remains interesting. Additionally, the potential of M. tuberculosis to survive under differentstress conditions leading to its dormant state in pathogenesis remains elusive. The exact ...

  7. Cell adhesion molecules and sleep. (United States)

    O'Callaghan, Emma Kate; Ballester Roig, Maria Neus; Mongrain, Valérie


    Cell adhesion molecules (CAMs) play essential roles in the central nervous system, where some families are involved in synaptic development and function. These synaptic adhesion molecules (SAMs) are involved in the regulation of synaptic plasticity, and the formation of neuronal networks. Recent findings from studies examining the consequences of sleep loss suggest that these molecules are candidates to act in sleep regulation. This review highlights the experimental data that lead to the identification of SAMs as potential sleep regulators, and discusses results supporting that specific SAMs are involved in different aspects of sleep regulation. Further, some potential mechanisms by which SAMs may act to regulate sleep are outlined, and the proposition that these molecules may serve as molecular machinery in the two sleep regulatory processes, the circadian and homeostatic components, is presented. Together, the data argue that SAMs regulate the neuronal plasticity that underlies sleep and wakefulness. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  8. Kondo Effect in Artificial and Real Molecules


    Kuzmenko, Tetyana


    In this Thesis we develop a novel direction in the theory of nano-objects, i.e., structures of nanometer size in a tunnel contact with macroscopic electron reservoirs (metallic leads). In particular we elucidate the Kondo effect predicted in tunneling through triple quantum dots and sandwich-type molecules adsorbed on metallic substrate, which are referred to as trimers. The unusual dynamical symmetry of nano-objects is one of the most intriguing problems, which arise in the theory of these s...

  9. Special Issue: Single Molecule Techniques


    Hans H. Gorris


    Technological advances in the detection and manipulation of single molecules have enabled new insights into the function, structure and interactions of biomolecules. This Special Issue was launched to account for the rapid progress in the field of “Single Molecule Techniques”. Four original research articles and seven review articles provide an introduction, as well as an in-depth discussion, of technical developments that are indispensable for the characterization of individual biomolecules....

  10. Plasmonic atoms and plasmonic molecules


    V. V. Klimov; Guzatov, D. V.


    The proposed paradigm of plasmonic atoms and plasmonic molecules allows one to describe and predict the strongly localized plasmonic oscillations in the clusters of nanoparticles and some other nanostructures in uniform way. Strongly localized plasmonic molecules near the contacting surfaces might become the fundamental elements (by analogy with Lego bricks) for a construction of fully integrated opto-electronic nanodevices of any complexity and scale of integration.

  11. Traversing the polymorphic landscape through tuning molecule-molecule, molecule-substrate and molecule-solvent interactions (United States)

    Purdum, Geoffrey; Gessner, Thomas; Weitz, R. Thomas; Loo, Yueh-Lin

    As subtle changes in the crystalline packing motif of molecular semiconductors can have a large impact on charge transport, a thorough understanding of the accessibility of polymorphs in thin films is needed. Using a series of core-chlorinated naphthalene tetracarboxylic diimides, we demonstrate that the choice of the alkyl substituents at the imide functionalities, as well as the choice of substrate and post-deposition processing conditions, tune the relative strengths of molecule-molecule, molecule-substrate and molecule-solvent interactions, providing a handle over polymorphic selection. We access the triclinic polymorph of NTCDI-CH2C3F7 in thermally evaporated thin films; solvent-vapor annealing induces a reversible transformation to its monoclinic polymorph. The addition of a fluoromethylene group in the alkyl substituent increases molecule-molecule interactions and, accordingly, improves the stability of its triclinic polymorph; this derivative does not undergo a polymorphic transformation with any of the post-deposition conditions we have explored.

  12. Single-Molecule Imaging of GPCR Interactions. (United States)

    Calebiro, Davide; Sungkaworn, Titiwat


    G protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors and are of great interest as pharmacological targets. Although the occurrence of GPCR signaling nanodomains has long been hypothesized based on indirect evidence, this and other fundamental aspects of GPCR signaling have been difficult to prove. The advent of single-molecule microscopy methods, which allow direct visualization of individual membrane proteins with unprecedented spatiotemporal resolution, provides unique opportunities to address several of these open questions. Indeed, recent single-molecule studies have revealed that GPCRs and G proteins transiently interact with each other as well as with structural components of the plasma membrane, leading to the formation of dynamic complexes and 'hot spots' for GPCR signaling. Whereas we are only beginning to understand the implications of this unexpected level of complexity, single-molecule approaches are likely to play a crucial role to further dissect the protein-protein interactions that are at the heart of GPCR signaling. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Small Talk: Children's Everyday `Molecule' Ideas (United States)

    Jakab, Cheryl


    This paper reports on 6-11-year-old children's `sayings and doings' (Harré 2002) as they explore molecule artefacts in dialectical-interactive teaching interviews (Fleer, Cultural Studies of Science Education 3:781-786, 2008; Hedegaard et al. 2008). This sociocultural study was designed to explore children's everyday awareness of and meaning-making with cultural molecular artefacts. Our everyday world is populated with an ever increasing range of molecular or nanoworld words, symbols, images, and games. What do children today say about these artefacts that are used to represent molecular world entities? What are the material and social resources that can influence a child's everyday and developing scientific ideas about `molecules'? How do children interact with these cognitive tools when given expert assistance? What meaning-making is afforded when children are socially and materially assisted in using molecular tools in early chemical and nanoworld thinking? Tool-dependent discursive studies show that provision of cultural artefacts can assist and direct developmental thinking across many domains of science (Schoultz et al., Human Development 44:103-118, 2001; Siegal 2008). Young children's use of molecular artefacts as cognitive tools has not received much attention to date (Jakab 2009a, b). This study shows 6-11-year-old children expressing everyday ideas of molecular artefacts and raising their own questions about the artefacts. They are seen beginning to domesticate (Erneling 2010) the words, symbols, and images to their own purposes when given the opportunity to interact with such artefacts in supported activity. Discursive analysis supports the notion that using `molecules' as cultural tools can help young children to begin `putting on molecular spectacles' (Kind 2004). Playing with an interactive game (ICT) is shown to be particularly helpful in assisting children's early meaning-making with representations of molecules, atoms, and their chemical symbols.

  14. The Molecule Cloud - compact visualization of large collections of molecules

    Directory of Open Access Journals (Sweden)

    Ertl Peter


    Full Text Available Abstract Background Analysis and visualization of large collections of molecules is one of the most frequent challenges cheminformatics experts in pharmaceutical industry are facing. Various sophisticated methods are available to perform this task, including clustering, dimensionality reduction or scaffold frequency analysis. In any case, however, viewing and analyzing large tables with molecular structures is necessary. We present a new visualization technique, providing basic information about the composition of molecular data sets at a single glance. Summary A method is presented here allowing visual representation of the most common structural features of chemical databases in a form of a cloud diagram. The frequency of molecules containing particular substructure is indicated by the size of respective structural image. The method is useful to quickly perceive the most prominent structural features present in the data set. This approach was inspired by popular word cloud diagrams that are used to visualize textual information in a compact form. Therefore we call this approach “Molecule Cloud”. The method also supports visualization of additional information, for example biological activity of molecules containing this scaffold or the protein target class typical for particular scaffolds, by color coding. Detailed description of the algorithm is provided, allowing easy implementation of the method by any cheminformatics toolkit. The layout algorithm is available as open source Java code. Conclusions Visualization of large molecular data sets using the Molecule Cloud approach allows scientists to get information about the composition of molecular databases and their most frequent structural features easily. The method may be used in the areas where analysis of large molecular collections is needed, for example processing of high throughput screening results, virtual screening or compound purchasing. Several example visualizations of large

  15. EDITORIAL: Focus on Cold and Ultracold Molecules FOCUS ON COLD AND ULTRACOLD MOLECULES (United States)

    Carr, Lincoln D.; Ye, Jun


    Cold and ultracold molecules are the next wave of ultracold physics, giving rise to an exciting array of scientific opportunities, including many body physics for novel quantum phase transitions, new states of matter, and quantum information processing. Precision tests of fundamental physical laws benefit from the existence of molecular internal structure with exquisite control. The study of novel collision and reaction dynamics will open a new chapter of quantum chemistry. Cold molecules bring together researchers from a variety of fields, including atomic, molecular, and optical physics, chemistry and chemical physics, quantum information science and quantum simulations, condensed matter physics, nuclear physics, and astrophysics, a truly remarkable synergy of scientific explorations. For the past decade there have been steady advances in direct cooling techniques, from buffer-gas cooling to cold molecular beams to electro- and magneto-molecular decelerators. These techniques have allowed a large variety of molecules to be cooled for pioneering studies. Recent amazing advances in experimental techniques combining the ultracold and the ultraprecise have furthermore brought molecules to the point of quantum degeneracy. These latter indirect cooling techniques magnetically associate atoms from a Bose-Einstein condensate and/or a quantum degenerate Fermi gas, transferring at 90% efficiency highly excited Fano-Feshbach molecules, which are on the order of 10 000 Bohr radii in size, to absolute ground state molecules just a few Bohr across. It was this latter advance, together with significant breakthroughs in internal state manipulations, which inspired us to coordinate this focus issue now, and is the reason why we say the next wave of ultracold physics has now arrived. Whether directly or indirectly cooled, heteronuclear polar molecules offer distinct new features in comparison to cold atoms, while sharing all of their advantages (purity, high coherence

  16. Proton affinities of hydrated molecules (United States)

    Valadbeigi, Younes


    Proton affinities (PA) of non-hydrated, M, and hydrated forms, M(H2O)1,2,3, of 20 organic molecules including alcohols, ethers, aldehydes, ketones and amines were calculated by the B3LYP/6-311++G(d,p) method. For homogeneous families, linear correlations were observed between PAs of the M(H2O)1,2,3 and the PAs of the non-hydrated molecules. Also, the absolute values of the hydration enthalpies of the protonated molecules decreased linearly with the PAs. The correlation functions predicted that for an amine with PA amine with PA > 1100 kJ/mol the PA(M(H2O)) is smaller than the PA.

  17. Single-Molecule Studies of Telomeres and Telomerase. (United States)

    Parks, Joseph W; Stone, Michael D


    Telomeres are specialized chromatin structures that protect chromosome ends from dangerous processing events. In most tissues, telomeres shorten with each round of cell division, placing a finite limit on cell growth. In rapidly dividing cells, including the majority of human cancers, cells bypass this growth limit through telomerase-catalyzed maintenance of telomere length. The dynamic properties of telomeres and telomerase render them difficult to study using ensemble biochemical and structural techniques. This review describes single-molecule approaches to studying how individual components of telomeres and telomerase contribute to function. Single-molecule methods provide a window into the complex nature of telomeres and telomerase by permitting researchers to directly visualize and manipulate the individual protein, DNA, and RNA molecules required for telomere function. The work reviewed in this article highlights how single-molecule techniques have been utilized to investigate the function of telomeres and telomerase.

  18. Technetium-aspirin molecule complexes

    Energy Technology Data Exchange (ETDEWEB)

    El-Shahawy, A.S.; Mahfouz, R.M.; Aly, A.A.M.; El-Zohry, M. (Assiut Univ. (Egypt))


    Technetium-aspirin and technetium-aspirin-like molecule complexes were prepared. The structure of N-acetylanthranilic acid (NAA) has been decided through CNDO calculations. The ionization potential and electron affinity of the NAA molecule as well as the charge densities were calculated. The electronic absorption spectra of Tc(V)-Asp and Tc(V)-ATS complexes have two characteristic absorption bands at 450 and 600 nm, but the Tc(V)-NAA spectrum has one characteristic band at 450 nm. As a comparative study, Mo-ATS complex was prepared and its electronic absorption spectrum is comparable with the Tc-ATS complex spectrum. (author).

  19. Exotic helium molecules; Molecules exotiques d'helium

    Energy Technology Data Exchange (ETDEWEB)

    Portier, M


    We study the photo-association of an ultracold cloud of magnetically trapped helium atoms: pairs of colliding atoms interact with one or two laser fields to produce a purely long range {sup 4}He{sub 2}(2{sup 3}S{sub 1}-2{sup 3}P{sub 0}) molecule, or a {sup 4}He{sub 2}(2{sup 3}S{sub 1}-2{sup 3}S{sub 1}) long range molecule. Light shifts in one photon photo-association spectra are measured and studied as a function of the laser polarization and intensity, and the vibrational state of the excited molecule. They result from the light-induced coupling between the excited molecule, and bound and scattering states of the interaction between two metastable atoms. Their analysis leads to the determination of the scattering length a = (7.2 {+-} 0.6) ruling collisions between spin polarized atoms. The two photon photo-association spectra show evidence of the production of polarized, long-range {sup 4}He{sub 2}(2{sup 3}S{sub 1}-2{sup 3}S{sub 1}) molecules. They are said to be exotic as they are made of two metastable atoms, each one carrying a enough energy to ionize the other. The corresponding lineshapes are calculated and decomposed in sums and products of Breit-Wigner and Fano profiles associated to one and two photon processes. The experimental spectra are fit, and an intrinsic lifetime {tau} = (1.4 {+-} 0.3) {mu}s is deduced. It is checked whether this lifetime could be limited by spin-dipole induced Penning autoionization. This interpretation requires that there is a quasi-bound state close to the dissociation threshold in the singlet interaction potential between metastable helium atoms for the theory to match the experiment. (author)

  20. Infrared light on molecule-molecule and molecule-surface collisions (United States)

    Tran, H.; Vander Auwera, J.; Landsheere, X.; Ngo, N. H.; Pangui, E.; Morales, S. B.; El Hamzaoui, H.; Capoen, B.; Bouazaoui, M.; Boulet, C.; Hartmann, J.-M.


    By analyzing measured infrared absorption of pure C H4 gas under both "free" (large sample cell) and "confined" (inside the pores of a silica xerogel sample) conditions we give a demonstration that molecule-molecule and molecule-surface collisions lead to very different propensity rules for rotational-state changes. Whereas the efficiency of collisions to change the rotational state (observed through the broadening of the absorption lines) decreases with increasing rotational quantum number J for C H4-CH4 interactions, C H4 -surface collisions lead to J -independent linewidths. In the former case, some (weak) collisions are inefficient whereas, in the latter case, a single collision is sufficient to remove the molecule from its initial rotational level. Furthermore, although some gas-phase collisions leave J unchanged and only modify the angular momentum orientation and/or symmetry of the level (as observed through the spectral effects of line mixing), this is not the case for the molecule-surface collisions since they always change J (in the studied J =0 -14 range).

  1. Biomimetic Nanoarchitectures for the Study of T Cell Activation with Single-Molecule Control (United States)

    Cai, Haogang

    Physical factors in the environment of a cell affect its function and behavior in a variety of ways. There is increasing evidence that, among these factors, the geometric arrangement of receptor ligands plays an important role in setting the conditions for critical cellular processes. The goal of this thesis is to develop new techniques for probing the role of extracellular ligand geometry, with a focus on T cell activation. In this work, top-down molecular-scale nanofabrication and bottom-up selective self-assembly were combined in order to present functional nanomaterials (primarily biomolecules) on a surface with precise spatial control and single-molecule resolution. Such biomolecule nanoarrays are becoming an increasingly important tool in surface-based in vitro assays for biosensing, molecular and cellular studies. The nanoarrays consist of metallic nanodots patterned on glass coverslips using electron beam and nanoimprint lithography, combined with self-aligned pattern transfer. The nanodots were then used as anchors for the immobilization of biological ligands, and backfilled with a protein-repellent passivation layer of polyethylene glycol. The passivation efficiency was improved to minimize nonspecific adsorption. In order to ensure true single-molecule control, we developed an on-chip protocol to measure the molecular occupancy of nanodot arrays based on fluorescence photobleaching, while accounting for quenching effects by plasmonic absorption. We found that the molecular occupancy can be interpreted as a packing problem, with the solution depending on the nanodot size and the concentration of self-assembly reagents, where the latter can be easily adjusted to control the molecular occupancy according to the dot size. The optimized nanoarrays were used as biomimetic architectures for the study of T cell activation with single-molecule control. T cell activation involves an elaborate arrangement of signaling, adhesion, and costimulatory molecules

  2. Controlling the alignment of neutral molecules by a strong laser field

    DEFF Research Database (Denmark)

    Sakai, H.; Hilligsøe, Karen Marie; Hald, K.


    A strong nonresonant nanosecond laser pulse is used to align neutral iodine molecules. The technique, applicable to both polar and nonpolar molecules, relies on the interaction between the strong laser field and the induced dipole moment of the molecules. The degree of alignment is enhanced...... is 〈cos2 θ〉 = 0.81...... by lowering the initial rotational energy of the molecules or by increasing the laser intensity. The alignment is measured by photodissociating the molecules with a femtosecond laser pulse and detecting the direction of the photofragments by imaging techniques. The strongest degree of alignment observed...

  3. Fascinating Organic Molecules from Nature

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 18; Issue 3. Fascinating Organic Molecules from Nature - Hunting with Poisoned Arrows: Story of Curare. N R Krishnaswamy C N Sundaresan. Series Article Volume 18 Issue 3 March 2013 pp 218-225 ...

  4. Ultrafast dynamics of single molecules. (United States)

    Brinks, Daan; Hildner, Richard; van Dijk, Erik M H P; Stefani, Fernando D; Nieder, Jana B; Hernando, Jordi; van Hulst, Niek F


    The detection of individual molecules has found widespread application in molecular biology, photochemistry, polymer chemistry, quantum optics and super-resolution microscopy. Tracking of an individual molecule in time has allowed identifying discrete molecular photodynamic steps, action of molecular motors, protein folding, diffusion, etc. down to the picosecond level. However, methods to study the ultrafast electronic and vibrational molecular dynamics at the level of individual molecules have emerged only recently. In this review we present several examples of femtosecond single molecule spectroscopy. Starting with basic pump-probe spectroscopy in a confocal detection scheme, we move towards deterministic coherent control approaches using pulse shapers and ultra-broad band laser systems. We present the detection of both electronic and vibrational femtosecond dynamics of individual fluorophores at room temperature, showing electronic (de)coherence, vibrational wavepacket interference and quantum control. Finally, two colour phase shaping applied to photosynthetic light-harvesting complexes is presented, which allows investigation of the persistent coherence in photosynthetic complexes under physiological conditions at the level of individual complexes.

  5. Fascinating Organic Molecules from Nature

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 18; Issue 1. Fascinating Organic Molecules from Nature - Colours in Flight - Pigments from Bird Feathers and Butterfly Wings. N R Krishnaswamy C N Sundaresan. Series Article Volume 18 Issue 1 January 2013 pp 12-21 ...

  6. Fascinating Organic Molecules from Nature

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 17; Issue 10. Fascinating Organic Molecules from Nature - Some Exotic Red Pigments of Plant Origin. N R Krishnaswamy C N Sundaresan. Series Article Volume 17 Issue 10 October 2012 pp 928-942 ...

  7. Absorption characteristics of bacteriorhodopsin molecules

    Indian Academy of Sciences (India)

    The analytical expression for the absorption coefficient of BR film is applied to study the absorption characteristics of BR molecules in a typical laser system operating at funda- mental wavelength 514 nm. The experimental data available for the absorption coefficients of the levels B and M corresponding to the wavelength ...

  8. Electrostatics of Atoms and Molecules

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 7; Issue 2. Electrostatics of Atoms and Molecules. G Narahari Sastry. Book Review Volume 7 Issue 2 February 2002 pp 90-91. Fulltext. Click here to view fulltext PDF. Permanent link: ...

  9. Absorption characteristics of bacteriorhodopsin molecules

    Indian Academy of Sciences (India)

    The bacteriorhodopsin molecule absorbs light and undergoes a series of structural transformation following a well-defined photocycle. The complex photocycle is transformed to an equivalent level diagram by considering the lifetime of the intermediate states. Assuming that only and states are appreciably populated at ...

  10. Lighting the World with Molecules

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 14; Issue 8. Lighting the World with Molecules. S Ramasesha. General Article Volume 14 Issue 8 August 2009 pp 782-798. Fulltext. Click here to view fulltext PDF. Permanent link: Keywords.

  11. Fascinating Organic Molecules from Nature

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 18; Issue 7. Fascinating Organic Molecules from Nature - Sweet Stimulants of the Olfactory Nerves - Muscone, Civetone and Related Compounds. N R Krishnaswamy C N Sundaresan. Series Article Volume 18 Issue 7 July 2013 pp 673-683 ...

  12. Far-Infrared Spectroscopy of Weakly Bound Hydrated Cluster Molecules

    DEFF Research Database (Denmark)

    Andersen, Jonas

    -sized molecular clusters with water by means of far-infrared and terahertz neon matrix isolation spectroscopy. The embedding of non-covalent cluster molecules in solid cryogenic neon matrices at 2.8 K ensures a high sensitivity for direct spectroscopic observations of the large-amplitude intermolecular...

  13. The properties and applications of single-molecule DNA sequencing (United States)


    Single-molecule sequencing enables DNA or RNA to be sequenced directly from biological samples, making it well-suited for diagnostic and clinical applications. Here we review the properties and applications of this rapidly evolving and promising technology. PMID:21349208

  14. Directed homology

    DEFF Research Database (Denmark)

    Fahrenberg, Uli


    We introduce a new notion of directed homology for semicubical sets. We show that it respects directed homotopy and is functorial, and that it appears to enjoy some good algebraic properties. Our work has applications to higher-dimensional automata.......We introduce a new notion of directed homology for semicubical sets. We show that it respects directed homotopy and is functorial, and that it appears to enjoy some good algebraic properties. Our work has applications to higher-dimensional automata....

  15. Large scale study of multiple-molecule queries

    Directory of Open Access Journals (Sweden)

    Nasr Ramzi J


    Full Text Available Abstract Background In ligand-based screening, as well as in other chemoinformatics applications, one seeks to effectively search large repositories of molecules in order to retrieve molecules that are similar typically to a single molecule lead. However, in some case, multiple molecules from the same family are available to seed the query and search for other members of the same family. Multiple-molecule query methods have been less studied than single-molecule query methods. Furthermore, the previous studies have relied on proprietary data and sometimes have not used proper cross-validation methods to assess the results. In contrast, here we develop and compare multiple-molecule query methods using several large publicly available data sets and background. We also create a framework based on a strict cross-validation protocol to allow unbiased benchmarking for direct comparison in future studies across several performance metrics. Results Fourteen different multiple-molecule query methods were defined and benchmarked using: (1 41 publicly available data sets of related molecules with similar biological activity; and (2 publicly available background data sets consisting of up to 175,000 molecules randomly extracted from the ChemDB database and other sources. Eight of the fourteen methods were parameter free, and six of them fit one or two free parameters to the data using a careful cross-validation protocol. All the methods were assessed and compared for their ability to retrieve members of the same family against the background data set by using several performance metrics including the Area Under the Accumulation Curve (AUAC, Area Under the Curve (AUC, F1-measure, and BEDROC metrics. Consistent with the previous literature, the best parameter-free methods are the MAX-SIM and MIN-RANK methods, which score a molecule to a family by the maximum similarity, or minimum ranking, obtained across the family. One new parameterized method introduced in

  16. Sisyphus Laser Cooling of a Polyatomic Molecule

    CERN Document Server

    Kozyryev, Ivan; Matsuda, Kyle; Augenbraun, Benjamin L; Anderegg, Loic; Sedlack, Alexander P; Doyle, John M


    We perform magnetically-assisted Sisyphus laser cooling of the triatomic free radical strontium monohydroxide (SrOH). This is achieved with principal optical cycling in the rotationally closed $P\\left(N"=1\\right)$ branch of either the $\\tilde{X}^{2}\\Sigma^{+}\\left(000\\right)\\leftrightarrow\\tilde{A}^{2}\\Pi_{1/2}\\left(000\\right)$ or the $\\tilde{X}^{2}\\Sigma^{+}\\left(000\\right)\\leftrightarrow\\tilde{B}^{2}\\Sigma^{+}\\left(000\\right)$ vibronic transitions. Molecules lost into the excited vibrational states during the cooling process are repumped back through the $\\tilde{B}\\left(000\\right)$ state for both the $\\left(100\\right)$ level of the Sr-O stretching mode and the $\\left(02^{0}0\\right)$ level of the bending mode. The transverse temperature of a SrOH molecular beam is reduced in one dimension by two orders of magnitude to $\\sim700\\ {\\rm \\mu K}$. This approach opens a path towards creating a variety of ultracold polyatomic molecules, including much larger ones, by means of direct laser cooling.

  17. Proteinaceous Molecules Mediating Bifidobacterium-Host Interactions (United States)

    Ruiz, Lorena; Delgado, Susana; Ruas-Madiedo, Patricia; Margolles, Abelardo; Sánchez, Borja


    Bifidobacteria are commensal microoganisms found in the gastrointestinal tract. Several strains have been attributed beneficial traits at local and systemic levels, through pathogen exclusion or immune modulation, among other benefits. This has promoted a growing industrial and scientific interest in bifidobacteria as probiotic supplements. However, the molecular mechanisms mediating this cross-talk with the human host remain unknown. High-throughput technologies, from functional genomics to transcriptomics, proteomics, and interactomics coupled to the development of both in vitro and in vivo models to study the dynamics of the intestinal microbiota and their effects on host cells, have eased the identification of key molecules in these interactions. Numerous secreted or surface-associated proteins or peptides have been identified as potential mediators of bifidobacteria-host interactions and molecular cross-talk, directly participating in sensing environmental factors, promoting intestinal colonization, or mediating a dialogue with mucosa-associated immune cells. On the other hand, bifidobacteria induce the production of proteins in the intestine, by epithelial or immune cells, and other gut bacteria, which are key elements in orchestrating interactions among bifidobacteria, gut microbiota, and host cells. This review aims to give a comprehensive overview on proteinaceous molecules described and characterized to date, as mediators of the dynamic interplay between bifidobacteria and the human host, providing a framework to identify knowledge gaps and future research needs. PMID:27536282

  18. Laser-coolable polyatomic molecules with heavy nuclei (United States)

    Isaev, T. A.; Zaitsevskii, A. V.; Eliav, E.


    Recently, a few diatomic and polyatomic molecules have been identified as prospective systems for Doppler/Sisyphus cooling. Doppler/Sisyphus cooling allows us to decrease the kinetic energy of molecules down to μK temperatures with high efficiency and allows their capture in molecular traps, including magneto-optical traps. Trapped molecules can be used for creating molecular fountains and/or performing controlled chemical reactions, high-precision spectra measurements, and a wealth of other applications. Polyatomic molecules with heavy nuclei are of considerable interest for the ‘new physics’ search outside of the Standard Model and other applications including cold chemistry and photochemistry, quantum informatics, etc. Here, we focus on the radium monohydroxide molecule (RaOH), which is on the one hand amenable to laser cooling and on the other hand opens excellent possibilities for { P }-odd and { P },{ T }-odd effects research. At present, RaOH is the heaviest polyatomic molecule proposed for direct cooling with lasers.

  19. Single-molecule manipulation experiments to explore friction and adhesion (United States)

    Pawlak, R.; Kawai, S.; Meier, T.; Glatzel, T.; Baratoff, A.; Meyer, E.


    Friction forces, which arise when two bodies that are in contact are moved with respect to one another, are ubiquitous phenomena. Although various measurement tools have been developed to study these phenomena at all length scales, such investigations are highly challenging when tackling the scale of single molecules in motion on a surface. This work reviews the recent advances in single-molecule manipulation experiments performed at low temperature with the aim of understanding the fundamental frictional response of single molecules. Following the advent of ‘nanotribology’ in the field based on the atomic force microscopy technique, we will show the technical requirements to direct those studies at the single-molecule level. We will also discuss the experimental prerequisites needed to obtain and interpret the phenomena, such as the implementation of single-molecule manipulation techniques, the processing of the experimental data or their comparison with appropriate numerical models. Finally, we will report examples of the controlled vertical and lateral manipulation of long polymeric chains, graphene nanoribbons or single porphyrin molecules that systematically reveal friction-like characteristics while sliding over atomically clean surfaces.

  20. Ballonet String Model of Molecules

    Directory of Open Access Journals (Sweden)

    Gavril NIAC


    Full Text Available Strings of ballonets, modelling rows of orbitals, are assembled to molecule models by crossing them properly. The ballonets at the ends of the strings of 2, 3, 4 or 5 spheres represent bonding orbitals of hydrogen with other elements like C, N or O (the proton being inside the sphere, as well as nonbonding orbitals. The ballonets between them are modelling bonding orbitals among elements other than hydrogen - except the double bond in diborane, the atomic cores laying at the junction of two or more spheres.Advantages of elastic sphere models range from self-adjusting bond angles to resistance when closing cycles like cyclopropane or modeling double bonds.Examples comprise alkanes, including platonic hydrocarbons, ethene, acetylene, and some inorganic molecules.

  1. Tunneling Ionization of Diatomic Molecules

    DEFF Research Database (Denmark)

    Svensmark, Jens Søren Sieg


    When a molecule is subject to a strong laser field, there is a probability that an electron can escape, even though the electrons are bound by a large potential barrier. This is possible because electrons are quantum mechanical in nature, and they are therefore able to tunnel through potential...... barriers, an ability classical particles do not possess. Tunnelling is a fundamental quantum mechanical process, a process that is distinctly non-classical, so solving this tunnelling problem is not only relevant for molecular physics, but also for quantum theory in general. In this dissertation the theory...... of tunneling ionizaion of molecules is presented and the results of numerical calculations are shown. One perhaps surprising result is, that the frequently used Born-Oppenheimer approximation breaks down for weak fields when describing tunneling ionization. An analytic theory applicable in the weak-field limit...

  2. Electrondriven processes in polyatomic molecules

    Energy Technology Data Exchange (ETDEWEB)

    McKoy, Vincent [California Inst. of Technology (CalTech), Pasadena, CA (United States)


    This project developed and applied scalable computational methods to obtain information about low-energy electron collisions with larger polyatomic molecules. Such collisions are important in modeling radiation damage to living systems, in spark ignition and combustion, and in plasma processing of materials. The focus of the project was to develop efficient methods that could be used to obtain both fundamental scientific insights and data of practical value to applications.

  3. Cellular Adhesion and Adhesion Molecules


    SELLER, Zerrin


    In recent years, cell adhesion and cell adhesion molecules have been shown to be important for many normal biological processes, including embryonic cell migration, immune system functions and wound healing. It has also been shown that they contribute to the pathogenesis of a large number of common human disorders, such as rheumatoid arthritis and tumor cell metastasis in cancer. In this review, the basic mechanisms of cellular adhesion and the structural and functional features of adhes...

  4. Optical highlighter molecules in neurobiology. (United States)

    Datta, Sandeep Robert; Patterson, George H


    The development of advanced optical methods has played a key role in propelling progress in neurobiology. Genetically-encoded fluorescent molecules found in nature have enabled labeling of individual neurons to study their physiology and anatomy. Here we discuss the recent use of both native and synthetic optical highlighter proteins to address key problems in neurobiology, including questions relevant to synaptic function, neuroanatomy, and the organization of neural circuits. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. Real-time submillisecond single-molecule FRET dynamics of freely diffusing molecules with liposome tethering (United States)

    Kim, Jae-Yeol; Kim, Cheolhee; Lee, Nam Ki


    Single-molecule fluorescence resonance energy transfer (smFRET) is one of the powerful techniques for deciphering the dynamics of unsynchronized biomolecules. However, smFRET is limited in its temporal resolution for observing dynamics. Here, we report a novel method for observing real-time dynamics with submillisecond resolution by tethering molecules to freely diffusing 100-nm-sized liposomes. The observation time for a diffusing molecule is extended to 100 ms with a submillisecond resolution, which allows for direct analysis of the transition states from the FRET time trace using hidden Markov modelling. We measure transition rates of up to 1,500 s-1 between two conformers of a Holliday junction. The rapid diffusional migration of Deinococcus radiodurans single-stranded DNA-binding protein (SSB) on single-stranded DNA is resolved by FRET, faster than that of Escherichia coli SSB by an order of magnitude. Our approach is a powerful method for studying the dynamics and movements of biomolecules at submillisecond resolution.

  6. Gas molecule-molecule interaction and the gas-surface scattering effect on the rarefied gas flow through a slit into a vacuum (United States)

    Sazhin, O.


    The effect of the gas molecule-molecule interaction and the gas-surface scattering on the gas flow through a slit into a vacuum are investigated in a wide range of the gas rarefaction using the direct simulation Monte Carlo method. To study the gas molecule-molecule interaction influence, we used the variable hard sphere and variable soft sphere models defined for an inverse-power-law potential and the generalized hard sphere model defined for the 12-6 Lennard-Jones potential. The Maxwell, Cercignani-Lampis, and Epstein models were used to simulate the gas-surface scattering. This study demonstrates that the gas molecule-molecule interaction can have a significant influence on the rarefied gas flow through a slit, while the influence of the gas-surface scattering is negligibly small. The presented numerical results are in agreement with the corresponding experimental ones.

  7. Single-molecule conductivity of non-redox and redox molecules at pure and gold-mined Au(111)-electrode surfaces

    DEFF Research Database (Denmark)

    Zhang, Jingdong; Chi, Qijin; Ulstrup, Jens

    The structure, two-dimensional organization, and function of molecules immobilized on solid surfaces can be addressed in a degree of detail that has reached the level of the single-molecule. In this context redox molecules are “smart” molecules adding sophisticated electronic function. Redox......-resolution in situ STM combined with large-scale theoretical computations have offered detailed insight in the surface binding modes of functionalized alkanethiols on Au-surfaces in particular. Such surfaces have disclosed a variety of surface structures that involve both direct binding to a planar Au and binding....... Single-molecule resolution has also here been achieved, both in structural mapping and in controlled single-molecule electron transport and enzyme function on SAM surfaces such as those now characterized to (sub)-molecular resolution....

  8. Review Article: Structures of phthalocyanine molecules on surfaces studied by STM

    Directory of Open Access Journals (Sweden)

    Yongfeng Wang


    Full Text Available This review mainly focuses on progress recently achieved in the growth of phthalocyanine molecules on single-crystal surfaces of sub-monolayer up to few-monolayer thin films studied by scanning tunneling microscopy in our groups. On metallic surfaces such as Au(111, Ag(111 and Cu(111, molecular superstructures are determined by combining directional intermolecular interactions caused by symmetry reduction, molecule-substrate interactions and indirect long-range interactions due to quantum interference of surface state electrons. On semiconducting TiO2 surface, molecular assembling structures are dictated by the strong molecule-substrate interaction. However, on insulating NaCl film, molecule-molecule interaction dominates over the molecule-NaCl coupling, leading to molecular growth behavior. Knowledge obtained from these studies would help people better understand the physicochemical properties of the phthalocyanine molecules at surfaces so that their new applications could be further explored and uncovered in the future.

  9. Probing the local environment of a single OPE3 molecule using inelastic tunneling electron spectroscopy. (United States)

    Frisenda, Riccardo; Perrin, Mickael L; van der Zant, Herre S J


    We study single-molecule oligo(phenylene ethynylene)dithiol junctions by means of inelastic electron tunneling spectroscopy (IETS). The molecule is contacted with gold nano-electrodes formed with the mechanically controllable break junction technique. We record the IETS spectrum of the molecule from direct current measurements, both as a function of time and electrode separation. We find that for fixed electrode separation the molecule switches between various configurations, which are characterized by different IETS spectra. Similar variations in the IETS signal are observed during atomic rearrangements upon stretching of the molecular junction. Using quantum chemistry calculations, we identity some of the vibrational modes which constitute a chemical fingerprint of the molecule. In addition, changes can be attributed to rearrangements of the local molecular environment, in particular at the molecule-electrode interface. This study shows the importance of taking into account the interaction with the electrodes when describing inelastic contributions to transport through single-molecule junctions.

  10. Selective laser photolysis of organic molecules in complex matrices (United States)

    Moulin, Christophe; Petit, Alain D.


    Natural extracts or essences are largely used in several fields (farm- produce industry, cosmetic, perfumery, biochemistry, etc.). However, most of these complex extracts contain also toxic, carcinogenic or non desirable molecules. By using a laser directly tuned to an absorption band of the unwanted molecules, selective elimination is obtained. Advantages of this procedure are the rapidity, in situ reaction and the possibility to perform quantitative elimination. Examples such as the destruction of thujone in extract of Salvia, bergaptene in essence of Bergamote, phycocyanin in Porphyridium Cruentum or simply dye will be presented and discussed.

  11. Matrix Infrared Spectroscopic and Computational Investigations of Novel Small Uranium Containing Molecules - Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Andrews, Lester


    Direct reactions of f-element uranium, thorium and lanthanide metal atoms were investigated with small molecules. These metal atoms were generated by laser ablation and mixed with the reagent molecules then condensed with noble gases at 4K. The products were analyzed by absorption of infrared light to measure vibrational frequencies which were confirmed by quantum chemical calculations. We have learned more about the reactivity of uranium atoms with common molecules, which will aid in the develolpment of further applications of uranium.

  12. Fluorescent Biosensors Based on Single-Molecule Counting. (United States)

    Ma, Fei; Li, Ying; Tang, Bo; Zhang, Chun-Yang


    fluorescence signals by specific in vitro/in vivo fluorescent labeling, and consequently, the fluorescent molecules indicate the presence of target molecules. The resultant fluorescence signals may be simply counted by either microfluidic device-integrated confocal microscopy or total internal reflection fluorescence-based single-molecule imaging. We have developed a series of single-molecule counting-based biosensors which can be classified as separation-free and separation-assisted assays. As a proof-of-concept, we demonstrate the applications of single-molecule counting-based biosensors for sensitive detection of various target biomolecules such as DNAs, miRNAs, proteins, enzymes, and intact cells, which may function as the disease-related biomarkers. Moreover, we give a summary of future directions to expand the usability of single-molecule counting-based biosensors including (1) the development of more user-friendly and automated instruments, (2) the discovery of new fluorescent labels and labeling strategies, and (3) the introduction of new concepts for the design of novel biosensors. Due to their high sensitivity, good selectivity, rapidity, and simplicity, we believe that the single-molecule counting-based fluorescent biosensors will indubitably find wide applications in biological research, clinical diagnostics, and drug discovery.

  13. Single-molecule, antibody-free fluorescent visualisation of replication tracts along barcoded DNA molecules. (United States)

    De Carli, Francesco; Gaggioli, Vincent; Millot, Gaël A; Hyrien, Olivier


    DNA combing is a standard technique to map DNA replication at the single molecule level. Typically, replicating DNA is metabolically labelled with nucleoside or nucleotide analogs, purified, stretched on coverslips and treated with fluorescent antibodies to reveal tracts of newly synthesized DNA. Fibres containing a locus of interest can then be identified by fluorescent in situ hybridization (FISH) with DNA probes. These steps are complex and the throughput is low. Here, we describe a simpler, antibody-free method to reveal replication tracts and identify the locus of origin of combed DNA replication intermediates. DNA was replicated in Xenopus egg extracts in the presence of a fluorescent dUTP. Purified DNA was barcoded by nicking with Nt.BspQI, a site-specific nicking endonuclease (NE), followed by limited nick-translation in the presence of another fluorescent dUTP. DNA was then stained with YOYO-1, a fluorescent DNA intercalator, and combed. Direct epifluorescence revealed the DNA molecules, their replication tracts and their Nt.BspQI sites in three distinct colours. Replication intermediates could thus be aligned to a reference genome map. In addition, replicated DNA segments showed a stronger YOYO-1 fluorescence than unreplicated segments. The entire length, replication tracts, and NE sites of combed DNA molecules can be simultaneously visualized in three distinct colours by standard epifluorescence microscopy, with no need for antibody staining and/or FISH detection. Furthermore, replication bubbles can be detected by quantitative YOYO-1 staining, eliminating the need for metabolic labelling. These results provide a starting point for genome-wide, single-molecule mapping of DNA replication in any organism.

  14. Direct Democracy

    DEFF Research Database (Denmark)

    Beramendi, Virginia; Ellis, Andrew; Kaufman, Bruno

    While many books on direct democracy have a regional or national approach, or simply focus on one of the many mechanisms associated with direct democracy, this Handbook delves into a global comparison of direct democracy mechanisms, including referendums, citizens' initiatives, agenda initiatives...... included as a chapter in the Handbook are possible measures for best practices of implementation, designed for those who wish to tailor direct democracy instruments to their specific needs. In order to further complement the best practices, a variety of global case studies detail the practical uses...... of direct democracy mechanisms in specific contexts. These country case studies allow for in depth discussion of particular issues, including signature collection and voter participation, campaign financing, media coverage, national variations in the usage of direct democracy procedures and national lessons...

  15. Electron and positron collisions with polar molecules: studies with the benchmark water molecule

    Energy Technology Data Exchange (ETDEWEB)

    Zhang Rui; Tennyson, Jonathan [Department of Physics and Astronomy, University College London, Gower Street, London WC1E 6BT (United Kingdom); Faure, Alexandre [Laboratoire d' Astrophysique, UMR 5571 CNRS, Universite Joseph-Fourier, BP 53, 38041 Grenoble cedex 09 (France)], E-mail:


    It is difficult to measure low-energy cross sections for collisions of charged particles with strongly dipolar systems since the magnitude of such cross sections is completely dominated by collisions in the forward direction. Theoretically, it is possible to account for the strong forward scattering using the Born approximation but the procedure for combining Born 'top-up' with the more sophisticated treatments required to treat the scattering in other directions is not unique. This comment describes recent progress in describing both electron and positron collisions with polar molecules taking the important water molecule as a benchmark. Previous calculations on electron water at collision energies below 7 eV are compared with new experiments. Positron water studies up to 10 eV are re-analysed based on given experimental acceptance profiles, which depend on the details of the apparatus and method used in the measurements. It is suggested that theory is capable of giving reliable results for elastic and rotationally inelastic electron/positron collisions with strongly dipolar species.

  16. Azobenzene-functionalized cascade molecules

    DEFF Research Database (Denmark)

    Archut, A.; Vogtle, F.; De Cola, L.


    Cascade molecules bearing up to 32 azobenzene groups in the periphery have been prepared from poly(propylene imine) dendrimers and N-hydroxysuccinimide esters. The dendritic azobenzene species show similar isomerization properties as the corresponding azobenzene monomers. The all-E azobenzene...... shows there is so far no effective steric constraint towards photoisomerism on increasing dimension (generation) of the dendrimer, The first attempts to use dendrimers for holography materials are described: It is shown that holographic gratings with diffraction efficiencies up to about 20 % can...

  17. The molecule-metal interface

    CERN Document Server

    Koch, Norbert; Wee, Andrew Thye Shen


    Reviewing recent progress in the fundamental understanding of the molecule-metal interface, this useful addition to the literature focuses on experimental studies and introduces the latest analytical techniques as applied to this interface.The first part covers basic theory and initial principle studies, while the second part introduces readers to photoemission, STM, and synchrotron techniques to examine the atomic structure of the interfaces. The third part presents photoelectron spectroscopy, high-resolution UV photoelectron spectroscopy and electron spin resonance to study the electroni

  18. XUV ionization of aligned molecules

    Energy Technology Data Exchange (ETDEWEB)

    Kelkensberg, F.; Siu, W.; Gademann, G. [FOM Institute AMOLF, Science Park 104, NL-1098 XG Amsterdam (Netherlands); Rouzee, A.; Vrakking, M. J. J. [FOM Institute AMOLF, Science Park 104, NL-1098 XG Amsterdam (Netherlands); Max-Born-Institut, Max-Born Strasse 2A, D-12489 Berlin (Germany); Johnsson, P. [FOM Institute AMOLF, Science Park 104, NL-1098 XG Amsterdam (Netherlands); Department of Physics, Lund University, Post Office Box 118, SE-221 00 Lund (Sweden); Lucchini, M. [Department of Physics, Politecnico di Milano, Istituto di Fotonica e Nanotecnologie CNR-IFN, Piazza Leonardo da Vinci 32, 20133 Milano (Italy); Lucchese, R. R. [Department of Chemistry, Texas A and M University, College Station, Texas 77843-3255 (United States)


    New extreme-ultraviolet (XUV) light sources such as high-order-harmonic generation (HHG) and free-electron lasers (FELs), combined with laser-induced alignment techniques, enable novel methods for making molecular movies based on measuring molecular frame photoelectron angular distributions. Experiments are presented where CO{sub 2} molecules were impulsively aligned using a near-infrared laser and ionized using femtosecond XUV pulses obtained by HHG. Measured electron angular distributions reveal contributions from four orbitals and the onset of the influence of the molecular structure.

  19. The neural cell adhesion molecule

    DEFF Research Database (Denmark)

    Berezin, V; Bock, E; Poulsen, F M


    During the past year, the understanding of the structure and function of neural cell adhesion has advanced considerably. The three-dimensional structures of several of the individual modules of the neural cell adhesion molecule (NCAM) have been determined, as well as the structure of the complex...... between two identical fragments of the NCAM. Also during the past year, a link between homophilic cell adhesion and several signal transduction pathways has been proposed, connecting the event of cell surface adhesion to cellular responses such as neurite outgrowth. Finally, the stimulation of neurite...

  20. Thermophoretic forces on DNA measured with a single-molecule spring balance

    DEFF Research Database (Denmark)

    Pedersen, Jonas Nyvold; Lüscher, Christopher James; Marie, Rodolphe


    We stretch a single DNA molecule with thermophoretic forces and measure these forces with a spring balance: the DNA molecule itself. It is an entropic spring which we calibrate, using as a benchmark its Brownian motion in the nanochannel that contains and prestretches it. This direct measurement...

  1. On deflection fields, weak-focusing and strong-focusing storage rings for polar molecules

    NARCIS (Netherlands)

    de Nijs, A.J.; Bethlem, H.L.


    In this paper, we analyze electric deflection fields for polar molecules in terms of a multipole expansion and derive a simple but rather insightful expression for the force on the molecules. Ideally, a deflection field exerts a strong, constant force in one direction, while the force in the other

  2. Single Molecule Study of Photoconversion and Spectral Heterogeneities of Fluorophores

    DEFF Research Database (Denmark)

    Liao, Zhiyu

    of conformational changes and dynamics. The photophysical properties of organic dyes directly determine the quality of the experiments. So the better understanding of the photophysical properties of organic dyes, the better we are able to design the experiments and interpret the data, especially in single molecule...... 104 single molecule measurements. A simple and practical method is introduced to study the characteristics of the photoproducts at the ensemble level. Control experiments reveal that the reaction leading to photobleaching is oxygen related, but the composition of the photoproducts remains inconclusive...... stimulate new pathways in engineering and designing photoconvertible fluorophores, based on the reaction with oxygen or other chemicals. Besides, this results show that dyes that convert into other emissive species could give problems when interpreting single molecule FRET systems. The revealed mechanism...

  3. Communication: Coordinate-dependent diffusivity from single molecule trajectories (United States)

    Berezhkovskii, Alexander M.; Makarov, Dmitrii E.


    Single-molecule observations of biomolecular folding are commonly interpreted using the model of one-dimensional diffusion along a reaction coordinate, with a coordinate-independent diffusion coefficient. Recent analysis, however, suggests that more general models are required to account for single-molecule measurements performed with high temporal resolution. Here, we consider one such generalization: a model where the diffusion coefficient can be an arbitrary function of the reaction coordinate. Assuming Brownian dynamics along this coordinate, we derive an exact expression for the coordinate-dependent diffusivity in terms of the splitting probability within an arbitrarily chosen interval and the mean transition path time between the interval boundaries. This formula can be used to estimate the effective diffusion coefficient along a reaction coordinate directly from single-molecule trajectories.

  4. Metric for three-dimensional alignment of molecules (United States)

    Makhija, Varun; Ren, Xiaoming; Kumarappan, Vinod


    In an effort to clarify the three-dimensional alignment dynamics of polyatomic molecules, we propose a single measure for the degree of angular confinement of such molecules. The measure proposed for three-dimensional orientation is the angle of the single rotation that takes the molecule to the desired target orientation. Further, taking into account the D2 symmetry of a three-dimensionally aligned distribution, a symmetrized version of the measure is constructed that serves as a direct indicator of the degree of three-dimensional alignment of a distribution. The calculation of the rotational dynamics of iodobenzene under the influence of two cross-polarized laser pulses demonstrates the effectiveness of the proposed metric.

  5. Insertion of liquid crystal molecules into hydrocarbon monolayers

    Energy Technology Data Exchange (ETDEWEB)

    Popov, Piotr, E-mail:; Mann, Elizabeth K. [Department of Physics, Kent State University, Kent, Ohio 44242 (United States); Lacks, Daniel J. [Department of Chemical Engineering, Case Western Reserve University, Cleveland, Ohio 44106 (United States); Jákli, Antal [Liquid Crystal Institute, Kent State University, Kent, Ohio 44242-0001 (United States)


    Atomistic molecular dynamics simulations were carried out to investigate the molecular mechanisms of vertical surface alignment of liquid crystals. We study the insertion of nCB (4-Cyano-4{sup ′}-n-biphenyl) molecules with n = 0,…,6 into a bent-core liquid crystal monolayer that was recently found to provide good vertical alignment for liquid crystals. The results suggest a complex-free energy landscape for the liquid crystal within the layer. The preferred insertion direction of the nCB molecules (core or tail first) varies with n, which can be explained by entropic considerations. The role of the dipole moments was found to be negligible. As vertical alignment is the leading form of present day liquid crystal displays (LCD), these results will help guide improvement of the LCD technology, as well as lend insight into the more general problem of insertion of biological and other molecules into lipid and surfactant layers.

  6. Electronic Single Molecule Identification of Carbohydrate Isomers by Recognition Tunneling

    CERN Document Server

    Im, JongOne; Liu, Hao; Zhao, Yanan; Sen, Suman; Biswas, Sudipta; Ashcroft, Brian; Borges, Chad; Wang, Xu; Lindsay, Stuart; Zhang, Peiming


    Glycans play a central role as mediators in most biological processes, but their structures are complicated by isomerism. Epimers and anomers, regioisomers, and branched sequences contribute to a structural variability that dwarfs those of nucleic acids and proteins, challenging even the most sophisticated analytical tools, such as NMR and mass spectrometry. Here, we introduce an electron tunneling technique that is label-free and can identify carbohydrates at the single-molecule level, offering significant benefits over existing technology. It is capable of analyzing sub-picomole quantities of sample, counting the number of individual molecules in each subset in a population of coexisting isomers, and is quantitative over more than four orders of magnitude of concentration. It resolves epimers not well separated by ion-mobility and can be implemented on a silicon chip. It also provides a readout mechanism for direct single-molecule sequencing of linear oligosaccharides.

  7. Molecules in Studio v. 1.0

    Energy Technology Data Exchange (ETDEWEB)


    A Powersim Studio implementation of the system dynamics’ ‘Molecules of Structure’. The original implementation was in Ventana’s Vensim language by James Hines. The molecules are fundamental constructs of the system dynamics simulation methodology.

  8. Is JPC = 3-+ molecule possible? (United States)

    Zhu, Wei; Liu, Yan-Rui; Yao, Tao


    The confirmation of charged charmonium-like states indicates that heavy quark molecules should exist. Here we discuss the possibility of a molecule state with JPC = 3-+. In a one-boson-exchange model investigation for the S wave C = + D*D¯2* states, one finds that the strongest attraction is in the case J = 3 and I = 0 for both π and σ exchanges. Numerical analysis indicates that this hadronic bound state might exist if a phenomenological cutoff parameter around 2.3 GeV (1.5 GeV) is reasonable with a dipole (monopole) type form factor in the one-pion-exchange model. The cutoff for binding solutions may be reduced to a smaller value once the σ exchange contribution is included. If a state around the D*D¯2* threshold (≈4472 MeV) in the channel J/ψω (P wave) is observed, the heavy quark spin symmetry implies that it is not a cc¯ meson and the JPC are likely to be 3-+. Supported by National Natural Science Foundation of China (11275115), Shandong Province Natural Science Foundation (ZR2010AM023), SRF for ROCS, SEM, and Independent Innovation Foundation of Shandong University

  9. Two-Photon Small Molecule Enzymatic Probes. (United States)

    Qian, Linghui; Li, Lin; Yao, Shao Q


    Enzymes are essential for life, especially in the development of disease and on drug effects, but as we cannot yet directly observe the inside interactions and only partially observe biochemical outcomes, tools "translating" these processes into readable information are essential for better understanding of enzymes as well as for developing effective tools to fight against diseases. Therefore, sensitive small molecule probes suitable for direct in vivo monitoring of enzyme activities are ultimately desirable. For fulfilling this desire, two-photon small molecule enzymatic probes (TSMEPs) producing amplified fluorescent signals based on enzymatic conversion with better photophysical properties and deeper penetration in intact tissues and whole animals have been developed and demonstrated to be powerful in addressing the issues described above. Nonetheless, currently available TSMEPs only cover a small portion of enzymes despite the distinct advantages of two-photon fluorescence microscopy. In this Account, we would like to share design principles for TSMEPs as potential indicators of certain pathology-related biomarkers together with their applications in disease models to inspire more elegant work to be done in this area. Highlights will be addressed on how to equip two-photon fluorescent probes with features amenable for direct assessment of enzyme activities in complex pathological environments. We give three recent examples from our laboratory and collaborations in which TSMEPs are applied to visualize the distribution and activity of enzymes at cellular and organism levels. The first example shows that we could distinguish endogenous phosphatase activity in different organelles; the second illustrates that TSMEP is suitable for specific and sensitive detection of a potential Parkinson's disease marker (monoamine oxidase B) in a variety of biological systems from cells to patient samples, and the third identifies that TSMEPs can be applied to other enzyme

  10. Molecular dynamics study of water molecule diffusion in oil-paper insulation materials (United States)

    Liao, Rui-Jin; Zhu, Meng-Zhao; Yang, Li-Jun; Zhou, Xin; Gong, Chun-Yan


    Moisture is an important factor that influences the safe operation of transformers. In this study, molecular dynamics was employed to investigate the diffusion behavior of water molecules in the oil-paper insulation materials of transformers. Two oil-cellulose models were built. In the first model, water molecules were initially distributed in oil, and in the second model, water molecules were distributed in cellulose. The non-bonding energies of interaction between water molecules and oil, and between water molecules and cellulose, were calculated by the Dreiding force field. The interaction energy was found to play a dominant role in influencing the equilibrium distribution of water molecules. The radial direction functions of water molecules toward oil and cellulose indicate that the hydrogen bonds between water molecules and cellulose are sufficiently strong to withstand the operating temperature of the transformer. Mean-square displacement analysis of water molecules diffusion suggests that water molecules initially distributed in oil showed anisotropic diffusion; they tended to diffuse toward cellulose. Water molecules initially distributed in cellulose diffused isotropically. This study provides a theoretical contribution for improvements in online monitoring of water in transformers, and for subsequent research on new insulation materials.

  11. The structure of DNA by direct imaging

    KAUST Repository

    Marini, Monica


    The structure of DNA was determined in 1953 by x-ray fiber diffraction. Several attempts have been made to obtain a direct image of DNA with alternative techniques. The direct image is intended to allow a quantitative evaluation of all relevant characteristic lengths present in a molecule. A direct image of DNA, which is different from diffraction in the reciprocal space, is difficult to obtain for two main reasons: the intrinsic very low contrast of the elements that form the molecule and the difficulty of preparing the sample while preserving its pristine shape and size. We show that through a preparation procedure compatible with the DNA physiological conditions, a direct image of a single suspended DNA molecule can be obtained. In the image, all relevant lengths of A-form DNA are measurable. A high-resolution transmission electron microscope that operates at 80 keV with an ultimate resolution of 1.5 Å was used for this experiment. Direct imaging of a single molecule can be used as a method to address biological problems that require knowledge at the single-molecule level, given that the average information obtained by x-ray diffraction of crystals or fibers is not sufficient for detailed structure determination, or when crystals cannot be obtained from biological molecules or are not sufficient in understanding multiple protein configurations.

  12. Dipolar collisions of polar molecules in the quantum regime. (United States)

    Ni, K-K; Ospelkaus, S; Wang, D; Quéméner, G; Neyenhuis, B; de Miranda, M H G; Bohn, J L; Ye, J; Jin, D S


    Ultracold polar molecules offer the possibility of exploring quantum gases with interparticle interactions that are strong, long-range and spatially anisotropic. This is in stark contrast to the much studied dilute gases of ultracold atoms, which have isotropic and extremely short-range (or 'contact') interactions. Furthermore, the large electric dipole moment of polar molecules can be tuned using an external electric field; this has a range of applications such as the control of ultracold chemical reactions, the design of a platform for quantum information processing and the realization of novel quantum many-body systems. Despite intense experimental efforts aimed at observing the influence of dipoles on ultracold molecules, only recently have sufficiently high densities been achieved. Here we report the experimental observation of dipolar collisions in an ultracold molecular gas prepared close to quantum degeneracy. For modest values of an applied electric field, we observe a pronounced increase in the loss rate of fermionic potassium-rubidium molecules due to ultracold chemical reactions. We find that the loss rate has a steep power-law dependence on the induced electric dipole moment, and we show that this dependence can be understood in a relatively simple model based on quantum threshold laws for the scattering of fermionic polar molecules. In addition, we directly observe the spatial anisotropy of the dipolar interaction through measurements of the thermodynamics of the dipolar gas. These results demonstrate how the long-range dipolar interaction can be used for electric-field control of chemical reaction rates in an ultracold gas of polar molecules. Furthermore, the large loss rates in an applied electric field suggest that creating a long-lived ensemble of ultracold polar molecules may require confinement in a two-dimensional trap geometry to suppress the influence of the attractive, 'head-to-tail', dipolar interactions.

  13. JSME: a free molecule editor in JavaScript. (United States)

    Bienfait, Bruno; Ertl, Peter


    A molecule editor, i.e. a program facilitating graphical input and interactive editing of molecules, is an indispensable part of every cheminformatics or molecular processing system. Today, when a web browser has become the universal scientific user interface, a tool to edit molecules directly within the web browser is essential. One of the most popular tools for molecular structure input on the web is the JME applet. Since its release nearly 15 years ago, however the web environment has changed and Java applets are facing increasing implementation hurdles due to their maintenance and support requirements, as well as security issues. This prompted us to update the JME editor and port it to a modern Internet programming language - JavaScript. The actual molecule editing Java code of the JME editor was translated into JavaScript with help of the Google Web Toolkit compiler and a custom library that emulates a subset of the GUI features of the Java runtime environment. In this process, the editor was enhanced by additional functionalities including a substituent menu, copy/paste, drag and drop and undo/redo capabilities and an integrated help. In addition to desktop computers, the editor supports molecule editing on touch devices, including iPhone, iPad and Android phones and tablets. In analogy to JME the new editor is named JSME. This new molecule editor is compact, easy to use and easy to incorporate into web pages. A free molecule editor written in JavaScript was developed and is released under the terms of permissive BSD license. The editor is compatible with JME, has practically the same user interface as well as the web application programming interface. The JSME editor is available for download from the project web page

  14. Ultrafast electron diffraction from aligned molecules

    Energy Technology Data Exchange (ETDEWEB)

    Centurion, Martin [Univ. of Nebraska, Lincoln, NE (United States)


    The aim of this project was to record time-resolved electron diffraction patterns of aligned molecules and to reconstruct the 3D molecular structure. The molecules are aligned non-adiabatically using a femtosecond laser pulse. A femtosecond electron pulse then records a diffraction pattern while the molecules are aligned. The diffraction patterns are then be processed to obtain the molecular structure.

  15. Controlled contact to a C-60 molecule

    DEFF Research Database (Denmark)

    Neel, N.; Kröger, J.; Limot, L.


    The tip of a low-temperature scanning tunneling microscope is approached towards a C-60 molecule adsorbed at a pentagon-hexagon bond on Cu(100) to form a tip-molecule contact. The conductance rapidly increases to approximate to 0.25 conductance quanta in the transition region from tunneling...... the tip-molecule distance....

  16. The Classical-Quantum Correspondence of Polyatomic Molecules (United States)

    Pittman, Suzanne Michelle

    In this thesis, we study the classical-quantum correspondence of polyatomic molecules to further understand their rotational and vibrational behavior. More specifically, we focus on two different scenarios: (1) completely rigid asymmetric top molecules and (2) molecules with purely vibrational behavior. In the first part, we study the dynamics of the two asymmetric top molecules ortho-aminobenzonitrile (OABN) and para-aminobenzonitrile (PABN) in a static electric field. These structural isomers feature differing asymmetries and dipole moments. We show that the dynamics of each molecule depends on the region of phase space of the initial rotational state, the asymmetry of the molecule, and the direction of the dipole. We also show that the ergodicity of the system varies gradually with energy, except where the rotational energy of the initial state is much less than the Stark interaction. We find that both molecules are far from full chaos for total angular momentum quanta J ∈ [0,45], which counters the results presented in reference 1. However, the initial rotational states in OABN access much more of the available phase space than in PABN, which is a strong cause for the experimental discrepancies observed in the molecular beam deflection experiment of reference 1. In the second part, we address the 0.01-0.1 cm-1 peak splittings found in high-resolution IR spectra of polyatomic molecules. Narrow splittings lead to energy flow on extremely long time scales. For polyatomics molecules, there are two main competing mechanisms that occur over such time scales: (1) dynamical tunneling, which connects classically disconnected regions of phase space by tunneling through dynamical barriers, and (2) Arnol'd Diffusion, which describes diffusion in phase space along a resonance network called the Arnol'd web. As a result of the ubiquitous numerical errors that accumulate during numerical studies of Arnol'd Diffusion, we use a physically motivated non-convex Hamiltonian that

  17. Methylene blue modulates adhesion molecule expression on microvascular endothelial cells. (United States)

    Werner, Isabella; Guo, Fengwei; Stock, Ulrich A; Lupinski, Michèle; Meybohm, Patrick; Moritz, Anton; Beiras-Fernandez, Andres


    As methylene blue (MB) has been recently proposed to preserve blood pressure in case of vasoplegic syndrome and shock, an entity directly related to systemic inflammation, we aimed to elucidate the effect of MB on the expression of adhesion-molecules in endothelial-cells. Human microvascular endothelial-cells (HuMEC-1) were treated with 10, 30 or 60 µM MB for 30 min and 2 h each. Additionally, the treated HuMEC-1 were co-cultured with either human peripheral blood mononuclear cells (PBMCs) or Jurkat cells (human T-lymphocytes) for 2 h. HuMEC-1 were analyzed after MB treatment and after co-culture experiments for expression of different adhesion-molecules (ICAM-1, VCAM-1, L-selectin, E-selectin) via FACS measurement and western blot analysis. The supernatants of the experiments were analyzed with regard to the soluble forms of the adhesion molecules. We found that MB is able to modulate the expression of adhesion-molecules on EC. Administration of MB increases the expression of E-selectin and VCAM-1 depending on the dosage and time of exposure. ICAM-1 measurements provide evidence that different circulating blood cells can differently alter the adhesion-molecule expression on EC after MB exposure. Our results provide evidence regarding the immunomodulatory effect of MB upon endothelial-cells after inflammation.

  18. Directing Creativity

    DEFF Research Database (Denmark)

    Darsø, Lotte; Ibbotson, Piers


    In this article we argue that leaders facing complex challenges can learn from the arts, specifically that leaders can learn by examining how theatre directors direct creativity through creative constraints. We suggest that perceiving creativity as a boundary phenomenon is helpful for directing it....... Like leaders, who are caught in paradoxical situations where they have to manage production and logistics simultaneously with making space for creativity and innovation, theatre directors need to find the delicate balance between on one hand renewal of perceptions, acting and interaction...... and on the other hand getting ready for the opening night. We conclude that the art of directing creativity is linked to developing competencies of conscious presence, attention and vigilance, whereas the craft of directing creativity concerns communication, framing and choice....

  19. Interactions between subunits in heterodimeric Ncd molecules. (United States)

    Kocik, Elzbieta; Skowronek, Krzysztof J; Kasprzak, Andrzej A


    The nonprocessive minus-end-directed kinesin-14 Ncd is involved in the organization of the microtubule (MT) network during mitosis. Only one of the two motor domains is involved in the interaction with the MT. The other head is tethered to the bound one. Here we prepared, purified, and characterized mutated Ncd molecules carrying point mutations in one of the heads, thus producing heterodimeric motors. The mutations tested included substitutions in Switch I and II: R552A, E585A, and E585D; the decoupling mutant N600K; and a deletion in the motor domain in one of the subunits resulting in a single-headed molecule (NcN). These proteins were isolated by two sequential affinity chromatography steps, followed by measurements of their affinities to MT, enzymatic properties, and the velocity of the microtubule gliding test in vitro. A striking observation is a low affinity of the single-headed NcN for MT both without nucleotides and in the presence of 5'-adenylyl-beta,gamma-imidodiphosphate, implying that the tethered head has a profound effect on the structure of the Ncd-MT complex. Mutated homodimers had no MT-activated ATPase and no motility, whereas NcN had motility comparable with that of the wild type Ncd. Although the heterodimers had one fully active and one inactive head, the ATPase and motility of Ncd heterodimers varied dramatically, clearly demonstrating that interactions between motor domains exist in Ncd. We also show that the bulk property of dimeric proteins that interact with the filament with only one of its heads depends also on the distribution of the filament-interacting subunits.

  20. Biased small-molecule ligands for selective inhibition of HIV-1 cell entry via CCR5

    DEFF Research Database (Denmark)

    Berg, Christian; Spiess, Katja; von Lüttichau, Hans Rudolf


    Since the discovery of HIV's use of CCR5 as the primary coreceptor in fusion, the focus on developing small-molecule receptor antagonists for inhibition hereof has only resulted in one single drug, Maraviroc. We therefore investigated the possibility of using small-molecule CCR5 agonists as HIV-1......, the efficacy switch mutation (Leu203Phe) - converting small-molecule antagonists/inverse agonists to full agonists biased toward G-protein activation - uncovered that also small-molecule agonists can function as direct HIV-1 cell entry inhibitors. Importantly, no agonist-induced receptor internalization...

  1. Anti-cancer Lead Molecule

    KAUST Repository

    Sagar, Sunil


    Derivatives of plumbagin can be selectively cytotoxic to breast cancer cells. Derivative `A` (Acetyl Plumbagin) has emerged as a lead molecule for testing against estrogen positive breast cancer and has shown low hepatotoxicity as well as overall lower toxicity in nude mice model. The toxicity of derivative `A` was determined to be even lower than vehicle control (ALT and AST markers). The possible mechanism of action identified based on the microarray experiments and pathway mapping shows that derivative `A` could be acting by altering the cholesterol-related mechanisms. The low toxicity profile of derivative `A` highlights its possible role as future anti-cancer drug and/or as an adjuvant drug to reduce the toxicity of highly toxic chemotherapeutic drugs

  2. Optoelectronics of Molecules and Polymers

    CERN Document Server

    Moliton, André


    Optoelectronic devices are being developed at an extraordinary rate. Organic light emitting diodes, photovoltaic devices and electro-optical modulators are pivotal to the future of displays, photosensors and solar cells, and communication technologies. This book details the theories underlying the relevant mechanisms in organic materials and covers, at a basic level, how the organic components are made. The first part of this book introduces the fundamental theories used to detail ordered solids and localised energy levels. The methods used to determine energy levels in perfectly ordered molecular and macromolecular systems are discussed, making sure that the effects of quasi-particles are not missed. The function of excitons and their transfer between two molecules are studied, and the problems associated with interfaces and charge injection into resistive media are presented. The second part details technological aspects such as the fabrication of devices based on organic materials by dry etching. The princ...

  3. Small-molecule arginase inhibitors. (United States)

    Ivanenkov, Yan A; Chufarova, Nina V


    Arginase is an enzyme that metabolizes L-arginine to L-ornithine and urea. In addition to its fundamental role in the hepatic ornithine cycle, it also influences the immune systems in humans and mice. Arginase participates in many inflammatory disorders by decreasing the synthesis of nitric oxide and inducing fibrosis and tissue regeneration. L-arginine deficiency, which is modulated by myeloid cell arginase, suppresses T-cell immune response. This mechanism plays a fundamental role in inflammation-associated immunosuppression. Pathogens can synthesize their own arginase to elude immune reaction. Small-molecule arginase inhibitors are currently described as promising therapeutics for the treatment of several diseases, including allergic asthma, inflammatory bowel disease, ulcerative colitis, cardiovascular diseases (atherosclerosis and hypertension), diseases associated with pathogens (e.g., Helicobacter pylori, Trypanosoma cruzi, Leishmania, Mycobacterium tuberculosis and Salmonella), cancer and induced or spontaneous immune disorders. This article summarizes recent patents in the area of arginase inhibitors and discusses their properties.

  4. Molecule Formation on Interstellar Grains (United States)

    Vidali, G.


    The first experiments that were expressively designed to be applicable to hydrogen formation reactions in the ISM measured the efficiency of formation of molecular hydrogen on a polycrystalline olivine (Pirronello et al. (1997a)). It soon turned out that more was needed, and research began on the mechanism of reaction, on the in uence of the surface morphology, and on the excitation of the just- ormed molecule. In this review, I summarize what we learned from these and other experiments, and where more work is needed: in the elementary steps of reaction, in the bridging of the laboratory-ISM gap (large ux/large surface - small ux/small grain) using simulations, and in using realistic samples of dust grains. Understanding what experiments can and cannot deliver will help in designing and targeting observations, and vice-versa.

  5. Nanopore Device for Reversible Ion and Molecule Sensing or Migration (United States)

    Pourmand, Nader (Inventor); Vilozny, Boaz (Inventor); Actis, Paolo (Inventor); Seger, R. Adam (Inventor); Singaram, Bakthan (Inventor)


    Disclosed are methods and devices for detection of ion migration and binding, utilizing a nanopipette adapted for use in an electrochemical sensing circuit. The nanopipette may be functionalized on its interior bore with metal chelators for binding and sensing metal ions or other specific binding molecules such as boronic acid for binding and sensing glucose. Such a functionalized nanopipette is comprised in an electrical sensor that detects when the nanopipette selectively and reversibly binds ions or small molecules. Also disclosed is a nanoreactor, comprising a nanopipette, for controlling precipitation in aqueous solutions by voltage-directed ion migration, wherein ions may be directed out of the interior bore by a repulsing charge in the bore.

  6. Human hematopoietic stem cell adherence to cytokines and matrix molecules.


    Long, M. W.; Briddell, R.; Walter, A W; Bruno, E; Hoffman, R.


    The hematopoietic microenvironment is a complex structure in which stem cells, progenitor cells, stromal cells, growth factors, and extracellular matrix (ECM) molecules each interact to direct the coordinate regulation of blood cell development. While much is known concerning the individual components of this microenvironment, little is understood of the interactions among these various components or, in particular, the nature of those interactions responsible for the regional localization of...

  7. The synthesis of organochlorine compounds from one-carbon molecules (United States)

    Treger, Yurii A.; Rozanov, V. N.


    Studies on the synthesis of organochlorine compounds from one-carbon molecules are surveyed. The thermodynamics, kinetics, and mechanisms of the direct and oxidative chlorination of methane, the esterification of methanol by hydrogen chloride, the hydrochlorination of acetylene, the hydrodechlorination of carbon tetrachloride, and the carbonylation of chloromethanes, the catalysts employed, and the practical applications of these reactions are examined. The bibliography includes 143 references.

  8. Small molecules enable highly efficient neuronal conversion of human fibroblasts. (United States)

    Ladewig, Julia; Mertens, Jerome; Kesavan, Jaideep; Doerr, Jonas; Poppe, Daniel; Glaue, Finnja; Herms, Stefan; Wernet, Peter; Kögler, Gesine; Müller, Franz-Josef; Koch, Philipp; Brüstle, Oliver


    Forced expression of proneural transcription factors has been shown to direct neuronal conversion of fibroblasts. Because neurons are postmitotic, conversion efficiencies are an important parameter for this process. We present a minimalist approach combining two-factor neuronal programming with small molecule-based inhibition of glycogen synthase kinase-3β and SMAD signaling, which converts postnatal human fibroblasts into functional neuron-like cells with yields up to >200% and neuronal purities up to >80%.

  9. Studies of G-quadruplex DNA structures at the single molecule level

    DEFF Research Database (Denmark)

    Kragh, Sofie Louise


    Folding of G-quaduplex structures adopted by the human telomeric repeat is here studied by single molecule FRET microscopy. This method allows for the investigation of G-quadruplex structures and their conformational dynamic. Telomeres are located at the ends of our chromosomes and end in a single...... range. FRET spectroscopy can be performed on an ensemble of molecules, or on the single molecule level. In single molecule FRET experiments it is possible to follow the behaviour in time for each molecule independently, allowing insight into both dynamically and statistically heterogeneous molecular...... populations and thus providing more information than traditional ensemble experiments. Using single molecule FRET microscopy different aspects of G-quadruplex folding were investigated. We have obtained direct insight into G-quadruplex structural polymorphism both in K+ and Na+ solutions. Polymorphism have...

  10. Probing the local environment of a single OPE3 molecule using inelastic tunneling electron spectroscopy

    Directory of Open Access Journals (Sweden)

    Riccardo Frisenda


    Full Text Available We study single-molecule oligo(phenylene ethynylenedithiol junctions by means of inelastic electron tunneling spectroscopy (IETS. The molecule is contacted with gold nano-electrodes formed with the mechanically controllable break junction technique. We record the IETS spectrum of the molecule from direct current measurements, both as a function of time and electrode separation. We find that for fixed electrode separation the molecule switches between various configurations, which are characterized by different IETS spectra. Similar variations in the IETS signal are observed during atomic rearrangements upon stretching of the molecular junction. Using quantum chemistry calculations, we identity some of the vibrational modes which constitute a chemical fingerprint of the molecule. In addition, changes can be attributed to rearrangements of the local molecular environment, in particular at the molecule–electrode interface. This study shows the importance of taking into account the interaction with the electrodes when describing inelastic contributions to transport through single-molecule junctions.

  11. The structure of DNA by direct imaging


    Marini, Monica; Falqui, Andrea; Moretti, Manola; Limongi, Tania; Allione, Marco; Genovese, Alessandro; Lopatin, Sergei; Tirinato, Luca; Das, Gobind; Torre, Bruno; Giugni, Andrea; Gentile, Francesco; Candeloro, Patrizio; Di Fabrizio, Enzo


    The structure of DNA was determined in 1953 by x-ray fiber diffraction. Several attempts have been made to obtain a direct image of DNA with alternative techniques. The direct image is intended to allow a quantitative evaluation of all relevant characteristic lengths present in a molecule. A direct image of DNA, which is different from diffraction in the reciprocal space, is difficult to obtain for two main reasons: the intrinsic very low contrast of the elements that form the molecule and th...

  12. Plasmodium falciparum-mediated induction of human CD25Foxp3 CD4 T cells is independent of direct TCR stimulation and requires IL-2, IL-10 and TGFbeta.

    Directory of Open Access Journals (Sweden)

    Anja Scholzen


    Full Text Available CD4(+CD25(+Foxp3(+ regulatory T cells (Tregs regulate disease-associated immunity and excessive inflammatory responses, and numbers of CD4(+CD25(+Foxp3(+ Tregs are increased during malaria infection. The mechanisms governing their generation, however, remain to be elucidated. In this study we investigated the role of commonly accepted factors for Foxp3 induction, TCR stimulation and cytokines such as IL-2, TGFbeta and IL-10, in the generation of human CD4(+CD25(+Foxp3(+ T cells by the malaria parasite Plasmodium falciparum. Using a co-culture system of malaria-infected red blood cells (iRBCs and peripheral blood mononuclear cells from healthy individuals, we found that two populations of Foxp3(hi and Foxp3(int CD4(+CD25(hi T cells with a typical Treg phenotype (CTLA-4(+, CD127(low, CD39(+, ICOS(+, TNFRII(+ were induced. Pro-inflammatory cytokine production was confined to the Foxp3(int subset (IFNgamma, IL-4 and IL-17 and inversely correlated with high relative levels of Foxp3(hi cells, consistent with Foxp3(hi CD4 T cell-mediated inhibition of parasite-induced effector cytokine T cell responses. Both Foxp3(hi and Foxp3(int cells were derived primarily from proliferating CD4(+CD25(- T cells with a further significant contribution from CD25(+Foxp3(+ natural Treg cells to the generation of the Foxp3(hi subset. Generation of Foxp3(hi, but not Foxp3(int, cells specifically required TGFbeta1 and IL-10. Add-back experiments showed that monocytes expressing increased levels of co-stimulatory molecules were sufficient for iRBC-mediated induction of Foxp3 in CD4 T cells. Foxp3 induction was driven by IL-2 from CD4 T cells stimulated in an MHC class II-dependent manner. However, transwell separation experiments showed that direct contact of monocytes with the cells that acquire Foxp3 expression was not required. This novel TCR-independent and therefore antigen-non specific mechanism for by-stander CD4(+CD25(hiFoxp3(+ cell induction is likely to reflect a

  13. Single molecule photobleaching (SMPB) technology for counting of RNA, DNA, protein and other molecules in nanoparticles and biological complexes by TIRF instrumentation. (United States)

    Zhang, Hui; Guo, Peixuan


    Direct counting of biomolecules within biological complexes or nanomachines is demanding. Single molecule counting using optical microscopy is challenging due to the diffraction limit. The single molecule photobleaching (SMPB) technology for direct counting developed by our team (Shu et al., 2007 [18]; Zhang et al., 2007 [19]) offers a simple and straightforward method to determine the stoichiometry of molecules or subunits within biocomplexes or nanomachines at nanometer scales. Stoichiometry is determined by real-time observation of the number of descending steps resulted from the photobleaching of individual fluorophore. This technology has now been used extensively for single molecule counting of protein, RNA, and other macromolecules in a variety of complexes or nanostructures. Here, we elucidate the SMPB technology, using the counting of RNA molecules within a bacteriophage phi29 DNA-packaging biomotor as an example. The method described here can be applied to the single molecule counting of other molecules in other systems. The construction of a concise, simple and economical single molecule total internal reflection fluorescence (TIRF) microscope combining prism-type and objective-type TIRF is described. The imaging system contains a deep-cooled sensitive EMCCD camera with single fluorophore detection sensitivity, a laser combiner for simultaneous dual-color excitation, and a Dual-View™ imager to split the multiple outcome signals to different detector channels based on their wavelengths. Methodology of the single molecule photobleaching assay used to elucidate the stoichiometry of RNA on phi29 DNA packaging motor and the mechanism of protein/RNA interaction are described. Different methods for single fluorophore labeling of RNA molecules are reviewed. The process of statistical modeling to reveal the true copy number of the biomolecules based on binomial distribution is also described. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Direct marketing

    Directory of Open Access Journals (Sweden)

    Čičić Muris


    Full Text Available Direct Marketing (DM is usually treated as unworthy activity, with actions at the edge of legality and activities minded cheating. Despite obvious problems regarding ethics and privacy threat, DM with its size, importance and role in a concept of integrated marketing communication deserves respect and sufficient analysis and review

  15. Following Directions. (United States)

    Bolger, Charlene

    Activities in this elementary unit focus on developing students' locational skills while strengthening their ability to read and follow instructions. Seven maps of varying complexity are accompanied by worksheets containing 8 to 13 direction exercises. Students are instructed to place buildings, landmarks, and labels in accurate locations on each…

  16. Coordination Programming of Photofunctional Molecules

    Directory of Open Access Journals (Sweden)

    Hiroshi Nishihara


    Full Text Available Our recent achievements relating to photofunctional molecules are addressed. Section 1 discloses a new concept of photoisomerization. Pyridylpyrimidine-copper complexes undergo a ring inversion that can be modulated by the redox state of the copper center. In combination with an intermolecular photoelectron transfer (PET initiated by the metal-to-ligand charge transfer (MLCT transition of the Cu(I state, we realize photonic regulation of the ring inversion. Section 2 reports on the first examples of heteroleptic bis(dipyrrinatozinc(II complexes. Conventional homoleptic bis(dipyrrinatozinc(II complexes suffered from low fluorescence quantum yields, whereas the heteroleptic ones feature bright fluorescence even in polar solvents. Section 3 describes our new findings on Pechmann dye, which was first synthesized in 1882. New synthetic procedures for Pechmann dye using dimethyl bis(arylethynylfumarate as a starting material gives rise to its new structural isomer. We also demonstrate potentiality of a donor-acceptor-donor type of Pechmann dye in organic electronics.

  17. Single-Molecule Stochastic Resonance

    Directory of Open Access Journals (Sweden)

    K. Hayashi


    Full Text Available Stochastic resonance (SR is a well-known phenomenon in dynamical systems. It consists of the amplification and optimization of the response of a system assisted by stochastic (random or probabilistic noise. Here we carry out the first experimental study of SR in single DNA hairpins which exhibit cooperatively transitions from folded to unfolded configurations under the action of an oscillating mechanical force applied with optical tweezers. By varying the frequency of the force oscillation, we investigate the folding and unfolding kinetics of DNA hairpins in a periodically driven bistable free-energy potential. We measure several SR quantifiers under varied conditions of the experimental setup such as trap stiffness and length of the molecular handles used for single-molecule manipulation. We find that a good quantifier of the SR is the signal-to-noise ratio (SNR of the spectral density of measured fluctuations in molecular extension of the DNA hairpins. The frequency dependence of the SNR exhibits a peak at a frequency value given by the resonance-matching condition. Finally, we carry out experiments on short hairpins that show how SR might be useful for enhancing the detection of conformational molecular transitions of low SNR.

  18. NMR studies of oriented molecules

    Energy Technology Data Exchange (ETDEWEB)

    Sinton, S.W.


    Deuterium and proton magnetic resonance are used in experiments on a number of compounds which either form liquid crystal mesophases themselves or are dissolved in a liquid crystal solvent. Proton multiple quantum NMR is used to simplify complicated spectra. The theory of nonselective multiple quantum NMR is briefly reviewed. Benzene dissolved in a liquid crystal are used to demonstrate several outcomes of the theory. Experimental studies include proton and deuterium single quantum ( = +-1) and proton multiple quantum spectra of several molecules which contain the biphenyl moiety. 4-Cyano-4'-n-pentyl-d/sub 11/-biphenyl (5CB-d/sub 11/) is studied as a pure compound in the nematic phase. The obtained chain order parameters and dipolar couplings agree closely with previous results. Models for the effective symmetry of the biphenyl group in 5CB-d/sub 11/ are tested against the experimental spectra. The dihedral angle, defined by the planes containing the rings of the biphenyl group, is found to be 30 +- 2/sup 0/ for 5DB-d/sub 11/. Experiments are also described for 4,4'-d/sub 2/-biphenyl, 4,4' - dibromo-biphenyl, and unsubstituted biphenyl.

  19. Ribosome display for improved biotherapeutic molecules. (United States)

    Rothe, Achim; Hosse, Ralf J; Power, Barbara E


    Ribosome display presents an innovative in vitro technology for the rapid isolation and evolution of high-affinity peptides or proteins. Displayed proteins are bound to and recovered from target molecules in multiple rounds of selection in order to enrich for specific binding proteins. No transformation step is necessary, which could lead to a loss of library diversity. A cycle of display and selection can be performed in one day, enabling the existing gene repertoire to be rapidly scanned. Proteins isolated from the panning rounds can be further modified through random or directed molecular evolution for affinity maturation, as well as selected for characteristics such as protein stability, folding and functional activity. Recently, the field of display technologies has become more prominent due to the generation of new scaffolds for ribosome display, isolation of high-affinity human antibodies by phage display, and their implementation in the discovery of novel protein-protein interactions. Applications for this technology extend into the broad field of antibody engineering, proteomics, and synthetic enzymes for diagnostics and therapeutics in cancer, autoimmune and infectious diseases, neurodegenerative diseases and inflammatory disorders. This review highlights the role of ribosome display in drug discovery, discusses advantages and disadvantages of the system, and attempts to predict the future impact of ribosome display technology on the development of novel engineered biopharmaceutical products for biological therapies.

  20. Rotational cooling of trapped polyatomic molecules

    CERN Document Server

    Glöckner, Rosa; Englert, Barbara G U; Rempe, Gerhard; Zeppenfeld, Martin


    Controlling the internal degrees of freedom is a key challenge for applications of cold and ultracold molecules. Here, we demonstrate rotational-state cooling of trapped methyl fluoride molecules (CH3F) by optically pumping the population of 16 M-sublevels in the rotational states J=3,4,5, and 6 into a single level. By combining rotational-state cooling with motional cooling, we increase the relative number of molecules in the state J=4, K=3, M=4 from a few percent to over 70%, thereby generating a translationally cold (~30mK) and nearly pure state ensemble of about 10^6 molecules. Our scheme is extendable to larger sets of initial states, other final states and a variety of molecule species, thus paving the way for internal-state control of ever larger molecules.

  1. Single molecule detection, thermal fluctuation and life (United States)

    YANAGIDA, Toshio; ISHII, Yoshiharu


    Single molecule detection has contributed to our understanding of the unique mechanisms of life. Unlike artificial man-made machines, biological molecular machines integrate thermal noises rather than avoid them. For example, single molecule detection has demonstrated that myosin motors undergo biased Brownian motion for stepwise movement and that single protein molecules spontaneously change their conformation, for switching to interactions with other proteins, in response to thermal fluctuation. Thus, molecular machines have flexibility and efficiency not seen in artificial machines. PMID:28190869

  2. Nonlinear transport through a nanoscale molecule. (United States)

    Hettler, Matthias H; Schoeller, Herbert


    A simple model of electrical transport through a metal-aromatic molecule-metal system that includes charging effects as well as aspects of the electronic structure of the molecule, is presented. The interplay of a large charging energy and an asymmetry of the metal-molecule coupling can lead to various effects in nonlinear electrical transport. In particular, strong negative differential conductance is observed under certain conditions.

  3. Direct ELISA. (United States)

    Lin, Alice V


    First described by Engvall and Perlmann, the enzyme-linked immunosorbent assay (ELISA) is a rapid and sensitive method for detection and quantitation of an antigen using an enzyme-labeled antibody. Besides routine laboratory usage, ELISA has been utilized in medical field and food industry as diagnostic and quality control tools. Traditionally performed in 96-well or 384-well polystyrene plates, the technology has expanded to other platforms with increase in automation. Depending on the antigen epitope and availability of specific antibody, there are variations in ELISA setup. The four basic formats are direct, indirect, sandwich, and competitive ELISAs. Direct ELISA is the simplest format requiring an antigen and an enzyme-conjugated antibody specific to the antigen. This chapter describes the individual steps for detection of a plate-bound antigen using a horseradish peroxidase (HRP)-conjugated antibody and luminol-based enhanced chemiluminescence (ECL) substrate. The methodological approach to optimize the assay by chessboard titration is also provided.

  4. High harmonic generation from axial chiral molecules. (United States)

    Wang, Dian; Zhu, Xiaosong; Liu, Xi; Li, Liang; Zhang, Xiaofan; Lan, Pengfei; Lu, Peixiang


    Axial chiral molecules, whose stereogenic element is an axis rather than a chiral center, have attracted widespread interest due to their important application, such as asymmetric synthesis and chirality transfer. We investigate high harmonic generation from axial chiral molecules with bichromatic counterrotating circularly polarized laser fields. High harmonic generation from three typical molecules: (Sa)-3-chloropropa-1,2-dien-1-ol, propadiene, and (Ra)-2,3-pentadiene is simulated with time-dependent density-functional theory and strong field approximation. We found that harmonic spectra for 3D oriented axial chiral molecules exhibit obvious circular dichroism. However, the circular dichroism of High harmonic generation from an achiral molecule is much trivial. Moreover, the dichroism of high harmonic generation still exists when axial chiral molecules are 1D oriented,such as (Sa) -3-chloropropa-1,2-dien-1-ol. For a special form of axial chiral molecules with the formula abC=C=Cab (a, b are different substituents), like (Ra)-2,3-pentadiene, the dichroism discriminations disappear when the molecules are only in 1D orientation. The circular dichroism of high harmonic generation from axial chiral molecules is well explained by the trajectory analysis based on the semiclassical three-step mechanism.

  5. Supramolecular nanotechnology: from molecules to devices

    National Research Council Canada - National Science Library

    Henrique E. Toma


    Supramolecular chemistry, also known as the chemistry beyond the molecules, provides the best route for molecular nanotechnology, allowing the design of versatile functional nanomaterials conveying...

  6. Electron-molecule interactions and their applications

    CERN Document Server

    Christophorou, L G


    Electron-Molecule Interactions and Their Applications, Volume 2 provides a balanced and comprehensive account of electron-molecule interactions in dilute and dense gases and liquid media. This book consists of six chapters. Chapter 1 deals with electron transfer reactions, while Chapter 2 discusses electron-molecular positive-ion recombination. The electron motion in high-pressure gases and electron-molecule interactions from single- to multiple-collision conditions is deliberated in Chapter 3. In Chapter 4, knowledge on electron-molecule interactions in gases is linked to that on similar proc

  7. Design of a small molecule against an oncogenic noncoding RNA. (United States)

    Velagapudi, Sai Pradeep; Cameron, Michael D; Haga, Christopher L; Rosenberg, Laura H; Lafitte, Marie; Duckett, Derek R; Phinney, Donald G; Disney, Matthew D


    The design of precision, preclinical therapeutics from sequence is difficult, but advances in this area, particularly those focused on rational design, could quickly transform the sequence of disease-causing gene products into lead modalities. Herein, we describe the use of Inforna, a computational approach that enables the rational design of small molecules targeting RNA to quickly provide a potent modulator of oncogenic microRNA-96 (miR-96). We mined the secondary structure of primary microRNA-96 (pri-miR-96) hairpin precursor against a database of RNA motif-small molecule interactions, which identified modules that bound RNA motifs nearby and in the Drosha processing site. Precise linking of these modules together provided Targaprimir-96 (3), which selectively modulates miR-96 production in cancer cells and triggers apoptosis. Importantly, the compound is ineffective on healthy breast cells, and exogenous overexpression of pri-miR-96 reduced compound potency in breast cancer cells. Chemical Cross-Linking and Isolation by Pull-Down (Chem-CLIP), a small-molecule RNA target validation approach, shows that 3 directly engages pri-miR-96 in breast cancer cells. In vivo, 3 has a favorable pharmacokinetic profile and decreases tumor burden in a mouse model of triple-negative breast cancer. Thus, rational design can quickly produce precision, in vivo bioactive lead small molecules against hard-to-treat cancers by targeting oncogenic noncoding RNAs, advancing a disease-to-gene-to-drug paradigm.

  8. The spontaneous synchronized dance of pairs of water molecules

    Energy Technology Data Exchange (ETDEWEB)

    Roncaratti, Luiz F. [Dipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia, 06123 Perugia (Italy); Instituto de Física, Universidade de Brasília, 70910-900 Brasília (Brazil); Cappelletti, David, E-mail:; Pirani, Fernando [Dipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia, 06123 Perugia (Italy)


    Molecular beam scattering experiments have been performed to study the effect of long-range anisotropic forces on the collision dynamics of two small polar molecules. The main focus of this paper is on water, but also ammonia and hydrogen sulphide molecules have been investigated, and some results will be anticipated. The intermolecular distances mainly probed are of the order of 1 nm and therefore much larger than the molecular dimensions. In particular, we have found that the natural electric field gradient, generated by different spatial orientations of the permanent electric dipoles, is able to promote the transformation of free rotations into coupled pendular states, letting the molecular partners involved in the collision complex swinging to and fro around the field direction. This long-ranged concerted motion manifested itself as large increases of the magnitude of the total integral cross section. The experimental findings and the theoretical treatment developed to shed light on the details of the process suggest that the transformation from free rotations to pendular states depends on the rotational level of both molecules, on the impact parameter, on the relative collision velocity, on the dipole moment product and occurs in the time scale of picoseconds. The consequences of this intriguing phenomenon may be important for the interpretation and, in perspective, for the control of elementary chemical and biological processes, given by polar molecules, ions, and free radicals, occurring in several environments under various conditions.

  9. Optimal Background Estimators in Single-Molecule FRET Microscopy. (United States)

    Preus, Søren; Hildebrandt, Lasse L; Birkedal, Victoria


    Single-molecule total internal reflection fluorescence (TIRF) microscopy constitutes an umbrella of powerful tools that facilitate direct observation of the biophysical properties, population heterogeneities, and interactions of single biomolecules without the need for ensemble synchronization. Due to the low signal/noise ratio in single-molecule TIRF microscopy experiments, it is important to determine the local background intensity, especially when the fluorescence intensity of the molecule is used quantitatively. Here we compare and evaluate the performance of different aperture-based background estimators used particularly in single-molecule Förster resonance energy transfer. We introduce the general concept of multiaperture signatures and use this technique to demonstrate how the choice of background can affect the measured fluorescence signal considerably. A new, to our knowledge, and simple background estimator is proposed, called the local statistical percentile (LSP). We show that the LSP background estimator performs as well as current background estimators at low molecular densities and significantly better in regions of high molecular densities. The LSP background estimator is thus suited for single-particle TIRF microscopy of dense biological samples in which the intensity itself is an observable of the technique. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  10. Distance measurement along DNA molecules using fluorecent quantum dots (United States)

    Strey, Helmut


    To create and design better micro- and nanofluidic devices, we need to understand how macromolecules behave when squeezed by lateral barriers to create pseudo-two-dimensional confinement. We present experiments in which we visualize DNA molecules of varying sizes (2 kbp - 50 kbp) trapped in 10 micrometer wide slits, the slit height varying from the radius of gyration of the unconfined molecule (micrometer) down to 25 nm (half the persistence length of DNA). We present data on the diffusion coefficient and electrophoretic mobility (no electroosmotic flow) of SYBR-gold labeled DNA molecules as a function of slit height. Simultaneously, we have assessed the DNA conformation by examining molecules that are end-labeled with differently colored fluorescent quantum dots. By determining the distance between labels, we measure directly the end-to-end distance - a conformational measure much discussed but rarely measured. Using the same approach but turning the problem around, we determined if contour length can be estimated from visualization experiments. The answer to this question becomes important when the distance between specific binding sites on the DNA backbone must be measured. One such application, for example, is the determination of haplotypes (genetic variability due to blocks of single nucleotide polymorphisms (SNP)) in diploid individuals.

  11. The spontaneous synchronized dance of pairs of water molecules (United States)

    Roncaratti, Luiz F.; Cappelletti, David; Pirani, Fernando


    Molecular beam scattering experiments have been performed to study the effect of long-range anisotropic forces on the collision dynamics of two small polar molecules. The main focus of this paper is on water, but also ammonia and hydrogen sulphide molecules have been investigated, and some results will be anticipated. The intermolecular distances mainly probed are of the order of 1 nm and therefore much larger than the molecular dimensions. In particular, we have found that the natural electric field gradient, generated by different spatial orientations of the permanent electric dipoles, is able to promote the transformation of free rotations into coupled pendular states, letting the molecular partners involved in the collision complex swinging to and fro around the field direction. This long-ranged concerted motion manifested itself as large increases of the magnitude of the total integral cross section. The experimental findings and the theoretical treatment developed to shed light on the details of the process suggest that the transformation from free rotations to pendular states depends on the rotational level of both molecules, on the impact parameter, on the relative collision velocity, on the dipole moment product and occurs in the time scale of picoseconds. The consequences of this intriguing phenomenon may be important for the interpretation and, in perspective, for the control of elementary chemical and biological processes, given by polar molecules, ions, and free radicals, occurring in several environments under various conditions.

  12. Biological Nanopores: Confined Spaces for Electrochemical Single-Molecule Analysis. (United States)

    Cao, Chan; Long, Yi-Tao


    , we develop an integrated current measurement system and an accurate data processing method for nanopore sensing. The unique geometric structure of a biological nanopore offers a distinct advantage as a nanosensor for single-molecule sensing. The construction of the pore entrance is responsible for capturing the target molecule, while the lumen region determines the translocation process of the single molecule. Since the capture of the target molecule is predominantly diffusion-limited, it is expected that the capture ability of the nanopore toward the target analyte could be effectively enhanced by site-directed mutations of key amino acids with desirable groups. Additionally, changing the side chains inside the wall of the biological nanopore could optimize the geometry of the pore and realize an optimal interaction between the single-molecule interface and the analyte. These improvements would allow for high spatial and current resolution of nanopore sensors, which would ensure the possibility of dynamic study of single biomolecules, including their metastable conformations, charge distributions, and interactions. In the future, data analysis with powerful algorithms will make it possible to automatically and statistically extract detailed information while an analyte translocates through the pore. We conclude that these improvements could have tremendous potential applications for nanopore sensing in the near future.

  13. Anisotropic diffusion of water molecules in hydroxyapatite nanopores (United States)

    Prakash, Muthuramalingam; Lemaire, Thibault; Caruel, Matthieu; Lewerenz, Marius; de Leeuw, Nora H.; Di Tommaso, Devis; Naili, Salah


    New insights into the dynamical properties of water in hydroxyapatite (HAP) nanopores, a model system for the fluid flow within nanosize spaces inside the collagen-apatite structure of bone, were obtained from molecular dynamics simulations of liquid water confined between two parallel HAP surfaces of different sizes (20 Å ≤ H ≤ 240 Å). Calculations were conducted using a core-shell interatomic potential for HAP together with the extended simple point charge model for water. This force field gives an activation energy for water diffusion within HAP nanopores that is in excellent agreement with available experimental data. The dynamical properties of water within the HAP nanopores were quantified in terms of the second-order water diffusion tensor. Results indicate that water diffuses anisotropically within the HAP nanopores, with the solvent molecules moving parallel to the surface twice as fast as the perpendicular direction. This unusual dynamic behaviour is linked to the strong polarizing effect of calcium ions, and the synergic interactions between the water molecules in the first hydration layer of HAP with the calcium, hydroxyl, and phosphate ions, which facilitates the flow of water molecules in the directions parallel to the HAP surface.

  14. Quantitative single molecule FRET efficiencies using TIRF microscopy. (United States)

    Hildebrandt, Lasse L; Preus, Søren; Birkedal, Victoria


    Förster resonance energy transfer (FRET) microscopy at the single molecule level has the potential to yield information on intra and intermolecular distances within the 2-10 nm range of molecules or molecular complexes that undergo frequent conformation changes. A pre-requirement for obtaining accurate distance information is to determine quantitative instrument independent FRET efficiency values. Here, we applied and evaluated a procedure to determine quantitative FRET efficiencies directly from individual fluorescence time traces of surface immobilized DNA molecules without the need for external calibrants. To probe the robustness of the approach over a wide range of FRET efficiencies we used a set of doubly labelled double stranded DNA samples, where the acceptor position was varied systematically. Interestingly, we found that fluorescence contributions arising from direct acceptor excitation following donor excitation are intrinsically taken into account in these conditions as other correction factors can compensate for inaccurate values of these parameters. We give here guidelines, that can be used through tools within the iSMS software (), for determining quantitative FRET and assess uncertainties linked with the procedure. Our results provide insights into the experimental parameters governing quantitative FRET determination, which is essential for obtaining accurate structural information from a wide range of biomolecules.

  15. Simultaneous measurement of orientational and spectral dynamics of single molecules in nanostructured host-guest materials. (United States)

    Jung, Christophe; Hellriegel, Christian; Platschek, Barbara; Wöhrle, Dieter; Bein, Thomas; Michaelis, Jens; Bräuchle, Christoph


    Nanostructured host-guest materials are important for various applications in nanoscience, and therefore, a thorough understanding of the dynamics of the guest molecules within the host matrix is needed. To this aim we used single-molecule fluorescence techniques to simultaneously examine the spectral and the orientational behavior of single molecules in nanostructured porous host materials. Two types of host-guest systems have been investigated. First, oxazine-1 dye molecules were fixed rigidly in the channels of microporous AlPO4-5 crystals. Second, it was shown that terrylenediimide (TDI) dye molecules move in the mesoporous network of an uncalcined M41S thin film. In the first sample both spectral fluctuations ( approximately 5 nm) and rare spectral jumps (>10 nm) of the emission maximum were observed. However, the orientation of the emission dipole of the dye molecules remained constant. In contrast, the second system showed orientational dynamics as well as substantially more spectral dynamics. In this system the molecules were found to move between different regions in the host. The typical motion of the TDI molecules in the pores of M41S was not continuous but characterized by jumps between specific sites. Moreover, the spectral and orientational dynamics were correlated and arose directly from the different environments that were being explored by the mobile molecule.

  16. Photonic Bandgaps in Photonic Molecules (United States)

    Smith, David D.; Chang, Hongrok; Gates, Amanda L.; Fuller, Kirk A.; Gregory, Don A.; Witherow, William K.; Paley, Mark S.; Frazier, Donald O.; Curreri, Peter A. (Technical Monitor)


    This talk will focus on photonic bandgaps that arise due to nearly free photon and tight-binding effects in coupled microparticle and ring-resonator systems. The Mie formulation for homogeneous spheres is generalized to handle core/shell systems and multiple concentric layers in a manner that exploits an analogy with stratified planar systems, thereby allowing concentric multi-layered structures to be treated as photonic bandgap (PBG) materials. Representative results from a Mie code employing this analogy demonstrate that photonic bands arising from nearly free photon effects are easily observed in the backscattering, asymmetry parameter, and albedo for periodic quarter-wave concentric layers, though are not readily apparent in extinction spectra. Rather, the periodicity simply alters the scattering profile, enhancing the ratio of backscattering to forward scattering inside the bandgap, in direct analogy with planar quarter-wave multilayers. PBGs arising from tight-binding may also be observed when the layers (or rings) are designed such that the coupling between them is weak. We demonstrate that for a structure consisting of N coupled micro-resonators, the morphology dependent resonances split into N higher-Q modes, in direct analogy with other types of oscillators, and that this splitting ultimately results in PBGs which can lead to enhanced nonlinear optical effects.

  17. Probing Polymers with Single Fluorescent Molecules

    NARCIS (Netherlands)

    Tomczak, N.; Vallée, R.A.L.; van Dijk, E.M.H.P.; Garcia Parajo, M.F.; Kuipers, L.; van Hulst, N.F.; Vancso, Gyula J.


    The use of single molecules to study local, nanoscale polymer dynamics is presented. Fluorescence lifetime fluctuations were used to extract the number of polymer segments (Ns) taking part in the rearranging volume around the probe molecule below the glass transition temperature. Ns was dependent on

  18. Molecular Wring Resonances in Chain Molecules

    DEFF Research Database (Denmark)

    Bohr, Henrik; Brunak, Søren; Bohr, Jakob


    It is shown that the eigenfrequency of collective twist excitations in chain molecules can be in the megahertz and gigahertz range. Accordingly, resonance states can be obtained at specific frequencies, and phenomena that involve structural properties can take place. Chain molecules can alter the...

  19. Thermodynamics properties of diatomic molecules with general ...

    Indian Academy of Sciences (India)



    Jan 10, 2018 ... S and vibrational specific heat capacity C. These thermodynamic functions are studied for the electronic state X1 + g of K2 diatomic molecules. Keywords. Asymptotic iteration method; diatomic molecules; general molecular potential; partition function. PACS Nos 03.65.Ge; 03.65.Ca. 1. Introduction.

  20. A storage ring for neutral molecules

    NARCIS (Netherlands)

    Crompvoets, F.M.H.


    Time-varying inhomogeneous electric fields can be used to manipulate the motion of neutral molecules in phase-space, i.e., position-momentum space, via their electric dipole moment. A theoretical background is given on the motion of the molecules in phase-space. As the forces exerted on the

  1. Hydrogen storage by polylithiated molecules and nanostructures

    NARCIS (Netherlands)

    Er, S.; de Wijs, Gilles A.; Brocks, G.


    We study polylithiated molecules as building blocks for hydrogen storage materials, using first-principles calculations. CLi4 and OLi2 bind 12 and 10 hydrogen molecules, respectively, with an average binding energy of 0.10 and 0.13 eV, leading to gravimetric densities of 37.8 and 40.3 wt % of H2.

  2. Molecule-oriented programming in Java

    NARCIS (Netherlands)

    Bergstra, J.A.


    Molecule-oriented programming is introduced as a programming style carrying some perspective for Java. A sequence of examples is provided. Supporting the development of the molecule-oriented programming style several matters are introduced and developed: profile classes allowing the representation

  3. Novel bifunctional molecule for photorefractive materials

    NARCIS (Netherlands)

    Bolink, H.J; Arts, C.; Krasnikov, V.V.; Malliaras, G.G; Hadziioannou, G

    We report on the synthesis and characterization of a novel photorefractive polymer composite that consists of a bifunctional molecule based on the charge-transport molecule N,N'-diphenyl-N,N'-bis(3-methylphenyl)-[1,1'-biphenyl]-4,4'-diamine (TPD). It is shown that the low values obtained for the

  4. Tumor suppressor molecules and methods of use (United States)

    Welch, Peter J.; Barber, Jack R.


    The invention provides substantially pure tumor suppressor nucleic acid molecules and tumor suppressor polypeptides. The invention also provides hairpin ribozymes and antibodies selective for these tumor suppressor molecules. Also provided are methods of detecting a neoplastic cell in a sample using detectable agents specific for the tumor suppressor nucleic acids and polypeptides.

  5. Nanopipette Delivery of Individual Molecules to Cellular Compartments for Single-Molecule Fluorescence Tracking

    National Research Council Canada - National Science Library

    Bruckbauer, Andreas; James, Peter; Zhou, Dejian; Yoon, Ji Won; Excell, David; Korchev, Yuri; Jones, Roy; Klenerman, David


    We have developed a new method, using a nanopipette, for controlled voltage-driven delivery of individual fluorescently labeled probe molecules to the plasma membrane which we used for single-molecule...

  6. Vibrationally coupled electron transport through single-molecule junctions

    Energy Technology Data Exchange (ETDEWEB)

    Haertle, Rainer


    vibrational effects have a profound influence on the transport characteristics of a single-molecule contact and play therefore a fundamental role in this transport problem. Our findings demonstrate that vibrationally coupled electron transport through a molecular junction involves two types of processes: (i) transport processes, where an electron tunnels through the molecular bridge from one lead to the other, and (ii) electron-hole pair creation processes, where an electron tunnels from one of the leads onto the molecular bridge and back to the same lead again. Transport processes directly contribute to the electrical current flowing through a molecular contact and involve both excitation and deexcitation processes of the vibrational modes of the junction. Electron-hole pair creation processes do not directly contribute to the electrical current and typically involve only deexcitation processes. Nevertheless, they constitute a cooling mechanism for the vibrational modes of a single-molecule junction that is as important as cooling by transport processes. As the level of vibrational excitation determines the efficiency of electron transport processes, they have an indirect influence on the electrical current flowing through the junction. As we show, however, this influence can be substantial, in particular, if the molecule is coupled asymmetrically to the leads. Accounting for all these processes and their complex interrelationship, we analyze a number of intriguing transport phenomena, including rectification, negative differential resistance, anomalous peak broadening, mode-selective vibrational excitation and vibrationally induced decoherence. Moreover, we show that higher levels of vibrational excitation are obtained for weaker electronic-vibrational coupling. Thus, based on physical grounds, we establish a relation between the weak electronic-vibrational coupling limit and the limit of large bias voltages, where the level of vibrational excitation in a molecular junction

  7. Periodic systems of N-atom molecules (United States)

    Hefferlin, R. A.; Zhuvikin, G. V.; Caviness, K. E.; Duerksen, P. J.


    The atoms have long been classified into a periodic system, which is now based on quantum mechanics and group theory. A classification of molecules containing any number (N) of atoms is proposed. It is an extension of the periodic system of the atoms. The approach in this paper is that of group theory, although the proposed system has been subjected to exhaustive comparison with experimental and ab initio computational results for diatomic molecules, and conforms to the commonly known behaviors of molecules with larger N. Orthonormal transformations are performed so that the molecules can be arranged according to their numbers of electrons and to the differences of atomic numbers of the constituent atoms. These arrangements parallel the physical reality of atomic bonding and permit partial three-dimensional models of the systems to be constructed for molecules with as many as four atoms.

  8. Parallel interactions of aromatic and heteroaromatic molecules

    Directory of Open Access Journals (Sweden)

    Malenov Dušan P.


    Full Text Available Parallel interactions of aromatic and heteroaromatic molecules are very important in chemistry and biology. In this review, recent findings on preferred geometries and interaction energies of these molecules are presented. Benzene and pyridine were used as model systems for studying aromatic and heteroaromatic molecules, respectively. Searches of Cambridge Structural Database show that both aromatic and heteroaromatic molecules prefer interacting at large horizontal displacements, even though previous calculations showed that stacking interactions (with offsets of about 1.5 Å are the strongest. Calculations of interaction energies at large horizontal displacements revealed that the large portion of interaction energy is preserved even when two molecules do not overlap. These substantial energies, as well as the possibility of forming larger supramolecular structures, make parallel interactions at large horizontal displacements more frequent in crystal structures than stacking interactions. [Projekat Ministarstva nauke Republike Srbije, br. 172065

  9. Small molecule inhibition of 6-phosphofructo-2-kinase suppresses t cell activation

    Directory of Open Access Journals (Sweden)

    Telang Sucheta


    Full Text Available Abstract Background T cell activation is associated with a rapid increase in intracellular fructose-2,6-bisphosphate (F2,6BP, an allosteric activator of the glycolytic enzyme, 6-phosphofructo-1-kinase. The steady state concentration of F2,6BP in T cells is dependent on the expression of the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4 and the fructose-2,6-bisphosphatase, TIGAR. Of the PFKFB family of enzymes, PFKFB3 has the highest kinase:bisphosphatase ratio and has been demonstrated to be required for T cell proliferation. A small molecule antagonist of PFKFB3, 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3PO, recently has been shown to reduce F2,6BP synthesis, glucose uptake and proliferation in transformed cells. We hypothesized that the induction of PFKFB3 expression may be required for the stimulation of glycolysis in T cells and that exposure to the PFKFB3 antagonist, 3PO, would suppress T cell activation. Methods We examined PFKFB1-4 and TIGAR expression and F2,6BP concentration in purified CD3+ T cells stimulated with microbead-conjugated agonist antibodies specific for CD3 and the co-stimulatory receptor, CD28. We then determined the effect of 3PO on anti-CD3/anti-CD28-induced T cell activation, F2,6BP synthesis, 2-[1-14C]-deoxy-d-glucose uptake, lactate secretion, TNF-α secretion and proliferation. Finally, we examined the effect of 3PO administration on the development of delayed type hypersensitivity to methylated BSA and on imiquimod-induced psoriasis in mice. Results We found that purified human CD3+ T cells express PFKFB2, PFKFB3, PFKFB4 and TIGAR, and that anti-CD3/anti-CD28 conjugated microbeads stimulated a >20-fold increase in F2,6BP with a coincident increase in protein expression of the PFKFB3 family member and a decrease in TIGAR protein expression. We then found that exposure to the PFKFB3 small molecule antagonist, 3PO (1–10 μM, markedly attenuated the stimulation of F2,6BP

  10. Prospects for sympathetic cooling of optically stark decelerated molecules (United States)

    Barletta, Paolo; Tennyson, Jonathan; Barker, Peter F.


    A novel approach has recently been proposed for producing ultra-cold molecules by sympathetic cooling with optically co-trapped rare gas (Rg) atoms [1]. For an efficient planning and realization of the experiment theoretical determination of atom-molecule cross sections at ultra-low energies is very important. In this contribution I will present calculations of scattering lengths and cross sections for he Rg-H2 and Rg-benzene complexes (Rg=He,Ne,Ar,Kr,Xe), with particular emphasis on Ar and Kr. H2 and benzene are considered in their lowest vibrational-rotational states. A direct Monte Carlo simulation of the dynamics of the cooling process has been made by means of the Bird method. This simulation will enable the optimization of the experimental apparatus, and to test the cooling capability of the different Rg gases. [1] P. Barletta, J. Tennyson, P.F. Barker, Phys. Rev. A, 78, 052707 (2008).

  11. Observation of rotating nuclear molecules and determination of their lifetimes

    Energy Technology Data Exchange (ETDEWEB)

    Comas, V.; Heinz, S.; Ackermann, D.; Heredia, J.; Hessberger, F.P.; Khuyagbaatar, J.; Kindler, B.; Lommel, B.; Mann, R. [GSI Helmholtzzentrum fuer Schwerionenforschung GmbH, Darmstadt (Germany); Hofmann, S. [GSI Helmholtzzentrum fuer Schwerionenforschung GmbH, Darmstadt (Germany); Goethe-Universitaet Frankfurt, Institut fuer Physik, Frankfurt (Germany)


    Long-living rotating nuclear molecules (or ''dinuclear systems'') have been observed at the velocity filter SHIP at GSI in reactions of {sup 64}Ni + {sup 207}Pb at Coulomb barrier energies. The rotation was directly revealed by the velocity spectra of deep inelastic target-like transfer products which are formed during the lifetime of the nuclear molecule and emitted after its breakup. The corresponding rotation angles were about 180 degree pointing to long nuclear interaction times or lifetimes of the system, respectively. We deduced the lifetimes from the lines in the velocity spectra originating from two different rotation angles. Further, the unambiguous correlation of a certain transfer product with its individual velocity spectrum allowed us to study the lifetimes as a function of the number of transferred protons. (orig.)

  12. Applications of optical trapping to single molecule DNA

    Energy Technology Data Exchange (ETDEWEB)

    Sonek, G.J.; Berns, M.W. [Univ. of California, Irvine, CA (United States). Beckman Laser Inst. and Medical Clinic; Keller, R.A. [Los Alamos National Lab., NM (United States). Chemical Science and Technology Div.


    This is the final report of a three-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The project focused on the methodologies required to integrate optical trapping with single molecule detection (SMD) so as to demonstrate high speed sequencing through optical micromanipulation of host substrates, nucleotide cleavage, and single molecule detection. As part of this effort, the new technology of optical tweezers was applied to the confinement and manipulation of microsphere handles containing attached DNA fragments. The authors demonstrated substrate optical trapping in rapid flow streams, the fluorescence excitation and detection of fluorescently labeled nucleotides in an optical trapping system, and the epifluorescent imaging of DNA fragments in flow streams. They successfully demonstrated optical trapping in laminar flow streams and completely characterized the trapping process as functions of fluid flow velocity, chamber dimension, trapping depth, incident laser power, and fluorescence measurement geometry.

  13. Radiation Pressure Force from Optical Cycling on a Polyatomic Molecule

    CERN Document Server

    Kozyryev, Ivan; Matsuda, Kyle; Hemmerling, Boerge; Doyle, John M


    We demonstrate multiple photon cycling and radiative force deflection on the triatomic free radical strontium monohydroxide (SrOH). Optical cycling is achieved on SrOH in a cryogenic buffer-gas beam by employing the rotationally closed $P\\left(N''=1\\right)$ branch of the vibronic transition $\\tilde{X}^{2}\\Sigma^{+}\\left(000\\right)\\leftrightarrow\\tilde{A}^{2}\\Pi_{1/2}\\left(000\\right)$. A single repumping laser excites the Sr-O stretching vibrational mode, and photon cycling of the molecule deflects the SrOH beam by an angle of $0.2^{\\circ}$ via scattering of $\\sim100$ photons per molecule. This approach can be used for direct laser cooling of SrOH and more complex, isoelectronic species.

  14. Design and elaboration of colloidal molecules: an overview. (United States)

    Duguet, Etienne; Désert, Anthony; Perro, Adeline; Ravaine, Serge


    The concept of colloidal molecules was first evoked by van Blaaderen in 2003 for describing small non-spherical colloids made of the aggregation of a small number of particles. He predicted original properties to the complex assemblies of such colloids, in particular in optics. This critical review deals with the different strategies reported for creating robust clusters of spherical particles which could mimic the space-filling models of simple conventional molecules. These routes concern either the controlled clustering of preformed colloids directed by coalescence, physical routes, chemical routes, or 2-D/3-D geometrical confinement, or strategies starting from a single colloid which is decorated by satellite colloids by taking advantage of controlled phase separation or nucleation and growth phenomena. These routes are compared from the viewpoint of the accessible shapes, their tunability and scalability (146 references).

  15. Gap junction modulation by extracellular signaling molecules: the thymus model

    Directory of Open Access Journals (Sweden)

    Alves L.A.


    Full Text Available Gap junctions are intercellular channels which connect adjacent cells and allow direct exchange of molecules of low molecular weight between them. Such a communication has been described as fundamental in many systems due to its importance in coordination, proliferation and differentiation. Recently, it has been shown that gap junctional intercellular communication (GJIC can be modulated by several extracellular soluble factors such as classical hormones, neurotransmitters, interleukins, growth factors and some paracrine substances. Herein, we discuss some aspects of the general modulation of GJIC by extracellular messenger molecules and more particularly the regulation of such communication in the thymus gland. Additionally, we discuss recent data concerning the study of different neuropeptides and hormones in the modulation of GJIC in thymic epithelial cells. We also suggest that the thymus may be viewed as a model to study the modulation of gap junction communication by different extracellular messengers involved in non-classical circuits, since this organ is under bidirectional neuroimmunoendocrine control.

  16. Distribution of soap molecules in flowing soap films (United States)

    Kim, Ildoo; Sane, Aakash; Mandre, Shreyas

    Flowing soap films are useful tools to simulate two-dimensional flows. The Marangoni elasticity due to the presence of soap molecules not only stabilizes the soap film but also imparts it compressibility to the two-dimensional flow in the soap film. Therefore, it is desirable to measure the surface concentration cs of soap molecules to understand the physics flowing soap films. In this study, we present an indirect measurement of cs, by making a direct measurement of the surface tension and the Marangoni elasticity. Using a two-stage model for soap distribution in the flows, the range of cs is calculated for different thickness and the soap solution concentration. Our model shows that the soap film will have the same cs for the range of parameters in popular use and in agreements with experimental data.

  17. Pulsed gas lasers based on electric transitions of diatomic molecules

    Energy Technology Data Exchange (ETDEWEB)

    Kaslin, V.M.; Petrash, G.G.


    A detailed experimental study was carried out on the most important laser systems based on electron-oscillatory-rotational transitions of diatomic molecules. A study was made of the following transitions: in the N/sub 2/ molecule the C/sup 3/P/sub u/-B/sup 3/P/sub g/ (second positive band system) and the B/sup 3/P/sub g/-A/sup 3/..sigma../sub u//sup +/ (first positive band system) transitions; in the CO molecule the transition B/sup 1/..sigma../sup +/-A/sup 1/P (band system of Angstrom); in the H/sub 2/ molecule the transition 2sE/sup 1/..sigma../sub g//sup +/-2psigmab/sup 1/..sigma../sub u//sup +/. It is shown that in all these systems a single mechanism is responsible for the inverse population. It is based on excitation of the working levels by direct electron shock from the ground state of the molecules. The distribution of excitation and amplification among the bands is determined by the Frank-Cordon principle. The energy and temporal characteristics of light generation in tubes of equal diameter is unambiguously defined by the parameter E/N, where E is the tension of the electric field in the discharge tube, and N is the density of the working gas. It was found that cooling the active substance in these lasers leads to a sharp increase of the amplification coefficient. This feature made it possible to obtain record radiation output in most of these lasers, to observe modes of high emission in the lasers, to observe a variation of intensities in the molecular spectra, and to realize more than 180 new lines of light generation.

  18. Future direction of direct writing (United States)

    Kim, Nam-Soo; Han, Kenneth N.


    Direct write technology using special inks consisting of finely dispersed metal nanoparticles in liquid is receiving an undivided attention in recent years for its wide range of applicability in modern electronic industry. The application of this technology covers radio frequency identification-tag (RFID-tag), flexible-electronics, organic light emitting diodes (OLED) display, e-paper, antenna, bumpers used in flip-chip, underfilling, frit, miniresistance applications and biological uses, artificial dental applications and many more. In this paper, the authors have reviewed various direct write technologies on the market and discussed their advantages and shortfalls. Emphasis has given on microdispensing deposition write (MDDW), maskless mesoscale materials deposition (M3D), and ink-jet technologies. All of these technologies allow printing various patterns without employing a mask or a resist with an enhanced speed with the aid of computer. MDDW and M3D are capable of drawing patterns in three-dimension and MDDW, in particular, is capable of writing nanoinks with high viscosity. However, it is still far away for direct write to be fully implemented in the commercial arena. One of the hurdles to overcome is in manufacturing conductive inks which are chemically and physically stable, capable of drawing patterns with acceptable conductivity, and also capable of drawing patterns with acceptable adhesiveness with the substrates. The authors have briefly discussed problems involved in manufacturing nanometal inks to be used in various writing devices. There are numerous factors to be considered in manufacturing such inks. They are reducing agents, concentrations, oxidation, compact ability allowing good conductivity, and stability in suspension.

  19. Conformation-based signal transfer and processing at the single-molecule level. (United States)

    Li, Chao; Wang, Zhongping; Lu, Yan; Liu, Xiaoqing; Wang, Li


    Building electronic components made of individual molecules is a promising strategy for the miniaturization and integration of electronic devices. However, the practical realization of molecular devices and circuits for signal transmission and processing at room temperature has proven challenging. Here, we present room-temperature intermolecular signal transfer and processing using SnCl 2 Pc molecules on a Cu(100) surface. The in-plane orientations of the molecules are effectively coupled via intermolecular interaction and serve as the information carrier. In the coupled molecular arrays, the signal can be transferred from one molecule to another in the in-plane direction along predesigned routes and processed to realize logical operations. These phenomena enable the use of molecules displaying intrinsic bistable states as complex molecular devices and circuits with novel functions.

  20. Minimizing pulling geometry errors in atomic force microscope single molecule force spectroscopy. (United States)

    Rivera, Monica; Lee, Whasil; Ke, Changhong; Marszalek, Piotr E; Cole, Daniel G; Clark, Robert L


    In atomic force microscopy-based single molecule force spectroscopy (AFM-SMFS), it is assumed that the pulling angle is negligible and that the force applied to the molecule is equivalent to the force measured by the instrument. Recent studies, however, have indicated that the pulling geometry errors can drastically alter the measured force-extension relationship of molecules. Here we describe a software-based alignment method that repositions the cantilever such that it is located directly above the molecule's substrate attachment site. By aligning the applied force with the measurement axis, the molecule is no longer undergoing combined loading, and the full force can be measured by the cantilever. Simulations and experimental results verify the ability of the alignment program to minimize pulling geometry errors in AFM-SMFS studies.

  1. Role of surfactants in the interaction of dye molecules in natural DNA polymers. (United States)

    You, H; Spaeth, H; Linhard, V N L; Steckl, A J


    Solutions and powders formed from salmon sperm deoxyribonucleic acid (DNA) reacted with the cationic surfactant cetyltrimethylammonium chloride (CTMA-Cl) incorporated fluorescent rhodamine molecules: anionic sulforhodamine 640 (SRh) or cationic/zwitterionic rhodamine 640 perchlorate (RhP). The role of the cationic surfactant in the interaction between rhodamine dye and DNA-surfactant molecules has been investigated in both solution and solid state using optical spectroscopy and electrophoresis. Unexpectedly, the dye molecules did not interact directly with DNA, rather the DNA double helix acted as a template for the interaction between dye molecules and CTMA in the DNA/CTMA complex. The SRh and RhP molecules yield different fluorescence characteristics with increasing DNA/CTMA amount, indicating different configurations between the CTMA ligands.

  2. Ionization of oriented carbonyl sulfide molecules by intense circularly polarized laser pulses

    DEFF Research Database (Denmark)

    Dimitrovski, Darko; Abu-Samha, Mahmoud; Madsen, Lars Bojer


    We present combined experimental and theoretical results on strong-field ionization of oriented carbonyl sulfide molecules by circularly polarized laser pulses. The obtained molecular frame photoelectron angular distributions show pronounced asymmetries perpendicular to the direction...... of the molecular electric dipole moment. These findings are explained by a tunneling model invoking the laser-induced Stark shifts associated with the dipoles and polarizabilities of the molecule and its unrelaxed cation. The focus of the present article is to understand the strong-field ionization of one......-dimensionally-oriented polar molecules, in particular asymmetries in the emission direction of the photoelectrons. In the following article [Phys. Rev. A 83, 023406 (2011)] the focus is to understand strong-field ionization from three-dimensionally-oriented asymmetric top molecules, in particular the suppression of electron...

  3. Line broadening of confined CO gas: From molecule-wall to molecule-molecule collisions with pressure (United States)

    Hartmann, J.-M.; Boulet, C.; Vander Auwera, J.; El Hamzaoui, H.; Capoen, B.; Bouazaoui, M.


    The infrared absorption in the fundamental band of CO gas confined in porous silica xerogel has been recorded at room temperature for pressures between about 5 and 920 hPa using a high resolution Fourier transform spectrometer. The widths of individual lines are determined from fits of measured spectra and compared with ab initio predictions obtained from requantized classical molecular dynamics simulations. Good agreement is obtained from the low pressure regime where the line shapes are governed by molecule-wall collisions to high pressures where the influence of molecule-molecule interactions dominates. These results, together with those obtained with a simple analytical model, indicate that both mechanisms contribute in a practically additive way to the observed linewidths. They also confirm that a single collision of a molecule with a wall changes its rotational state. These results are of interest for the determination of some characteristics of the opened porosity of porous materials through optical soundings.

  4. Predictive Power of Different Types of Experimental Restraints in Small Molecule Docking: A Review. (United States)

    Fu, Darwin Y; Meiler, Jens


    Incorporating experimental restraints is a powerful method of increasing accuracy in computational protein small molecule docking simulations. Different algorithms integrate distinct forms of biochemical data during the docking and/or scoring stages. These so-called hybrid methods make use of receptor-based information such as nuclear magnetic resonance (NMR) restraints or small molecule-based information such as structure-activity relationships (SARs). A third class of methods directly interrogates contacts between the protein receptor and the small molecule. This work reviews the current state of using such restraints in docking simulations, evaluates their feasibility across broad systems, and identifies potential areas of algorithm development.

  5. Single Molecule Biophysics Experiments and Theory

    CERN Document Server

    Komatsuzaki, Tamiki; Takahashi, Satoshi; Yang, Haw; Silbey, Robert J; Rice, Stuart A; Dinner, Aaron R


    Discover the experimental and theoretical developments in optical single-molecule spectroscopy that are changing the ways we think about molecules and atoms The Advances in Chemical Physics series provides the chemical physics field with a forum for critical, authoritative evaluations of advances in every area of the discipline. This latest volume explores the advent of optical single-molecule spectroscopy, and how atomic force microscopy has empowered novel experiments on individual biomolecules, opening up new frontiers in molecular and cell biology and leading to new theoretical approaches

  6. Conformational States of the Spiropyran Molecule

    Directory of Open Access Journals (Sweden)

    Olha Kovalenko


    Full Text Available The form of the potential surface of the ground state was investigated on the basis of indoline spiropyran. As a result of this work the rotamers of an open-ring form of the spiropyran molecule were discovered, and the existence of the most probable rotamers was justified. The 3D potential surface of the ground state of the spiropyran molecule was built. The route of the isomerization of the molecule was discovered and values of barriers for this reaction were found. The part of the isomerization route that is responsible for changing the hybridization of spiroatom from sp3 to sp2 was found.

  7. Aligning molecules with intense nonresonant laser fields

    DEFF Research Database (Denmark)

    Larsen, J.J.; Safvan, C.P.; Sakai, H.


    Molecules in a seeded supersonic beam are aligned by the interaction between an intense nonresonant linearly polarized laser field and the molecular polarizability. We demonstrate the general applicability of the scheme by aligning I2, ICl, CS2, CH3I, and C6H5I molecules. The alignment is probed...... by mass selective two dimensional imaging of the photofragment ions produced by femtosecond laser pulses. Calculations on the degree of alignment of I2 are in good agreement with the experiments. We discuss some future applications of laser aligned molecules....

  8. Tunable optical absorption in silicene molecules

    KAUST Repository

    Mokkath, Junais Habeeb


    Two-dimensional materials with a tunable band gap that covers a wide range of the solar spectrum hold great promise for sunlight harvesting. For this reason, we investigate the structural, electronic, and optical properties of silicene molecules using time dependent density functional theory. We address the influence of the molecular size, buckling, and charge state as well as that of a dielectric environment. Unlike planar graphene molecules, silicene molecules prefer to form low-buckled structures with strong visible to ultraviolet optical response. We also identify molecular plasmons.

  9. Kondo effect in molecules with strong correlations

    Energy Technology Data Exchange (ETDEWEB)

    Kuzmenko, Tetyana [Department of Physics, Ben-Gurion University, P.O. Box 653, Beer-Sheva 84105 (Israel)]. E-mail:; Kikoin, Konstantin [Department of Physics, Ben-Gurion University, P.O. Box 653, Beer-Sheva 84105 (Israel); Avishai, Yshai [Department of Physics, Ben-Gurion University, P.O. Box 653, Beer-Sheva 84105 (Israel)


    A theory of Kondo tunneling through molecules adsorbed on metallic substrate is constructed and the underlying physics is exposed. It is shown that in the case of weak chemisorption the sandwich-type molecules manifest a novel type of Kondo effect that has not been observed in magnetically doped bulk metals. The exchange Hamiltonian of these molecules unveils unusual dynamical SO(n) symmetries instead of conventional SU(2) symmetry. These symmetries can be experimentally realized and the specific value of n can be controlled by gate voltage.

  10. Single-molecule vibrational spectroscopy of water molecules using an LT-STM (United States)

    Matsumoto, Chikako; Kim, Yousoo; Motobayashi, Kenta; Kawai, Maki


    Single-molecule vibrational spectroscopy has attracted considerable attention as a powerful tool for nanoscale chemistry. The adsorption of water molecules on metal surfaces plays an important role in understanding many phenomena in nature, such as heterogeneous catalysis and corrosion, etc. The structure of water at low coverage has been investigated on a variety of transition-metal surfaces with various techniques. But the microscopic understanding of the adsorption feature of single water molecules is still unclear. We report molecular scale study of adsorption behaviors of water molecules on Pt (111) surface at 4.7 K by use of single-molecule vibrational spectroscopy with the scanning tunneling microscopy (STM). The Pt (111) surface was dosed with a small amount of water molecules (cherry blossom', which can be explained by one of the water molecules rotating around the other. Inelastic electron tunneling spectroscopy using the STM was utilized to determine vibrational modes of individual water dimers.

  11. Modulation and Control of Charge Transport Through Single-Molecule Junctions. (United States)

    Wang, Kun; Xu, Bingqian


    The ability to modulate and control charge transport though single-molecule junction devices is crucial to achieving the ultimate goal of molecular electronics: constructing real-world-applicable electronic components from single molecules. This review aims to highlight the progress made in single-molecule electronics, emphasizing the development of molecular junction electronics in recent years. Among many techniques that attempt to wire a molecule to metallic electrodes, the single-molecule break junction (SMBJ) technique is one of the most reliable and tunable experimental platforms for achieving metal-molecule-metal configurations. It also provides great freedom to tune charge transport through the junction. Soon after the SMBJ technique was introduced, it was extensively used to measure the conductances of individual molecules; however, different conductances were obtained for the same molecule, and it proved difficult to interpret this wide distribution of experimental data. This phenomenon was later found to be mainly due to a lack of precise experimental control and advanced data analysis methods. In recent years, researchers have directed considerable effort into advancing the SMBJ technique by gaining a deeper physical understanding of charge transport through single molecules and thus enhancing its potential applicability in functional molecular-scale electronic devices, such as molecular diodes and molecular transistors. In parallel with that research, novel data analysis methods and approaches that enable the discovery of hidden yet important features in the data are being developed. This review discusses various aspects of molecular junction electronics, from the initial goal of molecular electronics, the development of experimental techniques for creating single-molecule junctions and determining single-molecule conductance, to the characterization of functional current-voltage features and the investigation of physical properties other than charge

  12. Dissecting contact mechanics from quantum interference in single-molecule junctions of stilbene derivatives. (United States)

    Aradhya, Sriharsha V; Meisner, Jeffrey S; Krikorian, Markrete; Ahn, Seokhoon; Parameswaran, Radha; Steigerwald, Michael L; Nuckolls, Colin; Venkataraman, Latha


    Electronic factors in molecules such as quantum interference and cross-conjugation can lead to dramatic modulation and suppression of conductance in single-molecule junctions. Probing such effects at the single-molecule level requires simultaneous measurements of independent junction properties, as conductance alone cannot provide conclusive evidence of junction formation for molecules with low conductivity. Here, we compare the mechanics of the conducting para-terminated 4,4'-di(methylthio)stilbene and moderately conducting 1,2-bis(4-(methylthio)phenyl)ethane to that of insulating meta-terminated 3,3'-di(methylthio)stilbene single-molecule junctions. We simultaneously measure force and conductance across single-molecule junctions and use force signatures to obtain independent evidence of junction formation and rupture in the meta-linked cross-conjugated molecule even when no clear low-bias conductance is measured. By separately quantifying conductance and mechanics, we identify the formation of atypical 3,3'-di(methylthio)stilbene molecular junctions that are mechanically stable but electronically decoupled. While theoretical studies have envisaged many plausible systems where quantum interference might be observed, our experiments provide the first direct quantitative study of the interplay between contact mechanics and the distinctively quantum mechanical nature of electronic transport in single-molecule junctions. © 2012 American Chemical Society

  13. Measurement of the orientation of buffer-gas-cooled, electrostatically-guided ammonia molecules (United States)

    Steer, Edward W.; Petralia, Lorenzo S.; Western, Colin M.; Heazlewood, Brianna R.; Softley, Timothy P.


    The extent to which the spatial orientation of internally and translationally cold ammonia molecules can be controlled as molecules pass out of a quadrupole guide and through different electric field regions is examined. Ammonia molecules are collisionally cooled in a buffer gas cell, and are subsequently guided by a three-bend electrostatic quadrupole into a detection chamber. The orientation of ammonia molecules is probed using (2 + 1) resonance-enhanced multiphoton ionisation (REMPI), with the laser polarisation axis aligned both parallel and perpendicular to the time-of-flight axis. Even with the presence of a near-zero field region, the ammonia REMPI spectra indicate some retention of orientation. Monte Carlo simulations propagating the time-dependent Schrödinger equation in a full basis set including the hyperfine interaction enable the orientation of ammonia molecules to be calculated - with respect to both the local field direction and a space-fixed axis - as the molecules pass through different electric field regions. The simulations indicate that the orientation of ∼95% of ammonia molecules in JK =11 could be achieved with the application of a small bias voltage (17 V) to the mesh separating the quadrupole and detection regions. Following the recent combination of the buffer gas cell and quadrupole guide apparatus with a linear Paul ion trap, this result could enable one to examine the influence of molecular orientation on ion-molecule reaction dynamics and kinetics.

  14. Quantum state selection of polar molecules: Alignment, orientation and conformational control (United States)

    Stapelfeldt, Henrik


    Building on ideas that go back to Stern in the 1920s we use an inhomogeneous static electric field to deflect a cold beam of polar molecules. The deflection spatially disperses the rotational quantum states of the molecules. We show that the molecules residing in the lowest-lying rotational states can be selected and used as targets for further experiments. In particular, the quantum-state-selected molecules enable unprecedented strong alignment, induced by a moderately intense laser pulse, as well as strong orientation induced by a mixed laser and static electric field. Here, alignment refers to confinement of one or more molecule-fixed axes along laboratory-fixed axes, and orientation refers to the molecular dipole moments pointing in a specific direction. Also, it is shown that the deflection enables separation of the different conformers of a single molecule. We discuss new opportunities offered by the enhanced degree of orientational control, made possibly by quantum state selection, including time resolved studies of torsion, and eventually enantiomeric conversion, of axially chiral molecules. Collaborators: J. Küpper, G. Meijer, L. B. Madsen. [4pt] [1] Laser-Induced Alignment and Orientation of Quantum-State-Selected Large Molecules, L. Holmegaard, J. H. Nielsen, I. Nevo, H. Stapelfeldt, F. Filsinger, J. Küpper, and G. Meijer, Phys. Rev. Lett. 102. 023001 (2009).

  15. New developments in umami (enhancing) molecules. (United States)

    Winkel, Chris; de Klerk, Adri; Visser, Jan; de Rijke, Eva; Bakker, Jan; Koenig, Thorsten; Renes, Harry


    As health has become one of the main drivers in nutrition, the scientific interest in taste receptors and taste molecules has increased considerably. Academia as well as flavor and food companies are searching for molecules that make food more healthy but not less appetizing. In the savory area, salt and umami taste are being investigated. This review deals with the progress made in umami tasting molecules. Umami taste has been known as a separate taste for a long time in Asian countries and has been generally accepted as the fifth basic taste in the last decade of the previous century. In this review, first the current level of understanding of the umami receptors will be described. The main part of the paper will deal with the umami-tasting molecules that have been published recently, including the work that has been performed within Givaudan itself. Lactoyl amides of GMP (guanosine monophosphate) appeared to have remarkably strong umami-tasting properties.

  16. Hydrogen sulfide and polysulfides as signaling molecules

    National Research Council Canada - National Science Library

    KIMURA, Hideo


    .... Polysulfides, which have a higher number of inner sulfur atoms than that in H2S, were recently identified as potential signaling molecules that can activate ion channels, transcription factors...

  17. Single molecule interactions in biological systems

    CERN Document Server

    Tessmer, I


    The interactions of biological molecules are traditionally investigated using ensemble techniques. These provide information on the molecular behaviour based on averaged data resulting from collective ensemble properties. While this has enabled the resolution of structure and function of many proteins and other biomolecules, an understanding of how and why the molecules go about structural changes and modulate inter- and intra-molecular interactions is difficult to gain using these approaches. More recently, single molecule techniques have evolved. These allow us to follow the behaviour of the individual molecules over time and/or under changing conditions. From such data, subtle molecular changes can be resolved without the need to synchronise the system. Further, variations within a biological system can be detected which would be lost using the ensemble techniques, due to the concomitant averaging procedures. This is exploited to help understand the molecular procedures involved. In this thesis, the applic...

  18. Watching single protein molecules in action

    DEFF Research Database (Denmark)

    Heiðarsson, Pétur Orri

    . This knowledge-gap is partly due to our inability to unveil the details of folding mechanisms that can be buried in the ensemble-averaged output of traditional bulk methods. Single-molecule techniques have provided a perspective beyond the ensemble average and enable studying the folding trajectories of protein...... molecules in unprecedented detail. These methods can, in principle, detect rare folding or misfolding events, and ultimately lead to a reconstruction of the free energy landscape. In this thesis, the folding mechanism of both single- and double-domain proteins is unraveled using single-molecule optical......, with transition states located almost halfway between the native and unfolded states. When pulled from the N- and C-termini, both experiments and simulations suggested that the molecule populates a transition state that resembles that observed during chemical denaturation, with respect to structure and position...

  19. Proteins Are the Body's Worker Molecules (United States)

    ... The Structures of Life in PDF Chapter 1: Proteins are the Body's Worker Molecules You've probably ... abnormal shapes can cause disease. Back to Top Proteins Are Made From Small Building Blocks Proteins are ...

  20. Biological mechanisms, one molecule at a time (United States)

    Tinoco, Ignacio; Gonzalez, Ruben L.


    The last 15 years have witnessed the development of tools that allow the observation and manipulation of single molecules. The rapidly expanding application of these technologies for investigating biological systems of ever-increasing complexity is revolutionizing our ability to probe the mechanisms of biological reactions. Here, we compare the mechanistic information available from single-molecule experiments with the information typically obtained from ensemble studies and show how these two experimental approaches interface with each other. We next present a basic overview of the toolkit for observing and manipulating biology one molecule at a time. We close by presenting a case study demonstrating the impact that single-molecule approaches have had on our understanding of one of life's most fundamental biochemical reactions: the translation of a messenger RNA into its encoded protein by the ribosome. PMID:21685361

  1. Small molecule probes for cellular death machines. (United States)

    Li, Ying; Qian, Lihui; Yuan, Junying


    The past decade has witnessed a significant expansion of our understanding about the regulated cell death mechanisms beyond apoptosis. The application of chemical biological approaches had played a major role in driving these exciting discoveries. The discovery and use of small molecule probes in cell death research has not only revealed significant insights into the regulatory mechanism of cell death but also provided new drug targets and lead drug candidates for developing therapeutics of human diseases with huge unmet need. Here, we provide an overview of small molecule modulators for necroptosis and ferroptosis, two non-apoptotic cell death mechanisms, and discuss the molecular pathways and relevant pathophysiological mechanisms revealed by the judicial applications of such small molecule probes. We suggest that the development and applications of small molecule probes for non-apoptotic cell death mechanisms provide an outstanding example showcasing the power of chemical biology in exploring novel biological mechanisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. In search of multipath interference using large molecules. (United States)

    Cotter, Joseph P; Brand, Christian; Knobloch, Christian; Lilach, Yigal; Cheshnovsky, Ori; Arndt, Markus


    The superposition principle is fundamental to the quantum description of both light and matter. Recently, a number of experiments have sought to directly test this principle using coherent light, single photons, and nuclear spin states. We extend these experiments to massive particles for the first time. We compare the interference patterns arising from a beam of large dye molecules diffracting at single, double, and triple slit material masks to place limits on any high-order, or multipath, contributions. We observe an upper bound of less than one particle in a hundred deviating from the expectations of quantum mechanics over a broad range of transverse momenta and de Broglie wavelength.

  3. Small-molecule inhibition of inflammatory β-cell death

    DEFF Research Database (Denmark)

    Lundh, Morten; Scully, S S; Mandrup-Poulsen, T


    With the worldwide increase in diabetes prevalence there is a pressing unmet need for novel antidiabetic therapies. Insufficient insulin production due to impaired β-cell function and apoptotic reduction of β-cell mass is a common denominator in the pathogenesis of diabetes. Current treatments...... are directed at improving insulin sensitivity, and stimulating insulin secretion or replacing the hormone, but do not target progressive apoptotic β-cell loss. Here we review the current development of small-molecule inhibitors designed to rescue β-cells from apoptosis. Several distinct classes of small...

  4. Chiral Molecule in the Standard Model


    Fukuyama, Takeshi


    This review is based on the talk in the conference of "Spectroscopic Studies on Molecular Chirality" held on Dec 20-21 2013. The objects of the present paper are to (1) derive the energy difference between Laevorotatory, or left-handed, (L-) and Dextrotatory, or right-handed, (D-) molecules and to (2) discuss how this tiny energy difference leads us to the observed enantiomer excess. Relations with other parity violating phenomena in molecules, electric dipole moment and natural optical activ...

  5. High pressure structural studies of conjugated molecules

    DEFF Research Database (Denmark)

    Knaapila, Matti; Torkkeli, Mika; Scherf, Ullrich


    This chapter highlights high pressure GPa level structural studies of conjugated polymers and their analogues: conjugated oligomers and molecules, and rigid rod polymers. Attention is placed on our recent studies of polyfluorenes.......This chapter highlights high pressure GPa level structural studies of conjugated polymers and their analogues: conjugated oligomers and molecules, and rigid rod polymers. Attention is placed on our recent studies of polyfluorenes....

  6. Glycomics: revealing the dynamic ecology and evolution of sugar molecules. (United States)

    Springer, Stevan A; Gagneux, Pascal


    Sugars are the most functionally and structurally diverse molecules in the biological world. Glycan structures range from tiny single monosaccharide units to giant chains thousands of units long. Some glycans are branched, their monosaccharides linked together in many different combinations and orientations. Some exist as solitary molecules; others are conjugated to proteins and lipids and alter their collective functional properties. In addition to structural and storage roles, glycan molecules participate in and actively regulate physiological and developmental processes. Glycans also mediate cellular interactions within and between individuals. Their roles in ecology and evolution are pivotal, but not well studied because glycan biochemistry requires different methods than standard molecular biology practice. The properties of glycans are in some ways convenient, and in others challenging. Glycans vary on organismal timescales, and in direct response to physiological and ecological conditions. Their mature structures are physical records of both genetic and environmental influences during maturation. We describe the scope of natural glycan variation and discuss how studying glycans will allow researchers to further integrate the fields of ecology and evolution. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Sm-ChIPi: Single-Molecule Chromatin Immunoprecipitation Imaging. (United States)

    Tatavosian, Roubina; Ren, Xiaojun


    Epigenetic complexes regulate chromatin dynamics via binding to and assembling on chromatin. However, the mechanisms of chromatin binding and assembly of epigenetic complexes within cells remain incompletely understood, partly due to technical challenges. Here, we present a new approach termed single-molecule chromatin immunoprecipitation imaging (Sm-ChIPi) that enables to assess the cellular assembly stoichiometry of epigenetic complexes on chromatin. Sm-ChIPi was developed based on chromatin immunoprecipitation followed by single-molecule fluorescence microscopy imaging. In this method, an epigenetic complex subunit fused with a gene coding for a fluorescent protein is stably expressed in its corresponding knockout cells. Nucleosomes associated with epigenetic complexes are isolated from cells at native conditions and incubated with biotinylated antibodies. The resulting complexes are immobilized on a quartz slide that had been passivated and functionalized with NeutrAvidin. Image stacks are then acquired by using single-molecule TIRF microscopy. The individual spots imaged by TIRF microscopy represent single protein-nucleosome complexes. The number of copies of the protein complexes on a nucleosome is inferred from the fluorescence photobleaching measurements. Sm-ChIPi is a sensitive and direct method that can quantify the cellular assembly stoichiometry of epigenetic complexes on chromatin.

  8. Nanogap Electrodes towards Solid State Single-Molecule Transistors. (United States)

    Cui, Ajuan; Dong, Huanli; Hu, Wenping


    With the establishment of complementary metal-oxide-semiconductor (CMOS)-based integrated circuit technology, it has become more difficult to follow Moore's law to further downscale the size of electronic components. Devices based on various nanostructures were constructed to continue the trend in the minimization of electronics, and molecular devices are among the most promising candidates. Compared with other candidates, molecular devices show unique superiorities, and intensive studies on molecular devices have been carried out both experimentally and theoretically at the present time. Compared to two-terminal molecular devices, three-terminal devices, namely single-molecule transistors, show unique advantages both in fundamental research and application and are considered to be an essential part of integrated circuits based on molecular devices. However, it is very difficult to construct them using the traditional microfabrication techniques directly, thus new fabrication strategies are developed. This review aims to provide an exclusive way of manufacturing solid state gated nanogap electrodes, the foundation of constructing transistors of single or a few molecules. Such single-molecule transistors have the potential to be used to build integrated circuits. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Quantum Interference Contribution to the Dipole Moment of Diatomic Molecules. (United States)

    Oliveira de Sousa, David Wilian; Nascimento, Marco Antonio Chaer


    The interference energy partitioning analysis method developed by our group and used to study the nature of the chemical bond was extended to partition the electric dipole moment in quasi-classical and interference contributions. Our results show that interference participates in charge displacement in polar molecules, providing, directly or indirectly, a relevant contribution for the total dipole moment. A linear correlation was found between the interference contribution of the dipole moment from the bond electron group, μ INT (bond), and the difference of electronegativity of the atoms which form the bond, ΔX AB . This interesting result reinforces the fact that electronegativity is not a property of an atom alone, but rather a property of the atom in the molecule and that ΔX AB can only be associated with that part of the total charge displacement resulting from the formation of the chemical bond. The partitioning of the total dipole moment into quasi-classical and interference contributions provides new insights about the reasons for the failure of the ΔX AB criterion in predicting the correct orientation of the dipole moment in several molecules. The results of the present work also bring additional evidence for the previously proposed mechanism of formation of polar bonds.

  10. Human hematopoietic stem cell adherence to cytokines and matrix molecules. (United States)

    Long, M W; Briddell, R; Walter, A W; Bruno, E; Hoffman, R


    The hematopoietic microenvironment is a complex structure in which stem cells, progenitor cells, stromal cells, growth factors, and extracellular matrix (ECM) molecules each interact to direct the coordinate regulation of blood cell development. While much is known concerning the individual components of this microenvironment, little is understood of the interactions among these various components or, in particular, the nature of those interactions responsible for the regional localization of specific developmental signals. We hypothesized that cytokines act together with ECM molecules to anchor stem cells within the microenvironment, thus modulating their function. In order to analyze matrix-cytokine-stem cell interactions, we developed an ECM model system in which purified stem cell populations and plastic-immobilized individual proteins are used to assess the role of various matrix molecules and/or cytokines in human hematopoietic cell development. Analysis of these interactions revealed that a single ECM protein, thrombospondin, in conjunction with a single cytokine (e.g., c-kit ligand), constitutes a developmental signal that synergistically modulates hematopoietic stem cell function.

  11. Development of techniques for cooling and trapping polar diatomic molecules (United States)

    Glenn, David R.

    The study of ultracold dipolar molecules is an important emerging frontier in atomic physics. This thesis discusses the development of techniques for cooling diatomic molecules, focussing specifically on the idea of using a microwave frequency quasi-optical dipole trap for evaporative cooling. A prototype for such a trap has been designed, constructed, and tested. In order to load the microwave trap, a helium buffer gas cooled molecular beam source has been developed and characterized - in a variety of flow regimes, ranging from the effusive (thermal mean velocity, moderate flux), to the deeply hydrodynamic (large forward velocity, high-flux, high collimation). We explain the development of this source in detail. In particular, we describe recent work towards demonstrating direct laser cooling of a hydrodynamic SrF molecular beam. We have identified a set of quasi-closed transitions which should enable more than 104 photon scattering events, sufficient to decelerate a hydrodynamic beam to the Doppler limit. We present experimental results demonstrating optical deflection of a SrF beam by radiative force using this scheme, in which each molecule scatters on the order of 150 photons, limited by its interaction time with the lasers.

  12. Coherent interaction of single molecules and plasmonic nanowires (United States)

    Gerhardt, Ilja; Grotz, Bernhard; Siyushev, Petr; Wrachtrup, Jörg


    Quantum plasmonics opens the option to integrate complex quantum optical circuitry onto chip scale devices. In the past, often external light sources were used and nonclassical light was coupled in and out of plasmonic structures, such as hole arrays or waveguide structures. Another option to launch single plasmonic excitations is the coupling of single emitters in the direct proximity of, e.g., a silver or gold nanostructure. Here, we present our attempts to integrate the research of single emitters with wet-chemically grown silver nanowires. The emitters of choice are single organic dye molecules under cryogenic conditions, which are known to act as high-brightness and extremely narrow-band single photon sources. Another advantage is their high optical nonlinearity, such that they might mediate photon-photon interactions on the nanoscale. We report on the coupling of a single molecule fluorescence emission through the wire over the length of several wavelengths. The transmission of coherently emitted photons is proven by an extinction type experiment. As for influencing the spectral properties of a single emitter, we are able to show a remote change of the line-width of a single terrylene molecule, which is in close proximity to the nanowire.

  13. Multiplexed single-molecule force proteolysis measurements using magnetic tweezers. (United States)

    Adhikari, Arjun S; Chai, Jack; Dunn, Alexander R


    The generation and detection of mechanical forces is a ubiquitous aspect of cell physiology, with direct relevance to cancer metastasis(1), atherogenesis(2) and wound healing(3). In each of these examples, cells both exert force on their surroundings and simultaneously enzymatically remodel the extracellular matrix (ECM). The effect of forces on ECM has thus become an area of considerable interest due to its likely biological and medical importance(4-7). Single molecule techniques such as optical trapping(8), atomic force microscopy(9), and magnetic tweezers(10,11) allow researchers to probe the function of enzymes at a molecular level by exerting forces on individual proteins. Of these techniques, magnetic tweezers (MT) are notable for their low cost and high throughput. MT exert forces in the range of ~1-100 pN and can provide millisecond temporal resolution, qualities that are well matched to the study of enzyme mechanism at the single-molecule level(12). Here we report a highly parallelizable MT assay to study the effect of force on the proteolysis of single protein molecules. We present the specific example of the proteolysis of a trimeric collagen peptide by matrix metalloproteinase 1 (MMP-1); however, this assay can be easily adapted to study other substrates and proteases.

  14. Interface properties of organic molecules on metal surfaces; Grenzflaecheneigenschaften organischer Molekuele auf Metalloberflaechen

    Energy Technology Data Exchange (ETDEWEB)

    Karacuban, Hatice


    In this work, the growth of the archetype molecules CuPc and PTCDA was investigated on Cu(111). PTCDA was also studied on NaCl/Cu(111). The main experiments were carried out with a scanning tunneling microscope. Structural analysis of CuPc on Cu (111) is only possible at low temperatures, since at room temperature the molecules exhibit a high surface mobility. For the investigation of these structures and especially to enable scanning tunneling spectroscopy, a low-temperature scanning tunneling microscope was developed. Using this home built STM the experiments could be carried out at about 10 K. After the adsorption of CuPc on Cu (111) a substrate-induced symmetry reduction of the molecules can be observed in scanning tunneling microscopy. When the occupied states of the molecules are imaged, a switching between two distinct levels is found. These modifications are determined by the adsorption geometry of the molecules. Based on high resolution STM data, an on-top adsorption geometry of the CuPc-molecules on Cu (111)-substrate can be deducted. At low temperatures, two new superstructures of PTCDA on Cu(111) are observed. The molecules within these superstructures are tilted with respect to the substrate. Intermolecular interactions may be the crucial factor for the realignment of the molecules. If PTCDA molecules are adsorbed on a NaCl/Cu (111) substrate, at room temperature, also two new superstructures on the copper substrate were found. They indicate the formation of a metall-organic-complex. On top of the NaCl layer the molecules exclusively grow at polar NaCl step edges. This is an indication for electrostatic interaction between the PTCDA molecules and the NaCl layer. When the molecule density is further increased, a Vollmer-Weber growth sets in. If both molecules PTCDA and CuPc are present on the sample at the same time, local spectroscopy provides information on the metal-organic interface in direct comparison. The STS-results of CuPc/PTCDA on Cu (111

  15. Influence of Functionality on Direct Arylation of Model Systems as a Route Toward Fluorinated Copolymers via Direct Arylation Polymerization (DArP)

    DEFF Research Database (Denmark)

    Livi, Francesco; Gobalasingham, Nemal S.; Bundgaard, Eva


    A screening of direct arylation conditions on amodel small molecule system is carried out to develop suitableconditions for the direct arylation polymerization (DArP) of fluorinatedcopolymers, which are incompatible with conditionspreviously utilized successfully for nonfluorinated systems. Themo...

  16. Single-Molecule Interfacial Electron Transfer

    Energy Technology Data Exchange (ETDEWEB)

    Lu, H. Peter [Bowling Green State Univ., Bowling Green, OH (United States). Dept. of Chemistry and Center for Photochemical Sciences


    This project is focused on the use of single-molecule high spatial and temporal resolved techniques to study molecular dynamics in condensed phase and at interfaces, especially, the complex reaction dynamics associated with electron and energy transfer rate processes. The complexity and inhomogeneity of the interfacial ET dynamics often present a major challenge for a molecular level comprehension of the intrinsically complex systems, which calls for both higher spatial and temporal resolutions at ultimate single-molecule and single-particle sensitivities. Combined single-molecule spectroscopy and electrochemical atomic force microscopy approaches are unique for heterogeneous and complex interfacial electron transfer systems because the static and dynamic inhomogeneities can be identified and characterized by studying one molecule at a specific nanoscale surface site at a time. The goal of our project is to integrate and apply these spectroscopic imaging and topographic scanning techniques to measure the energy flow and electron flow between molecules and substrate surfaces as a function of surface site geometry and molecular structure. We have been primarily focusing on studying interfacial electron transfer under ambient condition and electrolyte solution involving both single crystal and colloidal TiO2 and related substrates. The resulting molecular level understanding of the fundamental interfacial electron transfer processes will be important for developing efficient light harvesting systems and broadly applicable to problems in fundamental chemistry and physics. We have made significant advancement on deciphering the underlying mechanism of the complex and inhomogeneous interfacial electron transfer dynamics in dyesensitized TiO2 nanoparticle systems that strongly involves with and regulated by molecule-surface interactions. We have studied interfacial electron transfer on TiO2 nanoparticle surfaces by using ultrafast single-molecule

  17. Our Galactic Neighbor Hosts Complex Organic Molecules (United States)

    Hensley, Kerry


    For the first time, data from the Atacama Large Millimeter/submillimeter Array (ALMA) reveal the presence of methyl formate and dimethyl ether in a star-forming region outside our galaxy. This discovery has important implications for the formation and survival of complex organic compounds importantfor the formation of life in low-metallicity galaxies bothyoung and old.No Simple Picture of Complex Molecule FormationALMA, pictured here with the Magellanic Clouds above, has observed organic molecules in our Milky Way Galaxy and beyond. [ESO/C. Malin]Complex organic molecules (those with at least six atoms, one or more of which must be carbon) are the precursors to the building blocks of life. Knowing how and where complex organic molecules can form is a key part of understanding how life came to be on Earth and how it might arise elsewhere in the universe. From exoplanet atmospheres to interstellar space, complex organic molecules are ubiquitous in the Milky Way.In our galaxy, complex organic molecules are often found in the intense environments of hot cores clumps of dense molecular gas surrounding the sites of star formation. However, its not yet fully understood how the complex organic molecules found in hot cores come to be. One possibility is that the compounds condense onto cold dust grains long before the young stars begin heating their natal shrouds. Alternatively, they might assemble themselves from the hot, dense gas surrounding the blazing protostars.Composite infrared and optical image of the N 113 star-forming region in the LMC. The ALMA coverage is indicated by the gray line. Click to enlarge. [Sewio et al. 2018]Detecting Complexity, a Galaxy AwayUsing ALMA, a team of researchers led by Marta Sewio (NASA Goddard Space Flight Center) recently detected two complex organic molecules methyl formate and dimethyl ether for the first time in our neighboring galaxy, the Large Magellanic Cloud (LMC). Previous searches for organic molecules in the LMC detected

  18. Scientists Discover Two New Interstellar Molecules: Point to Probable Pathways for Chemical Evolution in Space (United States)


    publication in the Astrophysical Journal Letters. In the GBT experiment, three aldehyde molecules were observed and appear to be related by simple hydrogen addition reactions, which probably occur on the surface of interstellar grains. An aldehyde is a molecule that contains the aldehyde group (CHO): a carbon atom singly bonded to a hydrogen atom and double-bonded to an oxygen atom; the remaining bond on that same carbon atom bonds to the rest of the molecule. Starting with previously reported propynal (HC2CHO), propenal (CH2CHCHO) is formed by adding two hydrogen atoms. By the same process propanal (CH3CH2CHO) is formed from propenal. After these molecules are formed on interstellar dust grains, they may be ejected as a diffuse gas. If enough molecules accumulate in the gas, they can be detected with a radio telescope. As the molecules rotate end-for-end, they change from one rotational energy state to another, emitting radio waves at precise frequencies. The "family" of radio frequencies emitted by a particular molecule forms a unique "fingerprint" that scientists can use to identify that molecule. The scientists identified the two new aldehydes by detecting a number of frequencies of radio emission in what is termed the K-band region (18 to 26 GHz) of the electromagnetic spectrum. "Interstellar molecules are identified by means of the frequencies that are unique to the rotational spectrum of each molecule," said Lovas. "These are either directly measured in the laboratory or calculated from the measured data. In this case we used the calculated spectral frequencies based on an analysis of the literature data." Complex molecules in space are of interest for many reasons, including their possible connection to the formation of biologically significant molecules on the early Earth. Complex molecules might have formed on the early Earth, or they might have first formed in interstellar clouds and been transported to the surface of the Earth. Molecules with the aldehyde group

  19. Astrocytes as a source for Extracellular matrix molecules and cytokines

    Directory of Open Access Journals (Sweden)

    Stefan eWiese


    Full Text Available Research of the past 25 years has shown that astrocytes do more than participating and building up the blood brain barrier and detoxify the active synapse by reuptake of neurotransmitters and ions. Indeed, astrocytes express neurotransmitter receptors and, as a consequence, respond to stimuli. Deeper knowledge of the differentiation processes during development of the central nervous system (CNS might help explaining and even help treating neurological diseases like Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS and psychiatric disorders in which astrocytes have been shown to play a role. Astrocytes and oligodendrocytes develop from a multipotent stem cell that prior to this has produced primarily neuronal precursor cells. This switch towards the more astroglial differentiation is regulated by a change in receptor composition on the cell surface and responsiveness of the respective trophic factors Fibroblast growth factor (FGF and Epidermal growth factor (EGF. The glial precursor cell is driven into the astroglial direction by signaling molecules like Ciliary neurotrophic factor (CNTF, Bone Morphogenetic Proteins (BMPs, and EGF. However, the early astrocytes influence their environment not only by releasing and responding to diverse soluble factors but also express a wide range of extracellular matrix (ECM molecules, in particular proteoglycans of the lectican family and tenascins. Lately these ECM molecules have been shown to participate in glial development. In this regard, especially the matrix protein Tenascin C (Tnc proved to be an important regulator of astrocyte precursor cell proliferation and migration during spinal cord development. On the other hand, ECM molecules expressed by reactive astrocytes are also known to act mostly in an inhibitory fashion under pathophysiological conditions. In this regard, we further summarize recent data concerning the role of chondroitin sulfate proteoglycans and Tnc under pathological

  20. Nanoscale contacts to organic molecules based on layered semiconductor substrates

    Energy Technology Data Exchange (ETDEWEB)

    Strobel, Sebastian


    This work reports on the integration of organic molecules as nanoelectronic device units on semiconductor substrates. Two novel preparation methods for sub-10-nm separated metal electrodes are presented using current microelectronics process technology. The first method utilises AlGaAs/GaAs heterostructures grown by molecular beam epitaxy (MBE) as mold to create planar metal electrodes employing a newly developed, high resolution nanotransfer printing (nTP) process. The second method uses commercially available Silicon-on-Insulator (SOI) substrates as base material for the fabrication of nanogap electrode devices. This sandwich-like material stack consists of a silicon substrate, a thin silicon oxide layer, and a capping silicon layer on top. Electronic transport measurements verified their excellent electrical properties at liquid helium temperatures. Specifically tailored nanogap devices featured an electrode insulation in the GW range even up to room temperature as well as within aqueous electrolyte solution. Finally, the well defined layer architecture facilitated the fabrication of electrodes with gap separations below-10-nm to be directly bridged by molecules. Approximately 12-nm-long conjugated molecules with extended -electron system were assembled onto the devices from solution. A large conductance gap was observed with a steep increase in current at a bias voltage of V{sub T}{approx}{+-}1.5 V. Theoretical calculations based on density functional theory and non-equilibrium Green's function formalism confirmed the measured non-linear IV-characteristics qualitatively and lead to the conclusion that the conductance gap mainly originates from the oxygen containing linker. Temperature dependent investigations of the conductance indicated a hopping charge transport mechanism through the central part of the molecule for bias voltages near but below V{sub T}. (orig.)

  1. Nanopipette Delivery of Individual Molecules to Cellular Compartments for Single-Molecule Fluorescence Tracking


    Bruckbauer, Andreas; James, Peter; Zhou, Dejian; Yoon, Ji Won; Excell, David; Korchev, Yuri; Jones, Roy; Klenerman, David


    We have developed a new method, using a nanopipette, for controlled voltage-driven delivery of individual fluorescently labeled probe molecules to the plasma membrane which we used for single-molecule fluorescence tracking (SMT). The advantages of the method are 1), application of the probe to predefined regions on the membrane; 2), release of only one or a few molecules onto the cell surface; 3), when combined with total internal reflection fluorescence microscopy, very low background due to...

  2. Mining for Molecules in the Milky Way (United States)


    Scientists are using the giant Robert C. Byrd Green Bank Telescope (GBT) to go prospecting in a rich molecular cloud in our Milky Way Galaxy. They seek to discover new, complex molecules in interstellar space that may be precursors to life. The GBT and Molecules The Robert C. Byrd Green Bank Telescope and some molecules it has discovered. CREDIT: Bill Saxton, NRAO/AUI/NSF "Clouds like this one are the raw material for new stars and planets. We know that complex chemistry builds prebiotic molecules in such clouds long before the stars and planets are formed. There is a good chance that some of these interstellar molecules may find their way to the surface of young planets such as the early Earth, and provide a head start for the chemistry of life. For the first time, we now have the capability to make a very thorough and methodical search to find all the chemicals in the clouds," said Anthony Remijan, of the National Radio Astronomy Observatory (NRAO). In the past three years, Remijan and his colleagues have used the GBT to discover ten new interstellar molecules, a feat unequalled in such a short time by any other team or telescope. The scientists discovered those molecules by looking specifically for them. However, they now are changing their strategy and casting a wide net designed to find whatever molecules are present, without knowing in advance what they'll find. In addition, they are making their data available freely to other scientists, in hopes of speeding the discovery process. The research team presented its plan to the American Astronomical Society's meeting in St. Louis, MO. As molecules rotate and vibrate, they emit radio waves at specific frequencies. Each molecule has a unique pattern of such frequencies, called spectral lines, that constitutes a "fingerprint" identifying that molecule. Laboratory tests can determine the pattern of spectral lines that identifies a specific molecule. Most past discoveries came from identifying a molecule's pattern in

  3. Rotational spectroscopy and observational astronomy of prebiotic molecules (United States)

    Widicus Weaver, Susanna Leigh

    It is now widely believed that prebiotic molecules were delivered to the early Earth by planetesimals and their associated interplanetary dust particles. Yet the formation pathways for these molecules are not clear. Amino acids and sugars have been found in carbonaceous chondrites, but only much simpler species have been detected in the interstellar medium (ISM). Prebiotic organics could have formed in the ISM and been directly incorporated into planetesimals, or simpler species could have: formed in the ISM and then been incorporated into planetesimals, undergone further processing, and been delivered to Earth. Limits on interstellar chemistry must therefore be established through observational astronomy before potential prebiotic formation pathways can be assessed. These observations require laboratory spectroscopic investigation of the species of interest. This thesis is an interdisciplinary study involving laboratory rotational spectroscopy and astronomical observations of several key prebiotic molecules. The laboratory work has focused on obtaining the rotational spectra of the simplest three-carbon ketose sugar, 1,3-dihydroxyacetone, and its structural isomers methyl glycolate and dimethyl carbonate, as well as aminoethanol, the predicted interstellar precursor to alanine. The pure rotational spectral analysis of the low-lying torsional states of the simplest a-hydroxy aldehyde, glycolaldehyde, has also been completed. The original Balle-Flygare Fourier transform microwave spectrometer was used to obtain the microwave spectra, while both the Jet Propulsion Laboratory and Caltech direct absorption flow cell spectrometers were used for additional direct absorption millimeter and submillimeter studies. The results of these laboratory experiments were used to guide observational searches with the Caltech Submillimeter Observatory, the Owens Valley Millimeter Array; and the Green Bank Telascope toward the hot core sources Sgr B2(N-LMH), Orion Hot Core

  4. Plasmonic band structure controls single-molecule fluorescence. (United States)

    Langguth, Lutz; Punj, Deep; Wenger, Jérôme; Koenderink, A Femius


    Plasmonics and photonic crystals are two complementary approaches to tailor single-emitter fluorescence, using strong local field enhancements near metals on one hand and spatially extended photonic band structure effects on the other hand. Here, we explore the emergence of spontaneous emission control by finite-sized hexagonal arrays of nanoapertures milled in gold film. We demonstrate that already small lattices enable highly directional and enhanced emission from single fluorescent molecules in the central aperture. Even for clusters just four unit cells across, the directionality is set by the plasmonic crystal band structure, as confirmed by full-wave numerical simulations. This realization of plasmonic phase array antennas driven by single quantum emitters opens a flexible toolbox to engineer fluorescence and its detection.

  5. Epithelial Cell Adhesion Molecule: More than a Carcinoma Marker and Adhesion Molecule

    National Research Council Canada - National Science Library

    Trzpis, Monika; McLaughlin, Pamela M.J; de Leij, Lou M.F.H; Harmsen, Martin C


    From the Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands The epithelial cell adhesion molecule (EpCAM, CD326...

  6. Programmable colloidal molecules from sequential capillarity-assisted particle assembly (United States)

    Ni, Songbo; Leemann, Jessica; Buttinoni, Ivo; Isa, Lucio; Wolf, Heiko


    The assembly of artificial nanostructured and microstructured materials which display structures and functionalities that mimic nature’s complexity requires building blocks with specific and directional interactions, analogous to those displayed at the molecular level. Despite remarkable progress in synthesizing “patchy” particles encoding anisotropic interactions, most current methods are restricted to integrating up to two compositional patches on a single “molecule” and to objects with simple shapes. Currently, decoupling functionality and shape to achieve full compositional and geometrical programmability remains an elusive task. We use sequential capillarity-assisted particle assembly which uniquely fulfills the demands described above. This is a new method based on simple, yet essential, adaptations to the well-known capillary assembly of particles over topographical templates. Tuning the depth of the assembly sites (traps) and the surface tension of moving droplets of colloidal suspensions enables controlled stepwise filling of traps to “synthesize” colloidal molecules. After deposition and mechanical linkage, the colloidal molecules can be dispersed in a solvent. The template’s shape solely controls the molecule’s geometry, whereas the filling sequence independently determines its composition. No specific surface chemistry is required, and multifunctional molecules with organic and inorganic moieties can be fabricated. We demonstrate the “synthesis” of a library of structures, ranging from dumbbells and triangles to units resembling bar codes, block copolymers, surfactants, and three-dimensional chiral objects. The full programmability of our approach opens up new directions not only for assembling and studying complex materials with single-particle-level control but also for fabricating new microscale devices for sensing, patterning, and delivery applications. PMID:27051882

  7. On the SIMS Ionization Probability of Organic Molecules (United States)

    Popczun, Nicholas J.; Breuer, Lars; Wucher, Andreas; Winograd, Nicholas


    The prospect of improved secondary ion yields for secondary ion mass spectrometry (SIMS) experiments drives innovation of new primary ion sources, instrumentation, and post-ionization techniques. The largest factor affecting secondary ion efficiency is believed to be the poor ionization probability (α+) of sputtered material, a value rarely measured directly, but estimated to be in some cases as low as 10-5. Our lab has developed a method for the direct determination of α+ in a SIMS experiment using laser post-ionization (LPI) to detect neutral molecular species in the sputtered plume for an organic compound. Here, we apply this method to coronene (C24H12), a polyaromatic hydrocarbon that exhibits strong molecular signal during gas-phase photoionization. A two-dimensional spatial distribution of sputtered neutral molecules is measured and presented. It is shown that the ionization probability of molecular coronene desorbed from a clean film under bombardment with 40 keV C60 cluster projectiles is of the order of 10-3, with some remaining uncertainty arising from laser-induced fragmentation and possible differences in the emission velocity distributions of neutral and ionized molecules. In general, this work establishes a method to estimate the ionization efficiency of molecular species sputtered during a single bombardment event. [Figure not available: see fulltext.

  8. Modelling the spectroscopic behaviour of hot molecules (United States)

    Tennyson, Jonathan


    At elevated temperatures the molecules absorb and emit light in a very complicated fashion which is hard to characterise on the basis of laboraroty measurement. Computed line lists of molecule transitions therefore provide a vital input for models of hot atmospheres. I will describe the calculation and use of such line lists including the BT2 water line list [1], which contains some 500 million distinct rotation-vibration transitions. This linelist proved crucial in the detection of water in extrasolar planet HD189733b and has been used extensively in atmospheric modelling. Illustrations will be given at the meeting. A new linelist for the ammonia molecule has just been completed [2] which shows that standard compilations for this molecule need to be improved. Progress on a more extensive linelist for hot ammonia and linelists for other molecules will be discussed at the meeting. [1] R.J. Barber, J. Tennyson, G.J. Harris and R.N. Tolchenov, Mon. Not. R. Astr. Soc., 368, 1087-1094 (2006) [2] S.N. Yurchenko, R.J. Barber, A. Yachmenev, W. Theil, P. Jensen and J. Tennyson, J. Phys. Chem. A, 113, 11845-11855 (2009).

  9. Single-molecule manipulation and detection. (United States)

    Zhao, Deyu; Liu, Siyun; Gao, Ying


    Compared to conventional ensemble methods, studying macromolecules at single-molecule level can reveal extraordinary clear and even surprising views for a biological reaction. In the past 20 years, single-molecule techniques have been undergoing a very rapid development, and these cutting edge technologies have revolutionized the biological research by facilitating single-molecule manipulation and detection. Here we give a brief review about these advanced techniques, including optical tweezers, magnetic tweezers, atomic force microscopy (AFM), hydrodynamic flow-stretching assay, and single-molecule fluorescence resonance energy transfer (smFRET). We are trying to describe their basic principles and provide a few examples of applications for each technique. This review aims to give a rather introductory survey of single-molecule techniques for audiences with biological or biophysical background. © The Author(s) 2018. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail:

  10. Direct patterning of a cyclotriveratrylene derivative for directed self-assembly of C{sub 60}

    Energy Technology Data Exchange (ETDEWEB)

    Osner, Zachary R; Holz, Richard C; Becker, Daniel P [Department of Chemistry, Loyola University Chicago, Chicago, IL 60626 (United States); Nyamjav, Dorjderem, E-mail: [Department of Mathematics, Physics and Statistics, University of Sciences, Philadelphia, PA 19104 (United States)


    A novel apex-modified cyclotriveratrylene (CTV) derivative with an attached thiolane-containing lipoic acid linker was directly patterned onto gold substrates via dip-pen nanolithography (DPN). The addition of a dithiolane-containing linker to the apex of CTV provides a molecule that can adhere to a gold surface with its bowl-shaped cavity directed away from the surface, thereby providing a surface-bound CTV host that can be used for the directed assembly of guest molecules. Subsequent exposure of these CTV microarrays to C{sub 60} in toluene resulted in the directed assembly of predesigned, spatially controlled, high-density microarrays of C{sub 60}. The molecular recognition capabilities of this CTV template toward C{sub 60} provides proof-of-concept that supramolecular CTV scaffolds can be directly patterned onto surfaces providing a foundation for the development of organic electronic and optoelectronic materials.

  11. The physics of pulling polyproteins: a review of single molecule force spectroscopy using the AFM to study protein unfolding. (United States)

    Hughes, Megan L; Dougan, Lorna


    One of the most exciting developments in the field of biological physics in recent years is the ability to manipulate single molecules and probe their properties and function. Since its emergence over two decades ago, single molecule force spectroscopy has become a powerful tool to explore the response of biological molecules, including proteins, DNA, RNA and their complexes, to the application of an applied force. The force versus extension response of molecules can provide valuable insight into its mechanical stability, as well as details of the underlying energy landscape. In this review we will introduce the technique of single molecule force spectroscopy using the atomic force microscope (AFM), with particular focus on its application to study proteins. We will review the models which have been developed and employed to extract information from single molecule force spectroscopy experiments. Finally, we will end with a discussion of future directions in this field.

  12. Vaccination against canine leishmaniosis increases the phagocytic activity, nitric oxide production and expression of cell activation/migration molecules in neutrophils and monocytes. (United States)

    Moreira, Marcela L; Costa-Pereira, Christiane; Alves, Marina Luiza Rodrigues; Marteleto, Bruno H; Ribeiro, Vitor M; Peruhype-Magalhães, Vanessa; Giunchetti, Rodolfo C; Martins-Filho, Olindo A; Araújo, Márcio S S


    Visceral leishmaniasis (VL) is transmitted by phlebotomine sandfly vectors and domestic dogs serve as a reservoir. The elimination of seropositive dogs has been a recommended strategy for managing the disease in Brazil. A protective canine vaccine would be an important tool for controlling the disease, reducing the parasites available to sandfly vectors and, consequently, reducing the number of human VL cases. Leishmune(®) is an anti-canine Leishmaniosis (VL Canine) vaccine produced by Zoetis (Pfizer, Brazil) that was commercially available in Brazil until 2014. The main goal of the present study was to investigate the protective immunological events induced by vaccination with Leishmune(®) in the time frame of one year. Healthy, non-vaccinated dogs and dogs of 1, 6 and 10 months post-vaccination were evaluated. Results showed that Leishmune(®) induced an increase in phagocytic activity of neutrophils and monocytes and also increased NO production. Immunological events were correlated with functional responses, as high levels of IgG and an increase of the receptor Fcγ were detected. Vaccination induced an increased expression of TLR (2, 4, 5, 9), integrin (CD29, CD49f), activation (MHCII) and co-stimulatory (CD80, CD81) molecules by neutrophils and monocytes. Vaccination led to decrease of IL-4 and an increase of IL-8 production by monocytes and higher IFN-γ and IL-17 production by T-cells. The results suggested that Leishmune(®) was able to induce a long-lasting change in immune response, mediated by supportive immunological events that may be participating in protective immunity against CL. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Relativistic Scott correction for atoms and molecules

    DEFF Research Database (Denmark)

    Solovej, Jan Philip; Sørensen, Thomas Østergaard; Spitzer, Wolfgang Ludwig


    We prove the first correction to the leading Thomas-Fermi energy for the ground state energy of atoms and molecules in a model where the kinetic energy of the electrons is treated relativistically. The leading Thomas-Fermi energy, established in [25], as well as the correction given here, are of ......We prove the first correction to the leading Thomas-Fermi energy for the ground state energy of atoms and molecules in a model where the kinetic energy of the electrons is treated relativistically. The leading Thomas-Fermi energy, established in [25], as well as the correction given here......, are of semiclassical nature. Our result on atoms and molecules is proved from a general semiclassical estimate for relativistic operators with potentials with Coulomb-like singularities. This semiclassical estimate is obtained using the coherent state calculus introduced in [36]. The paper contains a unified treatment...

  14. Prebiotically Important Molecules in Orion KL (United States)

    Kuan, Yi-Jehng; Chuang, Yo-Ling

    Many interstellar, complex organic molecules are known to be prebiotically important and have essential functions in terrestrial biochemistry. Observations of complex organic molecular species in molecular clouds can thus enable us to test the origin of the primitive organic material found in the Solar System. Interstellar pyrimidine and glycine, the building block of nucleic acid and the simplest amino acid, respectively, are key molecules for astrobiology and were both detected in meteorites and comets. Although the formation of prebiotic molecules in extraterrestrial environments and their contribution to prebiotic chemistry and the origin of life remains unsettled, the connection between interstellar organic chemistry, meteoritic pyrimidines and amino acids, and the emergence of life on the early Earth would be strengthened with the discovery of interstellar pyrimidine and glycine. We have therefore observed the Orion KL hot molecular core to search for interstellar pyrimidine and for the confirmation of interstellar glycine using the ALMA array. We will present some of the encouraging, positive results.

  15. Hydrogen sulfide and polysulfides as signaling molecules (United States)

    KIMURA, Hideo


    Hydrogen sulfide (H2S) is a familiar toxic gas that smells of rotten eggs. After the identification of endogenous H2S in the mammalian brain two decades ago, studies of this molecule uncovered physiological roles in processes such as neuromodulation, vascular tone regulation, cytoprotection against oxidative stress, angiogenesis, anti-inflammation, and oxygen sensing. Enzymes that produce H2S, such as cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase have been studied intensively and well characterized. Polysulfides, which have a higher number of inner sulfur atoms than that in H2S, were recently identified as potential signaling molecules that can activate ion channels, transcription factors, and tumor suppressors with greater potency than that of H2S. This article focuses on our contribution to the discovery of these molecules and their metabolic pathways and mechanisms of action. PMID:25864468

  16. Observational astrochemistry: The quest for interstellar molecules

    Directory of Open Access Journals (Sweden)

    Guélin M.


    Full Text Available Over 160 molecular species, not counting isotopologues, have been identified in circumstellar envelopes and interstellar clouds. These species have revealed a wealth of familiar, as much as exotic molecules and in complex organic (and silicon compounds, that was fully unexpected in view of the harshness of surrounding conditions: vanishingly low densities, extreme temperatures and intense embedding UV radiation. They illustrate the diversity of astrochemistry and show robust prebiotic molecules may be. In this lecture, we review the quest for interstellar molecules and show how tributary it is from theoretical ideas and technology developments. A. A. Penzias, who discovered interstellar CO and the 2.7 K Cosmic Background radiation, used to joke that astronomical research is easy: the great questions have largely been formulated; one only has to wait until technological progress makes it possible to answer.

  17. Morse basis expansion applied to diatomic molecules

    Energy Technology Data Exchange (ETDEWEB)

    Lima, Emanuel F. de, E-mail: [Departamento de Estatística, Matemática Aplicada e Computação, Instituto de Geociências e Ciências Exatas, Universidade Estadual Paulista – UNESP, Rio Claro, São Paulo 13506-900 (Brazil)


    This work explores the use of the eigenfunctions of the Morse potential with a infinite barrier at long range to solve the radial Schrödinger equation for diatomic molecules. Analytical formulas are obtained for the kinetic energy operator matrix elements in the Morse basis. The Morse basis expansion is applied to find the vibrational–rotational levels of the sodium molecule in the electronic ground state. -- Highlights: ► The Morse potential basis is invoked to find the rovibrational levels of diatomic molecules. ► Analytical formulas for the kinetic energy operator in the Morse basis are obtained. ► The results of the Morse basis expansion show good agreement with the Fourier Grid technique.

  18. Stochastic models for surface diffusion of molecules

    Energy Technology Data Exchange (ETDEWEB)

    Shea, Patrick, E-mail:; Kreuzer, Hans Jürgen [Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia B3H 3J5 (Canada)


    We derive a stochastic model for the surface diffusion of molecules, starting from the classical equations of motion for an N-atom molecule on a surface. The equation of motion becomes a generalized Langevin equation for the center of mass of the molecule, with a non-Markovian friction kernel. In the Markov approximation, a standard Langevin equation is recovered, and the effect of the molecular vibrations on the diffusion is seen to lead to an increase in the friction for center of mass motion. This effective friction has a simple form that depends on the curvature of the lowest energy diffusion path in the 3N-dimensional coordinate space. We also find that so long as the intramolecular forces are sufficiently strong, memory effects are usually not significant and the Markov approximation can be employed, resulting in a simple one-dimensional model that can account for the effect of the dynamics of the molecular vibrations on the diffusive motion.

  19. Protein Scaffolding for Small Molecule Catalysts

    Energy Technology Data Exchange (ETDEWEB)

    Baker, David [Univ. of Washington, Seattle, WA (United States)


    We aim to design hybrid catalysts for energy production and storage that combine the high specificity, affinity, and tunability of proteins with the potent chemical reactivities of small organometallic molecules. The widely used Rosetta and RosettaDesign methodologies will be extended to model novel protein / small molecule catalysts in which one or many small molecule active centers are supported and coordinated by protein scaffolding. The promise of such hybrid molecular systems will be demonstrated with the nickel-phosphine hydrogenase of DuBois et. al.We will enhance the hydrogenase activity of the catalyst by designing protein scaffolds that incorporate proton relays and systematically modulate the local environment of the catalyticcenter. In collaboration with DuBois and Shaw, the designs will be experimentally synthesized and characterized.

  20. RNA as a small molecule druggable target. (United States)

    Rizvi, Noreen F; Smith, Graham F


    Small molecule drugs have readily been developed against many proteins in the human proteome, but RNA has remained an elusive target for drug discovery. Increasingly, we see that RNA, and to a lesser extent DNA elements, show a persistent tertiary structure responsible for many diverse and complex cellular functions. In this digest, we have summarized recent advances in screening approaches for RNA targets and outlined the discovery of novel, drug-like small molecules against RNA targets from various classes and therapeutic areas. The link of structure, function, and small-molecule Druggability validates now for the first time that RNA can be the targets of therapeutic agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Metal-Controlled Magnetoresistance at Room Temperature in Single-Molecule Devices. (United States)

    Aragonès, Albert C; Aravena, Daniel; Valverde-Muñoz, Francisco J; Real, José Antonio; Sanz, Fausto; Díez-Pérez, Ismael; Ruiz, Eliseo


    The appropriate choice of the transition metal complex and metal surface electronic structure opens the possibility to control the spin of the charge carriers through the resulting hybrid molecule/metal spinterface in a single-molecule electrical contact at room temperature. The single-molecule conductance of a Au/molecule/Ni junction can be switched by flipping the magnetization direction of the ferromagnetic electrode. The requirements of the molecule include not just the presence of unpaired electrons: the electronic configuration of the metal center has to provide occupied or empty orbitals that strongly interact with the junction metal electrodes and that are close in energy to their Fermi levels for one of the electronic spins only. The key ingredient for the metal surface is to provide an efficient spin texture induced by the spin-orbit coupling in the topological surface states that results in an efficient spin-dependent interaction with the orbitals of the molecule. The strong magnetoresistance effect found in this kind of single-molecule wire opens a new approach for the design of room-temperature nanoscale devices based on spin-polarized currents controlled at molecular level.

  2. Small Molecule Subgraph Detector (SMSD toolkit

    Directory of Open Access Journals (Sweden)

    Rahman Syed


    Full Text Available Abstract Background Finding one small molecule (query in a large target library is a challenging task in computational chemistry. Although several heuristic approaches are available using fragment-based chemical similarity searches, they fail to identify exact atom-bond equivalence between the query and target molecules and thus cannot be applied to complex chemical similarity searches, such as searching a complete or partial metabolic pathway. In this paper we present a new Maximum Common Subgraph (MCS tool: SMSD (Small Molecule Subgraph Detector to overcome the issues with current heuristic approaches to small molecule similarity searches. The MCS search implemented in SMSD incorporates chemical knowledge (atom type match with bond sensitive and insensitive information while searching molecular similarity. We also propose a novel method by which solutions obtained by each MCS run can be ranked using chemical filters such as stereochemistry, bond energy, etc. Results In order to benchmark and test the tool, we performed a 50,000 pair-wise comparison between KEGG ligands and PDB HET Group atoms. In both cases the SMSD was shown to be more efficient than the widely used MCS module implemented in the Chemistry Development Kit (CDK in generating MCS solutions from our test cases. Conclusion Presently this tool can be applied to various areas of bioinformatics and chemo-informatics for finding exhaustive MCS matches. For example, it can be used to analyse metabolic networks by mapping the atoms between reactants and products involved in reactions. It can also be used to detect the MCS/substructure searches in small molecules reported by metabolome experiments, as well as in the screening of drug-like compounds with similar substructures. Thus, we present a robust tool that can be used for multiple applications, including the discovery of new drug molecules. This tool is freely available on

  3. Oriented Molecule Interactions with Atoms and Surfaces. (United States)

    Mackay, R. Scott

    Mutual orientation of reagents is second only to the energy requirement for a chemical reaction to take place. Since the introduction of the hexapole field focusing and orientation of symmetric-top molecules in 1965, considerable insight has been gained on the role of orientation in reactive scattering dynamics. The degree of laboratory orientation has been measured for (CH_3) _3CBr and has been found to follow the sequence (CH_3)_3CBr > (CH_3) _3CI > CH_3 I for previous measurements. Oriented molecule beams of thirteen different molecules have been scattered by a graphite(0001) surface. The results show a large diversity in the sign and magnitude of the steric effect (i.e., "heads" vs. "tails"). It appears from the bulk of data that the origin of the steric effect is the anisotropic molecule-graphite interaction potential, which is governed by the charge density distribution of the molecule. The steric effects have been quantitatively measured for seven of the molecules and have been analyzed in terms of a two component model which yields estimates for the anisotropy of the trapping probability. An effusive oven of Sr was used in a crossed beam reaction of Sr + CH_3I. In order to detect weak product signal, a sensitive detection technique utilizing single photon ionization of the reaction product was developed. By changing the relative velocity of the reactants, the excitation function (reactive cross section vs. collision energy) was measured. The experimental results were simulated by a modified angle dependent line -of-centers model, which gives the reaction potential energy surface. Excitation functions of other alkyl halides reactions, Sr + RX (R = H, CH_3, C_2H _5,C_3H_7, C_4H_9; X = Br, I), were also explored.

  4. Single-molecule fluorescence-based analysis of protein conformation, interaction, and oligomerization in cellular systems. (United States)

    Okamoto, Kenji; Hiroshima, Michio; Sako, Yasushi


    Single-molecule imaging (SMI) of proteins in operation has a history of intensive investigations over 20 years and is now widely used in various fields of biology and biotechnology. We review the recent advances in SMI of fluorescently-tagged proteins in structural biology, focusing on technical applicability of SMI to the measurements in living cells. Basic technologies and recent applications of SMI in structural biology are introduced. Distinct from other methods in structural biology, SMI directly observes single molecules and single-molecule events one-by-one, thus, explicitly analyzing the distribution of protein structures and the history of protein dynamics. It also allows one to detect single events of protein interaction. One unique feature of SMI is that it is applicable in complicated and heterogeneous environments, including living cells. The numbers, location, movements, interaction, oligomerization, and conformation of single-protein molecules have been determined using SMI in cellular systems.

  5. CdS nanowires formed by chemical synthesis using conjugated single-stranded DNA molecules (United States)

    Sarangi, S. N.; Sahu, S. N.; Nozaki, S.


    CdS nanowires were successfully grown by chemical synthesis using two conjugated single-stranded (ss) DNA molecules, poly G (30) and poly C (30), as templates. During the early stage of the synthesis with the DNA molecules, the Cd 2+ interacts with Poly G and Poly C and produces the (Cd 2+)-Poly GC complex. As the growth proceeds, it results in nanowires. The structural analysis by grazing angle x-ray diffraction and transmission electron microscopy confirmed the zinc-blende CdS nanowires with the growth direction of . Although the nanowires are well surface-passivated with the DNA molecules, the photoluminescence quenching was caused by the electron transfer from the nanowires to the DNA molecules. The quenching can be used to detect and label the DNAs.

  6. Cold Light from Hot Atoms and Molecules (United States)

    Lister, Graeme; Curry, John J.


    The introduction of rare earth atoms and molecules into lighting discharges led to great advances in efficacy of these lamps. Atoms such as Dy, Ho and Ce provide excellent radiation sources for lighting applications, with rich visible spectra, such that a suitable combination of these elements can provide high quality white light. Rare earth molecules have also proved important in enhancing the radiation spectrum from phosphors in fluorescent lamps. This paper reviews some of the current aspects of lighting research, particularly rare earth chemistry and radiation, and the associated fundamental atomic and molecular data.

  7. Quantum interference of large organic molecules


    Gerlich, Stefan; Eibenberger, Sandra; Tomandl, Mathias; Nimmrichter, Stefan; Hornberger, Klaus; Fagan, Paul J.; Tüxen, Jens; Mayor, Marcel; Arndt, Markus


    The wave nature of matter is a key ingredient of quantum physics and yet it defies our classical intuition. First proposed by Louis de Broglie a century ago, it has since been confirmed with a variety of particles from electrons up to molecules. Here we demonstrate new high-contrast quantum experiments with large and massive tailor-made organic molecules in a near-field interferometer. Our experiments prove the quantum wave nature and delocalization of compounds composed of up to 430 atoms, w...

  8. Chiral molecule in the Standard Model (United States)

    Fukuyama, Takeshi


    This paper is based on the talk at the conference of "Spectroscopic Studies on Molecular Chirality" held on December 20-21, 2013. The objects of the present paper are to (1) derive the energy difference between Laevorotatory, or left-handed, (L-) and Dextrorotatory, or right-handed, (D-) molecules and to (2) discuss how this tiny energy difference leads us to the observed enantiomer excess. Relations with other parity violating phenomena in molecules, electric dipole moment (EDM) and natural optical activity, are also discussed.

  9. Raman Optical Activity of Biological Molecules (United States)

    Blanch, Ewan W.; Barron, Laurence D.

    Now an incisive probe of biomolecular structure, Raman optical activity (ROA) measures a small difference in Raman scattering from chiral molecules in right- and left-circularly polarized light. As ROA spectra measure vibrational optical activity, they contain highly informative band structures sensitive to the secondary and tertiary structures of proteins, nucleic acids, viruses and carbohydrates as well as the absolute configurations of small molecules. In this review we present a survey of recent studies on biomolecular structure and dynamics using ROA and also a discussion of future applications of this powerful new technique in biomedical research.

  10. Extracellular Molecules Involved in Cancer Cell Invasion

    Energy Technology Data Exchange (ETDEWEB)

    Stivarou, Theodora; Patsavoudi, Evangelia, E-mail: [Department of Biochemistry, Hellenic Pasteur Institute, Athens 11521 (Greece); Technological Educational Institute of Athens, Egaleo, Athens 12210 (Greece)


    Nowadays it is perfectly clear that understanding and eradicating cancer cell invasion and metastasis represent the crucial, definitive points in cancer therapeutics. During the last two decades there has been a great interest in the understanding of the extracellular molecular mechanisms involved in cancer cell invasion. In this review, we highlight the findings concerning these processes, focusing in particular on extracellular molecules, including extracellular matrix proteins and their receptors, growth factors and their receptors, matrix metalloproteinases and extracellular chaperones. We report the molecular mechanisms underlying the important contribution of this pool of molecules to the complex, multi-step phenomenon of cancer cell invasion.

  11. Tunable Holstein model with cold polar molecules

    Energy Technology Data Exchange (ETDEWEB)

    Herrera, Felipe; Krems, Roman V. [Department of Chemistry, University of British Columbia, Vancouver, British Columbia, V6T 1Z1 (Canada)


    We show that an ensemble of polar molecules trapped in an optical lattice can be considered as a controllable open quantum system. The coupling between collective rotational excitations and the motion of the molecules in the lattice potential can be controlled by varying the strength and orientation of an external dc electric field as well as the intensity of the trapping laser. The system can be described by a generalized Holstein Hamiltonian with tunable parameters and can be used as a quantum simulator of excitation energy transfer and polaron phenomena. We show that the character of excitation energy transfer can be modified by tuning experimental parameters.

  12. Collisional Energy Exchange in Polyatomic Molecules. (United States)


    emplamation of what me have observed. 1frther work will be required before Me-o claim Oy Cfidece in such a Preliminary resIt . 9.......*.... ~ . -,- -~ .7...a-iMjn simply by heating the source gas to a appropriate ae.a r mid moasuing the radiatimn from the free jet molecules. After we obtained the MIS we...exadned in som detail the spectral character of the radiation from 0O2 CO 0 molecules after free jet expansion from a heated nozzle. The -sults were

  13. Single molecule genotyping by TIRF microscopy. (United States)

    Rüttinger, Steffen; Lamarre, Baptiste; Knight, Alex E


    As part of a programme to develop a metrological framework for single molecule measurements in biology, we have investigated the applications of single molecule imaging to genomics. Specifically, we have developed a technique for measuring the frequencies of single nucleotide polymorphisms (SNPs) in complex or pooled samples of DNA. We believe that this technique has applications to statistical genotyping-the identification of correlations between SNP frequencies and particular phenotypes-and other areas where it is desirable to track the frequencies of SNPs in complex DNA populations.

  14. A Circularly Arranged Sextuple Triptycene Gear Molecule. (United States)

    Ube, Hitoshi; Yamada, Ryo; Ishida, Jun-Ichi; Sato, Hiroyasu; Shiro, Motoo; Shionoya, Mitsuhiko


    Herein we report the synthesis of a circularly arranged sextuple triptycene gear molecule, hexakis(10-dodecyloxy-9-triptycyl)ethynylbenzene, via the trimerization of the corresponding triyne with a cobalt catalyst. The six triptycene gears are closely engaged with each other as confirmed by single crystal X-ray structure analysis, and their motion in solution was established by NMR spectroscopy. Notably, when one bulky RuCp* complex was attached to one triptycene gear, the whole movement of the six gears was highly restricted via their mechanical engagement. Development of such a multigear molecule would provide a structural basis for molecular motion transmission systems with a switching function.

  15. Making More-Complex Molecules Using Superthermal Atom/Molecule Collisions (United States)

    Shortt, Brian; Chutjian, Ara; Orient, Otto


    A method of making more-complex molecules from simpler ones has emerged as a by-product of an experimental study in outer-space atom/surface collision physics. The subject of the study was the formation of CO2 molecules as a result of impingement of O atoms at controlled kinetic energies upon cold surfaces onto which CO molecules had been adsorbed. In this study, the O/CO system served as a laboratory model, not only for the formation of CO2 but also for the formation of other compounds through impingement of rapidly moving atoms upon molecules adsorbed on such cold interstellar surfaces as those of dust grains or comets. By contributing to the formation of increasingly complex molecules, including organic ones, this study and related other studies may eventually contribute to understanding of the origins of life.

  16. Single-Molecule Electronics with Cross- Conjugated Molecules: Quantum Interference, IETS and Non-Equilibrium "Temperatures"

    DEFF Research Database (Denmark)

    Jørgensen, Jacob Lykkebo

    Abstract The idea of using single-molecules as components in electronic devices is fas- cinating. For this idea to come into fruition, a number of technical and theo- retical challenges must be overcome. In this PhD thesis, the electron-phonon interaction is studied for a special class of molecules......, the electrons can tunnel in- elastically from the left to the right electrode. This is the process behind inelastic electron tunnelling spectroscopy (IETS), which is a single-molecule spectroscopic method, where the vibrational ngerprint of a molecule is di- rectly observed by the tunnelling current...... This process has been studied in detail for ordinary conjugated or saturated molecules. Selection rules does not exist in IETS, but some modes are favoured over others, and this is the bases for the propensity rules in IETS that has been rationalised. In this thesis, we study IETS for cross...

  17. Single Molecule Analysis Research Tool (SMART: an integrated approach for analyzing single molecule data.

    Directory of Open Access Journals (Sweden)

    Max Greenfeld

    Full Text Available Single molecule studies have expanded rapidly over the past decade and have the ability to provide an unprecedented level of understanding of biological systems. A common challenge upon introduction of novel, data-rich approaches is the management, processing, and analysis of the complex data sets that are generated. We provide a standardized approach for analyzing these data in the freely available software package SMART: Single Molecule Analysis Research Tool. SMART provides a format for organizing and easily accessing single molecule data, a general hidden Markov modeling algorithm for fitting an array of possible models specified by the user, a standardized data structure and graphical user interfaces to streamline the analysis and visualization of data. This approach guides experimental design, facilitating acquisition of the maximal information from single molecule experiments. SMART also provides a standardized format to allow dissemination of single molecule data and transparency in the analysis of reported data.

  18. Single Molecule Analysis Research Tool (SMART): an integrated approach for analyzing single molecule data. (United States)

    Greenfeld, Max; Pavlichin, Dmitri S; Mabuchi, Hideo; Herschlag, Daniel


    Single molecule studies have expanded rapidly over the past decade and have the ability to provide an unprecedented level of understanding of biological systems. A common challenge upon introduction of novel, data-rich approaches is the management, processing, and analysis of the complex data sets that are generated. We provide a standardized approach for analyzing these data in the freely available software package SMART: Single Molecule Analysis Research Tool. SMART provides a format for organizing and easily accessing single molecule data, a general hidden Markov modeling algorithm for fitting an array of possible models specified by the user, a standardized data structure and graphical user interfaces to streamline the analysis and visualization of data. This approach guides experimental design, facilitating acquisition of the maximal information from single molecule experiments. SMART also provides a standardized format to allow dissemination of single molecule data and transparency in the analysis of reported data.

  19. Strategy to discover diverse optimal molecules in the small molecule universe. (United States)

    Rupakheti, Chetan; Virshup, Aaron; Yang, Weitao; Beratan, David N


    The small molecule universe (SMU) is defined as a set of over 10(60) synthetically feasible organic molecules with molecular weight less than ∼500 Da. Exhaustive enumerations and evaluation of all SMU molecules for the purpose of discovering favorable structures is impossible. We take a stochastic approach and extend the ACSESS framework ( Virshup et al. J. Am. Chem. Soc. 2013 , 135 , 7296 - 7303 ) to develop diversity oriented molecular libraries that can generate a set of compounds that is representative of the small molecule universe and that also biases the library toward favorable physical property values. We show that the approach is efficient compared to exhaustive enumeration and to existing evolutionary algorithms for generating such libraries by testing in the NKp fitness landscape model and in the fully enumerated GDB-9 chemical universe containing 3 × 10(5) molecules.

  20. Quantum Monte Carlo Calculations Applied to Magnetic Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Engelhardt, Larry [Iowa State Univ., Ames, IA (United States)


    ideas in hand, we then provide a detailed explanation of the current QMC method in Chapter 4. The remainder of the thesis is devoted to presenting specific results: Chapters 5 and 6 contain articles in which this method has been used to answer general questions that are relevant to broad classes of systems. Then, in Chapter 7, we provide an analysis of four different species of magnetic molecules that have recently been synthesized and studied. In all cases, comparisons between QMC calculations and experimental data allow us to distinguish a viable microscopic model and make predictions for future experiments. In Chapter 8, the infamous ''negative sign problem'' is described in detail, and we clearly indicate the limitations on QMC that are imposed by this obstacle. Finally, Chapter 9 contains a summary of the present work and the expected directions for future research.

  1. Attosecond pre-determination of reaction dynamics in polyatomic molecules (United States)

    Kitzler, Markus


    An important aim of Ultrafast Laser Science and Attosecond Physics is the measurement of valence electron dynamics in molecules during complex restructuring and fragmentation reactions. Such reactions may be triggered by the removal of electrons, e.g., by ionization with intense, ultrashort laser pulses. Depending on the valence-shell from which the electrons are removed, the molecular ion might be put into a binding state or a certain dissociative state. With control over the ionization process it might thus be possible to gain control over the subsequent restructuring and fragmentation processes on a purely electronic level. Detailed insight into the process of electron removal can be obtained from interferometric measurements using two bound state wavepackets released at different times within a sub-cycle of a laser field. I will present results of experiments that exploit this kind of electron wavepacket interferometry with sub-10 attosecond resolution for tracing the evolution of the phase of the bound state of an atom or molecule during the removal of an electron. I will furthermore present two conceptually similar schemes that allow pre-determining the outcome of molecular restructuring and fragmentation processes in polyatomic molecules on sub-femtosecond time-scales by gaining control over the process of electron removal. The first method involves recollision double ionization in intense few-cycle laser fields with a known carrier-envelope phase (CEP). Tuning of the CEP allows controlling the removal of inner-valence electrons and the controlled population of dissociative excited states. Using this method I will show experimental CEP-control over various fragmentation reactions of a series of polyatomic molecules. The second control scheme uses the strong preponderance of ionization from specific molecular orbitals to the alignment of the molecular axis with respect to the laser polarization direction for determining which valence level the electrons are

  2. Polypetide signaling molecules in plant development (United States)

    Intercellular communication mediated by small signaling molecules is a key mechanism for coordinating plant growth and development. In the past few years, polypeptide signals have been shown to play prominent roles in processes as diverse as shoot and root meristem maintenance, vascular differentiat...

  3. Single-molecule magnets: Iron lines up (United States)

    Bill, Eckhard


    For more than a decade, single-molecule magnets have relied on multinuclear transition metal clusters and lanthanide compounds. Now, a mononuclear, two-coordinate iron(I) complex has shown that single transition metals can compete with the lanthanides when certain design principles from magnetochemistry are borne in mind.

  4. Organic-and molecule-based magnets

    Indian Academy of Sciences (India)

    The discovery of organic- and molecule-based magnets has led to design and synthesis of several families with magnetic ordering temperatures as high as ∼ 125° C. Examples of soft and hard magnets with coercivities as high as 27 kOe have also been reported. Examples from our laboratory of organic-based magnets ...

  5. Origin of organic molecules and biomolecular homochirality. (United States)

    Podlech, J


    Theories about the origin of biomolecular homochirality, which seems to be a prerequisite for the creation of life, are discussed. First, possible terrestrial and extraterrestrial sources of organic molecules are outlined. Then, mechanisms for the formation of enantiomerically enriched compounds and for the amplification of their chirality are described.

  6. The MHC molecules of nonmammalian vertebrates

    DEFF Research Database (Denmark)

    Kaufman, J; Skjoedt, K; Salomonsen, J


    to develop. There is no molecular evidence yet to decide whether vertebrate immune systems (and particularly the MHC molecules) are evolutionarily related to invertebrate allorecognition systems, and the functional evidence can be interpreted either way. Even among the vertebrates, there is great...

  7. Photoinduced electron transfer in some photosensitive molecules ...

    Indian Academy of Sciences (India)

    An intramolecular charge transfer (ICT) molecule, -N,N-dimethylaminobenzoic acid (DMABA) has been studied in zeolite and colloidal media. The ratio of ICT to normal emission (ICT/LE) is greatly enhanced in zeolites compared to that in polar solvents. The ICT emission of DMABA was quenched by increasing the ...

  8. Kidney injury molecule-1 in renal disease

    NARCIS (Netherlands)

    Waanders, Femke; van Timmeren, Mirjan M.; Stegeman, Coen A.; Bakker, Stephan J. L.; van Goor, Harry

    Kidney injury molecule-1 (KIM-1) is a marker for renal proximal tubular damage, the hallmark of virtually all proteinuric, toxic and ischaemic kidney diseases. KIM-1 has gained increasing interest because of its possible pathophysiological role in modulating tubular damage and repair. In this

  9. Cluster ions and van der Waals molecules

    CERN Document Server

    Smirnov, Boris M


    This review discusses current ideas in the physics and chemistry of cluster ions and Van der Waals molecules as well as presenting numerical data on their parameters and the processes involving them. It is also a detailed reference on basic data relating to many species.

  10. The First Quantum Theory of Molecules

    Indian Academy of Sciences (India)

    IAS Admin

    by the vibrational motion of its parts”. Bjerrum was aware of the composite nature of bands in infrared ab- sorption spectra of simple gaseous substances, such as. HCl, whereby a sequence of lines comprises such a band. Bjerrum associated such a band with the vibration of a diatomic molecule and superimposed rotational ...

  11. The Molecules of the Cell Membrane. (United States)

    Bretscher, Mark S.


    Cell membrane molecules form a simple, two-dimensional liquid controlling what enters and leaves the cell. Discusses cell membrane molecular architecture, plasma membranes, epithelial cells, cycles of endocytosis and exocytosis, and other topics. Indicates that some cells internalize, then recycle, membrane area equivalent to their entire surface…

  12. Progress in Computational Electron-Molecule Collisions (United States)

    Rescigno, Tn


    The past few years have witnessed tremendous progress in the development of sophisticated ab initio methods for treating collisions of slow electrons with isolated small molecules. Researchers in this area have benefited greatly from advances in computer technology; indeed, the advent of parallel computers has made it possible to carry out calculations at a level of sophistication inconceivable a decade ago. But bigger and faster computers are only part of the picture. Even with today's computers, the practical need to study electron collisions with the kinds of complex molecules and fragments encountered in real-world plasma processing environments is taxing present methods beyond their current capabilities. Since extrapolation of existing methods to handle increasingly larger targets will ultimately fail as it would require computational resources beyond any imagined, continued progress must also be linked to new theoretical developments. Some of the techniques recently introduced to address these problems will be discussed and illustrated with examples of electron-molecule collision calculations we have carried out on some fairly complex target gases encountered in processing plasmas. Electron-molecule scattering continues to pose many formidable theoretical and computational challenges. I will touch on some of the outstanding open questions.

  13. Organic molecules in translucent interstellar clouds. (United States)

    Krełowski, Jacek


    Absorption spectra of translucent interstellar clouds contain many known molecular bands of CN, CH+, CH, OH, OH(+), NH, C2 and C3. Moreover, one can observe more than 400 unidentified absorption features, known as diffuse interstellar bands (DIBs), commonly believed to be carried by complex, carbon-bearing molecules. DIBs have been observed in extragalactic sources as well. High S/N spectra allow to determine precisely the corresponding column densities of the identified molecules, rotational temperatures which differ significantly from object to object in cases of centrosymmetric molecular species, and even the (12)C/(13)C abundance ratio. Despite many laboratory based studies of possible DIB carriers, it has not been possible to unambiguously link these bands to specific species. An identification of DIBs would substantially contribute to our understanding of chemical processes in the diffuse interstellar medium. The presence of substructures inside DIB profiles supports the idea that DIBs are very likely features of gas phase molecules. So far only three out of more than 400 DIBs have been linked to specific molecules but none of these links was confirmed beyond doubt. A DIB identification clearly requires a close cooperation between observers and experimentalists. The review presents the state-of-the-art of the investigations of the chemistry of interstellar translucent clouds i.e. how far our observations are sufficient to allow some hints concerning the chemistry of, the most common in the Galaxy, translucent interstellar clouds, likely situated quite far from the sources of radiation (stars).

  14. Field-free orientation of molecules

    DEFF Research Database (Denmark)

    Machholm, Mette; Henriksen, Niels Engholm


    The excitation of angular motion, in particular, the creation of a wave packet in the angular degrees of freedom via short-pulse, off-resonant excitation with respect to rotational transitions, was examined. The key result was that field-free time-dependent orientation for a molecule like LiH can...

  15. Small-molecule AT2 receptor agonists

    DEFF Research Database (Denmark)

    Hallberg, Mathias; Sumners, Colin; Steckelings, U Muscha


    The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist...

  16. Controlled transport through a single molecule

    NARCIS (Netherlands)

    Kumar, Avijit; Heimbuch, Rene; Poelsema, Bene; Zandvliet, Henricus J.W.


    We demonstrate how an electrode–molecule–electrode junction can be controllably opened and closed by careful tuning of the contacts' interspace and voltage. The molecule, an octanethiol, flips to bridge a ~1 nm interspace between substrate and scanning tunnelling microscope tip when an electric

  17. Exciting H2 Molecules for Graphene Functionalization

    DEFF Research Database (Denmark)

    Kyhl, Line; Bisson, Regis; Balog, Richard


    Hydrogen functionalization of graphene by exposure to vibrationally excited H2 molecules is investigated by combined scanning tunneling microscopy, high resolution electron energy loss spectroscopy, x-ray photoemission spectroscopy measurements and density functional theory calculations. The meas......Hydrogen functionalization of graphene by exposure to vibrationally excited H2 molecules is investigated by combined scanning tunneling microscopy, high resolution electron energy loss spectroscopy, x-ray photoemission spectroscopy measurements and density functional theory calculations....... The measurements reveal that vibrationally excited H2 molecules dissociatively adsorb on graphene on Ir(111) resulting in nano-patterned hydrogen functionalization structures. Calculations demonstrate that the presence of the Ir surface below the graphene lowers the H2 dissociative adsorption barrier and allows...... for the adsorption reaction at energies well below the dissociation threshold of the H-H bond. The first reacting H2 molecule must contain considerable vibrational energy to overcome the dissociative adsorption barrier. However, this initial adsorption further activates the surface resulting in reduced barriers...

  18. Laser Control of Atoms and Molecules

    CERN Document Server

    Letkhov, V S


    This text treats laser light as a universal tool to control matter at the atomic and molecular level, one of the most exciting applications of lasers. Lasers can heat matter, cool atoms to ultra-low temperatures where they show quantum collective behaviour, and can act selectively on specific atoms and molecules for their detection and separation.

  19. Monte Carlo calculations of atoms and molecules (United States)

    Schmidt, K. E.; Moskowitz, J. W.


    The variational and Green's function Monte Carlo (GFMC) methods can treat many interesting atomic and molecular problems. These methods can give chemical accuracy for up to 10 or so electrons. The various implementations of the GFMC method, including the domain Green's function method and the short-time approximation, are discussed. Results are presented for several representative atoms and molecules.

  20. Electrostatic Propulsion Using C60 Molecules (United States)

    Leifer, Stephanie D.; Saunders, Winston A.


    Report proposes use of C60 as propellant material in electrostatic propulsion system of spacecraft. C60, C70, and similar molecules, have recently been found to have characteristics proving advantageous in electrostatic propulsion. Report discusses these characteristics and proposes experiments to determine feasibility of concept.

  1. Properties of Organic Molecules at Metal Surfaces (United States)

    Rosei, Federico


    The adsorption and self assembly of organic molecules at surfaces has recently been investigated extensively, both because of the fundamental interest and for prospective applications in nanoelectronics and nanophotonics [1, 2]. Molecule molecule and molecule substrate interactions can be tuned by the appropriate choice of substrate material and symmetry. Upon molecular adsorption, surfaces typically do not behave as static templates, but often rearrange dramatically to accommodate different molecular species [3, 4]. This presentation reviews recent experimental work using Scanning Tunneling Microscopy, which is providing new insight into fundamental properties such as molecular diffusion [5, 6] and self assembly via surface templating [7] and hydrogen bonding driven by co-adsorption [8]. [1] F. Rosei et al., Prog. Surf. Science 71, 95 (2003). [2] F. Rosei, J. Phys. Condens. Matter 16, S1373 (2004). [3] F. Rosei et al., Science 296, 328 (2002). [4] R. Otero, F. Rosei, et al., Nanoletters 4, 75 (2004). [5] M. Schunack, T.R. Linderoth, F. Rosei, et al., Phys. Rev. Lett. 88, 156102 (2002). [6] J.A. Miwa, S. Weigelt, H. Gersen, F. Besenbacher, F. Rosei, T.R. Linderoth, submitted. [7] R. Otero, Y. Naitoh, F. Rosei et al., Angew. Chem. 43, 4092 (2004). [8] K.G. Nath, O. Ivasenko, J.A. Miwa, H. Dang, J.D. Wuest, A. Nanci, D.F. Perepichka, F. Rosei, submitted.

  2. Soluble endothelial cell molecules and circulating endothelial cells in patients with venous thromboembolism. (United States)

    Torres, Cláudia; Matos, Rui; Morais, Sara; Campos, Manuel; Lima, Margarida


    : To evaluate the plasma levels of soluble endothelial cell molecules in patients with venous thromboembolism (VTE) out of the acute phase as compared with healthy individuals. We also investigated the possible associations of the soluble endothelial cell molecules among them, as well as with other clinical and laboratory data, including the numbers of circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP), and CEC expressing activation-related [cluster of differentiation (CD)54 and CD62E] and procoagulant (CD142) markers. In total, 15 patients with VTE and 20 normal individuals were studied. The CEC and CEP were quantified and characterized by flow cytometry. The soluble molecules studied included P-selectin, E-selectin, intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1 and tissue factor (ELISA), and von Willebrand factor antigen (immunoturbidimetry). VTE patients had significantly higher levels of vascular cell adhesion molecule 1 and von Willebrand factor antigen and lower levels of soluble E-selectin than controls. They also showed significantly higher numbers of CEC, as of activated/procoagulant CEC and lower numbers of CEP, compared with controls. We did not find any correlation between the levels of soluble molecules and the numbers of endothelial cell in circulation, but there was with several clinical and laboratory data in VTE patients. Our results would suggest that in VTE patients, the endothelium remains activated and in some hypercoagulable state. The levels of soluble endothelial cell molecules did not seem to be directly related to the numbers of CEC and CEP neither reflected the number of activated CEC, which may be because of the different function that surface and soluble molecules may have.

  3. Single Molecule Nanoelectrochemistry in Electrical Junctions. (United States)

    Nichols, Richard J; Higgins, Simon J


    It is now possible to reliably measure single molecule conductance in a wide variety of environments including organic liquids, ultrahigh vacuum, water, ionic liquids, and electrolytes. The most commonly used methods deploy scanning probe microscopes, mechanically formed break junctions, or lithographically formed nanogap contacts. Molecules are generally captured between a pair of facing electrodes, and the junction current response is measured as a function of bias voltage. Gating electrodes can also be added so that the electrostatic potential at the molecular bridge can be independently controlled by this third noncontacting electrode. This can also be achieved in an electrolytic environment using a four-electrode bipotentiostatic configuration, which allows independent electrode potential control of the two contacting electrodes. This is commonly realized using an electrochemical STM and enables single molecule electrical characterization as a function of electrode potential and redox state of the molecular bridge. This has emerged as a powerful tool in modern interfacial electrochemistry and nanoelectrochemistry for studying charge transport across single molecules as a function of electrode potential and the electrolytic environments. Such measurements are possible in electrolytes ranging from aqueous buffers to nonaqueous ionic liquids. In this Account, we illustrate a number of examples of single molecule electrical measurements under electrode potential control use a scanning tunneling microscope (STM) and demonstrate how these can help in the understanding of charge transport in single molecule junctions. Examples showing charge transport following phase coherent tunneling to incoherent charge hopping across redox active molecular bridges are shown. In the case of bipyridinium (or viologen) molecular wires, it is shown how electrochemical reduction leads to an increase of the single molecule conductance, which is controlled by the liquid electrochemical

  4. The neural cell adhesion molecule binds to fibroblast growth factor receptor 2

    DEFF Research Database (Denmark)

    Christensen, Claus; Lauridsen, Jes B; Berezin, Vladimir


    The neural cell adhesion molecule (NCAM) can bind to and activate fibroblast growth factor receptor 1 (FGFR1). However, there are four major FGFR isoforms (FGFR1-FGFR4), and it is not known whether NCAM also interacts directly with the other three FGFR isoforms. In this study, we show by surface...

  5. NanoManipulator Lets Chemists Go Mano a Mano With Molecules. (United States)

    Sincell, M


    Because objects only a few molecules across are too small to be seen or touched directly, scientists approach them essentially blind and numb. Now a team of physicists, chemists, biologists, and computer scientists at the University of North Carolina, Chapel Hill, has developed a tool that restores their eyes and fingers. It's called the nanoManipulator.

  6. Molecular electronics: the single molecule switch and transistor

    NARCIS (Netherlands)

    Sotthewes, Kai; Geskin, Victor; Heimbuch, Rene; Kumar, Avijit; Zandvliet, Henricus J.W.


    In order to design and realize single-molecule devices it is essential to have a good understanding of the properties of an individual molecule. For electronic applications, the most important property of a molecule is its conductance. Here we show how a single octanethiol molecule can be connected

  7. Increased expression of intercellular adhesion molecules in biliary atresia.


    Dillon, P.; Belchis, D.; Tracy, T.; Cilley, R.; Hafer, L.; Krummel, T


    The expression of the inflammatory adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial leukocyte adhesion molecule-1, was studied in six infants with biliary atresia using an immunoperoxidase technique on frozen sections. Controls consisted of five patients with various conditions including total parenteral nutrition-induced cholestasis, choledochal cyst, viral hepatitis, metastatic carcinoma, and thrombotic thrombocytopenic purpura. None o...

  8. Single molecule fluorescence probes dynamics of barrier crossing (United States)

    Chung, Hoi Sung; Eaton, William A.


    Kramers developed the theory on how chemical reaction rates are influenced by the viscosity of the medium1,2. At the viscosity of water, the kinetics of unimolecular reactions are described by diffusion of a Brownian particle over a free-energy barrier separating reactants and products. For reactions in solution this famous theory extended Eyring's transition state theory, and is widely applied in physics, chemistry, and biology, including reactions as complex as protein folding3,4. Because the diffusion coefficient of Kramers theory is determined by the dynamics in the sparsely-populated region of the barrier top, its properties have not been directly measured for any molecular system. Here we show that the Kramers diffusion coefficient and free energy barrier can be characterized by measuring the temperature- and viscosity-dependence of the transition path time for protein folding. The transition path is the small fraction of an equilibrium trajectory for a single molecule when the free-energy barrier separating two states is actually crossed (Fig. 1a). Its duration, the transition path time, can now be determined from photon trajectories for single protein molecules undergoing folding/unfolding transitions5. Our finding of a long transition path time with an unusually small solvent viscosity-dependence suggests that internal friction as well as solvent friction determine the Kramers diffusion coefficient for α-helical proteins, as opposed to a breakdown of his theory that occurs for many small-molecule reactions2. It is noteworthy that the new and fundamental information concerning Kramers theory and the dynamics of barrier crossings obtained here come from experiments on a protein rather than a much simpler chemical or physical system. PMID:24153185

  9. Exploring single-molecule dynamics with fluorescence nanoscopy

    Energy Technology Data Exchange (ETDEWEB)

    Ringemann, Christian; Harke, Ben; Von Middendorff, Claas; Medda, Rebecca; Leutenegger, Marcel; Schoenle, Andreas; W Hell, Stefan; Eggeling, Christian [Department of Nanobiophotonics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Goettingen (Germany); Honigmann, Alf; Wagner, Richard [Biophysik, University Osnabrueck, FB Biologie/Chemie, Osnabrueck (Germany)], E-mail:


    The study of molecular dynamics at the single-molecule level with fluorescence correlation spectroscopy (FCS) and far-field optics has contributed greatly to the functional understanding of complex systems. Unfortunately, such studies are restricted to length scales of >200 nm because diffraction does not allow further reduction of the measurement volume. This sets an upper limit on the applicable concentration of fluorescently labeled molecules and even more importantly, averages out details of nanoscale dynamics. By combining FCS and fluorescence intensity distribution analysis (FIDA) with sub-diffraction-resolution stimulated emission depletion (STED) nanoscopy, we remove this restriction and obtain open measurement volumes of nanoscale dimensions which are tunable in size. As a consequence, single-molecule studies can now be extended to nanoscale dynamics and may be applied to much larger, often endogenous concentrations. In solution, low-brightness signal from axial out-of-focus volume shells was taken into account by using both FCS and FIDA in conjunction to analyze the data. In two-dimensional systems, such as lipid membranes, the background is greatly reduced and measurements feature excellent signal-to-noise ratios. Measurement foci of down to 30 nm in diameter directly reveal anomalous diffusion of lipids in the plasma membrane of living cells and allow for the determination of on/off rates of the binding of lipids to other membrane constituents. Such important insight into the prominent biological question of lipid membrane organization or 'lipid rafts' shows that combining fluctuation analysis with STED-engineered ultra-small measurement volumes is a viable and powerful new approach to probing molecular dynamics on the nanoscale.

  10. Single Molecule Studies on Dynamics in Liquid Crystals


    Daniela Täuber; Christian von Borczyskowski


    Single molecule (SM) methods are able to resolve structure related dynamics of guest molecules in liquid crystals (LC). Highly diluted small dye molecules on the one hand explore structure formation and LC dynamics, on the other hand they report about a distortion caused by the guest molecules. The anisotropic structure of LC materials is used to retrieve specific conformation related properties of larger guest molecules like conjugated polymers. This in particular sheds light on organization...

  11. Junctional adhesion molecule-A: functional diversity through molecular promiscuity. (United States)

    Steinbacher, Tim; Kummer, Daniel; Ebnet, Klaus


    Cell adhesion molecules (CAMs) of the immunoglobulin superfamily (IgSF) regulate important processes such as cell proliferation, differentiation and morphogenesis. This activity is primarily due to their ability to initiate intracellular signaling cascades at cell-cell contact sites. Junctional adhesion molecule-A (JAM-A) is an IgSF-CAM with a short cytoplasmic tail that has no catalytic activity. Nevertheless, JAM-A is involved in a variety of biological processes. The functional diversity of JAM-A resides to a large part in a C-terminal PDZ domain binding motif which directly interacts with nine different PDZ domain-containing proteins. The molecular promiscuity of its PDZ domain motif allows JAM-A to recruit protein scaffolds to specific sites of cell-cell adhesion and to assemble signaling complexes at those sites. Here, we review the molecular characteristics of JAM-A, including its dimerization, its interaction with scaffolding proteins, and the phosphorylation of its cytoplasmic domain, and we describe how these characteristics translate into diverse biological activities.

  12. Single-Molecule DNA Methylation Quantification Using Electro-optical Sensing in Solid-State Nanopores. (United States)

    Gilboa, Tal; Torfstein, Chen; Juhasz, Matyas; Grunwald, Assaf; Ebenstein, Yuval; Weinhold, Elmar; Meller, Amit


    Detection of epigenetic markers, including 5-methylcytosine, is crucial due to their role in gene expression regulation and due to the mounting evidence of aberrant DNA methylation patterns in cancer biogenesis. Single-molecule methods to date have primarily been focused on hypermethylation detection; however, many oncogenes are hypomethylated during cancer development, presenting an important unmet biosensing challenge. To this end, we have developed a labeling and single-molecule quantification method for multiple unmethylated cytosine-guanine dinucleotides (CpGs). Our method involves a single-step covalent coupling of DNA with synthetic cofactor analogues using DNA methyltransferases (MTases) followed by molecule-by-molecule electro-optical nanopore detection and quantification with single or multiple colors. This sensing method yields a calibrated scale to directly quantify the number of unmethylated CpGs in the target sequences of each DNA molecule. Importantly, our method can be used to analyze ∼10 kbp long double-stranded DNA while circumventing PCR amplification or bisulfite conversion. Expanding this technique to use two colors, as demonstrated here, would enable sensing of multiple DNA MTases through orthogonal labeling/sensing of unmethylated CpGs (or other epigenetic modifications) associated with specific recognition sites. Our proof-of-principle study may permit sequence-specific, direct targeting of clinically relevant hypomethylated sites in the genome.

  13. Blinking effect and the use of quantum dots in single molecule spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Rombach-Riegraf, Verena; Oswald, Peter; Bienert, Roland; Petersen, Jan [Albert-Ludwigs-Universitaet Freiburg, Institut fuer Physikalische Chemie, Albertstrasse 23a, 79104 Freiburg (Germany); Domingo, M.P. [Instituto de Carboquimica (CSIC), Miguel Luesma 4, 50018 Zaragoza (Spain); Pardo, Julian [Grupo Apoptosis, Inmunidad y Cancer, Departamento Bioquimica y Biologia Molecular y Celular, Fac. Ciencias, Universidad de Zaragoza, Zaragoza (Spain); Fundacion Aragon I-D (ARAID), Gobierno de Aragon, Zaragoza (Spain); Immune Effector Cells Group, Aragon Health Research Institute (IIS Aragon), Biomedical Research Centre of Aragon (CIBA) Fundacion Aragon I-D - ARAID, Gobierno de Aragon, Zaragoza (Spain); Graeber, P. [Albert-Ludwigs-Universitaet Freiburg, Institut fuer Physikalische Chemie, Albertstrasse 23a, 79104 Freiburg (Germany); Galvez, E.M., E-mail: [Instituto de Carboquimica (CSIC), Miguel Luesma 4, 50018 Zaragoza (Spain); Immune Effector Cells Group, Aragon Health Research Institute (IIS Aragon), Biomedical Research Centre of Aragon (CIBA) Fundacion Aragon I-D - ARAID, Gobierno de Aragon, Zaragoza (Spain)


    Highlights: Black-Right-Pointing-Pointer It is possible to eliminate the blinking effect of a water-soluble QD. Black-Right-Pointing-Pointer We provide a direct method to study protein function and dynamics at the single level. Black-Right-Pointing-Pointer QD, potent tool for single molecule studies of biochemical and biological processes. -- Abstract: Luminescent semiconductor nanocrystals (quantum dots, QD) have unique photo-physical properties: high photostability, brightness and narrow size-tunable fluorescence spectra. Due to their unique properties, QD-based single molecule studies have become increasingly more popular during the last years. However QDs show a strong blinking effect (random and intermittent light emission), which may limit their use in single molecule fluorescence studies. QD blinking has been widely studied and some hypotheses have been done to explain this effect. Here we summarise what is known about the blinking effect in QDs, how this phenomenon may affect single molecule studies and, on the other hand, how the 'on'/'off' states can be exploited in diverse experimental settings. In addition, we present results showing that site-directed binding of QD to cysteine residues of proteins reduces the blinking effect. This option opens a new possibility of using QDs to study protein-protein interactions and dynamics by single molecule fluorescence without modifying the chemical composition of the solution or the QD surface.


    Energy Technology Data Exchange (ETDEWEB)



    This research program is directed at obtaining detailed experimental information on the electronic interactions between metals and organic molecules. These interactions provide low energy pathways for many important chemical and catalytic processes. A major feature of the program is the continued development and application of our special high-resolution valence photoelectron spectroscopy (UPS), and high-precision X-ray core photoelectron spectroscopy (XPS) instrumentation for study of organometallic molecules in the gas phase. The study involves a systematic approach towards understanding the interactions and activation of bound carbonyls, C-H bonds, methylenes, vinylidenes, acetylides, alkenes, alkynes, carbenes, carbynes, alkylidenes, alkylidynes, and others with various monometal, dimetal, and cluster metal species. Supporting ligands include -aryls, alkoxides, oxides, and phosphines. We are expanding our studies of both early and late transition metal species and electron-rich and electron-poor environments in order to more completely understand the electronic factors that serve to stabilize particular organic fragments and intermediates on metals. Additional new directions for this program are being taken in ultra-high vacuum surface UPS, XPS, scanning tunneling microscopy (STM) and atomic force microscopy (AFM) experiments on both physisorbed and chemisorbed organometallic thin films. The combination of these methods provides additional electronic structure information on surface-molecule and molecule-molecule interactions. A very important general result emerging from this program is the identification of a close relationship between the ionization energies of the species and the thermodynamics of the chemical and catalytic reactions of these systems.

  15. Laboratory and observational studies of transient molecules at microwave and millimeter/submillimeter wavelengths (United States)

    Zack, Lindsay Nicole

    In this dissertation, techniques of high-resolution rotational spectroscopy have been used to measure the spectra of molecules in both laboratory and astronomical settings. In the laboratory, small metal-bearing molecules containing zinc, iron, nickel, titanium, yttrium, and scandium have been studied at microwave and millimeter/submillimeter wavelengths in order to determine their rotational, fine, and hyperfine constants. These molecules were synthesized in situ in direct-absorption and Fourier-transform microwave spectrometers using Broida-type ovens and laser ablation methods. From the spectroscopic parameters, information about fundamental physical properties and electronic character could be obtained. Radio telescopes were used to measure the spectra of molecules in different interstellar environments. A new molecule, FeCN, was detected toward the circumstellar envelope of the carbon-rich asymtotic giant branch star, IRC+10216, marking the first iron-bearing molecule detected in the interstellar medium. The telescopes were also used to conduct a study of the evolved planetary nebula, NGC 7293, or the Helix Nebula. In the Helix, CO, HCO+, and H2CO were observed at several positions offset from the central star to obtain densities and kinetic temperatures throughout the Helix. A map of the HCO+ J = 1→ 0 transition was also constructed, showing that HCO+ is widespread throughout the Helix, instead of being photodissociated and destroyed, as theoretical models of planetary nebulae predict.

  16. A quantum gas of polar KRb molecules in an optical lattice (United States)

    Covey, Jacob; Miecnikowski, Matthew; Moses, Steven; Fu, Zhengkun; Jin, Deborah; Ye, Jun


    Ultracold polar molecules provide new opportunities for investigation of strongly correlated many-body spin systems such as many-body localization and quantum magnetism. In an effort to access such phenomena, we load polar KRb molecules into a three-dimensional optical lattice. In this system, we observed many-body spin dynamics between molecules pinned in a deep lattice, even though the filling fraction of the molecules was only 5%. We have recently performed a thorough investigation of the molecule creation process in an optical lattice, and consequently improved our filling fraction to 30% by preparing and overlapping Mott and band insulators of the initial atomic gases. More recently, we switched to a second generation KRb apparatus that will allow application of large, stable electric fields as well as high-resolution addressing and detection of polar molecules in optical lattices. We plan to use these capabilities to study non-equilibrium spin dynamics in an optical lattice with nearly single site resolution. I will present the status and direction of the second generation apparatus.

  17. Viscosity, relaxation time, and dynamics within a model asphalt of larger molecules

    Energy Technology Data Exchange (ETDEWEB)

    Li, Derek D.; Greenfield, Michael L., E-mail: [Department of Chemical Engineering, University of Rhode Island, Kingston, Rhode Island 02881 (United States)


    The dynamics properties of a new “next generation” model asphalt system that represents SHRP AAA-1 asphalt using larger molecules than past models is studied using molecular simulation. The system contains 72 molecules distributed over 12 molecule types that range from nonpolar branched alkanes to polar resins and asphaltenes. Molecular weights range from 290 to 890 g/mol. All-atom molecular dynamics simulations conducted at six temperatures from 298.15 to 533.15 K provide a wealth of correlation data. The modified Kohlrausch-Williams-Watts equation was regressed to reorientation time correlation functions and extrapolated to calculate average rotational relaxation times for individual molecules. The rotational relaxation rate of molecules decreased significantly with increasing size and decreasing temperature. Translational self-diffusion coefficients followed an Arrhenius dependence. Similar activation energies of ∼42 kJ/mol were found for all 12 molecules in the model system, while diffusion prefactors spanned an order of magnitude. Viscosities calculated directly at 533.15 K and estimated at lower temperatures using the Debye-Stokes-Einstein relationship were consistent with experimental data for asphalts. The product of diffusion coefficient and rotational relaxation time showed only small changes with temperature above 358.15 K, indicating rotation and translation that couple self-consistently with viscosity. At lower temperatures, rotation slowed more than diffusion.

  18. Automated imaging system for single molecules (United States)

    Schwartz, David Charles; Runnheim, Rodney; Forrest, Daniel


    There is provided a high throughput automated single molecule image collection and processing system that requires minimal initial user input. The unique features embodied in the present disclosure allow automated collection and initial processing of optical images of single molecules and their assemblies. Correct focus may be automatically maintained while images are collected. Uneven illumination in fluorescence microscopy is accounted for, and an overall robust imaging operation is provided yielding individual images prepared for further processing in external systems. Embodiments described herein are useful in studies of any macromolecules such as DNA, RNA, peptides and proteins. The automated image collection and processing system and method of same may be implemented and deployed over a computer network, and may be ergonomically optimized to facilitate user interaction.

  19. Handbook of Single-Molecule Biophysics

    CERN Document Server

    Hinterdorfer, Peter


    The last decade has seen the development of a number of novel biophysical methods that allow the manipulation and study of individual biomolecules. The ability to monitor biological processes at this fundamental level of sensitivity has given rise to an improved understanding of the underlying molecular mechanisms. Through the removal of ensemble averaging, distributions and fluctuations of molecular properties can be characterized, transient intermediates identified, and catalytic mechanisms elucidated. By applying forces on biomolecules while monitoring their activity, important information can be obtained on how proteins couple function to structure. The Handbook of Single-Molecule Biophysics provides an introduction to these techniques and presents an extensive discussion of the new biological insights obtained from them. Coverage includes: Experimental techniques to monitor and manipulate individual biomolecules The use of single-molecule techniques in super-resolution and functional imaging Single-molec...

  20. Single-molecule Studies of Riboswitch Folding (United States)

    Savinov, Andrew; Perez, Christian F.; Block, Steven M.


    The folding dynamics of riboswitches are central to their ability to modulate gene expression in response to environmental cues. In most cases, a structural competition between the formation of a ligand-binding aptamer and an expression platform (or some other competing off-state) determines the regulatory outcome. Here, we review single-molecule studies of riboswitch folding and function, predominantly carried out using single-molecule FRET or optical trapping approaches. Recent results have supplied new insights into riboswitch folding energy landscapes, the mechanisms of ligand binding, the roles played by divalent ions, the applicability of hierarchical folding models, and kinetic vs. thermodynamic control schemes. We anticipate that future work, based on improved data sets and potentially combining multiple experimental techniques, will enable the development of more complete models for complex RNA folding processes. PMID:24727093