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Sample records for molecule programmed death-1

  1. Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules.

    PubMed

    Solaymani-Mohammadi, Shahram; Lakhdari, Omar; Minev, Ivelina; Shenouda, Steve; Frey, Blake F; Billeskov, Rolf; Singer, Steven M; Berzofsky, Jay A; Eckmann, Lars; Kagnoff, Martin F

    2016-03-01

    The programmed death-1 receptor is expressed on a wide range of immune effector cells, including T cells, natural killer T cells, dendritic cells, macrophages, and natural killer cells. In malignancies and chronic viral infections, increased expression of programmed death-1 by T cells is generally associated with a poor prognosis. However, its role in early host microbial defense at the intestinal mucosa is not well understood. We report that programmed death-1 expression is increased on conventional natural killer cells but not on CD4(+), CD8(+) or natural killer T cells, or CD11b(+) or CD11c(+) macrophages or dendritic cells after infection with the mouse pathogen Citrobacter rodentium. Mice genetically deficient in programmed death-1 or treated with anti-programmed death-1 antibody were more susceptible to acute enteric and systemic infection with Citrobacter rodentium. Wild-type but not programmed death-1-deficient mice infected with Citrobacter rodentium showed significantly increased expression of the conventional mucosal NK cell effector molecules granzyme B and perforin. In contrast, natural killer cells from programmed death-1-deficient mice had impaired expression of those mediators. Consistent with programmed death-1 being important for intracellular expression of natural killer cell effector molecules, mice depleted of natural killer cells and perforin-deficient mice manifested increased susceptibility to acute enteric infection with Citrobacter rodentium. Our findings suggest that increased programmed death-1 signaling pathway expression by conventional natural killer cells promotes host protection at the intestinal mucosa during acute infection with a bacterial gut pathogen by enhancing the expression and production of important effectors of natural killer cell function.

  2. Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma

    PubMed Central

    Schlößer, Hans A.; Drebber, Uta; Kloth, Michael; Thelen, Martin; Rothschild, Sacha I.; Haase, Simon; Garcia-Marquez, Maria; Wennhold, Kerstin; Berlth, Felix; Urbanski, Alexander; Alakus, Hakan; Schauss, Astrid; Shimabukuro-Vornhagen, Alexander; Theurich, Sebastian; Warnecke-Ebertz, Ute; Stippel, Dirk L.; Zippelius, Alfred; Büttner, Reinhard; Hallek, Michael; Hölscher, Arnulf H.; Zander, Thomas; Mönig, Stefan P.; von Bergwelt-Baildon, Michael

    2016-01-01

    ABSTRACT Remarkable efficacy of immune checkpoint inhibition has been reported for several types of solid tumors and early studies in gastric adenocarcinoma are promising. A detailed knowledge about the natural biology of immune checkpoints in gastric adenocarcinoma is essential for clinical and translational evaluation of these drugs. This study is a comprehensive analysis of cytotoxic T lymphocyte associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) expression in gastric adenocarcinoma. PD-L1 and CTLA-4 were stained on tumor sections of 127 Caucasian patients with gastric adenocarcinoma by immunohistochemistry (IHC) and somatic mutation profiling was performed using targeted next-generation sequencing. Expression of PD-L1 and CTLA-4 on lymphocytes in tumor sections, tumor-draining lymph nodes (TDLN) and peripheral blood were studied by flow-cytometry and immune-fluorescence microscopy in an additional cohort. PD-L1 and CTLA-4 were expressed in 44.9% (57/127) and 86.6% (110/127) of the analyzed gastric adenocarcinoma samples, respectively. Positive tumor cell staining for PD-L1 or CTLA-4 was associated with inferior overall survival. Somatic mutational analysis did not reveal a correlation to expression of PD-L1 or CTLA-4 on tumor cells. Expression of PD-1 (52.2%), PD-L1 (42.2%) and CTLA-4 (1.6%) on tumor infiltrating T cells was significantly elevated compared to peripheral blood. Of note, PD-1 and PD-L1 were expressed far higher by tumor-infiltrating lymphocytes than CTLA-4. In conclusion, specific immune checkpoint-inhibitors should be evaluated in this disease and the combination with molecular targeted therapies might be of benefit. An extensive immune monitoring should accompany these studies to better understand their mode of action in the tumor microenvironment. PMID:27467911

  3. Predictive Efficacy Biomarkers of Programmed Cell Death 1/Programmed Cell Death 1 Ligand Blockade Therapy.

    PubMed

    Fang, Xiao-Na; Fu, Li-Wu

    2016-01-01

    Inhibitors of immune check-point molecule, programmed cell death 1 (PD-1) and its ligand, programmed cell death ligand 1 (PD-L1) have attracted much attention in cancer immunotherapy recently due to their durable antitumor effects in various malignances, especially the advanced ones. Unfortunately, only a fraction of patients with advanced tumors could benefit from anti-PD-1/PD-L1 therapy, while others still worsened. The key to this point is that there are no efficient biomarkers for screening anti-PD-1/PD-L1-sensitive patients. In this review, we aim at summarizing the latest advances of anti-PD-1/PDL1 immunotherapy and the potential predictive efficacy biomarkers to provide evidences for identifying anti-PD-1/PDL1- sensitive patients. The present article also includes the patent review coverage on this topic.

  4. Programmed death 1 immune checkpoint inhibitors.

    PubMed

    Trivedi, Meghna S; Hoffner, Brianna; Winkelmann, Jennifer L; Abbott, Maura E; Hamid, Omid; Carvajal, Richard D

    2015-12-01

    Programmed death 1 (PD-1) is an immune checkpoint that provides inhibitory signals to the immune system in order to modulate the activity of T cells in peripheral tissues and maintain self-tolerance in the setting of infection and inflammation. In cancer, the immune checkpoints are exploited so that the tumor cells are able to evade the immune system. Immune checkpoint inhibitors are a type of cancer immunotherapy that targets pathways such as PD-1 in order to reinvigorate and enhance the immune response against tumor cells. The US Food and Drug Administration (FDA) has approved 2 PD-1 inhibitors, nivolumab and pembrolizumab, and several others are under investigation. Although PD-1 inhibitors have demonstrated activity in many different types of malignancies, FDA approval has been granted only in melanoma and in non-small cell lung cancer (NSCLC). Identifying biomarkers that can predict response to PD-1 inhibitors is critical to maximizing the benefit of these agents. Future directions for PD-1 inhibitors include investigation of combination therapies, use in malignancies other than melanoma and NSCLC, and refinement of biomarkers.

  5. Programmed death-1 & its ligands: promising targets for cancer immunotherapy.

    PubMed

    Shrimali, Rajeev K; Janik, John E; Abu-Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N

    2015-01-01

    Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit.

  6. Programmed death-1 pathway in cancer and autoimmunity.

    PubMed

    Pedoeem, Ariel; Azoulay-Alfaguter, Inbar; Strazza, Marianne; Silverman, Gregg J; Mor, Adam

    2014-07-01

    Programmed death-1 (PD-1) is a co-receptor that is expressed predominantly by T cells. The binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. A major functional role of the PD-1 signaling pathway is the inhibition of self-reactive T cells, which serve to protect against autoimmune diseases. Elimination of the PD-1 pathway can therefore result in the breakdown of immune tolerance that can ultimately lead to the development of pathogenic autoimmunity. Conversely, tumor cells can at times co-opt the PD-1 pathway to escape from immunosurveillance mechanisms. Therefore, blockade of the PD-1 pathway has become an attractive target in cancer therapy. Recent clinical trials have shown that anti-PD-1 agents have profound effects on solid tumor regression. Current approaches include six agents that are either PD-1 and PD-L1 targeted neutralizing antibodies or fusion proteins. More than forty clinical trials are underway to better define the role of PD-1 blockade in variety of tumor types. In this review we will highlight the basic biology of the PD-1 system and discuss its potential roles in both autoimmunity and cancer. We propose that future research on PD-1 may lead to the translation of fundamental regulatory pathways into the development of practical new approaches for the treatment of autoimmune diseases and cancer.

  7. Adrenal Insufficiency Related to Anti-Programmed Death-1 Therapy.

    PubMed

    Ariyasu, Ryo; Horiike, Atsushi; Yoshizawa, Takahiro; Dotsu, Yosuke; Koyama, Junji; Saiki, Masafumi; Sonoda, Tomoaki; Nishikawa, Shingo; Kitazono, Satoru; Yanagitani, Noriko; Nishio, Makoto

    2017-08-01

    Adrenal insufficiency is one of the adverse events (AEs) associated with anti-programmed death-1 (PD1) therapy. Delaying diagnoses can lead to serious conditions. It is necessary to elucidate detailed clinical features of these AEs. Patients treated with anti-PD-1 monotherapy or in combination with anti-cytotoxic T cell lymphocyte-4 therapy at our hospital from January 2013 to December 2016 were identified. The patients' clinical characteristics and laboratory and radiologic findings were collected. Adrenal insufficiency occurred in 3% of the patients. All patients were male. At the onset of symptoms, eosinophilia (>500/μl) was observed in four cases. Eosinophilia was observed more than a month before onset of symptoms in three cases. Other pituitary hormones remained relatively stable. Radiological evidence of pituitary inflammation was detected only in one case. Most anti-PD1-related adrenal insufficiency cases involved an isolated ACTH deficiency. Eosinophilia may be an early indicator before the onset of symptoms. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  8. Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1.

    PubMed

    Guzik, Katarzyna; Zak, Krzysztof M; Grudnik, Przemyslaw; Magiera, Katarzyna; Musielak, Bogdan; Törner, Ricarda; Skalniak, Lukasz; Dömling, Alexander; Dubin, Grzegorz; Holak, Tad A

    2017-07-13

    Blockade of the PD-1/PD-L1 immune checkpoint pathway with monoclonal antibodies has provided significant advances in cancer treatment. The antibody-based immunotherapies carry a number of disadvantages such as the high cost of the antibodies, their limited half-life, and immunogenicity. Development of small-molecule PD-1/PD-L1 inhibitors that could overcome these drawbacks is slow because of the incomplete structural information for this pathway. The first chemical PD-1/PD-L1 inhibitors have been recently disclosed by Bristol-Myers Squibb. Here we present NMR and X-ray characterization for the two classes of these inhibitors. The X-ray structures of the PD-L1/inhibitor complexes reveal one inhibitor molecule located at the center of the PD-L1 homodimer, filling a deep hydrophobic channel-like pocket between two PD-L1 molecules. Derivatives of (2-methyl-3-biphenylyl)methanol exhibit the structures capped on one side of the channel, whereas the compounds based on [3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methanol induce an enlarged interaction interface that results in the open "face-back" tunnel through the PD-L1 dimer.

  9. Programmed Cell Death-1/Programmed Death-ligand 1 Pathway: A New Target for Sepsis.

    PubMed

    Liu, Qiang; Li, Chun-Sheng

    2017-04-20

    Sepsis remains a leading cause of death in many Intensive Care Units worldwide. Immunosuppression has been a primary focus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L1 pathway to examine its potential as a new target for sepsis treatment. Studies of the association between PD-1/PD-L1 and sepsis published up to January 31, 2017, were obtained by searching the PubMed database. English language studies, including those based on animal models, clinical research, and reviews, with data related to PD-1/PD-L1 and sepsis, were evaluated. Immunomodulatory therapeutics could reverse the deactivation of immune cells caused by sepsis and restore immune cell activation and function. Blockade of the PD-1/PD-L1 pathway could reduce the exhaustion of T-cells and enhance the proliferation and activation of T-cells. The anti-PD-1/PD-L1 pathway shows promise as a new target for sepsis treatment. This review provides a basis for clinical trials and future studies aimed at revaluating the efficacy and safety of this targeted approach.

  10. Regulation of Neuroinflammation through Programed Death-1/Programed Death Ligand Signaling in Neurological Disorders

    PubMed Central

    Zhao, Shangfeng; Li, Fengwu; Leak, Rehana K.; Chen, Jun; Hu, Xiaoming

    2014-01-01

    Immune responses in the central nervous system (CNS), which involve both resident glial cells and infiltrating peripheral immune cells, play critical roles in the progress of brain injuries and neurodegeneration. To avoid inflammatory damage to the compromised brain, the immune cell activities in the CNS are controlled by a plethora of chemical mediators and signal transduction cascades, such as inhibitory signaling through programed death-1 (PD-1) and programed death ligand (PD-L) interactions. An increasing number of recent studies have highlighted the importance of PD-1/PD-L pathway in immune regulation in CNS disorders such as ischemic stroke, multiple sclerosis, and Alzheimer’s disease. Here, we review the current knowledge of the impact of PD-1/PD-L signaling on brain injury and neurodegeneration. An improved understanding of the function of PD-1/PD-L in the cross-talk between peripheral immune cells, CNS glial cells, and non-immune CNS cells is expected to shed further light on immunomodulation and help develop effective and safe immunotherapies for CNS disorders. PMID:25232304

  11. Anti program death-1/anti program death-ligand 1 in digestive cancers

    PubMed Central

    de Guillebon, Eléonore; Roussille, Pauline; Frouin, Eric; Tougeron, David

    2015-01-01

    Human tumors tend to activate the immune system regulatory checkpoints as a means of escaping immunosurveillance. For instance, interaction between program death-1 (PD-1) and program death-ligand 1 (PD-L1) will lead the activated T cell to a state of anergy. PD-L1 is upregulated on a wide range of cancer cells. Anti-PD-1 and anti-PD-L1 monoclonal antibodies (mAbs), called immune checkpoint inhibitors (ICIs), have consequently been designed to restore T cell activity. Accumulating data are in favor of an association between PD-L1 expression in tumors and response to treatment. A PD-L1 expression is present in 30% to 50% of digestive cancers. Multiple anti-PD-1 (nivolumab, pembrolizumab) and anti-PD-L1 mAbs (MPDL3280A, Medi4736) are under evaluation in digestive cancers. Preliminary results in metastatic gastric cancer with pembrolizumab are highly promising and phase II will start soon. In metastatic colorectal cancer (CRC), a phase III trial of MPDL3280A as maintenance therapy will shortly be initiated. Trials are also ongoing in metastatic CRC with high immune T cell infiltration (i.e., microsatellite instability). Major challenges are ahead in order to determine how, when and for which patients we should use these ICIs. New radiologic criteria to evaluate tumor response to ICIs are awaiting prospective validation. The optimal therapeutic sequence and association with cytotoxic chemotherapy needs to be established. Finally, biomarker identification will be crucial to selection of patients likely to benefit from ICIs. PMID:26306141

  12. Anti program death-1/anti program death-ligand 1 in digestive cancers.

    PubMed

    de Guillebon, Eléonore; Roussille, Pauline; Frouin, Eric; Tougeron, David

    2015-08-15

    Human tumors tend to activate the immune system regulatory checkpoints as a means of escaping immunosurveillance. For instance, interaction between program death-1 (PD-1) and program death-ligand 1 (PD-L1) will lead the activated T cell to a state of anergy. PD-L1 is upregulated on a wide range of cancer cells. Anti-PD-1 and anti-PD-L1 monoclonal antibodies (mAbs), called immune checkpoint inhibitors (ICIs), have consequently been designed to restore T cell activity. Accumulating data are in favor of an association between PD-L1 expression in tumors and response to treatment. A PD-L1 expression is present in 30% to 50% of digestive cancers. Multiple anti-PD-1 (nivolumab, pembrolizumab) and anti-PD-L1 mAbs (MPDL3280A, Medi4736) are under evaluation in digestive cancers. Preliminary results in metastatic gastric cancer with pembrolizumab are highly promising and phase II will start soon. In metastatic colorectal cancer (CRC), a phase III trial of MPDL3280A as maintenance therapy will shortly be initiated. Trials are also ongoing in metastatic CRC with high immune T cell infiltration (i.e., microsatellite instability). Major challenges are ahead in order to determine how, when and for which patients we should use these ICIs. New radiologic criteria to evaluate tumor response to ICIs are awaiting prospective validation. The optimal therapeutic sequence and association with cytotoxic chemotherapy needs to be established. Finally, biomarker identification will be crucial to selection of patients likely to benefit from ICIs.

  13. Nivolumab as Programmed Death-1 (PD-1) Inhibitor for Targeted Immunotherapy in Tumor

    PubMed Central

    Guo, Liting; Zhang, Haijun; Chen, Baoan

    2017-01-01

    Targeted immunotherapy has become the most promising approach for tumor patients. Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, can reverse immune suppression and release T cell activation. Nivolumab, a fully human immunoglobulin G4 PD-1 immune checkpoint inhibitor antibody, blocks PD-1 and promotes antitumor immunity, and it is effective for treating non-small-cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC) and other cancers. The present review summarizes the efficacy and current status of clinical trials of nivolumab and that enabled nivolumab to be investigated in patients. PMID:28261342

  14. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy.

    PubMed

    Naidoo, Jarushka; Wang, Xuan; Woo, Kaitlin M; Iyriboz, Tunc; Halpenny, Darragh; Cunningham, Jane; Chaft, Jamie E; Segal, Neil H; Callahan, Margaret K; Lesokhin, Alexander M; Rosenberg, Jonathan; Voss, Martin H; Rudin, Charles M; Rizvi, Hira; Hou, Xue; Rodriguez, Katherine; Albano, Melanie; Gordon, Ruth-Ann; Leduc, Charles; Rekhtman, Natasha; Harris, Bianca; Menzies, Alexander M; Guminski, Alexander D; Carlino, Matteo S; Kong, Benjamin Y; Wolchok, Jedd D; Postow, Michael A; Long, Georgina V; Hellmann, Matthew D

    2017-03-01

    Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher's exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti-PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P < .01). Incidence was similar in patients with melanoma and non-small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [ P = 1.0]; combination, 11 of 115 v four of 57 [ P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion

  15. Discovery of peptide inhibitors targeting human programmed death 1 (PD-1) receptor

    PubMed Central

    Lyu, Jiankun; He, Zenghui; Wang, Xia; Meng, Jiajia; Zhao, Zhenjiang; Zhu, Lili; Liu, Xiaofeng; Li, Honglin

    2016-01-01

    Blocking the interaction of human programmed death 1 (hPD-1) and its ligand hPD-L1 has been a promising immunotherapy in cancer treatment. In this paper, using a computational de novo peptide design method, we designed several hPD-1 binding peptides. The most potent peptide Ar5Y_4 showed a KD value of 1.38 ± 0.39 μM, comparable to the binding affinity of the cognate hPD-L1. A Surface Plasmon Resonance (SPR) competitive binding assay result indicated that Ar5Y_4 could inhibit the interaction of hPD-1/hPD-L1. Moreover, Ar5Y_4 could restore the function of Jurkat T cells which had been suppressed by stimulated HCT116 cells. Peptides described in this paper provide promising biologic candidates for cancer immunotherapy or diagnostics. PMID:27533458

  16. Programmed death-1/programmed death-L1 signaling pathway and its blockade in hepatitis C virus immunotherapy.

    PubMed

    Salem, Mohamed L; El-Badawy, Ahmed

    2015-10-18

    Chronic hepatitis C virus (HCV) infection is a public health issue that often progresses to life-threatening complications, including liver cirrhosis, fibrosis, and hepatocellular carcinoma. Impaired immune responses to HCV are key features of chronic HCV infection. Therefore, intervention strategies usually involve enhancing the immune responses against HCV. Cytotoxic CD8(+) T lymphocytes (CTLs) play a critical role in the control of HCV infection. However, their cytolytic function can be impaired by the expression of co-inhibitory molecules. Programmed death-1 (PD-1) receptor and its ligand PD-L1 function in a T cell co-inhibitory pathway, which either blocks the function of CTLs or the differentiation of CD8(+) T cells. During chronic HCV infection, the immune inhibitory receptor PD-1 is upregulated on dysfunctional HCV-specific CD8(+) T cells. As such, blockade of the PD-1/PD-L1 pathway in these CD8(+) T cells might restore their functional capabilities. Indeed, clinical trials using therapies to block this pathway have shown promise in the fostering of anti-HCV immunity. Understanding how chronic HCV infection induces upregulation of PD-1 on HCV specific T cells and how the PD-1/PD-L1 interaction develops HCV specific T cell dysfunction will accelerate the development of an efficacious prophylactic and therapeutic vaccination against chronic HCV infections, which will significantly improve HCV treatments and patient survival. In this review, we discuss the relationship between PD-1 expression and clinical responses and the potential use of PD-1 blockade for anti-HCV therapy.

  17. The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity.

    PubMed

    Ostrand-Rosenberg, Suzanne; Horn, Lucas A; Haile, Samuel T

    2014-10-15

    Programmed death ligand 1 (PD-L1, also known as B7 homolog 1 or CD274) is a major obstacle to antitumor immunity because it tolerizes/anergizes tumor-reactive T cells by binding to its receptor programmed death-1 (CD279), renders tumor cells resistant to CD8(+) T cell- and FasL-mediated lysis, and tolerizes T cells by reverse signaling through T cell-expressed CD80. PD-L1 is abundant in the tumor microenvironment, where it is expressed by many malignant cells, as well as by immune cells and vascular endothelial cells. The critical role of PD-L1 in obstructing antitumor immunity has been demonstrated in multiple animal models and in recent clinical trials. This article reviews the mechanisms by which PD-L1 impairs antitumor immunity and discusses established and experimental strategies for maintaining T cell activation in the presence of PD-L1-expressing cells in the tumor microenvironment.

  18. Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis.

    PubMed

    Cho, Hyosun; Kang, Hyojeung; Lee, Hwan Hee; Kim, Chang Wook

    2017-07-13

    Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others.

  19. Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis

    PubMed Central

    Cho, Hyosun; Kang, Hyojeung; Lee, Hwan Hee

    2017-01-01

    Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others. PMID:28703774

  20. Role of the Programmed Death-1 (PD-1) pathway in regulation of Theiler's murine encephalomyelitis virus-induced demyelinating disease.

    PubMed

    Takizawa, Sho; Kaneyama, Tomoki; Tsugane, Sayaka; Takeichi, Naoya; Yanagisawa, Satoshi; Ichikawa, Motoki; Yagita, Hideo; Kim, Byung S; Koh, Chang-Sung

    2014-09-15

    Programmed death-1 (PD-1) belongs to the CD28 family of co-stimulatory and co-inhibitory molecules and regulates adaptive immunity. This molecule induces the development of regulatory T cells, T cell tolerance, or apoptosis. We examined the role of PD-1 pathway in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) mice. Up-regulation of PD-1 and PD-1 ligand-1 (PD-L1) mRNA expression in bone marrow-derived dendritic cells were induced by TMEV infection in vitro. Furthermore, PD-1 and PD-L1 mRNA expression was increased in the spinal cords of the TMEV-infected mice in vivo. Treatment with a blocking monoclonal antibody (mAb) against PD-1, especially during the effector phase, resulted in significant deterioration of the TMEV-IDD both clinically and histologically. Flow cytometric analysis revealed a dramatically increase of CD4(+) T cells producing Th1 cytokines such as IFN-γ and TNF-α in the spinal cord of anti-PD-1 mAb-treated mice. These results indicate that the PD-1 pathway plays a pivotal regulatory role in the development of TMEV-IDD.

  1. A Quantitative Comparison of Antibodies to Programmed Cell Death 1 Ligand 1.

    PubMed

    Gaule, Patricia; Smithy, James W; Toki, Maria; Rehman, Jamaal; Patell-Socha, Farah; Cougot, Delphine; Collin, Philippe; Morrill, Paul; Neumeister, Veronique; Rimm, David L

    2016-08-18

    Assessment of PD-L1 (programmed cell death 1 ligand 1) expression by immunohistochemical analysis has been used as a predictive diagnostic test to identify responders and guide treatment in trials of the PD-1 (programmed cell death 1) axis inhibitors. The definition of PD-L1 positive lacks standardization, and prediction of response by immunohistochemical analysis is additionally limited by the subjective nature of this technique. To examine whether PD-L1 antibody reagents are interchangeable by quantitatively comparing the expression of the PD-L1 protein. In this immunohistochemistry standardization study, 30 randomly selected cases of lung cancer resected from January 1, 2008, through December 31, 2009, were obtained from Yale Pathology Archives with a range of expression of PD-L1. To test for protein measurement, rather than clinical utility, a PD-L1 index tissue microarray, including cell line and tissue controls, was used. The results were then validated on a commercially available, genetically defined PD-L1 engineered cell line array with a range of controlled protein-expressing cell lines using 6 monoclonal antibodies (SP142, E1L3N, 9A11, SP263, 22c3, and 28-8). Protein levels were measured by quantitative immunofluorescence and quantitative chromogenic assessment. Data analysis was performed from September 2015 through May 2016. Concordance between 4 antibodies revealed regression for tumor tissue cores (R2 = 0.42-0.91) and cell line cores (R2 = 0.83-0.97) by quantitative immunofluorescence in the PD-L1 index tissue microarray. All 6 antibodies had high levels of concordance (R2 = 0.76-0.99) when using chromogenic staining in isogenic cell lines. Because the antibodies are highly concordant, these results suggest that assays based on the use of these antibodies could yield concordant results. They further suggest that previously described differences in PD-L1 expression in tissue are independent of the antibody used and likely attributable to

  2. Enhanced expression of Programmed cell death 1 (PD-1) protein in benign vascular anomalies.

    PubMed

    Amaya, Clarissa N; Wians, Frank H; Bryan, Brad A; Torabi, Alireza

    2017-04-01

    Programmed cell death 1 (PD-1) and its ligands have been shown to play a significant role in evasion of malignant tumour cells from the immune system. Last year, the United States Food and Drug Administration (FDA) approved anti-PD-1 inhibitors for treatment of non-small cell lung carcinoma and recently has approved anti-PD-L1 blocker for treatment of metastatic urothelial cell carcinoma. However, the role that the immune system might have on benign tumours including vascular anomalies has received less attention. In this study, we evaluated PD-1 and PD-L1 expression on two benign vascular anomalies: infantile haemangiomas and venous malformations. Tissue microarrays (TMAs) from these two entities were stained for PD-1 and PD-L1 antibodies. Blood vessels from normal tissue were used as control. The endothelial cells in both infantile haemangioma and venous malformation showed high expression of PD-1 but were negative for PD-L1. Endothelial cells within the blood vessels in normal tissues were negative for both PD-1 and PD-L1. Our results showed over-expression of PD-1 in subsets of vascular anomalies, while PD-L1 was negative. This would raise the possibility of immunotherapy in benign vascular tumour when other options are exhausted.

  3. Expression of programmed death 1 is correlated with progression of osteosarcoma.

    PubMed

    Zheng, Wenjie; Xiao, Hong; Liu, Huan; Zhou, Yue

    2015-02-01

    Accumulating bodies of evidence indicate that immune dysregulation plays a key role in the development of osteosarcoma (OS). Programmed death 1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T-cell inhibition upon binding with its ligand. Researches on PD-1 and OS remain extremely limited. Here, we investigated whether PD-1 could be involved in the development of OS. Expression of PD-1 was measured by flow cytometry on peripheral CD4+ and CD8+ T cells from 56 OS cases and 42 healthy controls. Data revealed that percentages of PD-1 were significantly upregulated on both peripheral CD4+ and CD8+ T cells from OS patients (p < 0.001 and p < 0.001, respectively). Patients with different tumor locations did not present obvious variations in PD-1 level. However, patients with metastasis showed significantly higher level of PD-1 on CD4+ T cells than those without metastasis (p < 0.001). Furthermore, PD-1 expression on CD4+ T cells started to increase in stage III, whereas PD-1 expression on CD8+ T cells started to increase in stage II. In addition, patients with pathological fracture were observed to have elevated PD-1 on both CD4+ and CD8+ T cells. These data suggest that PD-1 is involved in the pathogenesis of OS, especially in the progression of disease.

  4. Global patent landscape of programmed cell death 1: implications of the rapid expansion.

    PubMed

    Kong, Xiangjun; Zhang, Qianru; Lai, Yunfeng; Hu, Hao; Chen, Xin; Hu, Yuanjia

    2017-09-19

    Inhibitors of programmed cell death 1 (PD-1) and its ligands are producing a paradigm shift in cancer treatment. The promising clinical outcomes and a multi-billion dollar market have prompted active research and development and resulted in relentless patent protection. However, the global patent landscape in this field remains unclear. Areas covered: The patent landscape encompassing global patenting activities and developing trends in the field is discussed based on a data set of 1287 patent families. Patenting activities have expanded rapidly in the past three years. Specific trends in relevant aspects are presented, including patent filing countries, patent ownership, co-patents, technical areas, and technological connections in terms of patent citation relationships. Expert opinion: Together with patenting momentum in recent years, fragmented ownership and dense technological connections of PD-1-related inventions raise the possibility of a patent thicket. The explosion of patent applications and complex citation relationships could also lead to considerable patent conflicts and disputes on overlapping intellectual property rights, in addition to existing legal uncertainties. Patent applicants in this field are encouraged to be aware of these concerns when developing valid patent strategies.

  5. Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy.

    PubMed

    Okamoto, Masahide; Okamoto, Mitsuhiro; Gotoh, Koro; Masaki, Takayuki; Ozeki, Yoshinori; Ando, Hisae; Anai, Manabu; Sato, Asami; Yoshida, Yuichi; Ueda, So; Kakuma, Tetsuya; Shibata, Hirotaka

    2016-11-01

    Anti-programmed cell death-1 (PD-1) antibodies are regarded as a risk factor for insulin-dependent diabetes mellitus as a side-effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin-dependent diabetes during anti-PD-1 therapy. A 55-year-old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C-peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti-PD-1 therapy can cause rapid onset of insulin-dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti-PD-1 therapy.

  6. Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: a meta-analysis.

    PubMed

    Lee, Y H; Woo, J H; Choi, S J; Ji, J D; Song, G G

    2009-01-01

    Programmed cell death 1 (PDCD1 or PD1) polymorphisms have been inconsistently reported to be associated with systemic lupus erythematosus (SLE). The aim of this study was to explore whether the PDCD1 polymorphisms confer a susceptibility to SLE and lupus nephritis (LN). We conducted a meta-analysis on the association of PDCD1 polymorphisms with SLE in overall and specific ethnic populations. A total of 15 separate comparisons were included in this meta-analysis consisting of nine Europeans, two Latin Americans, two Africans, one Asian and one unknown participant. In subgroup analysis, the PD1.3A allele was significantly associated with SLE in Latin Americans (OR = 3.073, 95% CI = 1.416-6.461, P = 0.003), but not in patients of European and African decent. The PD1.3A allele was a risk factor for LN in European descendants (OR = 2.207, 95% CI = 1.488-3.467, P < 0.001). The PD1.5C allele was a risk factor for SLE in Europeans (OR = 1.297, 95% CI = 1.024-1.643, P = 0.031). In conclusion, this meta-analysis demonstrated an association of the PD1.3A allele with LN in European and SLE in Latin-American populations. Furthermore, the PD1.5C allele was associated with SLE susceptibility in Europeans.

  7. Association of Acute Interstitial Nephritis With Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients.

    PubMed

    Shirali, Anushree C; Perazella, Mark A; Gettinger, Scott

    2016-08-01

    Immune checkpoint inhibitors that target the programmed death 1 (PD-1) signaling pathway have recently been approved for use in advanced pretreated non-small cell lung cancer and melanoma. Clinical trial data suggest that these drugs may have adverse effects on the kidney, but these effects have not been well described. We present 6 cases of acute kidney injury in patients with lung cancer who received anti-PD-1 antibodies, with each case displaying evidence of acute interstitial nephritis (AIN) on kidney biopsy. All patients were also treated with other drugs (proton pump inhibitors and nonsteroidal anti-inflammatory drugs) linked to AIN, but in most cases, use of these drugs long preceded PD-1 inhibitor therapy. The association of AIN with these drugs in our patients raises the possibility that PD-1 inhibitor therapy may release suppression of T-cell immunity that normally permits renal tolerance of drugs known to be associated with AIN. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  8. Program Death-1 Suppresses Autoimmune Arthritis by Inhibiting Th17 Response.

    PubMed

    Yang, Lifen; Qiao, Guilin; Hassan, Yassir; Li, Zhenping; Zhang, Xiaoqing; Kong, Huimin; Zeng, Weimin; Yin, Fei; Zhang, Jian

    2016-10-01

    Program death-1 (PD-1) is a co-inhibitory receptor inducibly expressed on activated T cells. PD-1 has been reported to be associated with the development of several autoimmune diseases including rheumatoid arthritis, but the precise cellular and molecular mechanisms have not been fully elucidated. To study the role of PD-1 in the pathogenesis of rheumatoid arthritis and the possible underlying mechanisms, we performed collagen-induced arthritis (CIA) in C57BL/6 mice. Here, we show that PD-1 deficiency leads to the development of severe CIA in mice. When analyzing T cells from CIA mice ex vivo, we noticed aberrant antigen-specific Th17 responses in mice lacking PD-1. This is possibly due to deregulated activation of PKC-θ and Akt. In support of this notion, treating Pdcd1 (-/-) mice with an inhibitor of PI3-kinase that is upstream of PKC-θ and Akt significantly suppressed the disease severity. Therefore, our data indicate that PD-1 dampens antigen-specific Th17 response, thus inhibiting the disease.

  9. Relationship between programmed cell death-1 polymorphisms and clearance of hepatitis B virus.

    PubMed

    Ülger, Y; Bayram, S; Sandıkçı, M Ü; Akgöllü, E; Bekar, A

    2015-06-01

    Programmed cell death-1 (PD-1) plays a critical role in regulating T-cell function during hepatitis B virus (HBV) infection. This study investigated the relationship between the polymorphisms of PD-1 gene and the susceptibility to HBV infection. Single nucleotide polymorphisms (SNPs) in PD-1 gene at positions +7146 G>A (guanine to adenine substitution) and +7209 C>T (cytosine to thymine substitution) were analysed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 220 subjects with chronic hepatitis B infection and 165 spontaneous clearance of HBV subjects. However, no statistically significant differences were found in the genotype distributions of the PD-1 +7146 G>A and PD-1 +7209 C>T polymorphisms among chronic hepatitis B and spontaneous clearance subjects. According to stratified analyses, borderline significance was observed between PD-1 +7146 GA genotype and risk of HBV chronicity in the subgroup of male gender (OR = 1.88, 95% 0.95-3.71; P = 0.07). Our findings demonstrate for the first time that the PD-1 +7146 G>A and PD-1 +7209 C>T polymorphisms have not been any major role in genetic susceptibility to chronicity of HBV infection, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins.

  10. Programmed death-1 controls T cell survival by regulating oxidative metabolism.

    PubMed

    Tkachev, Victor; Goodell, Stefanie; Opipari, Anthony W; Hao, Ling-Yang; Franchi, Luigi; Glick, Gary D; Ferrara, James L M; Byersdorfer, Craig A

    2015-06-15

    The coinhibitory receptor programmed death-1 (PD-1) maintains immune homeostasis by negatively regulating T cell function and survival. Blockade of PD-1 increases the severity of graft-versus-host disease (GVHD), but the interplay between PD-1 inhibition and T cell metabolism is not well studied. We found that both murine and human alloreactive T cells concomitantly upregulated PD-1 expression and increased levels of reactive oxygen species (ROS) following allogeneic bone marrow transplantation. This PD-1(Hi)ROS(Hi) phenotype was specific to alloreactive T cells and was not observed in syngeneic T cells during homeostatic proliferation. Blockade of PD-1 signaling decreased both mitochondrial H2O2 and total cellular ROS levels, and PD-1-driven increases in ROS were dependent upon the oxidation of fatty acids, because treatment with etomoxir nullified changes in ROS levels following PD-1 blockade. Downstream of PD-1, elevated ROS levels impaired T cell survival in a process reversed by antioxidants. Furthermore, PD-1-driven changes in ROS were fundamental to establishing a cell's susceptibility to subsequent metabolic inhibition, because blockade of PD-1 decreased the efficacy of later F1F0-ATP synthase modulation. These data indicate that PD-1 facilitates apoptosis in alloreactive T cells by increasing ROS in a process dependent upon the oxidation of fat. In addition, blockade of PD-1 undermines the potential for subsequent metabolic inhibition, an important consideration given the increasing use of anti-PD-1 therapies in the clinic.

  11. Programmed death-1 immune checkpoint blockade in the treatment of hematological malignancies.

    PubMed

    Tsirigotis, Panagiotis; Savani, Bipin N; Nagler, Arnon

    2016-09-01

    The use of tumor-specific monoclonal antibodies (MAbs) has revolutionize the field of cancer immunotherapy. Although treatment of malignant diseases with MAbs is promising, many patients fail to respond or relapse after an initial response. Both solid tumors and hematological malignancies develop mechanisms that enable them to evade the host immune system by usurping immune checkpoint pathways such as PD-1, PD-2, PDL-1, or PDL-2 (programmed cell death protein-1 or 2 and PD-Ligand 1 or 2), which are expressed on activated T cells and on T-regulatory, B cells, natural killers, monocytes, and dendritic cells. One of the most exciting anticancer development in recent years has been the immune checkpoint blockade therapy by using MAbs against immune checkpoint receptor and/or ligands. Anti-PD1 antibodies have been tested in clinical studies that included patients with hematological malignancies and showed remarkable efficacy in Hodgkin lymphoma (HL). In our review, we will focus on the effect of PD-1 activation on hematological malignancies and its role as a therapeutic target. Key messages The programmed death 1 (PD1) immune checkpoint is an important homeostatic mechanism of the immune system that helps in preventing autoimmunity and uncontrolled inflammation in cases of chronic infections. However, PD1 pathway is also operated by a wide variety of malignancies and represents one of the most important mechanisms by which tumor cells escape from the surveillance of the immune system. Blocking of immune checkpoints by the use of monoclonal antibodies opened a new era in the field of cancer immunotherapy. Results from clinical trials are promising, and currently, this approach has been proven effective and safe in patients with solid tumors and hematological malignancies.

  12. Anti-Bovine Programmed Death-1 Rat–Bovine Chimeric Antibody for Immunotherapy of Bovine Leukemia Virus Infection in Cattle

    PubMed Central

    Okagawa, Tomohiro; Konnai, Satoru; Nishimori, Asami; Maekawa, Naoya; Ikebuchi, Ryoyo; Goto, Shinya; Nakajima, Chie; Kohara, Junko; Ogasawara, Satoshi; Kato, Yukinari; Suzuki, Yasuhiko; Murata, Shiro; Ohashi, Kazuhiko

    2017-01-01

    Blockade of immunoinhibitory molecules, such as programmed death-1 (PD-1)/PD-ligand 1 (PD-L1), is a promising strategy for reinvigorating exhausted T cells and preventing disease progression in a variety of chronic infections. Application of this therapeutic strategy to cattle requires bovinized chimeric antibody targeting immunoinhibitory molecules. In this study, anti-bovine PD-1 rat–bovine chimeric monoclonal antibody 5D2 (Boch5D2) was constructed with mammalian expression systems, and its biochemical function and antiviral effect were characterized in vitro and in vivo using cattle infected with bovine leukemia virus (BLV). Purified Boch5D2 was capable of detecting bovine PD-1 molecules expressed on cell membranes in flow cytometric analysis. In particular, Biacore analysis determined that the binding affinity of Boch5D2 to bovine PD-1 protein was similar to that of the original anti-bovine PD-1 rat monoclonal antibody 5D2. Boch5D2 was also capable of blocking PD-1/PD-L1 binding at the same level as 5D2. The immunomodulatory and therapeutic effects of Boch5D2 were evaluated by in vivo administration of the antibody to a BLV-infected calf. Inoculated Boch5D2 was sustained in the serum for a longer period. Boch5D2 inoculation resulted in activation of the proliferation of BLV-specific CD4+ T cells and decrease in the proviral load of BLV in the peripheral blood. This study demonstrates that Boch5D2 retains an equivalent biochemical function to that of the original antibody 5D2 and is a candidate therapeutic agent for regulating antiviral immune response in vivo. Clinical efficacy of PD-1/PD-L1 blockade awaits further experimentation with a large number of animals. PMID:28638381

  13. Anti-Bovine Programmed Death-1 Rat-Bovine Chimeric Antibody for Immunotherapy of Bovine Leukemia Virus Infection in Cattle.

    PubMed

    Okagawa, Tomohiro; Konnai, Satoru; Nishimori, Asami; Maekawa, Naoya; Ikebuchi, Ryoyo; Goto, Shinya; Nakajima, Chie; Kohara, Junko; Ogasawara, Satoshi; Kato, Yukinari; Suzuki, Yasuhiko; Murata, Shiro; Ohashi, Kazuhiko

    2017-01-01

    Blockade of immunoinhibitory molecules, such as programmed death-1 (PD-1)/PD-ligand 1 (PD-L1), is a promising strategy for reinvigorating exhausted T cells and preventing disease progression in a variety of chronic infections. Application of this therapeutic strategy to cattle requires bovinized chimeric antibody targeting immunoinhibitory molecules. In this study, anti-bovine PD-1 rat-bovine chimeric monoclonal antibody 5D2 (Boch5D2) was constructed with mammalian expression systems, and its biochemical function and antiviral effect were characterized in vitro and in vivo using cattle infected with bovine leukemia virus (BLV). Purified Boch5D2 was capable of detecting bovine PD-1 molecules expressed on cell membranes in flow cytometric analysis. In particular, Biacore analysis determined that the binding affinity of Boch5D2 to bovine PD-1 protein was similar to that of the original anti-bovine PD-1 rat monoclonal antibody 5D2. Boch5D2 was also capable of blocking PD-1/PD-L1 binding at the same level as 5D2. The immunomodulatory and therapeutic effects of Boch5D2 were evaluated by in vivo administration of the antibody to a BLV-infected calf. Inoculated Boch5D2 was sustained in the serum for a longer period. Boch5D2 inoculation resulted in activation of the proliferation of BLV-specific CD4(+) T cells and decrease in the proviral load of BLV in the peripheral blood. This study demonstrates that Boch5D2 retains an equivalent biochemical function to that of the original antibody 5D2 and is a candidate therapeutic agent for regulating antiviral immune response in vivo. Clinical efficacy of PD-1/PD-L1 blockade awaits further experimentation with a large number of animals.

  14. Study of programmed cell death 1 (PDCD1) gene polymorphims in Iranian patients with ankylosing spondylitis.

    PubMed

    Soleimanifar, Narjes; Amirzargar, Ali Akbar; Mahmoudi, Mahdi; Pourfathollah, Ali Akbar; Azizi, Esfandiar; Jamshidi, Ahmad Reza; Rezaei, Nima; Tahoori, Mohammad Taher; Bidad, Katayoon; Nikbin, Behrouz; Nicknam, Mohammad Hossein

    2011-12-01

    Ankylosing spondylitis (AS) is a chronic inflammatory disease, characterized by axial arthritis in which the genetic-environmental factors seem to be involved in the pathogenesis of the disease. This study was performed to investigate the role of polymorphisms of the programmed cell death 1 (PDCD1) gene on susceptibility to AS. In this study, 161 Iranian patients with AS and 208 normal controls were enrolled; two single-nucleotide polymorphisms (SNPs) of the PDCD1 gene PD-1.3 (G, A) in nucleotide position +7146 of intron 4 and PD-1.9 (C, T) in nucleotide +7625 of exon 5 were studied. Analysis of PD-1.3 revealed that 82% of patients and 79% of controls had GG genotype, while GA and AA genotypes were detected in 17% and 0.6% of patients, respectively, and 20% and 1.4% of controls, respectively. Moreover, the genotype CC (PD-1.9) was present in 92% of patients and 97% of controls. Although these differences were not statistically significant between patients and controls, comparisons of genotypes frequencies in the AS patients, based on human leukocyte antigen (HLA)-B27, revealed that all patients who had CT genotype (PD-1.9) were HLA-B27 positive, whereas 30% of patients with CC genotype were HLA-B27 negative. There was no evidence of association for PDCD1 SNPs with AS in our study, but CT genotype (PD-1.9) seems to be associated with HLA-B27 positivity in the patients with AS.

  15. Program death 1 (PD1) haplotyping in patients with breast carcinoma.

    PubMed

    Haghshenas, Mohammad Reza; Naeimi, Sirous; Talei, Abdolrasoul; Ghaderi, Abbas; Erfani, Nasrollah

    2011-08-01

    Located on chromosome 2q37.3, the programmed death 1 (PD1) gene encodes for PD-1 (also known as CD279), a negative co-stimulator in the immune system. PD-1 renders potent inhibitory effects on T and B lymphocytes as well as monocyte responses. Expression of PD-1 ligands by tumor cells has been reported to contribute in immune system evasion. We aimed, in current study, to investigate the association of two single nucleotide polymorphisms in PD1 gene, +7146 G to A (PD-1.3) and +7785 C to T (PD-1.5 or +872), with susceptibility and/or progression of breast carcinoma. Four hundred forty-three women with breast cancer and 328 age-sex match healthy donors were recruited in present study. Genotyping was performed using Nested polymerase chain reaction-restriction fragment length polymorphisms. Arlequin software package was used to check for the Hardy-Weinberg equilibration and to determine the haplotypes. Results revealed no significant differences in the frequencies of genotypes and alleles at PD-1.3 (P=0.252 and 0.279 for genotypes and alleles, respectively) and PD-1.5 positions (P=0.522 and 0.278 for genotypes and alleles, respectively). Four haplotypes were observed among populations with no differences in the frequency between patients and controls. Our results also revealed no association between PD1 genotypes and tumor stage, tumor size, tumor grade, lymph node involvement, vascular invasion, distant metastasis, and Nottingham prognostic index. Present data do not confirm association of PD-1.3 (+7146) G/A and PD-1.5 (+7785 or +872) C/T genetic markers with susceptibility of Iranians to breast cancer.

  16. Programmed cell death 1 correlates with the occurrence and development of MG63 osteosarcoma

    PubMed Central

    Zhao, Fuyou; Wu, Qiong; Dai, Xiusong; Li, Yumei; Gan, Huaiyong; Wang, Ri; Lv, Jie; Chen, Yuqing

    2016-01-01

    The aim of the present study was to investigate the effect of programmed cell death 1 (PD-1) on osteosarcoma (OD) stem cells and T cells, and to determine their correlation. OS stem cells were sorted and identified from OS MG63 cells. Flow cytometry was used to detect the PD-1 expression of the OS tumor stem cell membrane surface. The expression of PD-1 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). MTT was used to detect the effect of PD-1 signals on T-cell proliferation. The results indicated that the cancer cells (cultured in DMEM medium containing 10% fetal bovine serum) exhibited clear proliferation within 1 week of cell culture, which showed their strong proliferation and aggressive ability. The formation of tumor cell spheres was dependent on the support of serum nutrition. The proliferation of MG63 cells in the serum culture medium was significantly higher than the number of OS cell spheres in serum-free suspension culture (P<0.05). Pluripotent stem cells in cancer cell spheres exhibited significantly higher cluster of differentiation 133 expression compared with the MG63 cells. The PD-1 expression levels of the cancer cell spheres was significantly increased compared with the MG63 cells, which is consistent with the results of the RT-PCR. In conclusion, the MG63 cell line possesses the features of OS stem cells. The MG63 cell line can express the certain cancer-associated cell markers. The expression of PD-1 in spheres was also increased significantly compared to the MG63 cells, which can reduce the immune function of patients and may be closely associated with the occurrence and development of tumors. PMID:28105229

  17. Blockade of the Programmed Death-1 Pathway Restores Sarcoidosis CD4+ T-Cell Proliferative Capacity

    PubMed Central

    Braun, Nicole A.; Celada, Lindsay J.; Herazo-Maya, Jose D.; Abraham, Susamma; Shaginurova, Guzel; Sevin, Carla M.; Grutters, Jan; Culver, Daniel A.; Dworski, Ryszard; Sheller, James; Massion, Pierre P.; Polosukhin, Vasiliy V.; Johnson, Joyce E.; Kaminski, Naftali; Wilkes, David S.; Oswald-Richter, Kyra A.

    2014-01-01

    Rationale: Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function. Objectives: To determine the effects of PD-1 pathway blockade on sarcoidosis CD4+ T-cell proliferative capacity. Methods: Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage–derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens. Measurements and Main Results: Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1+ CD4+ T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1+ CD4+ T cells with spontaneous clinical resolution but not with disease progression. Conclusions: Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4+ T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a

  18. Development and Fit-for-Purpose Validation of a Soluble Human Programmed Death-1 Protein Assay.

    PubMed

    Ni, Yan G; Yuan, Xiling; Newitt, John A; Peterson, Jon E; Gleason, Carol R; Haulenbeek, Jonathan; Santockyte, Rasa; Lafont, Virginie; Marsilio, Frank; Neely, Robert J; DeSilva, Binodh; Piccoli, Steven P

    2015-07-01

    Programmed death-1 (PD-1) protein is a co-inhibitory receptor which negatively regulates immune cell activation and permits tumors to evade normal immune defense. Anti-PD-1 antibodies have been shown to restore immune cell activation and effector function-an exciting breakthrough in cancer immunotherapy. Recent reports have documented a soluble form of PD-1 (sPD-1) in the circulation of normal and disease state individuals. A clinical assay to quantify sPD-1 would contribute to the understanding of sPD-1-function and facilitate the development of anti-PD-1 drugs. Here, we report the development and validation of a sPD-1 protein assay. The assay validation followed the framework for full validation of a biotherapeutic pharmacokinetic assay. A purified recombinant human PD-1 protein was characterized extensively and was identified as the assay reference material which mimics the endogenous analyte in structure and function. The lower limit of quantitation (LLOQ) was determined to be 100 pg/mL, with a dynamic range spanning three logs to 10,000 pg/mL. The intra- and inter-assay imprecision were ≤15%, and the assay bias (percent deviation) was ≤10%. Potential matrix effects were investigated in sera from both normal healthy volunteers and selected cancer patients. Bulk-prepared frozen standards and pre-coated Streptavidin plates were used in the assay to ensure consistency in assay performance over time. This assay appears to specifically measure total sPD-1 protein since the human anti-PD-1 antibody, nivolumab, and the endogenous ligands of PD-1 protein, PDL-1 and PDL-2, do not interfere with the assay.

  19. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

    PubMed Central

    Takamatsu, Masako; Kobayashi-Imanishi, Wakana; Hashimoto-Tane, Akiko; Azuma, Miyuki

    2012-01-01

    Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation. PMID:22641383

  20. Programmed death-1(+) T cells inhibit effector T cells at the pathological site of miliary tuberculosis.

    PubMed

    Singh, A; Mohan, A; Dey, A B; Mitra, D K

    2017-02-01

    Optimal T cell activation is vital for the successful resolution of microbial infections. Programmed death-1 (PD-1) is a key immune check-point receptor expressed by activated T cells. Aberrant/excessive inhibition mediated by PD-1 may impair host immunity to Mycobacterium tuberculosis infection, leading to disseminated disease such as miliary tuberculosis (MTB). PD-1 mediated inhibition of T cells in pulmonary tuberculosis and TB pleurisy is reported. However, their role in MTB, particularly at the pathological site, remains to be addressed. The objective of this study was to investigate the role of PD-1-PD-ligand 1 (PD-L1) in T cell responses at the pathological site from patients of TB pleurisy and MTB as clinical models of contained and disseminated forms of tuberculosis, respectively. We examined the expression and function of PD-1 and its ligands (PD-L1-PD-L2) on host immune cells among tuberculosis patients. Bronchoalveolar lavage-derived CD3 T cells in MTB expressed PD-1 (54·2 ± 27·4%, P ≥ 0·0009) with significantly higher PD-1 ligand-positive T cells (PD-L1: 19·8 ± 11·8%; P ≥ 0·019, PD-L2: 12·6 ± 6·2%; P ≥ 0·023), CD19(+) B cells (PD-L1: 14·4 ± 10·4%; P ≥ 0·042, PD-L2: 2·6 ± 1·43%; not significant) and CD14(+) monocytes (PD-L1: 40·2 ± 20·1%; P ≥ 0·047, PD-L2: 22·4 ± 15·6%; P ≥ 0·032) compared with peripheral blood (PB) of MTB and healthy controls. The expression of PD-1 was associated with a diminished number of cells producing effector cytokines interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-2 and elevated apoptosis. Locally accumulated T cells were predominantly PD-1(+) -PD-L1(+) , and blocking this pathway restores the protective T cell response. We conclude that M. tuberculosis exploits the PD-1 pathway to evade the host immune response by altering the T helper type 1 (Th1) and Th2 balance at the pathological site of MTB, thereby

  1. High programmed death 1 expression on T cells in aplastic anemia.

    PubMed

    Zhao, Wanhong; Zhang, Yilin; Zhang, Pengyu; Yang, Juan; Zhang, Longjin; He, Aili; Zhang, Wanggang; Hideto, Tamura

    2017-03-01

    Programmed death 1 (PD-1) has been reported to be associated with aberrant regulation of T cells activation in aplastic anemia (AA). However, the connection between PD-1 expression status and AA needs to be further explored. The aim of this study is to investigate PD-1 expression status on T cells in AA patients and to explore the effect of PD-1 on apoptosis of T cells and BMHSCs. The concentration of platelet, lymphocyte and hemoglobin in peripheral blood of AA patients and healthy volunteers was detected by automatic blood-counter system. Mononuclear cells (MNCs) of peripheral blood and marrow were isolated from AA patients and healthy volunteers. PD-1 expression level on CD3+, CD4+, CD8+, CD4+CD25+FOXP3+ T cells and bone marrow hematopoietic stem cells (BMHSCs) and B7-H1 expression level on peripheral blood mononuclear cells (PBMCs) and BMHSCs were detected by flow cytometry (FCM). Cell apoptosis on T cells and BMHSCs was also detected by FCM. PD-1, B7-H1, Bax and Bcl-2 mRNA expression levels on T cells of peripheral blood were detected by real-time PCR. MNCs from healthy volunteers were treated with ammonium pyrrolidine dithiocarbamate (PDTC) to block the nuclear factor (NF)-кB pathway. Our results showed that in AA patients, T cells had high levels of PD-1 expression and apoptosis rate. In BMHSCs, apoptosis rate was also higher than healthy volunteers. The expression of PD-1 on T cells was correlated with lymphocyte count and hemoglobin level. PD-1 was highly expressed on CD4+CD25+FOXP3+ T cells of AA patients and PD-1 expression was negatively correlated with the percentage of CD4+CD25+FOXP3+ T cells in AA patients. B7-H1, the ligand of PD-1, was also highly expressed on T cells, B cells, PBMCs and BMHSCs. When the NF-κB pathway was blocked by PDTC, the apoptosis of T cells and BMHSCs was reduced in a dose-dependent manner and PD-1 expression was also decreased in a dose-dependent manner. In conclusion, PD-1 was up-regulated in T cells in AA patients

  2. Neurological Complications Associated With Anti-Programmed Death 1 (PD-1) Antibodies.

    PubMed

    Kao, Justin C; Liao, Bing; Markovic, Svetomir N; Klein, Christopher J; Naddaf, Elie; Staff, Nathan P; Liewluck, Teerin; Hammack, Julie E; Sandroni, Paola; Finnes, Heidi; Mauermann, Michelle L

    2017-10-01

    Neurological complications are an increasingly recognized consequence of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established. To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti-PD-1 therapy. This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti-PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded. Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score. Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum

  3. Elevated Expression of Programmed Death-1 and Programmed Death Ligand-1 Negatively Regulates Immune Response against Cervical Cancer Cells

    PubMed Central

    Chen, Zhifang; Pang, Nannan; Du, Rong; Zhu, Yuejie; Fan, Lingling; Cai, Donghui

    2016-01-01

    The present study is to measure the expression of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), as well as its clinical significance in cervical cancer patients. Our results showed that different T cell subsets in patients with cervical cancer had high expression of PD-1, and DCs had high expression of PD-L1. High expression of PD-1 on Treg cells in cervical cancer patients facilitated the production of TGF-β and IL-10 but inhibited the production of IFN-γ. Cervical cancer elevated the expression of PD-1 and PD-L1 in mRNA level. PD-1 expression in peripheral blood of cervical cancer patients was related with tumor differentiation, lymph node metastasis, and invasiveness. PD-1/PD-L1 pathway inhibited lymphocyte proliferation but enhanced the secretion of IL-10 and TGF-β in vitro. In summary, our findings demonstrate that elevated levels of PD-1/PD-L1, TGF-β, and IL-10 in peripheral blood of cervical cancer patients may negatively regulate immune response against cervical cancer cells and contribute to the progression of cervical cancer. Therefore, PD-1/PD-L1 pathway may become an immunotherapy target in the future. PMID:27721577

  4. Influence of antiretroviral therapy on programmed death-1 (CD279) expression on T cells in lymph nodes of human immunodeficiency virus-infected individuals.

    PubMed

    Ehrhard, Simone; Wernli, Marion; Dürmüller, Ursula; Battegay, Manuel; Gudat, Fred; Erb, Peter

    2009-10-01

    Human immunodeficiency virus infection leads to T-cell exhaustion and involution of lymphoid tissue. Recently, the programmed death-1 pathway was found to be crucial for virus-specific T-cell exhaustion during human immunodeficiency virus infection. Programmed death-1 expression was elevated on human immunodeficiency virus-specific peripheral blood CD8+ and CD4+ T cells and correlated with disease severity. During human immunodeficiency infection, lymphoid tissue acts as a major viral reservoir and is an important site for viral replication, but it is also essential for regulatory processes important for immune recovery. We compared programmed death-1 expression in 2 consecutive inguinal lymph nodes of 14 patients, excised before antiretroviral therapy (antiretroviral therapy as of 1997-1999) and 16 to 20 months under antiretroviral therapy. In analogy to lymph nodes of human immunodeficiency virus-negative individuals, in all treated patients, the germinal center area decreased, whereas the number of germinal centers did not significantly change. Programmed death-1 expression was mostly found in germinal centers. The absolute extent of programmed death 1 expression per section was not significantly altered after antiretroviral therapy resulting in a significant-relative increase of programmed death 1 per shrunken germinal center. In colocalization studies, CD45R0+ cells that include helper/inducer T cells strongly expressed programmed death-1 before and during therapy, whereas CD8+ T cells, fewer in numbers, showed a weak expression for programmed death-1. Thus, although antiretroviral therapy seems to reduce the number of programmed death-1-positive CD8+ T lymphocytes within germinal centers, it does not down-regulate programmed death-1 expression on the helper/inducer T-cell subset that may remain exhausted and therefore unable to trigger immune recovery.

  5. Programmed Death-Ligand 1 Expression and Response to the Anti–Programmed Death 1 Antibody Pembrolizumab in Melanoma

    PubMed Central

    Wolchok, Jedd D.; Robert, Caroline; Hwu, Wen-Jen; Weber, Jeffrey S.; Ribas, Antoni; Hodi, F. Stephen; Joshua, Anthony M.; Kefford, Richard; Hersey, Peter; Joseph, Richard; Gangadhar, Tara C.; Dronca, Roxana; Patnaik, Amita; Zarour, Hassane; Roach, Charlotte; Toland, Grant; Lunceford, Jared K.; Li, Xiaoyun Nicole; Emancipator, Kenneth; Dolled-Filhart, Marisa; Kang, S. Peter; Ebbinghaus, Scot; Hamid, Omid

    2016-01-01

    Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti–programmed death 1 (PD-1). This study explored the relationship between anti–PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1–positive tumors. Demographic and staging variables were equally distributed among PD-L1–positive and –negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed (P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1–negative tumors may also achieve durable responses. PMID:27863197

  6. Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma.

    PubMed

    Daud, Adil I; Wolchok, Jedd D; Robert, Caroline; Hwu, Wen-Jen; Weber, Jeffrey S; Ribas, Antoni; Hodi, F Stephen; Joshua, Anthony M; Kefford, Richard; Hersey, Peter; Joseph, Richard; Gangadhar, Tara C; Dronca, Roxana; Patnaik, Amita; Zarour, Hassane; Roach, Charlotte; Toland, Grant; Lunceford, Jared K; Li, Xiaoyun Nicole; Emancipator, Kenneth; Dolled-Filhart, Marisa; Kang, S Peter; Ebbinghaus, Scot; Hamid, Omid

    2016-12-01

    Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score ≥ 2 (membranous staining in ≥ 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed ( P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.

  7. Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in advanced cancers.

    PubMed

    Rajan, Arun; Kim, Chul; Heery, Christopher R; Guha, Udayan; Gulley, James L

    2016-09-01

    The development of immune checkpoint inhibitors has altered the landscape of treatment of advanced cancers. These drugs are well tolerated and have shown clinical activity against a wide variety of solid tumors and hematological malignancies. The durability of response is particularly impressive when compared to other forms of systemic therapy. Nivolumab (Opdivo) is an IgG4 antibody that causes immune checkpoint blockade by diminishing inhibitory signaling through the programmed death receptor-1 pathway. It is approved for treatment of recurrent non-small cell lung cancer, melanoma, and renal cell carcinoma. Efforts to identify biomarkers of response to nivolumab are ongoing. Clinical trials are also being conducted to determine the benefits of combining nivolumab with other forms of treatment including chemotherapy, molecular-targeted therapy, radiation therapy, and other forms of immune therapy. This review outlines the clinical trials that have led to the emergence of nivolumab as a treatment option for patients with advanced cancers.

  8. Blockade of programmed death-1/programmed death ligand pathway enhances the antitumor immunity of human invariant natural killer T cells.

    PubMed

    Kamata, Toshiko; Suzuki, Akane; Mise, Naoko; Ihara, Fumie; Takami, Mariko; Makita, Yuji; Horinaka, Atsushi; Harada, Kazuaki; Kunii, Naoki; Yoshida, Shigetoshi; Yoshino, Ichiro; Nakayama, Toshinori; Motohashi, Shinichiro

    2016-12-01

    The role of invariant natural killer T (iNKT) cells in antitumor immunity has been studied extensively, and clinical trials in patients with advanced cancer have revealed a prolonged survival in some cases. In recent years, humanized blocking antibodies against co-stimulatory molecules such as PD-1 have been developed. The enhancement of T cell function is reported to improve antitumor immunity, leading to positive clinical effects. However, there are limited data on the role of PD-1/programmed death ligand (PDL) molecules in human iNKT cells. In this study, we investigated the interaction between PD-1 on iNKT cells and PDL on antigen-presenting cells (APCs) in the context of iNKT cell stimulation. The blockade of PDL1 at the time of stimulation resulted in increased release of helper T cell (Th) 1 cytokines from iNKT cells, leading to the activation of NK cells. The direct antitumor function of iNKT cells was also enhanced after stimulation with anti-PDL1 antibody-treated APCs. According to these results, we conclude that the co-administration of anti-PDL1 antibody and alpha-galactosylceramide (αGalCer)-pulsed APCs enhances iNKT cell-mediated antitumor immunity.

  9. Programmed death 1 and B and T lymphocyte attenuator immunoreceptors and their association with malignant T-lymphoproliferative disorders: brief review.

    PubMed

    Karakatsanis, Stamatis; Bertsias, George; Roussou, Paraskevi; Boumpas, Dimitrios

    2014-09-01

    Malignant T-cell lymphoproliferative diseases are relatively rare. T cells are activated through the T-cell receptor with the aid of costimulating molecules that can be either excitatory or inhibitory. Such pathways have been also implicated in mechanisms of malignant T-cell lymphoproliferative diseases' persistence and relapse by circumventing immune responses. To date, three major immunoinhibitory molecules have been recognized, namely programmed cell death-1 (PD-1), B and T lymphocyte attenuator (BTLA) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Although CTLA-4 is considered the 'gatekeeper' of immune tolerance, PD-1 negatively regulates immune responses broadly, whereas BTLA activation has been shown to inhibit CD8+ cancer-specific T cells. Both PD-1 and BTLA downregulate proximal T-cell receptor signalling cascade and are involved in immune evasion of leukaemias and lymphomas, even after allogeneic stem cell transplantation. These immunoregulatory molecules can have seemingly a synergistic effect on weakening the immune response of patients with haematological malignancies, and their manipulation represents a very active field of preclinical as well as clinical interest. Copyright © 2013 John Wiley & Sons, Ltd

  10. Programmed death 1 expression in variant immunoarchitectural patterns of nodular lymphocyte predominant Hodgkin lymphoma: comparison with CD57 and lymphomas in the differential diagnosis.

    PubMed

    Churchill, Hywyn R O; Roncador, Giovanna; Warnke, Roger A; Natkunam, Yasodha

    2010-12-01

    Recent studies have exploited an antibody directed against programmed death 1 expressed by follicular helper T-cells in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma. We had previously described clinically relevant, variant immunoarchitectural patterns of nodular lymphocyte predominant Hodgkin lymphoma and, in this study, sought to address the diagnostic utility of programmed death 1 in comparison with CD57 in variant nodular lymphocyte predominant Hodgkin lymphoma. Immunohistologic staining for programmed death 1 was carried out on biopsies of 67 patients with variant nodular lymphocyte predominant Hodgkin lymphoma. Thirty-four additional cases of nodular lymphocyte predominant Hodgkin lymphoma with associated diffuse areas, de novo T-cell and histiocyte-rich large B-cell lymphoma, and lymphocyte-rich classic Hodgkin lymphoma were also studied. Our results show that programmed death 1 positivity was found in the majority of nodular lymphocyte predominant Hodgkin lymphoma cases with a classic nodular architecture (87%) as compared with 50% for CD57 and was particularly helpful in identifying extranodular large atypical cells. Nodular lymphocyte predominant Hodgkin lymphoma with diffuse areas showed a gradual decrease in programmed death 1 reactivity from nodular to diffuse areas, although a significant proportion (40%-50%) of cases retained programmed death 1 positivity also in diffuse areas. In addition, T-cell and histiocyte-rich large B-cell lymphoma and lymphocyte-rich classic Hodgkin lymphoma displayed programmed death 1 positivity in a significant subset of cases (33%-40%). In conclusion, our study supports the utility of programmed death 1 in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma and shows greater sensitivity of staining of programmed death 1 as compared with CD57 across all variants of nodular lymphocyte predominant Hodgkin lymphoma. Loss of programmed death 1 reactivity did not correlate with diffuse areas

  11. Crystal Structure of the Complex Between Programmed Death-1 (PD-1) and its Ligand PD-L2

    SciTech Connect

    Lazar-Molnar,E.; Yan, Q.; Cao, E.; Ramagopal, U.; Nathenson, S.; Almo, S.

    2008-01-01

    Programmed death-1 (PD-1) is a member of the CD28/B7 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. The high-resolution crystal structure of the complex formed by the complete ectodomains of murine PD-1 and PD-L2 revealed a 1:1 receptor:ligand stoichiometry and displayed a binding interface and overall molecular organization distinct from that observed in the CTLA-4/B7 inhibitory complexes. Furthermore, our structure also provides insights into the association between PD-1 and PD-L1 and highlights differences in the interfaces formed by the two PD-1 ligands (PD-Ls) Mutagenesis studies confirmed the details of the proposed PD-1/PD-L binding interfaces and allowed for the design of a mutant PD-1 receptor with enhanced affinity. These studies define spatial and organizational constraints that control the localization and signaling of PD-1/PD-L complexes within the immunological synapse and provide a basis for manipulating the PD-1 pathways for immunotherapy.

  12. Attenuation of the programmed cell death-1 pathway increases the M1 polarization of macrophages induced by zymosan

    PubMed Central

    Chen, W; Wang, J; Jia, L; Liu, J; Tian, Y

    2016-01-01

    Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals on interaction with its 2 ligands, PD-L1 and PD-L2. We assessed the contribution of the PD-1 pathway to regulating the polarization of macrophages that promote inflammation induced by zymosan. We found that PD-1−/− mice developed robust peritonitis with more abundant infiltration of M1 macrophages, accompanied by higher levels of pro-inflammation factors, especially monocyte chemotactic protein-1 (MCP-1) compared with wild-type controls ex vivo and in vitro. Our results indicated that PD-1 deficiency promotes M1 rather than M2 polarization of macrophages by enhancing the expression of p-STAT1/p-NF-κB p65 and downregulating p-STAT6. We found that PD-1 engagement followed by zymosan stimulation might primarily attenuate the phosphorylation of tyrosine residue in PD-1 receptor/ligand and the recruitment of SHP-2 to PD-1 receptor/ligand, leading to the reduction of M1 type cytokine production. PMID:26913605

  13. T-bet regulates differentiation of forkhead box protein 3+ regulatory T cells in programmed cell death-1-deficient mice

    PubMed Central

    Tahara, M; Kondo, Y; Yokosawa, M; Tsuboi, H; Takahashi, S; Shibayama, S; Matsumoto, I; Sumida, T

    2015-01-01

    Programmed cell death-1 (PD-1) plays an important role in peripheral T cell tolerance, but whether or not it affects the differentiation of helper T cell subsets remains elusive. Here we describe the importance of PD-1 in the control of T helper type 1 (Th1) cell activation and development of forkhead box protein 3 (FoxP3+) regulatory T cells (Tregs). PD-1-deficient T cell-specific T-bet transgenic (P/T) mice showed growth retardation, and the majority died within 10 weeks. P/T mice showed T-bet over-expression, increased interferon (IFN)-γ production by CD4+ T cells and significantly low FoxP3+ Treg cell percentage. P/T mice developed systemic inflammation, which was probably induced by augmented Th1 response and low FoxP3+ Treg count. The study identified a unique, previously undescribed role for PD-1 in Th1 and Treg differentiation, with potential implication in the development of Th1 cell-targeted therapy. PMID:25219397

  14. Soluble Programmed Death 1 (PD-1) Is Decreased in Patients With Immune Thrombocytopenia (ITP): Potential Involvement of PD-1 Pathway in ITP Immunopathogenesis.

    PubMed

    Birtas Atesoglu, Elif; Tarkun, Pinar; Demirsoy, Esra Terzi; Geduk, Ayfer; Mehtap, Ozgur; Batman, Adnan; Kaya, Fatih; Cekmen, Mustafa Baki; Gulbas, Zafer; Hacıhanefioglu, Abdullah

    2016-04-01

    Immune thrombocytopenia (ITP) is an autoimmune disease characterized by dysregulation of T cells. Programmed death (PD) 1 and programmed death 1 ligand 1 (PD-L1) are cosignaling molecules, and the major role of the PD-1 pathway is the inhibition of self-reactive T cells and to protect against autoimmune diseases. We measured levels of serum soluble PD 1 (sPD-1) and serum soluble PD-L1 (sPD-L1) in 67 patients with ITP (24 newly diagnosed ITP [ndITP], 43 chronic ITP [cITP]) and 21 healthy controls (HCs). We determined decreased serum sPD-1 levels both in patients with ndITP and in patients with cITP when compared to HC. Moreover, there was a positive correlation between sPD-1 levels and platelet counts. The sPD-L1 levels were decreased in patients with ndITP when compared to patients with cITP. This is the first study investigating PD-1 signaling pathway in ITP. Decreased sPD-1 levels may have a role in ITP pathogenesis as without the inhibitory regulation of PD-1, sustained activation of T cells may cause inflammatory responses which is the case in ITP. © The Author(s) 2014.

  15. Clinical Use of Programmed Cell Death-1 and Its Ligand Expression as Discriminatory and Predictive Markers in Ovarian Cancer.

    PubMed

    Chatterjee, Jayanta; Dai, Wei; Aziz, Nor Haslinda Abd; Teo, Pei Yun; Wahba, John; Phelps, David L; Maine, Christian J; Whilding, Lynsey M; Dina, Roberto; Trevisan, Giorgia; Flower, Kirsty J; George, Andrew J T; Ghaem-Maghami, Sadaf

    2017-07-01

    Purpose: We aimed to establish whether programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, in ovarian cancer tumor tissue and blood, could be used as biomarkers for discrimination of tumor histology and prognosis of ovarian cancer.Experimental Design: Immune cells were separated from blood, ascites, and tumor tissue obtained from women with suspected ovarian cancer and studied for the differential expression of possible immune biomarkers using flow cytometry. PD-L1 expression on tumor-associated inflammatory cells was assessed by immunohistochemistry and tissue microarray. Plasma soluble PD-L1 was measured using sandwich ELISA. The relationships among immune markers were explored using hierarchical cluster analyses.Results: Biomarkers from the discovery cohort that associated with PD-L1(+) cells were found. PD-L1(+) CD14(+) cells and PD-L1(+) CD11c(+) cells in the monocyte gate showed a distinct expression pattern when comparing benign tumors and epithelial ovarian cancers (EOCs)-confirmed in the validation cohort. Receiver operating characteristic curves showed PD-L1(+) and PD-L1(+) CD14(+) cells in the monocyte gate performed better than the well-established tumor marker CA-125 alone. Plasma soluble PD-L1 was elevated in patients with EOC compared with healthy women and patients with benign ovarian tumors. Low total PD-1(+) expression on lymphocytes was associated with improved survival.Conclusions: Differential expression of immunological markers relating to the PD-1/PD-L1 pathway in blood can be used as potential diagnostic and prognostic markers in EOC. These data have implications for the development and trial of anti-PD-1/PD-L1 therapy in ovarian cancer. Clin Cancer Res; 23(13); 3453-60. ©2016 AACR. ©2016 American Association for Cancer Research.

  16. Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy.

    PubMed

    Lázár-Molnár, Eszter; Scandiuzzi, Lisa; Basu, Indranil; Quinn, Thomas; Sylvestre, Eliezer; Palmieri, Edith; Ramagopal, Udupi A; Nathenson, Stanley G; Guha, Chandan; Almo, Steven C

    2017-03-01

    Programmed Cell Death-1 (PD-1) is an inhibitory immune receptor, which plays critical roles in T cell co-inhibition and exhaustion upon binding to its ligands PD-L1 and PD-L2. We report the crystal structure of the human PD-1 ectodomain and the mapping of the PD-1 binding interface. Mutagenesis studies confirmed the crystallographic interface, and resulted in mutant PD-1 receptors with altered affinity and ligand-specificity. In particular, a high-affinity mutant PD-1 (HA PD-1) exhibited 45 and 30-fold increase in binding to PD-L1 and PD-L2, respectively, due to slower dissociation rates. This mutant (A132L) was used to engineer a soluble chimeric Ig fusion protein for cell-based and in vivo studies. HA PD-1 Ig showed enhanced binding to human dendritic cells, and increased T cell proliferation and cytokine production in a mixed lymphocyte reaction (MLR) assay. Moreover, in an experimental model of murine Lewis lung carcinoma, HA PD-1 Ig treatment synergized with radiation therapy to decrease local and metastatic tumor burden, as well as in the establishment of immunological memory responses. Our studies highlight the value of structural considerations in guiding the design of a high-affinity chimeric PD-1 Ig fusion protein with robust immune modulatory properties, and underscore the power of combination therapies to selectively manipulate the PD-1 pathway for tumor immunotherapy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  17. An IL-27/Stat3 axis induces expression of programmed cell death 1 ligands (PD-L1/2) on infiltrating macrophages in lymphoma.

    PubMed

    Horlad, Hasita; Ma, Chaoya; Yano, Hiromu; Pan, Cheng; Ohnishi, Koji; Fujiwara, Yukio; Endo, Shinya; Kikukawa, Yoshitaka; Okuno, Yutaka; Matsuoka, Masao; Takeya, Motohiro; Komohara, Yoshihiro

    2016-11-01

    Immune escape and tolerance in the tumor microenvironment are closely involved in tumor progression, and are caused by T-cell exhaustion and mediated by the inhibitory signaling of immune checkpoint molecules including programmed death-1 (PD-1), cytotoxic T-lymphocyte associated protein 4, and T-cell immunoglobulin and mucin domaincontaining molecule-3. In the present study, we investigated the expression of the PD-1 ligand 1 (PD-L1) in a lymphoma microenvironment using paraffin-embedded tissue samples, and subsequently studied the detailed mechanism of upregulation of PD-L1 on macrophages using cultured human macrophages and lymphoma cell lines. We found that macrophages in lymphoma tissues of almost all cases of adult T-cell leukemia/lymphoma (ATLL), follicular lymphoma and diffuse large B-cell lymphoma expressed PD-L1. Cell culture studies showed that the conditioned medium of ATL-T and SLVL cell lines induced increased expression of PD-L1/2 on macrophages, and that this PD-L1/2 overexpression was dependent on activation of signal transducer and activator of transcription 3 (Stat3). In vitro studies including cytokine array analysis showed that IL-27 (heterodimer of p28 and EBI3) induced overexpression of PD-L1/2 on macrophages via Stat3 activation. Because lymphoma cell lines produced IL-27B (EBI3) but not IL-27p28, it was proposed that the IL-27p28 derived from macrophages and the IL-27B (EBI3) derived from lymphoma cells formed an IL-27 (heterodimer) that induced PD-L1/2 overexpression. Although the significance of PD-L1/2 expressions on macrophages in lymphoma progression has never been clarified, an IL-27-Stat3 axis might be a target for immunotherapy for lymphoma patients.

  18. Aspirin Use and Colorectal Cancer Survival According to Tumor CD274 (Programmed Cell Death 1 Ligand 1) Expression Status.

    PubMed

    Hamada, Tsuyoshi; Cao, Yin; Qian, Zhi Rong; Masugi, Yohei; Nowak, Jonathan A; Yang, Juhong; Song, Mingyang; Mima, Kosuke; Kosumi, Keisuke; Liu, Li; Shi, Yan; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Keum, NaNa; Zhang, Xuehong; Wu, Kana; Meyerhardt, Jeffrey A; Giovannucci, Edward L; Giannakis, Marios; Rodig, Scott J; Freeman, Gordon J; Nevo, Daniel; Wang, Molin; Chan, Andrew T; Fuchs, Charles S; Nishihara, Reiko; Ogino, Shuji

    2017-06-01

    Purpose Blockade of the programmed cell death 1 (PDCD1, PD-1) immune checkpoint pathway can improve clinical outcomes in various malignancies. Evidence suggests that aspirin (a widely used nonsteroidal anti-inflammatory drug) not only prolongs colorectal cancer survival, but can also activate T cell-mediated antitumor immunity and synergize with immunotherapy through inhibition of prostaglandin E2 production. We hypothesized that the survival benefit associated with aspirin might be stronger in colorectal carcinoma with a lower CD274 (PDCD1 ligand 1, PD-L1) expression level that resulted in lower signaling of the immune checkpoint pathway. Patients and Methods Using data from 617 patients with rectal and colon cancer in the Nurses' Health Study and the Health Professionals Follow-Up Study, we examined the association of postdiagnosis aspirin use with patient survival in strata of tumor CD274 expression status measured by immunohistochemistry. We used multivariable Cox proportional hazards regression models to control for potential confounders, including disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, cyclooxygenase-2 (PTGS2), and CDX2 expression, and KRAS, BRAF, and PIK3CA mutations. Results The association of postdiagnosis aspirin use with colorectal cancer-specific survival differed by CD274 expression status ( Pinteraction < .001); compared with aspirin nonusers; multivariable-adjusted hazard ratios for regular aspirin users were 0.16 (95% CI, 0.06 to 0.41) in patients with low CD274 and 1.01 (95% CI, 0.61 to 1.67) in patients with high CD274. This differential association seemed consistent in patients with microsatellite-stable or PIK3CA wild-type disease and in strata of PTGS2 expression, CDX2 expression, tumor-infiltrating lymphocytes, or prediagnosis aspirin use status. Conclusion The association of aspirin use with colorectal cancer survival is stronger in patients with

  19. Programmed death-1 (PD-1) rs2227981 C > T polymorphism is associated with cancer susceptibility: a meta-analysis.

    PubMed

    Tang, Weifeng; Wang, Yafeng; Jiang, Heping; Liu, Pinghua; Liu, Chao; Gu, Haiyong; Chen, Shuchen; Kang, Mingqiang

    2015-01-01

    Several studies have focused on the correlation between the programmed death-1 (PD-1) rs2227981 C > T polymorphism and the risk of cancer; however, the results of such studies remain conflicting. To address this gap, we performed this meta-analysis to identify the potential association. Search strategies were performed in PubMed and EMBASE using appropriate terms. In total, 2,977 cancer cases and 2,642 controls from seven publications were recruited in our study. According to the seven eligible publications, the odds ratios (ORs) and 95% confidence intervals (CIs) on the risk of cancer for the TT vs. CC and TT vs. CT+CC genotypes were 0.67 and 0.50-0.91 and 0.65 and 0.47-0.90, respectively. In a subgroup analysis by cancer type, PD-1 rs2227981 C > T polymorphism was associated with a significantly decreased risk of breast cancer (OR, 0.82; 95% CI, 0.71-0.95; P = 0.009 for T vs. C and OR, 0.76; 95% CI, 0.63-0.92; P = 0.005 for TT+CT vs. CC) and of other cancer (OR, 0.58; 95% CI, 0.36-0.92; P = 0.004 for TT vs. CT+CC). In a subgroup analysis by ethnicity, a significant decreased cancer risk was identified among Asians (OR, 0.74; 95% CI, 0.63-0.86; P < 0.001 for T vs. C and OR, 0.71; 95% CI, 0.59-0.87; P = 0.001 for TT+CT vs. CC) and among Caucasians (OR, 0.66; 95% CI, 0.44-0.99; P = 0.047 for TT vs. CT+CC). These findings highlight the fact that the T allele of PD-1 rs2227981 C > T polymorphism modestly decreases the susceptibility of cancer. Nevertheless, further large and well-designed studies are needed to enrich the evidence of this association.

  20. Catching up with solid tumor oncology: what is the evidence for a prognostic role of programmed cell death-ligand 1/programmed cell death-1 expression in B-cell lymphomas?

    PubMed Central

    McClanahan, Fabienne; Sharp, Thomas G.; Gribben, John G.

    2016-01-01

    Therapeutic strategies targeting the programmed cell death-ligand 1/programmed cell death-1 pathway have shown significant responses and good tolerability in solid malignancies. Although preclinical studies suggest that inhibiting programmed cell death-ligand 1/programmed cell death-1 interactions might also be highly effective in hematological malignancies, remarkably few clinical trials have been published. Determining patients who will benefit most from programmed cell death-ligand 1/programmed cell death-1-directed immunotherapy and whether programmed cell death-ligand 1/programmed cell death-1 are adequate prognostic markers becomes an increasingly important clinical question, especially as aberrant programmed cell death-ligand 1/programmed cell death-1 expression are key mediators of impaired anti-tumor immune responses in a range of B-cell lymphomas. Herein, we systematically review the published literature on the expression and prognostic value of programmed cell death-ligand 1/programmed cell death-1 in these patients and identify considerable differences in expression patterns, distribution and numbers of programmed cell death-ligand 1+/programmed cell death-1+cells, both between and within lymphoma subtypes, which is reflected in conflicting findings regarding the prognostic value of programmed cell death-ligand 1+/programmed cell death-1+ cells. This can be partly explained by differences in methodologies (techniques, protocols, cutoff values) and definitions of positivity. Moreover, lymphomagenesis, disease progression, and prognosis appear to be determined not only by the presence, numbers and distribution of specific subtypes of T cells, but also by other cells and additional immune checkpoints. Collectively, our findings indicate that programmed cell death-ligand 1/programmed cell death-1 interactions play an essential role in B-cell lymphoma biology and are of clinical importance, but that the overall outcome is determined by additional components

  1. Phase I Study of Single-Agent Anti–Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates

    PubMed Central

    Brahmer, Julie R.; Drake, Charles G.; Wollner, Ira; Powderly, John D.; Picus, Joel; Sharfman, William H.; Stankevich, Elizabeth; Pons, Alice; Salay, Theresa M.; McMiller, Tracee L.; Gilson, Marta M.; Wang, Changyu; Selby, Mark; Taube, Janis M.; Anders, Robert; Chen, Lieping; Korman, Alan J.; Pardoll, Drew M.; Lowy, Israel; Topalian, Suzanne L.

    2010-01-01

    Purpose Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti–PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. Patients and Methods Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non–small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti–PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. Results Anti–PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti–PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells ≥ 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. Conclusion Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted. PMID:20516446

  2. Expression of programmed death 1 ligand 1 on periodontal tissue cells as a possible protective feedback mechanism against periodontal tissue destruction.

    PubMed

    Zhang, Jiehua; Wang, Chieh-Mei; Zhang, Ping; Wang, Xiaoqian; Chen, Jiao; Yang, Jun; Lu, Wanlu; Zhou, Wenjie; Yuan, Wenwen; Feng, Yun

    2016-03-01

    Programmed death 1 ligand 1 (PD‑L1) is a negative co‑stimulatory molecule in immune responses. Previous reports have indicated that inflammatory cytokines can upregulate the expression of PD‑L1 in tumor cells, which in turn suppresses host immune responses. Periodontitis is characterized by persistent inflammation of the periodontium, which is initiated by infection with oral bacteria and results in damage to cells and the matrices of the periodontal connective tissues. In the present study, the expression and function of PD‑L1 in periodontal tissue destruction were examined. Periodontal ligament cells (PDLCs) were stimulated by inflammatory cytokines and periodontal pathogens. The expression and function of PD‑L1 on the surface of PDLCs was investigated using flow cytometry in vitro. Periodontal disease was induced by the injection of Porphyromonas gingivalis in mouse models. The expression levels of PD‑L1 in the periodontal tissues of the mice were analyzed using flow cytometry and immunohistochemistry. PD‑L1 was inducibly expressed on the PDLCs by the inflammatory cytokines and periodontal pathogens. The inflammation‑induced expression of PD‑L1 was shown to cause the apoptosis of activated T lymphocytes and improve the survival of PDLCs. Furthermore, in the mouse model of experimental periodontitis, the expression of PD‑L1 in severe cases of periodontitis was significantly lower, compared with that in mild cases. By contrast, no significant differences were observed between the healthy control and severe periodontitis groups. The results of the present study showed that the expression of PD‑L1 may inhibit the destruction of periodontal tissues, indicating the involvement of a possible protective feedback mechanism against periodontal infection.

  3. Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: Comparison of sarcomatous and carcinomatous areas.

    PubMed

    Kim, Sehui; Kim, Moon-Young; Koh, Jaemoon; Go, Heounjeong; Lee, Dong Soo; Jeon, Yoon Kyung; Chung, Doo Hyun

    2015-11-01

    Pleomorphic carcinoma (PC) of the lung is a rare type of poorly differentiated non-small cell lung carcinoma (NSCLC) that belongs to sarcomatoid carcinoma (SC). It exhibits aggressive behaviour and resistance to chemotherapy and radiotherapy. Recently, immunotherapy targeting the programmed death-1 (PD-1)/PD ligand 1 (PD-L1) pathway has demonstrated favourable clinical outcomes in NSCLC. However, the expression patterns of PD-1-related molecules in pulmonary PC remain elusive. PD-L1 and PD-L2 expression was estimated in 41 cases of PC using immunohistochemistry. CD8(+) and PD-1(+) tumour-infiltrating lymphocytes (TILs) were also evaluated. PD-L1 and PD-L2 were highly expressed in pulmonary PCs (90.2% [37/41)]; 87.8% [36/41]). The amount of CD8(+) or PD-1(+) TILs and the ratio of PD-1(+)/CD8(+) TILs in PC were higher in males, smokers and older patients. PD-L1-positive PCs were infiltrated by higher numbers of CD8(+) TILs compared to PD-L1-negative cases (P=0.006). Of note, PD-L1 expression in pulmonary PCs was significantly higher in sarcomatous areas than in the carcinomatous portion (P=0.006). PC patients with a high ratio of PD-1(+)/CD8(+) TILs showed a shorter progression-free survival (P=0.036), whereas PD-L1 and PD-L2 expression had no prognostic implications. Our study demonstrates that pulmonary PCs very frequently express PD-L1 and PD-L2. Moreover, their expression is higher in sarcomatous cells than in carcinomatous areas. Thus, targeting the PD-1/PD-L1 pathway may represent a potential therapeutic candidate for this aggressive tumour.

  4. IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

    PubMed Central

    Stephen-Victor, Emmanuel; Sharma, Varun Kumar; Das, Mrinmoy; Karnam, Anupama; Saha, Chaitrali; Lecerf, Maxime; Galeotti, Caroline; Kaveri, Srinivas V.; Bayry, Jagadeesh

    2016-01-01

    The programed death-1 (PD-1)–programed death ligand-1 (PD-L1) and PD-L2 co-inhibitory pathway has been implicated in the evasion strategies of Mycobacterium tuberculosis. Specifically, M. tuberculosis-induced PD-L1 orchestrates expansion of regulatory T cells and suppression of Th1 response. However, the role of PD pathway in regulating Th17 response to M. tuberculosis has not been investigated. In the present report, we demonstrate that M. tuberculosis and M. tuberculosis-derived antigen fractions have differential abilities to mediate human monocyte- and dendritic cell (DC)-mediated Th17 response and were independent of expression of PD-L1 or PD-L2 on aforementioned antigen-presenting cells. Importantly, we observed that blockade of PD-L1 or PD-1 did not significantly modify either the frequencies of Th17 cells or the production of IL-17 from CD4+ T cells though IFN-γ response was significantly enhanced. On the contrary, IL-1β from monocytes and DCs were critical for the Th17 response to M. tuberculosis. Together, our results indicate that IL-1β, but not members of the programed death pathway, is critical for human Th17 response to M. tuberculosis. PMID:27867382

  5. Update on Programmed Death-1 and Programmed Death-Ligand 1 Inhibition in the Treatment of Advanced or Metastatic Non-Small Cell Lung Cancer.

    PubMed

    Iafolla, Marco A J; Juergens, Rosalyn A

    2017-01-01

    Non-small-cell lung cancer (NSCLC) has a large worldwide prevalence with a high mortality rate. Chemotherapy has offered modest improvements in survival over the past two decades. Immune checkpoint modulation with programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibition has shown the promise of changing the future landscape of cancer therapy. This update reviews recent advances in the treatment of NSCLC with immune checkpoint modulation. Publications and proceedings were identified from searching PubMed and proceedings from the annual meetings of the American Society of Clinical Oncology, European Society for Medical Oncology, and European Lung Cancer Conference. Atezolizumab, nivolumab, and pembrolizumab increase overall survival in second-line treatment of Stage III/IV squamous and non-squamous NSCLC when compared to docetaxel. Pembrolizumab increases progression-free survival in the first-line treatment of Stage IV NSCLC with 50% PD-L1 expression when compared to platinum-based chemotherapy. Combination therapy with chemotherapy and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors has shown promise in early trials. Immune checkpoint modulation produces durable responses and overall survival benefits with less toxicity compared to conventional chemotherapy. Future investigations are combining PD-1/L1 inhibition with chemotherapy, targeted therapy, or other immuno-oncology agents in an effort to further improve efficacy.

  6. Serum levels of soluble programmed death-1 and programmed death ligand-1 in systemic sclerosis: Association with extent of skin sclerosis.

    PubMed

    Yanaba, Koichi; Hayashi, Mitsuha; Yoshihara, Yuki; Nakagawa, Hidemi

    2016-08-01

    The interaction of programmed death-1 (PD-1) with its ligand, programmed death ligand-1 (PD-L1), has been considered to play a key role in the negative regulation of immune responses. Patients with diffuse cutaneous systemic sclerosis (SSc) had higher levels of soluble PD-1 (sPD-1) than those with limited cutaneous SSc and healthy individuals. Serum sPD-1 levels positively correlated with the severity of skin sclerosis. In contrast, serum sPD-L1 levels were significantly increased in patients with SSc compared with healthy individuals. Moreover, serum sPD-L1 levels were not associated with the extent of skin sclerosis and were elevated not only in patients with diffuse cutaneous SSc, but also in those with limited cutaneous SSc. These results suggested that serum sPD-1 levels may increase in patients with SSc and correlate with the severity of skin sclerosis. PD-1/PD-L1 interaction may contribute to the development of skin sclerosis in SSc.

  7. Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis.

    PubMed

    Greisen, S R; Rasmussen, T K; Stengaard-Pedersen, K; Hetland, M L; Hørslev-Petersen, K; Hvid, M; Deleuran, B

    2014-01-01

    Programmed death-1 (PD-1) is an immunoregulatory molecule functioning by down-regulating immune responses. PD-1 is present on follicular helper T cells (TFH) and is important in the formation of plasma cells. PD-1 exists in a bioactive soluble form (sPD-1) and is thought to be implicated in disease activity in chronic rheumatoid arthritis (RA). We measured sPD-1 at baseline and 9 months after treatment initiation in plasma from early RA patients (n = 34). We tested for correlations with the Disease Activity Score using 28 joint counts (DAS28), the Health Assessment Questionnaire (HAQ) score, immunoglobulin M rheumatoid factor (IgM-RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, C-reactive protein (CRP), interleukin-21 (IL-21), and total Sharp score (TSS). We also measured sPD-1 in plasma from healthy volunteers (HV) (n = 20) and in plasma and synovial fluid (SF) from patients with chronic RA (> 8 years of disease, n = 30). We further investigated the cellular expression of PD-1 and its ligand PD-L1. sPD-1 concentrations in early [median 0.421 ng/mL, interquartile range (IQR) 0.04-2.560 ng/mL] and chronic (median 0.239 ng/mL, IQR 0.184-0.584 ng/mL) RA were increased compared with HV (median 0.04 ng/mL, IQR 0.04-0.04 ng/mL) (all p < 0.005). In early RA the change in sPD-1 was associated with DAS28 (r = 0.363, p < 0.05) and HAQ score (r = 0.554, p < 0.05) and inversely with TSS at 3-5 years (r = -0.468, p < 0.05). sPD-1 concentration correlated with IgM-RF, anti-CCP antibodies, and IL-21 (all p < 0.05). PD-1 was primarily expressed by synovial memory T cells whereas PD-L1 was mainly expressed by synovial monocytes. The significantly elevated plasma levels of sPD-1 in early RA, the association with core disease parameters, and the inverse correlation with TSS suggest that sPD-1 is an important mediator in inflammatory and radiographic disease progression.

  8. Programmed death-1 ligands 1 and 2 expression in cutaneous squamous cell carcinoma and their relationship with tumour- infiltrating dendritic cells.

    PubMed

    Jiao, Q; Liu, C; Li, W; Li, W; Fang, F; Qian, Q; Zhang, X

    2017-06-01

    The programmed death-1 (PD-1) receptor ligands, PD-L1 and PD-L2, are co-stimulatory molecules that contribute to the negative regulation of T lymphocyte activation. It is still unclear whether there is correlation between PD-L1 or PD-L2 and tumour-infiltrating dendritic cells (TIDCs) in cutaneous squamous cell carcinoma (CSCC). The aim of this study was to analyse PD-L1 and PD-L2 expression and dendritic cells infiltration in tumour tissue of CSCC patients and investigate their clinical significance. Immunohistochemical analysis was used to evaluate the expression of PD-L1, PD-L2, CD1a and CD83 in 61 CSCC tissues. The immunofluoresence double-labelling technique was performed to detect the co-expression of PD-L1 or PD-L2 and CD1a or CD83 in tumour tissues. We found that 25 of 61 cases CSCC (40·98%) exhibited positivity for PD-L1, whereas 37 of 61 cases CSCC (60·66%) exhibited positivity for PD-L2. A higher percentage of CD1a-positive cases were observed on both PD-L1-positive and PD-L2-positive specimens compared with that of CD83-positive cases (92·29% versus 37·60%, 83·20% versus 33·16%). The expression of PD-L1 and PD-L2 on CD1a(+) cells was significantly higher than that on CD83(+) cells in tumour tissues of CSCC patients. Furthermore, the expression rate of PD-L1 was associated with UICC stage, and the expression rate of PD-L2 was associated with predominant differentiation and tumour size in CSCC. Our results indicated that higher expression of PD-L1 and PD-L2 on CD1a(+) cells than that on CD83(+) cells in CSCC tumour tissues may contribute to negative regulation in anti-tumour immune responses. © 2017 British Society for Immunology.

  9. Expression of programmed cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type.

    PubMed

    Jo, Jae-Cheol; Kim, Misung; Choi, Yunsuk; Kim, Hyun-Jung; Kim, Ji Eun; Chae, Seoung Wan; Kim, Hawk; Cha, Hee Jeong

    2017-01-01

    Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) are new therapeutic targets in cancer immunotherapy. The aim of this study was to investigate the clinicopathological characteristics of PD-1 and PD-L1 expression in extranodal natural killer/T‑cell lymphoma, nasal type (ENKTL). We performed PD-1 and PD-L1 immunostaining in 79 ENKTL biopsy samples and retrospectively analyzed medical records of all 79 patients from four tertiary referral hospitals. The expression of PD-1 and PD-L1 by tumor cells and/or infiltrating immune cells was evaluated. The expression rates of PD-L1 in tumor cells and infiltrating immune cells were 79.7 and 78.5 %, respectively, whereas PD-1 in tumor cells and infiltrating immune cells were 1.3 and 11.4 %. The PD-L1 positivity in tumor cells and infiltrating immune cells was significantly associated with low international prognostic index (IPI) (P = 0.044 and 0.037, respectively). Patients with normal range of serum lactate dehydrogenase demonstrated a significantly higher PD-L1 positivity in tumor cells (P = 0.020). PD-L1-positive patients had a trend toward better overall survival compared with that in patients with PD-L1-negative in tumor cells and infiltrating immune cells (P = 0.498 and 0.435, respectively). The expression rate of PD-L1 was up to 79.7 % in ENKTL, while PD-1 expression rate was very low. This is the first report describing the clinicopathological features and survival outcome according to expression of PD-1 and PD-L1 in ENKTL.

  10. Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1.

    PubMed

    Zak, Krzysztof M; Kitel, Radoslaw; Przetocka, Sara; Golik, Przemyslaw; Guzik, Katarzyna; Musielak, Bogdan; Dömling, Alexander; Dubin, Grzegorz; Holak, Tad A

    2015-12-01

    Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has recently provided breakthrough progress in the treatment of melanoma, non-small cell lung cancer, and other types of cancer. Small-molecule drugs interfering with this pathway are highly awaited, but their development is hindered by insufficient structural information. This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. First, it is shown that the ligand binding to human PD-1 is associated with significant plasticity within the receptor. Second, a detailed molecular map of the interaction surface is provided, allowing definition of the regions within both interacting partners that may likely be targeted by small molecules.

  11. New-onset third-degree atrioventricular block because of autoimmune-induced myositis under treatment with anti-programmed cell death-1 (nivolumab) for metastatic melanoma.

    PubMed

    Behling, Juliane; Kaes, Joachim; Münzel, Thomas; Grabbe, Stephan; Loquai, Carmen

    2017-04-01

    There has been considerable progress in treating malignant melanoma over the last few years. The immune-checkpoint-inhibitors nivolumab and pembrolizumab have been approved by the Food and Drug Administration in 2014 for the therapy of metastatic melanoma. Anti-programmed cell death-1-blocking antibodies are known to cause immune-related adverse events. Physicians should be aware of common and rare side effects and pay attention to new ones. We therefore report a severe and life-threatening side effect of anti-programmed cell death-1 immunotherapy with nivolumab that has not been previously reported: the development of a third-degree atrioventricular block. After a second infusion with nivolumab, our patient developed a troponin I-positive and autoantibody-positive myositis and a few days later a new-onset third-degree atrioventricular block. This is most likely because of an autoimmune-induced myositis with a cardiac impairment in terms of a myocarditis, which led to an impairment of the conduction of cardiac electrical stimuli.

  12. In situ and in silico kinetic analyses of the Programmed Cell Death 1, Programmed Cell Death-Ligands, and B7-1 interaction network.

    PubMed

    Li, Kaitao; Cheng, Xiaoxiao; Tilevik, Andreas; Davis, Simon J; Zhu, Cheng

    2017-03-06

    Programmed cell death-1 (PD-1) is an inhibitory receptor with an essential role in maintaining peripheral tolerance, and among the most promising immunotherapeutic targets for treating cancer, autoimmunity, and infectious diseases. A complete understanding of the consequences of PD-1 engagement by its ligands, PD-L1 and PD-L2, and of PD-L1 binding to B7-1, requires quantitative analysis of their interactions at the cell surface. We present here the first complete in situ kinetic analysis of the PD-1/PD-1 ligands/B7-1 system. Consistent with previous solution measurements, we observed higher in situ affinities for human (h) than murine (m) PD-1 interactions, stronger binding of hPD-1 to hPD-L2 than hPD-L1, and comparable binding of mPD-1 to both ligands. However, in contrast to the relatively weak solution affinities, the in situ affinities of PD-1 are as high as those of the TCR for agonist pMHC and of LFA-1 for ICAM-1, but significantly lower than that of the B7-1-CTLA-4 interaction, suggesting a distinct basis for PD-1 versus CTLA-4 mediated inhibition. Notably, the in situ interactions of PD-1 are much stronger than that of B7-1 with PD-L1. Overall, the in situ affinity ranking greatly depends on the on-rate instead of the off-rate. In silico simulations predict that PD-1-PD-L1 interactions dominate at interfaces between activated T cells and mature dendritic cells, and that these interactions will be highly sensitive to the dynamics of PD-L1 and PD-L2 expression. Our results provide a kinetic framework for better understanding inhibitory PD-1 activity in health and disease.

  13. Programmed cell death-1, PD-1, is dysregulated in T cells from children with new onset type 1 diabetes.

    PubMed

    Granados, Hector M; Draghi, Andrew; Tsurutani, Naomi; Wright, Kyle; Fernandez, Marina L; Sylvester, Francisco A; Vella, Anthony T

    2017-01-01

    Programmed death cell 1 (PD-1) is an inhibitor of T cell activation and is also functionally linked to glycolysis. We hypothesized that PD-1 expression is defective in activated T cells from children with type 1 diabetes (T1D), resulting in abnormal T cell glucose metabolism. In this pilot study, we enrolled children with new onset T1D within 2 weeks of diagnosis (T1D), unaffected siblings of T1D (SIBS), unaffected, unrelated children (CTRL), children with new onset, and untreated Crohn disease (CD). We repeated the assays 4-6 months post-diagnosis in T1D (T1D follow up). We analyzed anti-CD3/-CD28-stimulated peripheral blood mononuclear cells (PBMC) subsets for PD-1 expression by flow cytometry at baseline and after 24 h in culture. We measured cytokines in the culture medium by multiplex ELISA and glycolytic capacity with a flux analyzer. We enrolled 37 children. T cells derived from subjects with T1D had decreased PD-1 expression compared to the other study groups. However, in T1D follow-up T cells expressed PD-1 similarly to controls, but had no differences in PBMC cytokine production. Nonetheless, T1D follow up PBMCs had enhanced glycolytic capacity compared to T1D. Activated T cells from T1D fail to upregulate PD-1 upon T-cell receptor stimulation, which may contribute to the pathogenesis of T1D. T1D follow up PBMC expression of PD-1 normalizes, together with a significant increase in glycolysis compared to T1D. Thus, insulin therapy in T1D children is associated with normal PD1 expression and heightened glycolytic capacity in PBMC.

  14. Coordination programming of photofunctional molecules.

    PubMed

    Sakamoto, Ryota; Kusaka, Shinpei; Hayashi, Mikihiro; Nishikawa, Michihiro; Nishihara, Hiroshi

    2013-04-05

    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(dipyrrinato)zinc(II) complexes. Conventional homoleptic bis(dipyrrinato)zinc(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(arylethynyl)fumarate 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.

  15. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation.

    PubMed

    Chemnitz, Jens M; Parry, Richard V; Nichols, Kim E; June, Carl H; Riley, James L

    2004-07-15

    To study the cis- and trans-acting factors that mediate programmed death 1 (PD-1) signaling in primary human CD4 T cells, we constructed a chimeric molecule consisting of the murine CD28 extracellular domain and human PD-1 cytoplasmic tail. When introduced into CD4 T cells, this construct mimics the activity of endogenous PD-1 in terms of its ability to suppress T cell expansion and cytokine production. The cytoplasmic tail of PD-1 contains two structural motifs, an ITIM and an immunoreceptor tyrosine-based switch motif (ITSM). Mutation of the ITIM had little effect on PD-1 signaling or functional activity. In contrast, mutation of the ITSM abrogated the ability of PD-1 to block cytokine synthesis and to limit T cell expansion. Further biochemical analyses revealed that the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.

  16. Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults

    PubMed Central

    Tebas, Pablo; Spitsin, Sergei; Barrett, Jeffrey S.; Tuluc, Florin; Elci, Okan; Korelitz, James J.; Wagner, Wayne; Winters, Angela; Kim, Deborah; Catalano, Renae; Evans, Dwight L.; Douglas, Steven D.

    2015-01-01

    Objective: We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant – a neurokinin 1 receptor antagonist. Design: Phase IB randomized, placebo-controlled, double-blinded study. Methods: Eighteen patients were randomized (nine to aprepitant and nine to placebo). The patients received once-daily treatment (375 mg aprepitant or placebo by oral administration) for 2 weeks and were followed off drug for 4 weeks. Results: There were no significant changes in the plasma viremia or CD4+ T cells during the dosing period. Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4+ T cells expressing programmed death 1 (−4.8%; P = 0.04), plasma substance P (−34.0 pg/ml; P = 0.05) and soluble CD163 (−563 ng/ml; P = 0.02), with no significant changes in the placebo arm. Mean peak aprepitant plasma concentration on day 14 was 7.6 ± 3.1 μg/ml. The use of aprepitant was associated with moderate increases in total cholesterol, low-density lipoprotein and high-density lipoprotein (median change = +31 mg/dl, P = 0.01; +26 mg/dl, P = 0.02; +3 mg/dl, P = 0.02, respectively). Conclusion: Aprepitant was safe and well tolerated. At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity. Aprepitant-treated patients had decreased numbers of CD4+ programmed death 1-positive cells and decreased plasma levels of substance P and soluble CD163, suggesting that blockade of the neurokinin 1 receptor pathway has a role in modulating monocyte activation in HIV infection. Prospective studies in virologically-suppressed individuals are warranted to evaluate the immunomodulatory properties of aprepitant. Exposures exceeding those attained in this trial are more likely to elicit clinical benefit. PMID:25915168

  17. Treatment with anti-programmed cell death 1 (PD-1) antibody restored postoperative CD8+ T cell dysfunction by surgical stress.

    PubMed

    Sun, Zhirong; Mao, Anrong; Wang, Yun; Zhao, Yanjun; Chen, Jiawei; Xu, Pingbo; Miao, Changhong

    2017-03-15

    Millions of patients benefit from surgery and are exposed to surgical stress. However, ample studies suggest that surgical stress contributes to tumor recurrence or distant metastases. Surgical stress suppresses CD8+ T cells (CTL) function which is vital for eliminating the malignant cells. Anti-programmed cell death 1 (PD-1) therapy is an effective and safe treatment that increases survival rate of patients with multiple cancers, however, whether anti-PD-1 therapy is able to reverse the immunosuppression following surgery remains largely unknown. Using a surgical stress mice model, we found that surgical stress reduced CD8+ T cell total numbers in the spleen and impaired CTLs function. Surgical induced CD8+ T cells had impaired anti-tumor effects in a tumor bearing models. Blockade of PD-1 with specific antibody restored CD8+ T cell numbers and secretion ability. PGE2 expression was dramatically upregulated in the postoperative serum, and anti-PD-1 together with PGE2 inhibitor restored CTLs dysfunction induced by surgery. Collectively, blockade of PD-1 with monoclonal antibody may be an effective treatment during the postoperative period for restoring surgery-induced immunosuppression.

  18. Programmed Death-1 Ligand 2-Mediated Regulation of the PD-L1 to PD-1 Axis Is Essential for Establishing CD4(+) T Cell Immunity.

    PubMed

    Karunarathne, Deshapriya S; Horne-Debets, Joshua M; Huang, Johnny X; Faleiro, Rebecca; Leow, Chiuan Yee; Amante, Fiona; Watkins, Thomas S; Miles, John J; Dwyer, Patrick J; Stacey, Katryn J; Yarski, Michael; Poh, Chek Meng; Lee, Jason S; Cooper, Matthew A; Rénia, Laurent; Richard, Derek; McCarthy, James S; Sharpe, Arlene H; Wykes, Michelle N

    2016-08-16

    Many pathogens, including Plasmodium spp., exploit the interaction of programmed death-1 (PD-1) with PD-1-ligand-1 (PD-L1) to "deactivate" T cell functions, but the role of PD-L2 remains unclear. We studied malarial infections to understand the contribution of PD-L2 to immunity. Here we have shown that higher PD-L2 expression on blood dendritic cells, from Plasmodium falciparum-infected individuals, correlated with lower parasitemia. Mechanistic studies in mice showed that PD-L2 was indispensable for establishing effective CD4(+) T cell immunity against malaria, because it not only inhibited PD-L1 to PD-1 activity but also increased CD3 and inducible co-stimulator (ICOS) expression on T cells. Importantly, administration of soluble multimeric PD-L2 to mice with lethal malaria was sufficient to dramatically improve immunity and survival. These studies show immuno-regulation by PD-L2, which has the potential to be translated into an effective treatment for malaria and other diseases where T cell immunity is ineffective or short-lived due to PD-1-mediated signaling.

  19. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia

    PubMed Central

    Zhou, Qing; Munger, Meghan E.; Highfill, Steven L.; Tolar, Jakub; Weigel, Brenda J.; Riddle, Megan; Sharpe, Arlene H.; Vallera, Daniel A.; Azuma, Miyuki; Levine, Bruce L.; June, Carl H.; Murphy, William J.; Munn, David H.

    2010-01-01

    Tumor-induced immune defects can weaken host immune response and permit tumor cell growth. In a systemic model of murine acute myeloid leukemia (AML), tumor progression resulted in increased regulatory T cells (Treg) and elevation of program death-1 (PD-1) expression on CD8+ cytotoxic T cells (CTLs) at the tumor site. PD-1 knockout mice were more resistant to AML despite the presence of similar percentage of Tregs compared with wild type. In vitro, intact Treg suppression of CD8+ T-cell responses was dependent on PD-1 expression by T cells and Tregs and PD-L1 expression by antigen-presenting cells. In vivo, the function of adoptively transferred AML-reactive CTLs was reduced by AML-associated Tregs. Anti–PD-L1 monoclonal antibody treatment increased the proliferation and function of CTLs at tumor sites, reduced AML tumor burden, and resulted in long-term survivors. Treg depletion followed by PD-1/PD-L1 blockade showed superior efficacy for eradication of established AML. These data demonstrated that interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression of T-effector cells and dampen the antitumor immune response. PD-1/PD-L1 blockade coupled with Treg depletion represents an important new approach that can be readily translated into the clinic to improve the therapeutic efficacy of adoptive AML-reactive CTLs in advanced AML disease. PMID:20570856

  20. A new frontier for targeted therapy in NSCLC: clinical efficacy of pembrolizumab in the inhibition of programmed cell death 1 (PD-1).

    PubMed

    Addeo, Raffaele

    2017-03-01

    Non-small-cell lung cancer (NSCLC) is the main pathological type among lung cancers, and it is often diagnosed at an advanced stage of the disease when it is no longer amenable to curative treatments. During recent decades, the survival rate for lung cancer patients has improved significantly in only those whose tumours harbour a driver mutation. Immune checkpoint inhibition is a promising therapeutic strategy for lung cancer. The Keynote 024 is randomized, open-label, international, phase III study to evaluate the efficacy of pembrolizumab, an antibody directed to programmed death 1 (PD-1), an immune checkpoint inhibitor, compared with platinum-based chemotherapy in patients with previously untreated advanced NSCLC and PD-L1 expression in at least 50% of the tumour cells. Pembrolizumab treatment achieved statistically significant clinical benefits in terms of progression free survival, overall survival and objective responses. The high quality of data and the novelty of the information obtained created the conditions for a new standard of care driven by the expression of PD-L1.

  1. Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer.

    PubMed

    Zhang, Yan; Huang, Shengdong; Gong, Dejun; Qin, Yanghua; Shen, Qian

    2010-09-01

    T-cell tolerance is an important mechanism for tumor escape, but the molecular pathways involved in T-cell tolerance remain poorly understood. It remains unknown whether the inhibitory immunoreceptor programmed death-1 (PD-1) plays a role in conditions of human non-small cell lung cancer (NSCLC). In this study, we detected PD-1 expression on CD8+ T cells from healthy control peripheral blood mononuclear cells (PBMCs) and the PBMCs of NSCLC patients as well as NSCLC tissues. Results showed that tumor-infiltrating CD8+ T cells had increased PD-1 expression and impaired immune function, including reducing cytokine production capability and impairing capacity to proliferate. Blockade of the PD-1/PD-L1 pathway by the PD-L1-specific antibody partially restored cytokine production and cell proliferation. These data provide direct evidence that the PD-1/PD-L1 pathway is involved in CD8+ T-cell dysfunction in NSCLC patients. Moreover, blocking this pathway provides a potential therapy target in lung cancer.

  2. Epitope mapping reveals the binding mechanism of a functional antibody cross-reactive to both human and murine programmed death 1.

    PubMed

    Li, Dong; Xu, Jianqing; Wang, Zhuozhi; Gong, Zhen; Liu, Jieying; Zheng, Yong; Li, Jian; Li, Jing

    2017-02-23

    Of the inhibitory checkpoints in the immune system, programmed death 1 (PD-1) is one of the most promising targets for cancer immunotherapy. The anti-PD-1 antibodies currently approved for clinical use or under development bind to human PD-1 (hPD-1), but not murine PD-1. To facilitate studies in murine models, we developed a functional antibody against both human and murine PD-1, and compared the epitopes of such antibody to a counterpart that only bound to hPD-1. To quickly identify the epitopes of the 2 antibodies, we used alanine scanning and mammalian cell expression cassette. The epitope identification was based on PD-1-binding ELISA and supported by affinity ranking of surface plasmon resonance results. The hPD-1 epitopes of the 2 functional antibodies were also compared with the binding region on hPD-1 that is responsible for PD-L1 interaction. In silico modeling were conducted to explain the different binding modes of the 2 antibodies, suggesting a potential mechanism of the antibody cross-species binding.

  3. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization.

    PubMed

    Pesce, Silvia; Greppi, Marco; Tabellini, Giovanna; Rampinelli, Fabio; Parolini, Silvia; Olive, Daniel; Moretta, Lorenzo; Moretta, Alessandro; Marcenaro, Emanuela

    2017-01-01

    Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. We performed multiparametric cytofluorimetric analysis of PD-1(+) NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. We provide unequivocal evidence that PD-1 is highly expressed (PD-1(bright)) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56(dim) but not CD56(bright) NK cells and is confined to fully mature NK cells characterized by the NKG2A(-)KIR(+)CD57(+) phenotype. Proportions of PD-1(bright) NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their possible induction/expansion in tumor environments. Functional analysis revealed a reduced proliferative capability in response to cytokines, low degranulation, and impaired cytokine production on interaction with tumor targets. We have identified and characterized a novel subpopulation of human NK cells expressing high levels of PD-1. These cells have the phenotypic characteristics of fully mature NK cells and are increased in patients with ovarian carcinoma. They display low proliferative responses and impaired antitumor activity that can be partially restored by antibody-mediated disruption of PD-1/programmed death ligand interaction. Copyright © 2016 American Academy of Allergy, Asthma

  4. Inflammatory cytokines compromise programmed cell death-1 (PD-1)-mediated T cell suppression in inflammatory arthritis through up-regulation of soluble PD-1.

    PubMed

    Bommarito, D; Hall, C; Taams, L S; Corrigall, V M

    2017-02-28

    The programmed cell death 1 (PD-1) receptor plays a major role in regulating T cell activation. Our aim was to determine how inflammation influences PD-1-mediated T cell suppression. Flow cytometry analysis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) synovial fluid (SF) mononuclear cells showed an increase in the percentage of PD-1(+) cells within the CD4(+) and CD8(+) T cell compartment compared to paired peripheral blood (PB). Upon in-vitro T cell receptor (TCR) stimulation of healthy control (HC) CD4(+) T cells in the presence of plate-bound PD-L1fc chimera, significantly decreased proliferation and interferon (IFN)-γ secretion was observed. In contrast, CD4(+) T cells from RA and PsA PB and SF appeared resistant to such PD-1-mediated inhibition. Addition of the proinflammatory cytokines tumour necrosis factor (TNF)α, interleukin (IL)-6 and IL-1β, which were increased in RA and PsA SF compared to osteoarthritis (OA) SF, consistently abrogated PD-1-mediated suppression in HC CD4(+) T cell cultures. This effect was reversed by inhibitors of these cytokines. Soluble PD-1 (sPD-1) levels were increased in cell culture supernatants from TNFα and IL-6-stimulated cultures compared to untreated controls, and also in RA and PsA, but not in OA, serum and SF. Functionally, addition of sPD-1fc counteracted PD-1-mediated suppression of HC CD4(+) T cells, and increased T cell proliferation in HC CD4(+) T cell/monocyte co-cultures. These in-vitro findings indicate that CD4(+) T cells from patients with RA and PsA show increased resistance to PD-1-mediated suppression, which may be explained in part by the presence of soluble PD-1 in the inflammatory environment.

  5. Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease1

    PubMed Central

    Palmer, Brent E.; Mack, Douglas G.; Martin, Allison K.; Gillespie, May; Mroz, Margaret M.; Maier, Lisa A.; Fontenot, Andrew P.

    2015-01-01

    Chronic beryllium disease (CBD) is caused by workplace exposure to beryllium and is characterized by the accumulation of memory CD4+ T cells in the lung. These cells respond vigorously to beryllium salts in culture by producing proinflammatory Th1-type cytokines. The presence of these inflammatory cytokines leads to the recruitment of alveolar macrophages, alveolitis, and subsequent granuloma development. It has been shown that chronic exposure to conventional Ags leads to up-regulation in the expression of negative regulators of T cells such as programmed death-1 (PD-1). Due to the persistence of beryllium in the lung after the cessation of exposure, aberrant regulation of the PD-1 pathway may play an important role in CBD development. In the present study, PD-1 expression was measured on blood and bronchoalveolar lavage (BAL) CD4+ T cells from beryllium-sensitized and CBD subjects. PD-1 expression was significantly higher on BAL CD4+ T cells compared with those cells in blood, with the highest expression on the beryllium-specific T cell subset. In addition, the expression of PD-1 on BAL CD4+ T cells directly correlated with the severity of the T cell alveolitis. Increased expression of the PD-1 ligands, PD-L1 and PD-L2, on BAL CD14+ cells compared with blood was also seen. The addition of anti-PD-1 ligand mAbs augmented beryllium-induced CD4+ T cell proliferation, and an inverse correlation was seen between PD-1 expression on beryllium-specific CD4+ T cells and beryllium-induced proliferation. Thus, the PD-1 pathway is active in beryllium-induced disease and plays a key role in controlling beryllium-induced T cell proliferation. PMID:18250483

  6. Programmed death-1 expression on HIV-1-specific CD8+ T cells is shaped by epitope specificity, T-cell receptor clonotype usage and antigen load

    PubMed Central

    Kløverpris, Henrik N.; McGregor, Reuben; McLaren, James E.; Ladell, Kristin; Stryhn, Anette; Koofhethile, Catherine; Brener, Jacqui; Chen, Fabian; Riddell, Lynn; Graziano, Luzzi; Klenerman, Paul; Leslie, Alasdair; Buus, Søren; Price, David A.; Goulder, Philip

    2014-01-01

    Objectives: Although CD8+ T cells play a critical role in the control of HIV-1 infection, their antiviral efficacy can be limited by antigenic variation and immune exhaustion. The latter phenomenon is characterized by the upregulation of multiple inhibitory receptors, such as programmed death-1 (PD-1), CD244 and lymphocyte activation gene-3 (LAG-3), which modulate the functional capabilities of CD8+ T cells. Design and methods: Here, we used an array of different human leukocyte antigen (HLA)-B∗15 : 03 and HLA-B∗42 : 01 tetramers to characterize inhibitory receptor expression as a function of differentiation on HIV-1-specific CD8+ T-cell populations (n = 128) spanning 11 different epitope targets. Results: Expression levels of PD-1, but not CD244 or LAG-3, varied substantially across epitope specificities both within and between individuals. Differential expression of PD-1 on T-cell receptor (TCR) clonotypes within individual HIV-1-specific CD8+ T-cell populations was also apparent, independent of clonal dominance hierarchies. Positive correlations were detected between PD-1 expression and plasma viral load, which were reinforced by stratification for epitope sequence stability and dictated by effector memory CD8+ T cells. Conclusion: Collectively, these data suggest that PD-1 expression on HIV-1-specific CD8+ T cells tracks antigen load at the level of epitope specificity and TCR clonotype usage. These findings are important because they provide evidence that PD-1 expression levels are influenced by peptide/HLA class I antigen exposure. PMID:24906112

  7. Programmed Death-1 Inhibition of Phosphatidylinositol 3-Kinase/AKT/Mechanistic Target of Rapamycin Signaling Impairs Sarcoidosis CD4(+) T Cell Proliferation.

    PubMed

    Celada, Lindsay J; Rotsinger, Joseph E; Young, Anjuli; Shaginurova, Guzel; Shelton, Debresha; Hawkins, Charlene; Drake, Wonder P

    2017-01-01

    Patients with progressive sarcoidosis exhibit increased expression of programmed death-1 (PD-1) receptor on their CD4(+) T cells. Up-regulation of this marker of T cell exhaustion is associated with a reduction in the proliferative response to T cell receptor (TCR) stimulation, a defect that is reversed by PD-1 pathway blockade. Genome-wide association studies and microarray analyses have correlated signaling downstream from the TCR with sarcoidosis disease severity, but the mechanism is not yet known. Reduced phosphatidylinositol 3-kinase (PI3K)/AKT expression inhibits proliferation by inhibiting cell cycle progression. To test the hypothesis that PD-1 expression attenuates TCR-dependent activation of PI3K/AKT activity in progressive systemic sarcoidosis, we analyzed PI3K/AKT/mechanistic target of rapamycin (mTOR) expression at baseline and after PD-1 pathway blockade in CD4(+) T cells isolated from patients with sarcoidosis and healthy control subjects. We confirmed an increased percentage of PD-1(+) CD4(+) T cells and reduced proliferative capacity in patients with sarcoidosis compared with healthy control subjects (P < 0.001). There was a negative correlation with PD-1 expression and proliferative capacity (r = -0.70, P < 0.001). Expression of key mediators of cell cycle progression, including PI3K and AKT, were significantly decreased. Gene and protein expression levels reverted to healthy control levels after PD-1 pathway blockade. Reduction in sarcoidosis CD4(+) T cell proliferative capacity is secondary to altered expression of key mediators of cell cycle progression, including the PI3K/AKT/mTOR pathway, via PD-1 up-regulation. This supports the concept that PD-1 up-regulation drives the immunologic deficits associated with sarcoidosis severity by inducing signaling aberrancies in key mediators of cell cycle progression.

  8. Circulating soluble programmed death-1 levels may differentiate immune-tolerant phase from other phases and hepatocellular carcinoma from other clinical diseases in chronic hepatitis B virus infection

    PubMed Central

    Li, Fang; Sang, Jiao; Han, Qunying; Lv, Yi; Zhao, Wenxuan; Li, Chunyan; Liu, Zhengwen

    2017-01-01

    Programmed death-1 (PD-1) is involved in the immune dysfunction of hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study analyzed the association of circulating soluble PD-1 (sPD-1) levels with the phases and clinical diseases in chronic HBV infection. Serum sPD-1 levels were determined by enzyme linked immunosorbent assay in patients with different phases and liver diseases of chronic HBV infection. The sPD-1 levels in patients with chronic HBV infection were significantly elevated compared with HBV infection resolvers or healthy controls. According to phases, sPD-1 level in immune-tolerant phase (IT) was significantly lower than in other phases. Multivariate analysis showed that sPD-1 was an independent factor associated with IT. Area under the receiver operating characteristic (ROC) curves (AUC) showed that sPD-1 was significantly discriminative of IT from other phases with a cut-off of 1.535 ng/mL (AUC, 0.984; P<0.001). According to clinical diseases, sPD-1 level in HBV-related HCC was significantly higher than in other clinical diseases. Multivariate analysis showed that sPD-1 was an independent factor associated with HCC. The sPD-1 was significantly discriminative of HCC from other clinical diseases with a cut-off of 6.058 ng/mL (AUC, 0.962; P<0.001). The sPD-1 levels were significantly associated with HCC patients’ overall survival. HCC resection resulted in remarkable reduction in sPD-1 levels. These results demonstrate the involvement of sPD-1 in the disease course of chronic HBV infection and indicate the potential to apply sPD-1 as a biomarker for differentiating IT from other phases and HCC from other disease conditions in chronic HBV infection. PMID:28545019

  9. Programmed Death 1 Regulates Memory Phenotype CD4 T Cell Accumulation, Inhibits Expansion of the Effector Memory Phenotype Subset and Modulates Production of Effector Cytokines

    PubMed Central

    Charlton, Joanna J.; Tsoukatou, Debbie; Mamalaki, Clio; Chatzidakis, Ioannis

    2015-01-01

    Memory phenotype CD4 T cells are found in normal mice and arise through response to environmental antigens or homeostatic mechanisms. The factors that regulate the homeostasis of memory phenotype CD4 cells are not clear. In the present study we demonstrate that there is a marked accumulation of memory phenotype CD4 cells, specifically of the effector memory (TEM) phenotype, in lymphoid organs and tissues of mice deficient for the negative co-stimulatory receptor programmed death 1 (PD-1). This can be correlated with decreased apoptosis but not with enhanced homeostatic turnover potential of these cells. PD-1 ablation increased the frequency of memory phenotype CD4 IFN-γ producers but decreased the respective frequency of IL-17A-producing cells. In particular, IFN-γ producers were more abundant but IL-17A producing cells were more scarce among PD-1 KO TEM-phenotype cells relative to WT. Transfer of peripheral naïve CD4 T cells suggested that accumulated PD-1 KO TEM-phenotype cells are of peripheral and not of thymic origin. This accumulation effect was mediated by CD4 cell-intrinsic mechanisms as shown by mixed bone marrow chimera experiments. Naïve PD-1 KO CD4 T cells gave rise to higher numbers of TEM-phenotype lymphopenia-induced proliferation memory cells. In conclusion, we provide evidence that PD-1 has an important role in determining the composition and functional aspects of memory phenotype CD4 T cell pool. PMID:25803808

  10. Treatment with a programmed cell death-1-specific antibody has little effect on afatinib- and naphthalene-induced acute pneumonitis in mice.

    PubMed

    Hamada, Naoki; Yanagihara, Toyoshi; Suzuki, Kunihiro; Ogata-Suetsugu, Saiko; Harada, Eiji; Mikumo, Hironori; Arimura-Omori, Masako; Nakanishi, Yoichi

    2017-09-23

    Although several antibodies developed to target programmed cell death-1 (PD-1) and its ligand (PD-L1) have demonstrated great promise for the treatment of non-small cell lung cancer (NSCLC), and other malignancies, these therapeutic antibodies can cause pneumonitis. Furthermore, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-induced pneumonitis was reported after treatment with anti PD-1 antibodies. We previously demonstrated that mice with naphthalene-induced airway epithelial injury developed severe gefitinib-induced pneumonitis through a neutrophil-dependent mechanism. The present study aimed to investigate whether treatment with afatinib, an EGFR-TKI that effectively targets EGFR mutation-positive NSCLC, and anti PD-1 antibodies induces pneumonitis in mice. C57BL/6J mice were treated intraperitoneally with naphthalene (200 mg/kg) on day 0. Afatinib (20 mg/kg) was administered orally on days -1 to 13. An anti-PD-1 antibody (0.2 mg/mice) was also administered intraperitoneally every 3 days from day 1 until day 13. The bronchoalveolar lavage fluid (BALF) and lung tissues were sampled on day 14. As observed previously with gefitinib, afatinib significantly increased the severity of histopathologic findings and the level of protein in BALF on day 14, compared to treatment with naphthalene alone. A combined anti-PD-1 antibody and afatinib treatment after naphthalene administration had yielded the same histopathological grade of lung inflammation as did afatinib treatment alone. Our results suggest that anti-PD-1 antibody treatment has little effect on afatinib-induced lung injury. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Chronic thoracic spinal cord injury impairs CD8+ T-cell function by up-regulating programmed cell death-1 expression

    PubMed Central

    2014-01-01

    Background Chronic spinal cord injury (SCI) induces immune depression in patients, which contributes to their higher risk of developing infections. While defects in humoral immunity have been reported, complications in T-cell immunity during the chronic phase of SCI have not yet been explored. Methods To assess the impact of chronic SCI on peripheral T-cell number and function we used a mouse model of severe spinal cord contusion at thoracic level T9 and performed flow cytometry analysis on the spleen for T-cell markers along with intracellular cytokine staining. Furthermore we identified alterations in sympathetic activity in the spleen of chronic SCI mice by measuring splenic levels of tyrosine hydroxylase (TH) and norepinephrine (NE). To gain insight into the neurogenic mechanism leading to T-cell dysfunction we performed in vitro NE stimulation of T-cells followed by flow cytometry analysis for T-cell exhaustion marker. Results Chronic SCI impaired both CD4+ and CD8+ T-cell cytokine production. The observed T-cell dysfunction correlated with increased expression of programmed cell death 1 (PD-1) exhaustion marker on these cells. Blocking PD-1 signaling in vitro restored the CD8+ T-cell functional defect. In addition, we showed that chronic SCI mice had higher levels of splenic NE, which contributed to the T-cell exhaustion phenotype, as PD-1 expression on both CD4+ and CD8+ T-cells was up-regulated following sustained exposure to NE in vitro. Conclusions These studies indicate that alteration of sympathetic activity following chronic SCI induces CD8+ T-cell exhaustion, which in turn impairs T-cell function and contributes to immune depression. Inhibition of the exhaustion pathway should be considered as a new therapeutic strategy for chronic SCI-induced immune depression. PMID:24690491

  12. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma

    PubMed Central

    Kulbe, Hagen; Sehouli, Jalid; Wienert, Stephan; Lindner, Judith; Budczies, Jan; Bockmayr, Michael; Dietel, Manfred; Denkert, Carsten; Braicu, Ioana; Jöhrens, Korinna

    2016-01-01

    Aims Antibodies targeting the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma. Methods PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measured by quantitative reverse transcription PCR. An in silico validation of mRNA data was performed in The Cancer Genome Atlas (TCGA) dataset. Results PD-1 and PD-L1 expression in cancer cells, CD3+, PD-1+, and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free (PFS) and overall survival (OS), with all factors being significant for PFS (p < 0.035 each), and most being significant for OS. Most factors also had prognostic value that was independent from age, stage, and residual tumor. Moreover, high PD-1+ TILs as well as PD-L1+ TILs densities added prognostic value to CD3+TILs (PD-1+: p = 0.002,; PD-L1+: p = 0.002). The significant positive prognostic impact of PD-1 and PD-L1 mRNA expression could be reproduced in the TCGA gene expression datasets (p = 0.02 and p < 0.0001, respectively). Conclusions Despite their reported immune-modulatory function, high PD-1 and PD-L1 levels are indicators of a favorable prognosis in ovarian cancer. Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity. PMID:26625204

  13. The expression status and prognostic significance of programmed cell death 1 ligand 1 in gastrointestinal tract cancer: a systematic review and meta-analysis.

    PubMed

    Huang, Baohua; Chen, Lei; Bao, Cuixia; Sun, Chengming; Li, Jie; Wang, Lipeng; Zhang, Xia

    2015-01-01

    Programmed cell death 1 ligand 1 (PD-L1) expression has been observed in various malignancies. However, the association between PD-L1 expression and the survival of patients with gastrointestinal tract cancer remains controversial. Besides, the rate of PD-L1 positivity on tumor cells of digestive tract cancer is not clear. Thus, we performed a meta-analysis by incorporating all available evidence to evaluate the rate of PD-L1 positivity and the overall survival (OS) according to PD-L1 status in patients with gastrointestinal tract cancer. Electronic databases were searched for eligible literature. Hazard ratios (HRs) for OS with 95% confidence intervals (CIs) according to the expression status of PD-L1 evaluated by immunohistochemistry were extracted. The outcomes were synthesized based on a random-effects model. Fifteen studies (only nine reported OS) that involved 2,993 gastrointestinal tract cancer patients stratified by PD-L1 status were eligible for inclusion in our study. We found the PD-L1-positive expression rate was 0.495 (95% CI 0.415-0.576) if 10% was taken as the cut-off value. When the H-score method was used to evaluate PD-L1 expression, it showed that the PD-L1 positive rate was 0.639 (95% CI 0.490-0.765) if the cut-off value was <50, which was higher than when using >50 as the cut-off point (0.449, 95% CI 0.417-0.483). Additionally, PD-L1-positive gastrointestinal tract cancer patients were associated with significantly poorer OS when compared to negative ones (HR 1.61, 95% CI 1.10-2.35, P=0.014). Subgroup analysis presented similar significant results in patients with esophageal cancer (HR 2.56, 95% CI 1.55-4.21, P<0.001). The positive expression rate of PD-L1 was nearly 50% no matter which method for immunohistochemistry evaluation we chose. Additionally, positive PD-L1 expression status in tumor cells is a risk factor for prognosis of gastrointestinal tract cancer, especially esophageal cancer.

  14. Coregulatory Interactions among CD8α Dendritic Cells, the Latency-Associated Transcript, and Programmed Death 1 Contribute to Higher Levels of Herpes Simplex Virus 1 Latency

    PubMed Central

    Mott, Kevin R.; Allen, Sariah J.; Zandian, Mandana

    2014-01-01

    ABSTRACT The latency-associated transcript (LAT) of herpes simplex virus 1 (HSV-1), CD8α+ dendritic cells (DCs), and programmed death 1 (PD-1) have all been implicated in the HSV-1 latency-reactivation cycle. It is not known, however, whether an interaction between LAT and CD8α+ DCs regulates latency and T-cell exhaustion. To address this question, we used LAT-expressing [LAT(+)] and LAT-negative [LAT(−)] viruses. Depletion of DCs in mice ocularly infected with LAT(+) virus resulted in a reduction in the number of T cells expressing PD-1 in the trigeminal ganglia (TG), whereas depletion of DCs in mice similarly infected with LAT(−) virus did not alter PD-1 expression. CD8α+ DCs, but not CD4+ DCs, infected with LAT(+) virus had higher levels of ICP0, ICP4, thymidine kinase (TK), and PD-1 ligand 1 (PD-L1) transcripts than those infected with LAT(−) virus. Coculture of infected bone marrow (BM)-derived DCs from wild-type (WT) mice, but not infected DCs from CD8α−/− mice, with WT naive T cells contributed to an increase in PD-1 expression. Transfer of bone marrow from WT mice but not CD8α−/− mice to recipient Rag1−/− mice increased the number of latent viral genomes in reconstituted mice infected with the LAT(+) virus. Collectively, these data indicated that a reduction in latency correlated with a decline in the levels of CD8α+ DCs and PD-1 expression. In summary, our results demonstrate an interaction among LAT, PD-1, and CD11c CD8α+ cells that regulates latency in the TG of HSV-1-infected mice. IMPORTANCE Very little is known regarding the interrelationship of LAT, PD-1, and CD8α+ DCs and how such interactions might contribute to relative numbers of latent viral genomes. We show here that (i) in both in vivo and in vitro studies, deficiency of CD8α+ DCs significantly reduced T-cell exhaustion in the presence of LAT(+) virus but not LAT(−) virus; (ii) HSV-1 infectivity was significantly lower in LAT(−)-infected DCs than in their LAT

  15. Two cases of anti-programmed cell death 1-associated bullous pemphigoid-like disease and eruptive keratoacanthomas featuring combined histopathology.

    PubMed

    Bandino, Justin P; Perry, David M; Clarke, Christina E; Marchell, Richard M; Elston, Dirk M

    2017-02-21

    Programmed cell death protein 1 (PD-1) inhibitors (pembrolizumab, nivolumab) are novel immunotherapies revolutionizing the management of advanced malignancy with an improved adverse effect profile, yet the immune-related side effects are still being characterized.(1,2) We report the unique concurrence of bullous pemphigoid-like disease (BP) with keratoacanthomas and squamous cell carcinomas in two patients receiving anti-PD-1 immunotherapy for metastatic melanoma. This article is protected by copyright. All rights reserved.

  16. Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) regulate CD4+ T cells to induce Type 2 helper T cell (Th2) bias at the maternal-fetal interface.

    PubMed

    Wang, SongCun; Zhu, XiaoYong; Xu, YuanYuan; Zhang, Di; Li, YanHong; Tao, Yu; Piao, HaiLan; Li, DaJin; Du, MeiRong

    2016-04-01

    Are the immune regulatory molecules programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) involved in regulating CD4+ T cell function during pregnancy? PD-1 and Tim-3 promote Type 2 helper T cell (Th2) bias and pregnancy maintenance by regulating CD4+ T cell function at the maternal-fetal interface. The maternal CD4+ T cell response to fetal antigens is thought to be an important component of maternal-fetal tolerance during pregnancy. PD-1 and Tim-3 are important for limiting immunopathology. The co-expression of PD-1 and Tim-3 on T cells identifies a T cell subset with impaired proliferation and cytokine production. Combined blockade of Tim-3 and PD-1 could restore T cell function to the greatest degree. The expression of PD-1 and Tim-3 on CD4+ T cells was analyzed by flow cytometry, and in vitro and in vivo analyses were used to investigate the role of PD-1/Tim-3 signal in the regulation of CD4+ T cells function and pregnancy outcome. A total of 88 normal pregnant women, 37 women with recurrent spontaneous abortion, 36 normal pregnant mice and 45 abortion-prone mice were included. We measure the expression of PD-1 and Tim-3 on CD4+ T cells and their relationship to the function of CD4+ T cells and pregnancy outcome, as well as the effects of blocking PD-1 and Tim-3 pathways on decidual CD4+ T (dCD4+ T) cells during early pregnancy. PD-1 and Tim-3, by virtue of their up-regulation on dCD4+ T cells during pregnancy, define a specific effector/memory subset of CD4+ T cells and promote Th2 bias at the maternal-fetal interface. Using in vitro and in vivo experiments, we also found that combined targeting of PD-1 and Tim-3 pathways results in decreased production of Th2-type cytokines by dCD4+ T cells and increased fetal resorption of normal pregnant murine models. Moreover, decreased PD-1 and Tim-3 on dCD4+ T cells may be associated with miscarriage. Further study is required to examine the mechanism of PD-1 and Tim-3 effects on Th2 cytokine

  17. Transgenic Plant Cells Lacking Mitochondrial Alternative Oxidase Have Increased Susceptibility to Mitochondria-Dependent and -Independent Pathways of Programmed Cell Death1

    PubMed Central

    Robson, Christine A.; Vanlerberghe, Greg C.

    2002-01-01

    The plant mitochondrial electron transport chain is branched such that electrons at ubiquinol can be diverted to oxygen via the alternative oxidase (AOX). This pathway does not contribute to ATP synthesis but can dampen the mitochondrial generation of reactive oxygen species. Here, we establish that transgenic tobacco (Nicotiana tabacum L. cv Petit Havana SR1) cells lacking AOX (AS8 cells) show increased susceptibility to three different death-inducing compounds (H2O2, salicylic acid [SA], and the protein phosphatase inhibitor cantharidin) in comparison with wild-type cells. The timing and extent of AS8 cell death are very similar among the three treatments and, in each case, are accompanied by the accumulation of oligonucleosomal fragments of DNA, indicative of programmed cell death. Death induced by H2O2 or SA occurs by a mitochondria-dependent pathway characterized by cytochrome c release from the mitochondrion. Conversely, death induced by cantharidin occurs by a pathway without any obvious mitochondrial involvement. The ability of AOX to attenuate these death pathways may relate to its ability to maintain mitochondrial function after insult with a death-inducing compound or may relate to its ability to prevent chronic oxidative stress within the mitochondrion. In support of the latter, long-term treatment of AS8 cells with an antioxidant compound increased the resistance of AS8 cells to SA- or cantharidin-induced death. The results indicate that plants maintain both mitochondria-dependent and -independent pathways of programmed cell death and that AOX may act as an important mitochondrial “survival protein” against such death. PMID:12177505

  18. Induction of Mitochondrial Alternative Oxidase in Response to a Cell Signal Pathway Down-Regulating the Cytochrome Pathway Prevents Programmed Cell Death1

    PubMed Central

    Vanlerberghe, Greg C.; Robson, Christine A.; Yip, Justine Y.H.

    2002-01-01

    Treatment of tobacco (Nicotiana tabacum L. cv Petit Havana SR1) cells with cysteine (Cys) triggers a signal pathway culminating in a large loss of mitochondrial cytochrome (cyt) pathway capacity. This down-regulation of the cyt path likely requires events outside the mitochondrion and is effectively blocked by cantharidin or endothall, indicating that protein dephosphorylation is one critical process involved. Generation of reactive oxygen species, cytosolic protein synthesis, and Ca2+ flux from organelles also appear to be involved. Accompanying the loss of cyt path is a large induction of alternative oxidase (AOX) protein and capacity. Induction of AOX allows the cells to maintain high rates of respiration, indicating that the lesion triggered by Cys is in the cyt path downstream of ubiquinone. Consistent with this, transgenic (AS8) cells unable to induce AOX (due to the presence of an antisense transgene) lose all respiratory capacity upon Cys treatment. This initiates in AS8 a programmed cell death pathway, as evidenced by the accumulation of oligonucleosomal fragments of DNA as the culture dies. Alternatively, wild-type cells remain viable and eventually recover their cyt path. Induction of AOX in response to a chemical inhibition of the cyt path (by antimycin A) is also dependent upon protein dephosphorylation and the generation of reactive oxygen species. Common events required for both down-regulation of the cyt path and induction of AOX may represent a mechanism to coordinate the biogenesis of these two electron transport paths. Such coordinate regulation may be necessary, not only to satisfy metabolic demands, but also to modulate the initiation of a programmed cell death pathway responsive to mitochondrial respiratory status. PMID:12177496

  19. Attenuation of lymphocyte immune responses during Mycobacterium avium complex-induced lung disease due to increasing expression of programmed death-1 on lymphocytes

    PubMed Central

    Shu, Chin-Chung; Wang, Jann-Yuan; Wu, Ming-Fang; Wu, Chen-Tu; Lai, Hsin-Chih; Lee, Li-Na; Chiang, Bor-Luen; Yu, Chong-Jen

    2017-01-01

    Mycobacterium avium complex-induced lung disease (MAC-LD) becomes important due to its increasing prevalence. Attenuated cellular immunity associated with programmed cell death (PD)–1 may play a pathophysiological role in MAC-LD but lacks of investigation. We enrolled 80 participants in this prospective study, including 50 with MAC-LD and 30 healthy controls. Peripheral blood mononuclear cells (PBMCs), lymphocytes and monocyte-derived macrophages were used for MAC antigen stimulation. Patients with MAC-LD had lower tumor necrosis factor-α and interferon-γ responses compared to the healthy controls in PBMC stimulation assays with MAC bacilli. These responses improved after MAC treatment. The PD-1 and PD ligand expressions and apoptosis were higher in the lymphocytes of the patients with MAC-LD compared to the controls. Both PD-1 and apoptosis on T lymphocytes were significantly increased in the patients with MAC-LD, either by direct MAC stimulation or by MAC-primed macrophage activation. Partially blocking PD-1 and the PD ligand with antagonizing antibodies in the stimulation assay significantly increased the cytokine production of IFN-γ and decreased the apoptosis on T lymphocytes. In conclusion, the patients with MAC-LD have attenuated lymphocyte immunity, which might be associated with increasing activation of PD-1 and PD-1 ligand. Regulating such activation might improve the lymphocytic secretion of IFN-γ and reduce apoptosis. PMID:28169347

  20. CD8+ T cells undergo activation and programmed death-1 repression in the liver of aged Ae2a,b−/− mice favoring autoimmune cholangitis

    PubMed Central

    Concepcion, Axel R.; Salas, January T.; Sáez, Elena; Sarvide, Sarai; Ferrer, Alex; Portu, Ainhoa; Uriarte, Iker; Hervás-Stubbs, Sandra; Oude Elferink, Ronald P.J.; Prieto, Jesús; Medina, Juan F.

    2015-01-01

    Primary biliary cirrhosis (PBC) is a chronic cholestatic disease of unknown etiopathogenesis showing progressive autoimmune-mediated cholangitis. In PBC patients, the liver and lymphocytes exhibit diminished expression of AE2/SLC4A2, a Cl−/HCO3− anion exchanger involved in biliary bicarbonate secretion and intracellular pH regulation. Decreased AE2 expression may be pathogenic as Ae2a,b−/− mice reproduce hepatobiliary and immunological features resembling PBC. To understand the role of AE2 deficiency for autoimmunity predisposition we focused on the phenotypic changes of T cells that occur over the life-span of Ae2a,b−/− mice. At early ages (1-9 months), knockout mice had reduced numbers of intrahepatic T cells, which exhibited increased activation, programmed-cell-death (PD)-1 expression, and apoptosis. Moreover, young knockouts had upregulated PD-1 ligand (PD-L1) on bile-duct cells, and administration of neutralizing anti-PD-L1 antibodies prevented their intrahepatic T-cell deletion. Older (≥10 months) knockouts, however, showed intrahepatic accumulation of cytotoxic CD8+ T cells with downregulated PD-1 and diminished apoptosis. In-vitro DNA demethylation with 5-aza-2′-deoxycytidine partially reverted PD-1 downregulation of intrahepatic CD8+ T cells from aged knockouts. Conclusion: Early in life, AE2 deficiency results in intrahepatic T-cell activation and PD-1/PD-L1 mediated deletion. With aging, intrahepatic CD8+ T cells epigenetically suppress PD-1, and their consequential expansion and further activation favor autoimmune cholangitis. PMID:26396175

  1. Vitiligo-like lesions occurring in patients receiving anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo.

    PubMed

    Larsabal, Maiana; Marti, Aurélie; Jacquemin, Clément; Rambert, Jérôme; Thiolat, Denis; Dousset, Léa; Taieb, Alain; Dutriaux, Caroline; Prey, Sorilla; Boniface, Katia; Seneschal, Julien

    2017-05-01

    The use of anti-programmed cell death (PD)-1 therapies in metastatic tumors is associated with cutaneous side effects including vitiligo-like lesions. We sought to characterize clinically and biologically vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies by studying a case series of 8 patients with metastatic tumors and 30 control subjects with vitiligo. Eight patients receiving anti-PD-1 therapies with features of vitiligo-like lesions seen in our department were recruited. Clinical features and photographs were analyzed. For some patients, skin and blood samples were obtained. Results were compared with the vitiligo group. All patients developed lesions localized on photoexposed areas with a specific depigmentation pattern consisting of multiple flecked lesions without Koebner phenomenon. In contrast to vitiligo, patients receiving anti-PD-1 therapies who developed vitiligo-like lesions did not report any personal or family histories of vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin samples revealed increased C-X-C motif ligand 10 levels in serum of patients developing vitiligo-like lesions, associated with skin infiltration of CD8 T-cells expressing C-X-C motif receptor 3 and producing elevated levels of interferon-γ and tumor necrosis factor-alfa. This cross-sectional study concerned a single center. Clinical and biological patterns of vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  2. Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma.

    PubMed

    Kroon, Paula; Gadiot, Jules; Peeters, Marlies; Gasparini, Alessia; Deken, Marcel A; Yagita, Hideo; Verheij, Marcel; Borst, Jannie; Blank, Christian U; Verbrugge, Inge

    2016-06-01

    T cell checkpoint blockade with antibodies targeting programmed cell death (ligand)-1 (PD-1/PD-L1) and/or cytotoxic T lymphocyte-antigen 4 (CTLA-4) has improved therapy outcome in melanoma patients. However, a considerable proportion of patients does not benefit even from combined α-CTLA-4 and α-PD-1 therapy. We therefore examined to which extent T cell (co)stimulation and/or stereotactic body radiation therapy (SBRT) could further enhance the therapeutic efficacy of T cell checkpoint blockade in a genetically engineered mouse melanoma model that is driven by PTEN-deficiency, and BRAFV600 mutation, as in human, but lacks the sporadic UV-induced mutations. Tumor-bearing mice were treated with different combinations of immunomodulatory antibodies (α-CTLA-4, α-PD-1, α-CD137) or interleukin-2 (IL-2) alone or in combination with SBRT. None of our immunotherapeutic approaches (alone or in combination) had any anti-tumor efficacy, while SBRT alone delayed melanoma outgrowth. However, α-CD137 combined with α-PD-1 antibodies significantly enhanced the anti-tumor effect of SBRT, while the anti-tumor effect of SBRT was not enhanced by interleukin-2, or the combination of α-CTLA-4 and α-PD-1. We conclude that α-CD137 and α-PD-1 antibodies were most effective in enhancing SBRT-induced tumor growth delay in this mouse melanoma model, outperforming the ability of IL-2, or the combination of α-CTLA-4 and α-PD-1 to synergize with SBRT. Given the high mutational load and increased immunogenicity of human melanoma with the same genotype, our findings encourage testing α-CD137 and α-PD-1 alone or in combination with SBRT clinically, particularly in patients refractory to α-CTLA-4 and/or α-PD-1 therapy.

  3. Prevalence of immune-related systemic adverse events in patients treated with anti-Programmed cell Death 1/anti-Programmed cell Death-Ligand 1 agents: A single-centre pharmacovigilance database analysis.

    PubMed

    Le Burel, Sébastien; Champiat, Stéphane; Mateus, Christine; Marabelle, Aurélien; Michot, Jean-Marie; Robert, Caroline; Belkhir, Rakiba; Soria, Jean-Charles; Laghouati, Salim; Voisin, Anne-Laure; Fain, Olivier; Mékinian, Arsène; Coutte, Laetitia; Szwebel, Tali-Anne; Dunogeant, Laetitia; Lioger, Bertrand; Luxembourger, Cécile; Mariette, Xavier; Lambotte, Olivier

    2017-09-01

    The growing use of immune checkpoint inhibitors (ICIs) is associated with the occurrence of immune-related adverse events (irAEs). Few data are published on systemic, immunohaematological and rheumatic irAEs. In a pharmacovigilance database analysis, we screened for these irAEs and calculated their prevalence. Participants were recruited via Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC)(1) a French registry of grade ≥2 irAEs occurring in ICI-treated patients. The pathologies of interest were systemic autoimmune and inflammatory diseases, rheumatic diseases and immune cytopenia. Out of 908 patients treated with anti-Programmed cell Death 1 (PD1)/anti-Programmed cell Death-Ligand 1 (PD-L1) agents (together with an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) agent in 40 cases) between December 2012 and December 2016 at a single centre, 21 patients experienced systemic irAEs. The types and the prevalence of irAEs were as follows: immune thrombocytopenia (0.2%), Sjögren syndrome (0.3%), rheumatoid arthritis (0.2%), polymyalgia rheumatica (0.2%), psoriatic arthritis (0.2%), seronegative polyarthritis (0.7%) and sarcoidosis (0.2%). Patients with Sjögren syndrome or seronegative polyarthritis were more likely to have received combination therapy with ipilimumab (2.5% for both). We described these 21 cases, together with nine additional cases from five other centres. Most irAE were moderately severe (grade 2, 63%). The median time to onset was 57°days (interquartile range (IQR) 24-117). The ICI was withdrawn in 12 cases, 25 patients (83%) received corticosteroids, and five patients (17%) received immunosuppressant/immunomodulatory agents. The irAEs resolved fully or partially in 28 cases (93%). Although systemic, immunohaematological and rheumatic diseases are rarely associated with ICI use, the prevalence is higher when two ICIs are combined. Corticosteroids are often effective and may enable

  4. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer.

    PubMed

    Gettinger, Scott N; Horn, Leora; Gandhi, Leena; Spigel, David R; Antonia, Scott J; Rizvi, Naiyer A; Powderly, John D; Heist, Rebecca S; Carvajal, Richard D; Jackman, David M; Sequist, Lecia V; Smith, David C; Leming, Philip; Carbone, David P; Pinder-Schenck, Mary C; Topalian, Suzanne L; Hodi, F Stephen; Sosman, Jeffrey A; Sznol, Mario; McDermott, David F; Pardoll, Drew M; Sankar, Vindira; Ahlers, Christoph M; Salvati, Mark; Wigginton, Jon M; Hellmann, Matthew D; Kollia, Georgia D; Gupta, Ashok K; Brahmer, Julie R

    2015-06-20

    Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing. © 2015 by American Society of Clinical Oncology.

  5. Overall Survival and Long-Term Safety of Nivolumab (Anti–Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer

    PubMed Central

    Gettinger, Scott N.; Horn, Leora; Gandhi, Leena; Spigel, David R.; Antonia, Scott J.; Rizvi, Naiyer A.; Powderly, John D.; Heist, Rebecca S.; Carvajal, Richard D.; Jackman, David M.; Sequist, Lecia V.; Smith, David C.; Leming, Philip; Carbone, David P.; Pinder-Schenck, Mary C.; Topalian, Suzanne L.; Hodi, F. Stephen; Sosman, Jeffrey A.; Sznol, Mario; McDermott, David F.; Pardoll, Drew M.; Sankar, Vindira; Ahlers, Christoph M.; Salvati, Mark; Wigginton, Jon M.; Hellmann, Matthew D.; Kollia, Georgia D.; Gupta, Ashok K.; Brahmer, Julie R.

    2015-01-01

    Purpose Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non–small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients and Methods Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Results Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Conclusion Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing. PMID:25897158

  6. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial.

    PubMed

    Armand, Philippe; Nagler, Arnon; Weller, Edie A; Devine, Steven M; Avigan, David E; Chen, Yi-Bin; Kaminski, Mark S; Holland, H Kent; Winter, Jane N; Mason, James R; Fay, Joseph W; Rizzieri, David A; Hosing, Chitra M; Ball, Edward D; Uberti, Joseph P; Lazarus, Hillard M; Mapara, Markus Y; Gregory, Stephanie A; Timmerman, John M; Andorsky, David; Or, Reuven; Waller, Edmund K; Rotem-Yehudar, Rinat; Gordon, Leo I

    2013-11-20

    The Programmed Death-1 (PD-1) immune checkpoint pathway may be usurped by tumors, including diffuse large B-cell lymphoma (DLBCL), to evade immune surveillance. The reconstituting immune landscape after autologous hematopoietic stem-cell transplantation (AHSCT) may be particularly favorable for breaking immune tolerance through PD-1 blockade. We conducted an international phase II study of pidilizumab, an anti-PD-1 monoclonal antibody, in patients with DLBCL undergoing AHSCT, with correlative studies of lymphocyte subsets. Patients received three doses of pidilizumab beginning 1 to 3 months after AHSCT. Sixty-six eligible patients were treated. Toxicity was mild. At 16 months after the first treatment, progression-free survival (PFS) was 0.72 (90% CI, 0.60 to 0.82), meeting the primary end point. Among the 24 high-risk patients who remained positive on positron emission tomography after salvage chemotherapy, the 16-month PFS was 0.70 (90% CI, 0.51 to 0.82). Among the 35 patients with measurable disease after AHSCT, the overall response rate after pidilizumab treatment was 51%. Treatment was associated with increases in circulating lymphocyte subsets including PD-L1E-bearing lymphocytes, suggesting an on-target in vivo effect of pidilizumab. This is the first demonstration of clinical activity of PD-1 blockade in DLBCL. Given these results, PD-1 blockade after AHSCT using pidilizumab may represent a promising therapeutic strategy in this disease.

  7. Disabling Immune Tolerance by Programmed Death-1 Blockade With Pidilizumab After Autologous Hematopoietic Stem-Cell Transplantation for Diffuse Large B-Cell Lymphoma: Results of an International Phase II Trial

    PubMed Central

    Armand, Philippe; Nagler, Arnon; Weller, Edie A.; Devine, Steven M.; Avigan, David E.; Chen, Yi-Bin; Kaminski, Mark S.; Holland, H. Kent; Winter, Jane N.; Mason, James R.; Fay, Joseph W.; Rizzieri, David A.; Hosing, Chitra M.; Ball, Edward D.; Uberti, Joseph P.; Lazarus, Hillard M.; Mapara, Markus Y.; Gregory, Stephanie A.; Timmerman, John M.; Andorsky, David; Or, Reuven; Waller, Edmund K.; Rotem-Yehudar, Rinat; Gordon, Leo I.

    2013-01-01

    Purpose The Programmed Death-1 (PD-1) immune checkpoint pathway may be usurped by tumors, including diffuse large B-cell lymphoma (DLBCL), to evade immune surveillance. The reconstituting immune landscape after autologous hematopoietic stem-cell transplantation (AHSCT) may be particularly favorable for breaking immune tolerance through PD-1 blockade. Patients and Methods We conducted an international phase II study of pidilizumab, an anti–PD-1 monoclonal antibody, in patients with DLBCL undergoing AHSCT, with correlative studies of lymphocyte subsets. Patients received three doses of pidilizumab beginning 1 to 3 months after AHSCT. Results Sixty-six eligible patients were treated. Toxicity was mild. At 16 months after the first treatment, progression-free survival (PFS) was 0.72 (90% CI, 0.60 to 0.82), meeting the primary end point. Among the 24 high-risk patients who remained positive on positron emission tomography after salvage chemotherapy, the 16-month PFS was 0.70 (90% CI, 0.51 to 0.82). Among the 35 patients with measurable disease after AHSCT, the overall response rate after pidilizumab treatment was 51%. Treatment was associated with increases in circulating lymphocyte subsets including PD-L1E–bearing lymphocytes, suggesting an on-target in vivo effect of pidilizumab. Conclusion This is the first demonstration of clinical activity of PD-1 blockade in DLBCL. Given these results, PD-1 blockade after AHSCT using pidilizumab may represent a promising therapeutic strategy in this disease. PMID:24127452

  8. Upregulation of interleukin 7 receptor alpha and programmed death 1 marks an epitope-specific CD8+ T-cell response that disappears following primary Epstein-Barr virus infection.

    PubMed

    Sauce, Delphine; Larsen, Martin; Abbott, Rachel J M; Hislop, Andrew D; Leese, Alison M; Khan, Naeem; Papagno, Laura; Freeman, Gordon J; Rickinson, Alan B

    2009-09-01

    In immunocompetent individuals, the stability of the herpesvirus-host balance limits opportunities to study the disappearance of a virus-specific CD8(+) T-cell response. However, we noticed that in HLA-A 0201-positive infectious mononucleosis (IM) patients undergoing primary Epstein-Barr virus (EBV) infection, the initial CD8 response targets three EBV lytic antigen-derived epitopes, YVLDHLIVV (YVL), GLCTLVAML (GLC), and TLDYKPLSV (TLD), but only the YVL and GLC reactivities persist long-term; the TLD response disappears within 10 to 27 months. While present, TLD-specific cells remained largely indistinguishable from YVL and GLC reactivities in many phenotypic and functional respects but showed unique temporal changes in two markers of T-cell fate, interleukin 7 receptor alpha (IL-7Ralpha; CD127) and programmed death 1 (PD-1). Thus, following the antigen-driven downregulation of IL-7Ralpha seen on all populations in acute IM, in every case, the TLD-specific population recovered expression unusually quickly post-IM. As well, in four of six patients studied, TLD-specific cells showed very strong PD-1 upregulation in the last blood sample obtained before the cells' disappearance. Our data suggest that the disappearance of this individual epitope reactivity from an otherwise stable EBV-specific response (i) reflects a selective loss of cognate antigen restimulation (rather than of IL-7-dependent signals) and (ii) is immediately preceded, and perhaps mediated, by PD-1 upregulation to unprecedented levels.

  9. Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition

    PubMed Central

    Kleinpeter, Patricia; Fend, Laetitia; Thioudellet, Christine; Geist, Michel; Sfrontato, Nathalie; Koerper, Véronique; Fahrner, Catherine; Schmitt, Doris; Gantzer, Murielle; Remy-Ziller, Christelle; Brandely, Renée; Villeval, Dominique; Rittner, Karola; Silvestre, Nathalie; Erbs, Philippe; Zitvogel, Laurence; Quéméneur, Eric; Préville, Xavier; Marchand, Jean-Baptiste

    2016-01-01

    ABSTRACT We report here the successful vectorization of a hamster monoclonal IgG (namely J43) recognizing the murine Programmed cell death-1 (mPD-1) in Western Reserve (WR) oncolytic vaccinia virus. Three forms of mPD-1 binders have been inserted into the virus: whole antibody (mAb), Fragment antigen-binding (Fab) or single-chain variable fragment (scFv). MAb, Fab and scFv were produced and assembled with the expected patterns in supernatants of cells infected by the recombinant viruses. The three purified mPD-1 binders were able to block the binding of mPD-1 ligand to mPD-1 in vitro. Moreover, mAb was detected in tumor and in serum of C57BL/6 mice when the recombinant WR-mAb was injected intratumorally (IT) in B16F10 and MCA 205 tumors. The concentration of circulating mAb detected after IT injection was up to 1,900-fold higher than the level obtained after a subcutaneous (SC) injection (i.e., without tumor) confirming the virus tropism for tumoral cells and/or microenvironment. Moreover, the overall tumoral accumulation of the mAb was higher and lasted longer after IT injection of WR-mAb1, than after IT administration of 10 µg of J43. The IT injection of viruses induced a massive infiltration of immune cells including activated lymphocytes (CD8+ and CD4+). Interestingly, in the MCA 205 tumor model, WR-mAb1 and WR-scFv induced a therapeutic control of tumor growth similar to unarmed WR combined to systemically administered J43 and superior to that obtained with an unarmed WR. These results pave the way for next generation of oncolytic vaccinia armed with immunomodulatory therapeutic proteins such as mAbs. PMID:27853644

  10. Expression of Programmed Cell Death 1 Ligand 2 (PD-L2) is a Distinguishing Feature of Primary Mediastinal (Thymic) Large B-cell Lymphoma and Associated with PDCD1LG2 Copy Gain

    PubMed Central

    Shi, Min; Roemer, Margaretha GM; Chapuy, Bjoern; Liao, Xiaoyun; Sun, Heather; Pinkus, Geraldine S.; Shipp, Margaret A.; Freeman, Gordon J.; Rodig, Scott J.

    2016-01-01

    Primary mediastinal (thymic) large B-cell lymphoma (PMBL) and diffuse large B-cell lymphoma (DLBCL) are tumors with distinct clinical and molecular characteristics that are difficult to distinguish by histopathological and phenotypic analyses alone. Programmed cell death 1 ligand 2 (PD-L2) is a cell surface protein expressed by activated macrophages and dendritic cells that binds PD-1 on T-cells to inhibit immune responses. Amplification and/or translocations involving chromosome 9p24.1, a region that includes PDCD1LG2 encoding PD-L2, is a common event in PMBL but not DLBCL and suggests that PD-L2 expression might be a distinguishing feature of PMBL. We developed an assay for the immunohistochemical detection of PD-L2 protein in fixed biopsy specimens (PD-L2 IHC) which we applied to a cohort of PMBLs and DLBCLs. For a subset of cases, we correlated the results of PD-L2 IHC with PDCD1LG2 copy number as determined by qPCR. Twenty-three of 32 (72%) PMBLs but only 1 of 37 (3%) DLBCLs were positive by PD-L2 IHC. Among PMBLs with PDCD1LG2 copy number gain, all were positive by PD-L2 IHC. One PMBL without copy number gain was positive by PD-L2 IHC. When expressed in PMBL, PD-L2 was restricted to tumor cells and not detected on intra-tumoral macrophages. We conclude that PD-L2 protein is robustly expressed by the majority of PMBLs but only rare DLBCLs and often associated with PDCD1LG2 copy gain. PD-L2 IHC may serve as a useful ancillary test for distinguishing PMBL from DLBCL and for the rational selection of patients for therapeutic antibodies that inhibit PD-1 signaling. PMID:25025450

  11. Tonsil-derived mesenchymal stem cells (T-MSCs) prevent Th17-mediated autoimmune response via regulation of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway.

    PubMed

    Kim, Ji-Yon; Park, Minhwa; Kim, Yu-Hee; Ryu, Kyung-Ha; Lee, Kyung Ho; Cho, Kyung-Ah; Woo, So-Youn

    2017-01-20

    Our knowledge of the immunomodulatory role of mesenchymal stem cells (MSCs) in both the innate and adaptive immune systems has dramatically expanded, providing great promise for treating various autoimmune diseases. However, the contribution of MSCs to Th17 dominant immune disease, such as psoriasis and its underlying mechanism remains elusive. In this study, we demonstrated that human palatine tonsil-derived MSCs (T-MSCs) constitutively express both the membrane-bound and soluble forms of programmed death-ligand 1 (PD-L1), which enables T-MSCs to be distinguished from MSCs originating from other organs (i.e., bone marrow or adipose tissue). We also found that T-MSC-derived PD-L1 effectively represses Th17 differentiation via both cell-to-cell contact and a paracrine effect. Further, T-MSCs increase PD-1 expression on T cells by secreting IFN-β, which may enhance engagement with PD-L1. Finally, transplantation of T-MSCs into imiquimod induced psoriatic skin inflammation in mice significantly abrogated disease symptoms, mainly by blunting the Th17 response in a PD-L1 dependent manner. This study suggests that T-MSCs might be a promising cell source to treat autoimmune diseases such as psoriasis, via its unique immunoregulatory features.

  12. Prokaryotic expression of the extracellular domain of porcine programmed death 1 (PD-1) and its ligand PD-L1 and identification of the binding with peripheral blood mononuclear cells in vitro.

    PubMed

    Zhu, Yan-Ping; Yue, Feng; He, Yong; Li, Peng; Yang, Yuan; Han, Yu-Ting; Zhang, Yan-Fang; Sun, Guo-Peng; Guo, Dong-Guang; Yin, Mei; Wang, Xuan-Nian

    2017-04-01

    Programmed cell death protein 1 (PD-1), a costimulatory molecule of the CD28 family, has 2 ligands, PD-L1 and PD-L2. Our previous studies showed that the expression of PD-1 and PD-L1 is up-regulated during viral infection in pigs. Extensive studies have shown that blockade of the PD-1/PD-L1 pathways by anti-PD-L1 antibody or soluble PD-1 restores exhausted T-cells in humans and mice. In the present study the extracellular domains of PD-1 and PD-L1 were used to evaluate the binding of PD-1 and PD-L1 with peripheral blood mononuclear cells (PBMCs). We amplified the cDNA encoding the extracellular domains of PD-1 and PD-L1 to construct recombinant expression plasmids and obtain soluble recombinant proteins, which were then labeled with fluorescein isothiocyanate (FITC). The His-ExPD-1 and His-ExPD-L1 recombinant proteins were expressed in the form of inclusion bodies with a relative molecular weight of 33.0 and 45.0 kDa, respectively. We then prepared polyclonal antibodies against the proteins with a multi-antiserum titer of 1:102 400. Binding of the proteins with PBMCs was evaluated by flow cytometry. The fluorescence signals of His-ExPD-1-FITC and His-ExPD-L1-FITC were greater than those for the FITC control. These results suggest that the soluble recombinant proteins may be used to prepare monoclonal antibodies to block the PD-1/PD-L1 pathway.

  13. Effects of a healthy life exercise program on arteriosclerosis adhesion molecules in elderly obese women

    PubMed Central

    Lim, Seung-Taek; Min, Seok-Ki; Park, Hyuntae; Park, Jong-Hwan; Park, Jin-Kee

    2015-01-01

    [Purpose] The aim of this study was to investigate the change in the arteriosclerosis adhesion molecules after a healthy life exercise program that included aerobic training, anaerobic training, and traditional Korean dance. [Subjects] The subjects were 20 elderly women who were over 65 years of age and had 30% body fat. [Methods] The experimental group underwent a 12-week healthy life exercise program. To evaluate the effects of the healthy life exercise program, measurements were performed before and after the healthy life exercise program in all the subjects. [Results] After the healthy life exercise program, MCP-1 and the arteriosclerosis adhesion molecules sE-selectin and sVCAM-1 were statistically significantly decreased. [Conclusion] The 12-week healthy life exercise program reduced the levels of arteriosclerosis adhesion molecules. Therefore, the results of our study suggest that a healthy life exercise program may be useful in preventing arteriosclerosis and improving quality of life in elderly obese women. PMID:26157257

  14. Expression of programmed cell death1 in T follicular helper cells is regulated by prostaglandin E2 secreted by HBV-infected HepG2.2.1.5 cells.

    PubMed

    Sui, Zhefeng; Shi, Ying; Gao, Zhiling; Yang, Deguang; Wang, Zhihao

    2017-06-01

    The present study aimed to investigate the distribution of T follicular helper (Tfh)-cell subsets in patients with hepatitis B virus (HBV) and determine the underlying mechanism of HBV regulation of Tfh cells. The frequency of peripheral blood Tfh subsets was analyzed using flow cytometry. The expression level of programmed cell death‑1 (PD‑1) and prostaglandin E2 (PGE2) was quantified using reverse transcription‑quantitative polymerase chain reaction and western blotting. The PGE2 level in culture supernatant was detected using enzyme‑linked immunosorbent assay. A Transwell chamber was used to co‑culture Tfh cells with HepG2 and HepG2.2.1.5. The percentage of inducible T‑cell costimulator (ICOS)+ and total Tfh cells was high at the immune activation (IA) group; however, it was reduced in the immune tolerance (IT), responders with HBsAg seroconversion (RP) and healthy control (HC) groups. The percentage of PD‑1+ Tfh cells was significantly higher in IA and IT compared with RP and HC. The ratio of PD‑1+/total Tfh cells was positively correlated with the load of HBV DNA; therefore, this ratio may act as an indicator for HBV replication. The expression level of PD‑1 in Tfh cells was higher in the HepG2.2.1.5 co‑cultured group compared with the HepG2 group, this may be due to the high PGE2 expression level in HBV‑infected HepG2.2.1.5 cells. The findings of the present study revealed an imbalanced distribution of PD‑1+ Tfh cells in patients with HBV at different immune phases. Additionally, HBV may upregulate the expression of PD‑1 in Tfh cells by promoting HepG2.2.1.5 to secret PGE2. Identifying the effect of HBV on Tfh‑cell subsets is crucial for improving immuno-based therapy for HBV.

  15. SYVA: A program to analyze symmetry of molecules based on vector algebra

    NASA Astrophysics Data System (ADS)

    Gyevi-Nagy, László; Tasi, Gyula

    2017-06-01

    Symmetry is a useful concept in physics and chemistry. It can be used to find out some simple properties of a molecule or simplify complex calculations. In this paper a simple vector algebraic method is described to determine all symmetry elements of an arbitrary molecule. To carry out the symmetry analysis, a program has been written, which is also capable of generating the framework group of the molecule, revealing the symmetry properties of normal modes of vibration and symmetrizing the structure. To demonstrate the capabilities of the program, it is compared to other common widely used stand-alone symmetry analyzer (SYMMOL, Symmetrizer) and molecular modeling (NWChem, ORCA, MRCC) software. SYVA can generate input files for molecular modeling programs, e.g. Gaussian, using precisely symmetrized molecular structures. Possible applications are also demonstrated by integrating SYVA with the GAMESS and MRCC software.

  16. Using Small Molecules to Dissect Non-apoptotic Programmed Cell Death: Necroptosis, Ferroptosis, and Pyroptosis.

    PubMed

    Dong, Ting; Liao, Daohong; Liu, Xiaohui; Lei, Xiaoguang

    2015-12-01

    Genetically programmed cell death is a universal and fundamental cellular process in multicellular organisms. Apoptosis and necroptosis, two common forms of programmed cell death, play vital roles in maintenance of homeostasis in metazoans. Dysfunction of the regulatory machinery of these processes can lead to carcinogenesis or autoimmune diseases. Inappropriate death of essential cells can lead to organ dysfunction or even death; ischemia-reperfusion injury and neurodegenerative disorders are examples of this. Recently, novel forms of non-apoptotic programmed cell death have been identified. Although these forms of cell death play significant roles in both physiological and pathological conditions, the detailed molecular mechanisms underlying them are still poorly understood. Here, we discuss progress in using small molecules to dissect three forms of non-apoptotic programmed cell death: necroptosis, ferroptosis, and pyroptosis.

  17. Programmed Lab Experiments for Biochemical Investigation of Quorum-Sensing Signal Molecules in Rhizospheric Soil Bacteria.

    PubMed

    Nievas, Fiorela L; Bogino, Pablo C; Giordano, Walter

    2016-05-06

    Biochemistry courses in the Department of Molecular Biology at the National University of Río Cuarto, Argentina, are designed for undergraduate students in biology, microbiology, chemistry, agronomy, and veterinary medicine. Microbiology students typically have previous coursework in general, analytical, and organic chemistry. Programmed sequences of lab experiments allow these students to investigate biochemical problems whose solution is feasible within the context of their knowledge and experience. We previously designed and reported a programmed lab experiment that familiarizes microbiology students with techniques for detection and characterization of quorum-sensing (QS) and quorum-quenching (QQ) signal molecules. Here, we describe a sequence of experiments designed to expand the understanding and capabilities of biochemistry students using techniques for extraction and identification of QS and QQ signal molecules from peanut rhizospheric soil bacteria, including culturing and manipulation of bacteria under sterile conditions. The program provides students with an opportunity to perform useful assays, draw conclusions from their results, and discuss possible extensions of the study. © 2016 by The International Union of Biochemistry and Molecular Biology, 44:256-262, 2016. © 2016 The International Union of Biochemistry and Molecular Biology.

  18. A finite difference Hartree-Fock program for atoms and diatomic molecules

    NASA Astrophysics Data System (ADS)

    Kobus, Jacek

    2013-03-01

    The newest version of the two-dimensional finite difference Hartree-Fock program for atoms and diatomic molecules is presented. This is an updated and extended version of the program published in this journal in 1996. It can be used to obtain reference, Hartree-Fock limit values of total energies and multipole moments for a wide range of diatomic molecules and their ions in order to calibrate existing and develop new basis sets, calculate (hyper)polarizabilities (αzz, βzzz, γzzzz, Az,zz, Bzz,zz) of atoms, homonuclear and heteronuclear diatomic molecules and their ions via the finite field method, perform DFT-type calculations using LDA or B88 exchange functionals and LYP or VWN correlations ones or the self-consistent multiplicative constant method, perform one-particle calculations with (smooth) Coulomb and Krammers-Henneberger potentials and take account of finite nucleus models. The program is easy to install and compile (tarball+configure+make) and can be used to perform calculations within double- or quadruple-precision arithmetic. Catalogue identifier: ADEB_v2_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADEB_v2_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU General Public License version 2 No. of lines in distributed program, including test data, etc.: 171196 No. of bytes in distributed program, including test data, etc.: 9481802 Distribution format: tar.gz Programming language: Fortran 77, C. Computer: any 32- or 64-bit platform. Operating system: Unix/Linux. RAM: Case dependent, from few MB to many GB Classification: 16.1. Catalogue identifier of previous version: ADEB_v1_0 Journal reference of previous version: Comput. Phys. Comm. 98(1996)346 Does the new version supersede the previous version?: Yes Nature of problem: The program finds virtually exact solutions of the Hartree-Fock and density functional theory type equations for atoms, diatomic molecules and their ions

  19. Regulation Effects by Programmed Molecules for Transcription-Based Diagnostic Automata towards Therapeutic Use

    NASA Astrophysics Data System (ADS)

    Hirabayashi, Miki; Ohashi, Hirotada; Kubo, Tai

    We have presented experimental analysis on the controllability of our transcription-based diagnostic biomolecular automata by programmed molecules. Focusing on the noninvasive transcriptome diagnosis by salivary mRNAs, we already proposed the novel concept of diagnostic device using DNA computation. This system consists of the main computational element which has a stem shaped promoter region and a pseudo-loop shaped read-only memory region for transcription regulation through the conformation change caused by the recognition of disease-related biomarkers. We utilize the transcription of malachite green aptamer sequence triggered by the target recognition for observation of detection. This algorithm makes it possible to release RNA-aptamer drugs multiply, different from the digestion-based systems by the restriction enzyme which was proposed previously, for the in-vivo use, however, the controllability of aptamer release is not enough at the previous stage. In this paper, we verified the regulation effect on aptamer transcription by programmed molecules in basic conditions towards the developm! ent of therapeutic automata. These results would bring us one step closer to the realization of new intelligent diagnostic and therapeutic automata based on molecular circuits.

  20. SASSIE: A program to study intrinsically disordered biological molecules and macromolecular ensembles using experimental scattering restraints

    NASA Astrophysics Data System (ADS)

    Curtis, Joseph E.; Raghunandan, Sindhu; Nanda, Hirsh; Krueger, Susan

    2012-02-01

    A program to construct ensembles of biomolecular structures that are consistent with experimental scattering data are described. Specifically, we generate an ensemble of biomolecular structures by varying sets of backbone dihedral angles that are then filtered using experimentally determined restraints to rapidly determine structures that have scattering profiles that are consistent with scattering data. We discuss an application of these tools to predict a set of structures for the HIV-1 Gag protein, an intrinsically disordered protein, that are consistent with small-angle neutron scattering experimental data. We have assembled these algorithms into a program called SASSIE for structure generation, visualization, and analysis of intrinsically disordered proteins and other macromolecular ensembles using neutron and X-ray scattering restraints. Program summaryProgram title: SASSIE Catalogue identifier: AEKL_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEKL_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU General Public License v3 No. of lines in distributed program, including test data, etc.: 3 991 624 No. of bytes in distributed program, including test data, etc.: 826 Distribution format: tar.gz Programming language: Python, C/C++, Fortran Computer: PC/Mac Operating system: 32- and 64-bit Linux (Ubuntu 10.04, Centos 5.6) and Mac OS X (10.6.6) RAM: 1 GB Classification: 3 External routines: Python 2.6.5, numpy 1.4.0, swig 1.3.40, scipy 0.8.0, Gnuplot-py-1.8, Tcl 8.5, Tk 8.5, Mac installation requires aquaterm 1.0 (or X window system) and Xcode 3 development tools. Nature of problem: Open source software to generate structures of disordered biological molecules that subsequently allow for the comparison of computational and experimental results is limiting the use of scattering resources. Solution method: Starting with an all atom model of a protein, for example, users can input

  1. A program for calculating and plotting soft x-ray optical interaction coefficients for molecules

    SciTech Connect

    Thomas, M.M.; Davis, J.C.; Jacobsen, C.J.; Perera, R.C.C.

    1989-08-01

    Comprehensive tables for atomic scattering factor components, f1 and f2, were compiled by Henke et al. for the extended photon region 50 - 10000 eV. Accurate calculations of optical interaction coefficients for absorption, reflection and scattering by material systems (e.g. filters, multi-layers, etc...), which have widespread application, can be based simply upon the atomic scattering factors for the elements comprising the material, except near the absorption threshold energies. These calculations based upon the weighted sum of f1 and f2 for each atomic species present can be very tedious if done by hand. This led us to develop a user friendly program to perform these calculations on an IBM PC or compatible computer. By entering the chemical formula, density and thickness of up to six molecules, values of the f1, f2, mass absorption transmission efficiencies, attenuation lengths, mirror reflectivities and complex indices of refraction can be calculated and plotted as a function of energy or wavelength. This program will be available distribution. 7 refs., 1 fig.

  2. CAL3JHH: a Java program to calculate the vicinal coupling constants (3 J H,H) of organic molecules

    NASA Astrophysics Data System (ADS)

    Aguirre-Valderrama, Alonso; Dobado, José A.

    2008-12-01

    Here, we present a free web-accessible application, developed in the JAVA programming language for the calculation of vicinal coupling constant (3 J H,H) of organic molecules with the H-Csp3-Csp3-H fragment. This JAVA applet is oriented to assist chemists in structural and conformational analyses, allowing the user to calculate the averaged 3 J H,H values among conformers, according to its Boltzmann populations. Thus, the CAL3JHH program uses the Haasnoot-Leeuw-Altona equation, and, by reading the molecule geometry from a protein data bank (PDB) file format or from multiple pdb files, automatically detects all the coupled hydrogens, evaluating the data needed for this equation. Moreover, a "Graphical viewer" menu allows the display of the results on the 3D molecule structure, as well as the plotting of the Newman projection for the couplings.

  3. CAL3JHH: a Java program to calculate the vicinal coupling constants (3J H,H) of organic molecules.

    PubMed

    Aguirre-Valderrama, Alonso; Dobado, José A

    2008-12-01

    Here, we present a free web-accessible application, developed in the JAVA programming language for the calculation of vicinal coupling constant (3J(H,H)) of organic molecules with the H-Csp3-Csp3-H fragment. This JAVA applet is oriented to assist chemists in structural and conformational analyses, allowing the user to calculate the averaged 3J(H,H) values among conformers, according to its Boltzmann populations. Thus, the CAL3JHH program uses the Haasnoot-Leeuw-Altona equation, and, by reading the molecule geometry from a protein data bank (PDB) file format or from multiple pdb files, automatically detects all the coupled hydrogens, evaluating the data needed for this equation. Moreover, a "Graphical viewer" menu allows the display of the results on the 3D molecule structure, as well as the plotting of the Newman projection for the couplings.

  4. a New Hybrid Program for Fitting Rotationally Resolved Spectra of Methylamine-Like Molecules: Application to 2-METHYLMALONALDEHYDE

    NASA Astrophysics Data System (ADS)

    Kleiner, Isabelle; Hougen, Jon T.

    2015-06-01

    A new hybrid-model fitting program for methylamine-like molecules has been developed, based on an effective Hamiltonian in which the ammonia-like inversion motion is treated using a tunneling formalism, while the internal-rotation motion is treated using an explicit kinetic energy operator and potential energy function. The Hamiltonian in the computer program is set up as a 2x2 partitioned matrix, where each diagonal block consists of a traditional torsion-rotation Hamiltonian (as in the earlier program BELGI), and the two off-diagonal blocks contain all tunneling terms. This hybrid formulation permits the use of the permutation-inversion group G6 (isomorphic to C3v) for terms in the two diagonal blocks, but requires G12 for terms in the off-diagonal blocks. Our first application of the new program is to 2-methylmalonaldehyde. Microwave data for this molecule were previously fit (essentially to experimental measurement error) using an all-tunneling Hamiltonian formalism to treat both large-amplitude-motions. For 2-methylmalonaldehyde, the hybrid program achieves a fit of nearly the same quality as that obtained by the all-tunneling program, but fits with the hybrid program eliminate a large discrepancy between internal rotation barriers in the OH and OD isotopologues of 2-methylmalonaldehyde that arose in fits with the all-tunneling program. Other molecules for application of the hybrid program will be mentioned. V.V. Ilyushin, E.A. Alekseev, Yung-Ching Chou, Yen-Chu Hsu, J. T. Hougen, F.J. Lovas, L. Picraux, J. Mol. Spectrosc. 251 (2008) 56-63

  5. Programmed cell death in Acanthamoeba castellanii Neff induced by several molecules present in olive leaf extracts.

    PubMed

    Sifaoui, Ines; López-Arencibia, Atteneri; Martín-Navarro, Carmen Mª; Reyes-Batlle, María; Wagner, Carolina; Chiboub, Olfa; Mejri, Mondher; Valladares, Basilio; Abderrabba, Manef; Piñero, José E; Lorenzo-Morales, Jacob

    2017-01-01

    Therapy against Acanthamoeba infections such as Granulomatous Amoebic Encephalitis (GAE) and Acanthamoeba Keratitis (AK), remains as an issue to be solved due to the existence of a cyst stage which is highly resistant to most chemical and physical agents. Recently, the activity of Olive Leaf Extracts (OLE) was demonstrated against Acanthamoeba species. However, the molecules involved in this activity were not identified and/or evaluated. Therefore, the aim of this study was to evaluate the activity of the main molecules which are present in OLE and secondly to study their mechanism of action in Acanthamoeba. Among the tested molecules, the observed activities ranged from an IC50 of 6.59 in the case of apigenine to an IC50 > 100 μg/ml for other molecules. After that, elucidation of the mechanism of action of these molecules was evaluated by the detection of changes in the phosphatidylserine (PS) exposure, the permeability of the plasma membrane, the mitochondrial membrane potential and the ATP levels in the treated cells. Vanillic, syringic and ursolic acids induced the higher permeabilization of the plasma membrane. Nevertheless, the mitochondrial membrane was altered by all tested molecules which were also able to decrease the ATP levels to less than 50% in IC90 treated cells after 24 h. Therefore, all the molecules tested in this study could be considered as a future therapeutic alternative against Acanthamoeba spp. Further studies are needed in order to establish the true potential of these molecules against these emerging opportunistic pathogenic protozoa.

  6. Programmed cell death in Acanthamoeba castellanii Neff induced by several molecules present in olive leaf extracts

    PubMed Central

    Sifaoui, Ines; López-Arencibia, Atteneri; Martín-Navarro, Carmen Mª.; Reyes-Batlle, María; Wagner, Carolina; Chiboub, Olfa; Mejri, Mondher; Valladares, Basilio; Abderrabba, Manef; Piñero, José E.; Lorenzo-Morales, Jacob

    2017-01-01

    Therapy against Acanthamoeba infections such as Granulomatous Amoebic Encephalitis (GAE) and Acanthamoeba Keratitis (AK), remains as an issue to be solved due to the existence of a cyst stage which is highly resistant to most chemical and physical agents. Recently, the activity of Olive Leaf Extracts (OLE) was demonstrated against Acanthamoeba species. However, the molecules involved in this activity were not identified and/or evaluated. Therefore, the aim of this study was to evaluate the activity of the main molecules which are present in OLE and secondly to study their mechanism of action in Acanthamoeba. Among the tested molecules, the observed activities ranged from an IC50 of 6.59 in the case of apigenine to an IC50 > 100 μg/ml for other molecules. After that, elucidation of the mechanism of action of these molecules was evaluated by the detection of changes in the phosphatidylserine (PS) exposure, the permeability of the plasma membrane, the mitochondrial membrane potential and the ATP levels in the treated cells. Vanillic, syringic and ursolic acids induced the higher permeabilization of the plasma membrane. Nevertheless, the mitochondrial membrane was altered by all tested molecules which were also able to decrease the ATP levels to less than 50% in IC90 treated cells after 24 h. Therefore, all the molecules tested in this study could be considered as a future therapeutic alternative against Acanthamoeba spp. Further studies are needed in order to establish the true potential of these molecules against these emerging opportunistic pathogenic protozoa. PMID:28859105

  7. Cbl-b Deficiency Mediates Resistance to Programmed Death-Ligand 1/Programmed Death-1 Regulation

    PubMed Central

    Fujiwara, Mai; Anstadt, Emily J.; Clark, Robert B.

    2017-01-01

    Casitas B-lineage lymphoma-b (Cbl-b) is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b−/− T cells are hyper-reactive and co-stimulation independent, and Cbl-b−/− mice demonstrate robust T cell and NK cell-mediated antitumor immunity. As a result of these murine studies, Cbl-b is considered a potential target for therapeutic manipulation in human cancer immunotherapy. The PD-L1/PD-1 pathway of immune regulation is presently an important therapeutic focus in tumor immunotherapy, and although Cbl-b−/− mice have been shown to be resistant to several immuno-regulatory mechanisms, the sensitivity of Cbl-b−/− mice to PD-L1-mediated suppression has not been reported. We now document that Cbl-b−/− T cells and NK cells are resistant to PD-L1/PD-1-mediated suppression. Using a PD-L1 fusion protein (PD-L1 Ig), this resistance is shown for both in vitro proliferative responses and IFN-γ production and is not associated with decreased PD-1 expression on Cbl-b−/− cells. In coculture studies, Cbl-b−/− CD8+, but not CD4+ T cells, diminish the PD-L1 Ig-mediated suppression of bystander naïve WT CD8+ T cells. Using an in vivo model of B16 melanoma in which numerous liver metastases develop in WT mice in a PD-1 dependent manner, Cbl-b−/− mice develop significantly fewer liver metastases without the administration of anti-PD-1 antibody. Overall, our findings identify a new mode of immuno-regulatory resistance associated with Cbl-b deficiency and suggest that resistance to PD-L1/PD-1-mediated suppression is a novel mechanism by which Cbl-b deficiency leads to enhanced antitumor immunity. Our results suggest that targeting Cbl-b in cancer immunotherapy offers the opportunity to simultaneously override numerous relevant “checkpoints,” including sensitivity to regulatory T cells, suppression by TGF-β, and immune regulation by both CTLA-4 and, as we now report, by the PD-L1/PD-1 pathway. PMID:28184224

  8. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1)

    PubMed Central

    Zak, Krzysztof M.; Grudnik, Przemyslaw; Guzik, Katarzyna; Zieba, Bartosz J.; Musielak, Bogdan; Dömling, Alexander; Dubin, Grzegorz; Holak, Tad A.

    2016-01-01

    Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has provided unprecedented results in cancer treatment in the recent years. Development of chemical inhibitors for this pathway lags the antibody development because of insufficient structural information. The first nonpeptidic chemical inhibitors that target the PD-1/PD-L1 interaction have only been recently disclosed by Bristol-Myers Squibb. Here, we show that these small-molecule compounds bind directly to PD-L1 and that they potently block PD-1 binding. Structural studies reveal a dimeric protein complex with a single small molecule which stabilizes the dimer thus occluding the PD-1 interaction surface of PD-L1s. The small-molecule interaction “hot spots” on PD-L1 surfaces suggest approaches for the PD-1/PD-L1 antagonist drug discovery. PMID:27083005

  9. Programmed self-assembly of large π-conjugated molecules into electroactive one-dimensional nanostructures

    PubMed Central

    Yamamoto, Yohei

    2012-01-01

    Electroactive one-dimensional (1D) nano-objects possess inherent unidirectional charge and energy transport capabilities along with anisotropic absorption and emission of light, which are of great advantage for the development of nanometer-scale electronics and optoelectronics. In particular, molecular nanowires formed by self-assembly of π-conjugated molecules attract increasing attention for application in supramolecular electronics. This review introduces recent topics related to electroactive molecular nanowires. The nanowires are classified into four categories with respect to the electronic states of the constituent molecules: electron donors, acceptors, donor–acceptor pairs and miscellaneous molecules that display interesting electronic properties. Although many challenges still remain for practical use, state-of-the-art 1D supramolecular nanomaterials have already brought significant advances to both fundamental chemical sciences and technological applications. PMID:27877488

  10. Suppression of the FOXM1 transcriptional program via novel small molecule inhibition

    PubMed Central

    Gormally, Michael V.; Dexheimer, Thomas S.; Marsico, Giovanni; Sanders, Deborah A.; Lowe, Christopher; Matak-Vinkovi, Dijana; Michael, Sam; Jadhav, Ajit; Rai, Ganesha; Maloney, David J.; Simeonov, Anton; Balasubramanian, Shankar

    2014-01-01

    The transcription factor FOXM1 binds to sequence-specific motifs on DNA (C/TAAACA) through its DNA binding domain (DBD), and activates proliferation- and differentiation-associated genes. Aberrant overexpression of FOXM1 is a key feature in oncogenesis and progression of many human cancers. Here — from a high-throughput screen applied to a library of 54,211 small molecules — we identify novel small molecule inhibitors of FOXM1 that block DNA binding. One of the identified compounds: FDI-6 (NCGC00099374) is characterized in depth and is shown to bind directly to FOXM1 protein, to displace FOXM1 from genomic targets in MCF-7 breast cancer cells, and induce concomitant transcriptional down-regulation. Global transcript profiling of MCF-7 cells by RNA-seq shows that FDI-6 specifically down regulates FOXM1-activated genes with FOXM1 occupancy confirmed by ChIP-seq. This small molecule mediated effect is selective for FOXM1-controlled genes with no effect on genes regulated by homologous forkhead family factors. PMID:25387393

  11. Interaction between water molecules and zinc sulfide nanoparticles studied by temperature-programmed desorption and molecular dynamics simulations.

    PubMed

    Zhang, Hengzhong; Rustad, James R; Banfield, Jillian F

    2007-06-14

    We have investigated the bonding of water molecules to the surfaces of ZnS nanoparticles (approximately 2-3 nm sphalerite) using temperature-programmed desorption (TPD). The activation energy for water desorption was derived as a function of the surface coverage through kinetic modeling of the experimental TPD curves. The binding energy of water equals the activation energy of desorption if it is assumed that the activation energy for adsorption is nearly zero. Molecular dynamics (MD) simulations of water adsorption on 3 and 5 nm sphalerite nanoparticles provided insights into the adsorption process and water binding at the atomic level. Water binds with the ZnS nanoparticle surface mainly via formation of Zn-O bonds. As compared with bulk ZnS crystals, ZnS nanoparticles can adsorb more water molecules per unit surface area due to the greatly increased curvature, which increases the distance between adjacent adsorbed molecules. Results from both TPD and MD show that the water binding energy increases with decreasing the water surface coverage. We attribute the increase in binding energy with decreasing surface water coverage to the increasing degree of surface under-coordination as removal of water molecules proceeds. MD also suggests that the water binding energy increases with decreasing particle size due to the further distance and hence lower interaction between adsorbed water molecules on highly curved smaller particle surfaces. Results also show that the binding energy, and thus the strength of interaction of water, is highest in isolated nanoparticles, lower in nanoparticle aggregates, and lowest in bulk crystals. Given that water binding is driven by surface energy reduction, we attribute the decreased binding energy for aggregated as compared to isolated particles to the decrease in surface energy that occurs as the result of inter-particle interactions.

  12. Computer program for determining rotational line intensity factors for diatomic molecules

    NASA Technical Reports Server (NTRS)

    Whiting, E. E.

    1973-01-01

    A FORTRAN IV computer program, that provides a new research tool for determining reliable rotational line intensity factors (also known as Honl-London factors), for most electric and magnetic dipole allowed diatomic transitions, is described in detail. This users manual includes instructions for preparing the input data, a program listing, detailed flow charts, and three sample cases. The program is applicable to spin-allowed dipole transitions with either or both states intermediate between Hund's case (a) and Hund's case (b) coupling and to spin-forbidden dipole transitions with either or both states intermediate between Hund's case (c) and Hund's case (b) coupling.

  13. Theoretical research program to predict the properties of molecules and clusters containing transition metal atoms

    NASA Technical Reports Server (NTRS)

    Walch, S.

    1984-01-01

    The primary focus of this research has been the theoretical study of transition metal (TM) chemistry. A major goal of this work is to provide reliable information about the interaction of H atoms with iron metal. This information is needed to understand the effect of H atoms on the processes of embrittlement and crack propagation in iron. The method in the iron hydrogen studies is the cluster method in which the bulk metal is modelled by a finite number of iron atoms. There are several difficulties in the application of this approach to the hydrogen iron system. First the nature of TM-TM and TM-H bonding for even diatomic molecules was not well understood when these studies were started. Secondly relatively large iron clusters are needed to provide reasonable results.

  14. Programmed Lab Experiments for Biochemical Investigation of Quorum-Sensing Signal Molecules in Rhizospheric Soil Bacteria

    ERIC Educational Resources Information Center

    Nievas, Fiorela L.; Bogino, Pablo C.; Giordano, Walter

    2016-01-01

    Biochemistry courses in the Department of Molecular Biology at the National University of Río Cuarto, Argentina, are designed for undergraduate students in biology, microbiology, chemistry, agronomy, and veterinary medicine. Microbiology students typically have previous coursework in general, analytical, and organic chemistry. Programmed sequences…

  15. Programmed Lab Experiments for Biochemical Investigation of Quorum-Sensing Signal Molecules in Rhizospheric Soil Bacteria

    ERIC Educational Resources Information Center

    Nievas, Fiorela L.; Bogino, Pablo C.; Giordano, Walter

    2016-01-01

    Biochemistry courses in the Department of Molecular Biology at the National University of Río Cuarto, Argentina, are designed for undergraduate students in biology, microbiology, chemistry, agronomy, and veterinary medicine. Microbiology students typically have previous coursework in general, analytical, and organic chemistry. Programmed sequences…

  16. Modeling Molecules

    NASA Technical Reports Server (NTRS)

    2000-01-01

    The molecule modeling method known as Multibody Order (N) Dynamics, or MBO(N)D, was developed by Moldyn, Inc. at Goddard Space Flight Center through funding provided by the SBIR program. The software can model the dynamics of molecules through technology which stimulates low-frequency molecular motions and properties, such as movements among a molecule's constituent parts. With MBO(N)D, a molecule is substructured into a set of interconnected rigid and flexible bodies. These bodies replace the computation burden of mapping individual atoms. Moldyn's technology cuts computation time while increasing accuracy. The MBO(N)D technology is available as Insight II 97.0 from Molecular Simulations, Inc. Currently the technology is used to account for forces on spacecraft parts and to perform molecular analyses for pharmaceutical purposes. It permits the solution of molecular dynamics problems on a moderate workstation, as opposed to on a supercomputer.

  17. DVR3D: a program suite for the calculation of rotation-vibration spectra of triatomic molecules

    NASA Astrophysics Data System (ADS)

    Tennyson, Jonathan; Kostin, Maxim A.; Barletta, Paolo; Harris, Gregory J.; Polyansky, Oleg L.; Ramanlal, Jayesh; Zobov, Nikolai F.

    2004-11-01

    The DVR3D program suite calculates energy levels, wavefunctions, and where appropriate dipole transition moments, for rotating and vibrating triatomic molecules. Potential energy and, where necessary, dipole surfaces must be provided. Expectation values of geometrically defined functions can be calculated, a feature which is particularly useful for fitting potential energy surfaces. The programs use an exact (within the Born-Oppenheimer approximation) Hamiltonian and offer a choice of Jacobi or Radau internal coordinates and several body-fixed axes. Rotationally excited states are treated using an efficient two-step algorithm. The programs uses a Discrete Variable Representation (DVR) based on Gauss-Jacobi and Gauss-Laguerre quadrature for all 3 internal coordinates and thus yields a fully point-wise representation of the wavefunctions. The vibrational step uses successive diagonalisation and truncation which is implemented for a number of possible coordinate orderings. The rotational, expectation value and transition dipole programs exploit the savings offered by performing integrals on a DVR grid. The new version has been rewritten in FORTRAN 90 to exploit the dynamic array allocations and the algorithm for dipole and spectra calculations have been substantially improved. New modules allow the z-axis to be embedded perpendicular to the plane of the molecule and for the calculation of expectation values. Program summaryTitle of the program: DVR3D suite Catalogue number: ADTI Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADTI Program obtainable from: CPC Program Library, Queen's University of Belfast, N. Ireland Programming language: Fortran 90 No. of lines in distributed program, including test data, etc.: 61 574 No. of bytes in distributed program, including test data, etc.: 972 404 Distribution format: tar.gz New version summaryTitle of program: DVR3DRJZ Catalogue number: ADTB Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADTB Program obtainable

  18. MSTor: A program for calculating partition functions, free energies, enthalpies, entropies, and heat capacities of complex molecules including torsional anharmonicity

    NASA Astrophysics Data System (ADS)

    Zheng, Jingjing; Mielke, Steven L.; Clarkson, Kenneth L.; Truhlar, Donald G.

    2012-08-01

    We present a Fortran program package, MSTor, which calculates partition functions and thermodynamic functions of complex molecules involving multiple torsional motions by the recently proposed MS-T method. This method interpolates between the local harmonic approximation in the low-temperature limit, and the limit of free internal rotation of all torsions at high temperature. The program can also carry out calculations in the multiple-structure local harmonic approximation. The program package also includes six utility codes that can be used as stand-alone programs to calculate reduced moment of inertia matrices by the method of Kilpatrick and Pitzer, to generate conformational structures, to calculate, either analytically or by Monte Carlo sampling, volumes for torsional subdomains defined by Voronoi tessellation of the conformational subspace, to generate template input files, and to calculate one-dimensional torsional partition functions using the torsional eigenvalue summation method. Catalogue identifier: AEMF_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEMF_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 77 434 No. of bytes in distributed program, including test data, etc.: 3 264 737 Distribution format: tar.gz Programming language: Fortran 90, C, and Perl Computer: Itasca (HP Linux cluster, each node has two-socket, quad-core 2.8 GHz Intel Xeon X5560 “Nehalem EP” processors), Calhoun (SGI Altix XE 1300 cluster, each node containing two quad-core 2.66 GHz Intel Xeon “Clovertown”-class processors sharing 16 GB of main memory), Koronis (Altix UV 1000 server with 190 6-core Intel Xeon X7542 “Westmere” processors at 2.66 GHz), Elmo (Sun Fire X4600 Linux cluster with AMD Opteron cores), and Mac Pro (two 2.8 GHz Quad-core Intel Xeon

  19. Perinatal programming of emotional brain circuits: an integrative view from systems to molecules

    PubMed Central

    Bock, Jörg; Rether, Kathy; Gröger, Nicole; Xie, Lan; Braun, Katharina

    2014-01-01

    Environmental influences such as perinatal stress have been shown to program the developing organism to adapt brain and behavioral functions to cope with daily life challenges. Evidence is now accumulating that the specific and individual effects of early life adversity on the functional development of brain and behavior emerge as a function of the type, intensity, timing and the duration of the adverse environment, and that early life stress (ELS) is a major risk factor for developing behavioral dysfunctions and mental disorders. Results from clinical as well as experimental studies in animal models support the hypothesis that ELS can induce functional “scars” in prefrontal and limbic brain areas, regions that are essential for emotional control, learning and memory functions. On the other hand, the concept of “stress inoculation” is emerging from more recent research, which revealed positive functional adaptations in response to ELS resulting in resilience against stress and other adversities later in life. Moreover, recent studies indicate that early life experiences and the resulting behavioral consequences can be transmitted to the next generation, leading to a transgenerational cycle of adverse or positive adaptations of brain function and behavior. In this review we propose a unifying view of stress vulnerability and resilience by connecting genetic predisposition and programming sensitivity to the context of experience-expectancy and transgenerational epigenetic traits. The adaptive maturation of stress responsive neural and endocrine systems requires environmental challenges to optimize their functions. Repeated environmental challenges can be viewed within the framework of the match/mismatch hypothesis, the outcome, psychopathology or resilience, depends on the respective predisposition and on the context later in life. PMID:24550772

  20. Perinatal programming of emotional brain circuits: an integrative view from systems to molecules.

    PubMed

    Bock, Jörg; Rether, Kathy; Gröger, Nicole; Xie, Lan; Braun, Katharina

    2014-01-01

    Environmental influences such as perinatal stress have been shown to program the developing organism to adapt brain and behavioral functions to cope with daily life challenges. Evidence is now accumulating that the specific and individual effects of early life adversity on the functional development of brain and behavior emerge as a function of the type, intensity, timing and the duration of the adverse environment, and that early life stress (ELS) is a major risk factor for developing behavioral dysfunctions and mental disorders. Results from clinical as well as experimental studies in animal models support the hypothesis that ELS can induce functional "scars" in prefrontal and limbic brain areas, regions that are essential for emotional control, learning and memory functions. On the other hand, the concept of "stress inoculation" is emerging from more recent research, which revealed positive functional adaptations in response to ELS resulting in resilience against stress and other adversities later in life. Moreover, recent studies indicate that early life experiences and the resulting behavioral consequences can be transmitted to the next generation, leading to a transgenerational cycle of adverse or positive adaptations of brain function and behavior. In this review we propose a unifying view of stress vulnerability and resilience by connecting genetic predisposition and programming sensitivity to the context of experience-expectancy and transgenerational epigenetic traits. The adaptive maturation of stress responsive neural and endocrine systems requires environmental challenges to optimize their functions. Repeated environmental challenges can be viewed within the framework of the match/mismatch hypothesis, the outcome, psychopathology or resilience, depends on the respective predisposition and on the context later in life.

  1. RKR1: A computer program implementing the first-order RKR method for determining diatomic molecule potential energy functions

    NASA Astrophysics Data System (ADS)

    Le Roy, Robert J.

    2017-01-01

    This paper describes computer program RKR1, which implements the first-order semiclassical Rydberg-Klein-Rees procedure for determining the potential energy function for a diatomic molecule from a knowledge of the dependence of the molecular vibrational energies Gv and inertial rotation constants Bv on the vibrational quantum number v. RKR1 allows the vibrational energies and rotational constants to be defined in terms of: (i) conventional Dunham polynomial expansions, (ii) near-dissociation expansions (NDE's), or (iii) the mixed Dunham/NDE "MXR" functions introduced by Tellinghuisen [J Chem Phys 2003; 118: 3532]. Internal convergence tests ascertain and report on the precision of the resulting turning points. For cases in which only vibrational data are available, RKR1 also allows an overall potential to be constructed by combining directly-calculated well widths with inner turning points generated from a Morse function. It can also automatically smooth over irregular or unphysical behavior of the steep inner wall of the potential.

  2. Structure and interactions of the human programmed cell death 1 receptor.

    PubMed

    Cheng, Xiaoxiao; Veverka, Vaclav; Radhakrishnan, Anand; Waters, Lorna C; Muskett, Frederick W; Morgan, Sara H; Huo, Jiandong; Yu, Chao; Evans, Edward J; Leslie, Alasdair J; Griffiths, Meryn; Stubberfield, Colin; Griffin, Robert; Henry, Alistair J; Jansson, Andreas; Ladbury, John E; Ikemizu, Shinji; Carr, Mark D; Davis, Simon J

    2013-04-26

    PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC' sheet, which is flexible and completely lacks a C" strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC' sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1 · ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.

  3. Programmed death-1 receptor suppresses γ-IFN producing NKT cells in human tuberculosis.

    PubMed

    Singh, Amar; Dey, Aparajit Ballav; Mohan, Anant; Mitra, Dipendra Kumar

    2014-05-01

    IFN-γ biased Th1 effector immune response is crucial for containment of Mycobacterium tuberculosis infection. Various T cell subsets with regulatory function dictate the generation of Th1 like cells. NKT cells are a specialized T cell subset known to be activated early in immune response and control T cell response via release of immunoregulatory cytokines like IFN-γ, IL-4 and IL-10. M. tuberculosis, with abundance of its cell wall lipids may potently activate NKT cells resulting in cytokine production and PD-1 expression. In this study, among 49 treatment naive active pulmonary tuberculosis patients, we found a higher percentage of PD1(+) NKT cells correlating with sputum bacillary load. Furthermore, blocking PD-1 increased the number of IFN-γ producing NKT cells by inhibiting their apoptosis. Moreover, peripheral frequency of NKT cells declined with therapy suggesting their role in host T cell response. In this study, we concluded that PD-1 preferentially induces apoptosis of IFN-γ producing NKT cells while sparing NKT cells that produce IL-4. Such a polarized NKT cell function may impose a Th2 bias on the ensuing effector T cell response leading to inefficient clearance of M. tuberculosis. Inhibiting PD-1 may therefore alter the T cell response in favor of the host by rescuing type 1 NKT cells from apoptosis and boosting Th1 effector T cell functions against M. tuberculosis.

  4. A Hybrid Program for Fitting Rotationally Resolved Spectra of Floppy Molecules with One Large-Amplitude Rotatory Motion and One Large-Amplitude Oscillatory Motion

    PubMed Central

    Kleiner, Isabelle; Hougen, Jon T.

    2015-01-01

    A new hybrid-model fitting program for methylamine-like molecules has been developed, based on an effective Hamiltonian in which the ammonia-like inversion motion is treated using a tunneling formalism, while the internal-rotation motion is treated using an explicit kinetic energy operator and potential energy function. The Hamiltonian in the computer program is set up as a 2×2 partitioned matrix, where each diagonal block contains a traditional torsion-rotation Hamiltonian (as in the earlier program BELGI), and the two off-diagonal blocks contain tunneling terms. This hybrid formulation permits the use of the permutation-inversion group G6 (isomorphic to C3v) for terms in the two diagonal blocks, but requires G12 for terms in the off-diagonal blocks. The first application of the new program is to 2-methylmalonaldehyde. Microwave data for this molecule were previously fit using an all-tunneling Hamiltonian formalism to treat both large-amplitude-motions. For 2-methylmalonaldehyde, the hybrid program achieves the same quality of fit as was obtained with the all-tunneling program, but fits with the hybrid program eliminate a large discrepancy between internal rotation barriers in the OH and OD isotopologs of 2-methylmalonaldehyde that arose in fits with the all-tunneling program. This large isotopic shift in internal rotation barrier is thus almost certainly an artifact of the all-tunneling model. Other molecules for application of the hybrid program are mentioned. PMID:26439709

  5. CONDORR--CONstrained Dynamics of Rigid Residues: a molecular dynamics program for constrained molecules.

    PubMed

    York, William S; Yi, Xiaobing

    2004-08-01

    A computer program CONDORR (CONstrained Dynamics of Rigid Residues) was developed for molecular dynamics simulations of large and/or constrained molecular systems, particularly carbohydrates. CONDORR efficiently calculates molecular trajectories on the basis of 2D or 3D potential energy maps, and can generate such maps based on a simple force field. The simulations involve three translational and three rotational degrees of freedom for each rigid, asymmetrical residue in the model. Total energy and angular momentum are conserved when no stochastic or external forces are applied to the model, if the time step is kept sufficiently short. Application of Langevin dynamics allows longer time steps, providing efficient exploration of conformational space. The utility of CONDORR was demonstrated by application to a constrained polysaccharide model and to the calculation of residual dipolar couplings for a disaccharide. [Figure: see text]. Molecular models (bottom) are created by cloning rigid residue archetypes (top) and joining them together. As defined here, the archetypes AX, HM and BG respectively correspond to an alpha-D-Xyl p residue, a hydroxymethyl group, and a beta-D-Glc p residue lacking O6, H6a and H6b. Each archetype contains atoms (indicated by boxes) that can be shared with other archetypes to form a linked structure. For example, the glycosidic link between the two D-Glc p residues is established by specifying that O1 of the nonreducing beta-D-Glc p (BG) residue (2) is identical to O4 of the reducing Glc p (BG) residue (1). The coordinates of the two residues are adjusted so as to superimpose these two (nominally distinct) atoms. Flexible hydroxymethyl (HM) groups (3 and 4) are treated as separate residues, and the torsional angles (normally indicated by the symbol omega) that define their geometric relationships to the pyranosyl rings of the BG residues are specified as psi3 and psi4, respectively. The torsional angles phi3 and phi4, defined solely to

  6. dParFit: A computer program for fitting diatomic molecule spectral data to parameterized level energy expressions

    NASA Astrophysics Data System (ADS)

    Le Roy, Robert J.

    2017-01-01

    This paper describes FORTRAN program dParFit, which performs least-squares fits of diatomic molecule spectroscopic data involving one or more electronic states and one or more isotopologues, to parameterized expressions for the level energies. The data may consist of any combination of microwave, infrared or electronic vibrotational bands, fluorescence series or binding energies (from photo-association spectroscopy). The level energies for each electronic state may be described by one of: (i) band constants {Gv ,Bv ,Dv , … } for each vibrational level, (ii) generalized Dunham expansions, (iii) pure near-dissociation expansions (NDEs), (iv) mixed Dunham/NDE expressions, or (v) individual term values for each distinct level of each isotopologue. Different representations may be used for different electronic states and/or for different types of constants in a given fit (e.g., Gv and Bv may be represented one way and centrifugal distortion constants another). The effect of Λ-doubling or 2Σ splittings may be represented either by band constants (qvB or γvB, qvD or γvD, etc.) for each vibrational level of each isotopologue, or by using power series expansions in (v + 1/2) to represent those constants. Fits to Dunham or NDE expressions automatically incorporate normal first-order semiclassical mass scaling to allow combined analyses of multi-isotopologue data. In addition, dParFit may fit to determine atomic-mass-dependent terms required to account for breakdown of the Born-Oppenheimer and first-order semiclassical approximations. In any of these types of fits, one or more subsets of these parameters for one or more of the electronic states may be held fixed, while a limited parameter set is varied. The program can also use a set of read-in constants to make predictions and calculate deviations [ycalc -yobs ] for any chosen input data set, or to generate predictions of arbitrary data sets.

  7. dPotFit: A computer program to fit diatomic molecule spectral data to potential energy functions

    NASA Astrophysics Data System (ADS)

    Le Roy, Robert J.

    2017-01-01

    This paper describes program dPotFit, which performs least-squares fits of diatomic molecule spectroscopic data consisting of any combination of microwave, infrared or electronic vibrational bands, fluorescence series, and tunneling predissociation level widths, involving one or more electronic states and one or more isotopologs, and for appropriate systems, second virial coefficient data, to determine analytic potential energy functions defining the observed levels and other properties of each state. Four families of analytical potential functions are available for fitting in the current version of dPotFit: the Expanded Morse Oscillator (EMO) function, the Morse/Long-Range (MLR) function, the Double-Exponential/Long-Range (DELR) function, and the 'Generalized Potential Energy Function' (GPEF) of Šurkus, which incorporates a variety of polynomial functional forms. In addition, dPotFit allows sets of experimental data to be tested against predictions generated from three other families of analytic functions, namely, the 'Hannover Polynomial' (or "X-expansion") function, and the 'Tang-Toennies' and Scoles-Aziz 'HFD', exponential-plus-van der Waals functions, and from interpolation-smoothed pointwise potential energies, such as those obtained from ab initio or RKR calculations. dPotFit also allows the fits to determine atomic-mass-dependent Born-Oppenheimer breakdown functions, and singlet-state Λ-doubling, or 2Σ splitting radial strength functions for one or more electronic states. dPotFit always reports both the 95% confidence limit uncertainty and the "sensitivity" of each fitted parameter; the latter indicates the number of significant digits that must be retained when rounding fitted parameters, in order to ensure that predictions remain in full agreement with experiment. It will also, if requested, apply a "sequential rounding and refitting" procedure to yield a final parameter set defined by a minimum number of significant digits, while ensuring no

  8. Transcriptomics and Functional Genomics of ROS-Induced Cell Death Regulation by RADICAL-INDUCED CELL DEATH1

    PubMed Central

    Salojärvi, Jarkko; Cui, Fuqiang; Sipari, Nina; Leppälä, Johanna; Lamminmäki, Airi; Tomai, Gloria; Narayanasamy, Shaman; Reddy, Ramesha A.; Keinänen, Markku; Overmyer, Kirk; Kangasjärvi, Jaakko

    2014-01-01

    Plant responses to changes in environmental conditions are mediated by a network of signaling events leading to downstream responses, including changes in gene expression and activation of cell death programs. Arabidopsis thaliana RADICAL-INDUCED CELL DEATH1 (RCD1) has been proposed to regulate plant stress responses by protein-protein interactions with transcription factors. Furthermore, the rcd1 mutant has defective control of cell death in response to apoplastic reactive oxygen species (ROS). Combining transcriptomic and functional genomics approaches we first used microarray analysis in a time series to study changes in gene expression after apoplastic ROS treatment in rcd1. To identify a core set of cell death regulated genes, RCD1-regulated genes were clustered together with other array experiments from plants undergoing cell death or treated with various pathogens, plant hormones or other chemicals. Subsequently, selected rcd1 double mutants were constructed to further define the genetic requirements for the execution of apoplastic ROS induced cell death. Through the genetic analysis we identified WRKY70 and SGT1b as cell death regulators functioning downstream of RCD1 and show that quantitative rather than qualitative differences in gene expression related to cell death appeared to better explain the outcome. Allocation of plant energy to defenses diverts resources from growth. Recently, a plant response termed stress-induced morphogenic response (SIMR) was proposed to regulate the balance between defense and growth. Using a rcd1 double mutant collection we show that SIMR is mostly independent of the classical plant defense signaling pathways and that the redox balance is involved in development of SIMR. PMID:24550736

  9. Molecule nanoweaver

    DOEpatents

    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

    2009-03-10

    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.

  10. Formation of Ultracold Molecules

    SciTech Connect

    Cote, Robin

    2016-01-28

    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.

  11. Using Symmetry Group Correlation Tables to Explain why Erham (and Other Programs) cannot BE Used to Analyze Torsional Splittings of Some Molecules

    NASA Astrophysics Data System (ADS)

    Groner, Peter

    2016-06-01

    ERHAM has been used to analyze rotational spectra of many molecules with torsional splitting caused by one or two internal rotors. The gauche form of dimethyl ether-d1 whose equilibrium structure has C1 symmetry is an example of a molecule for which ERHAM could not model additional small splittings resolvable for many transitions, whereas the spectrum of the symmetric (anti, trans) form with a C{_s} equilibrium structure could be analyzed successfully with ERHAM. A more recent example where ERHAM failed is pinacolone CH_3-CO-C(CH_3)_3. In this case, the barriers to internal rotation of the methyl groups within the -C(CH_3)_3 unit are too high to produce observable internal rotation splittings, but the splittings due to the CH_3-CO methyl group could not be modeled correctly with ERHAM nor with any other available program (XIAM, BELGI-Cs, BELGI-C1, RAM36). In the paper, it was speculated that BELGI-Cs-2tops might be able to the job, but arguments against this possibility have also been put forward. The correlation between irreducible representations of groups and their subgroups according to Watson can be used not only to determine the total number of substates (components) to be expected but also to help decide which particular program has a chance for a successful analysis. As it turns out, the number of components of split lines depends on the molecular symmetry at equilibrium in relation to the highest possible symmetry for a given molecular symmetry group. Therefore, for pinacolone, the vibrational ground state is split into 10 torsional substates. P. Groner, J. Mol. Spectrosc. 278 (2012) 52-67. C. Richard et al. A&A 552 (2013), A117. Y. Zhao et al., J. Mol. Spectrosc. 318 (2015) 91-100, with references to all other programs mentioned in the abstract. J. K. G. Watson, Can. J. Physics 43 (1965) 1996-2007.

  12. Novel Checkpoints and Cosignaling Molecules in Cancer Immunotherapy.

    PubMed

    Giuroiu, Iulia; Weber, Jeffrey

    The recent demonstration of the antitumor efficacy of checkpoint protein inhibition has resulted in the approval of blocking antibodies against the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway in multiple different histologic findings. Therapeutic successes with PD-1/PD-L1 antibodies in melanoma and lung cancer have been followed by approvals in bladder, renal, and head and neck cancers and Hodgkin lymphoma, with others undoubtedly to come. However, PD-1 is only one of many checkpoints and agonistic regulatory molecules expressed on T cells by which maintenance of the balance between costimulatory and coinhibitory signaling pathways is perturbed in cancer. The manipulation of many of these molecules in cancer patients might be associated with clinical benefit. The majority of the T-cell cosignaling receptors belong to either the immunoglobulin superfamily or the tumor necrosis factor receptor superfamily. A total of 29 immunoglobulin superfamily and 26 tumor necrosis factor receptor superfamily cosignaling receptors have been identified that are expressed on T cells, providing fertile ground for development of inhibitory or agonistic antibodies and small molecules as cancer therapeutics. In the current work, we focus on some of the most promising new checkpoints and agonistic or cosignaling molecules that are in early clinical development as single agents or in combinations with PD-1/PD-L1, cytotoxic T-lymphocyte-associated protein 4 blockade, or chemotherapy with an emphasis on those that have reached the clinic and on important targets that are in late preclinical development.

  13. Interstellar molecules

    NASA Technical Reports Server (NTRS)

    Townes, C. H.

    1976-01-01

    Progress in the discovery and study of interstellar molecules is summarized. The 36 molecular species thus far identified in interstellar space are listed in several groups which include simple hydrides, oxides, and sulfides, various derivatives of ammonia, molecules involving linear carbon chains, cyanides, and molecules related in structure to formaldehyde, alcohols, or ethers. Several free radicals are described, the discovery of molecules in external galaxies is discussed, and possible mechanisms for molecular formation are noted. Methods for examining relative isotopic abundances by measuring molecules in interstellar clouds are outlined, mechanisms for the excitation of interstellar molecules are reviewed, and values are presented for the C-12/C-13 abundance ratio in a number of interstellar clouds. The detection of interstellar masers is discussed along with pumping mechanisms and masing transitions in H2CO, CH, OH, and SiO. The nature of dense interstellar clouds is examined in terms of several simple and complex cloud models, with emphasis on multiple condensation models.

  14. Dehydroascorbate: a possible surveillance molecule of oxidative stress and programmed cell death in the green alga Chlamydomonas reinhardtii.

    PubMed

    Murik, Omer; Elboher, Ahinoam; Kaplan, Aaron

    2014-04-01

    Chlamydomonas reinhardtii tolerates relatively high H2 O2 levels that induce an array of antioxidant activities. However, rather than rendering the cells more resistant to oxidative stress, the cells become far more sensitive to an additional H2 O2 dose. If H2 O2 is provided 1.5-9 h after an initial dose, it induces programmed cell death (PCD) in the wild-type, but not in the dum1 mutant impaired in the mitochondrial respiratory complex III. This mutant does not exhibit a secondary oxidative burst 4-5 h after the inducing H2 O2 , nor does it activate metacaspase-1 after the second H2 O2 treatment. The intracellular dehydroascorbate level, a product of ascorbate peroxidase, increases under conditions leading to PCD. The addition of dehydroascorbate induces PCD in the wild-type and dum1 cultures, but higher levels are required in dum1 cells, where it is metabolized faster. The application of dehydroascorbate induces the expression of metacaspase-2, which is much stronger than the expression of metacaspase-1. The presence or absence of oxidative stress, in addition to the rise in internal dehydroascorbate, may determine which metacaspase is activated during Chlamydomonas PCD. Cell death is strongly affected by the timing of H2 O2 or dehydroascorbate admission to synchronously grown cultures, suggesting that the cell cycle phase may distinguish cells that perish from those that do not.

  15. Comprehensive Analysis of the Therapeutic IgG4 Antibody Pembrolizumab: Hinge Modification Blocks Half Molecule Exchange In Vitro and In Vivo.

    PubMed

    Yang, Xiaoyu; Wang, Fengqiang; Zhang, Ying; Wang, Larry; Antonenko, Svetlana; Zhang, Shuli; Zhang, Yi Wei; Tabrizifard, Mohammad; Ermakov, Grigori; Wiswell, Derek; Beaumont, Maribel; Liu, Liming; Richardson, Daisy; Shameem, Mohammed; Ambrogelly, Alexandre

    2015-12-01

    IgG4 antibodies are evolving as an important class of cancer immunotherapies. However, human IgG4 can undergo Fab arm (half molecule) exchange with other IgG4 molecules in vivo. The hinge modification by a point mutation (S228P) prevents half molecule exchange of IgG4. However, the experimental confirmation is still expected by regulatory agencies. Here, we report for the first time the extensive analysis of half molecule exchange for a hinge-modified therapeutic IgG4 molecule, pembrolizumab (Keytruda) targeting programmed death 1 (PD1) receptor that was approved for advanced melanoma. Studies were performed in buffer or human serum using multiple exchange partners including natalizumab (Tysabri) and human IgG4 pool. Formation of bispecific antibodies was monitored by fluorescence resonance energy transfer, exchange with Fc fragments, mixed mode chromatography, immunoassays, and liquid chromatography-mass spectrometry. The half molecule exchange was also examined in vivo in SCID (severe combined immunodeficiency) mice. Both in vitro and in vivo results indicate that the hinge modification in pembrolizumab prevented half molecule exchange, whereas the unmodified counterpart anti-PD1 wt showed active exchange activity with other IgG4 antibodies or self-exchange activity with its own molecules. Our work, as an example expected for meeting regulatory requirements, contributes to establish without ambiguity that hinge-modified IgG4 antibodies are suitable for biotherapeutic applications. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  16. Mobius Molecules

    ERIC Educational Resources Information Center

    Eckert, J. M.

    1973-01-01

    Discusses formation of chemical molecules via Mobius strip intermediates, and concludes that many special physics-chemical properties of the fully closed circular form (1) of polyoma DNA are explainable by this topological feature. (CC)

  17. Interstellar Molecules

    ERIC Educational Resources Information Center

    Solomon, Philip M.

    1973-01-01

    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)

  18. Interstellar Molecules

    ERIC Educational Resources Information Center

    Solomon, Philip M.

    1973-01-01

    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)

  19. Mobius Molecules

    ERIC Educational Resources Information Center

    Eckert, J. M.

    1973-01-01

    Discusses formation of chemical molecules via Mobius strip intermediates, and concludes that many special physics-chemical properties of the fully closed circular form (1) of polyoma DNA are explainable by this topological feature. (CC)

  20. Enumerating molecules.

    SciTech Connect

    Visco, Donald Patrick, Jr.; Faulon, Jean-Loup Michel; Roe, Diana C.

    2004-04-01

    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. Phytoglobins Improve Hypoxic Root Growth by Alleviating Apical Meristem Cell Death1[OPEN

    PubMed Central

    Stasolla, Claudio

    2016-01-01

    Hypoxic root growth in maize (Zea mays) is influenced by the expression of phytoglobins (ZmPgbs). Relative to the wild type, suppression of ZmPgb1.1 or ZmPgb1.2 inhibits the growth of roots exposed to 4% oxygen, causing structural abnormalities in the root apical meristems. These effects were accompanied by increasing levels of reactive oxygen species (ROS), possibly through the transcriptional induction of four Respiratory Burst Oxidase Homologs. TUNEL-positive nuclei in meristematic cells indicated the involvement of programmed cell death (PCD) in the process. These cells also accumulated nitric oxide and stained heavily for ethylene biosynthetic transcripts. A sharp increase in the expression level of several 1-aminocyclopropane synthase (ZmAcs2, ZmAcs6, and ZmAcs7), 1-aminocyclopropane oxidase (Aco15, Aco20, Aco31, and Aco35), and ethylene-responsive (ZmErf2 and ZmEbf1) genes was observed in hypoxic ZmPgb-suppressing roots, which overproduced ethylene. Inhibiting ROS synthesis with diphenyleneiodonium or ethylene perception with 1-methylcyclopropene suppressed PCD, increased BAX inhibitor-1, an effective attenuator of the death programs in eukaryotes, and restored root growth. Hypoxic roots overexpressing ZmPgbs had the lowest level of ethylene and showed a reduction in ROS staining and TUNEL-positive nuclei in the meristematic cells. These roots retained functional meristems and exhibited the highest growth performance when subjected to hypoxic conditions. Collectively, these results suggest a novel function of Pgbs in protecting root apical meristems from hypoxia-induced PCD through mechanisms initiated by nitric oxide and mediated by ethylene via ROS. PMID:27702845

  2. The paralogous genes RADICAL-INDUCED CELL DEATH1 and SIMILAR TO RCD ONE1 have partially redundant functions during Arabidopsis development.

    PubMed

    Teotia, Sachin; Lamb, Rebecca S

    2009-09-01

    RADICAL-INDUCED CELL DEATH1 (RCD1) and SIMILAR TO RCD ONE1 (SRO1) are the only two proteins encoded in the Arabidopsis (Arabidopsis thaliana) genome containing both a putative poly(ADP-ribose) polymerase catalytic domain and a WWE protein-protein interaction domain, although similar proteins have been found in other eukaryotes. Poly(ADP-ribose) polymerases mediate the attachment of ADP-ribose units from donor NAD(+) molecules to target proteins and have been implicated in a number of processes, including DNA repair, apoptosis, transcription, and chromatin remodeling. We have isolated mutants in both RCD1 and SRO1, rcd1-3 and sro1-1, respectively. rcd1-3 plants display phenotypic defects as reported for previously isolated alleles, most notably reduced stature. In addition, rcd1-3 mutants display a number of additional developmental defects in root architecture and maintenance of reproductive development. While single mutant sro1-1 plants are relatively normal, loss of a single dose of SRO1 in the rcd1-3 background increases the severity of several developmental defects, implying that these genes do share some functions. However, rcd1-3 and sro1-1 mutants behave differently in several developmental events and abiotic stress responses, suggesting that they also have distinct functions. Remarkably, rcd1-3; sro1-1 double mutants display severe defects in embryogenesis and postembryonic development. This study shows that RCD1 and SRO1 are at least partially redundant and that they are essential genes for plant development.

  3. Immunoregulatory molecules are master regulators of inflammation during the immune response

    PubMed Central

    Sánchez-Madrid, Francisco

    2014-01-01

    The balance between pro- and anti-inflammatory signalling is critical to maintain the immune homeostasis under physiological conditions as well as for the control of inflammation in different pathological settings. Recent progress in the signalling pathways that control this balance has led to the development of novel therapeutic agents for diseases characterized by alterations in the activation/suppression of the immune response. Different molecules have a key role in the regulation of the immune system, including the receptors PD-1 (Programmed cell Death 1), CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) and galectins; or the intracellular enzyme IDO (indoleamine 2,3-dioxygenase). In addition, other molecules as CD69, AhR (Aryl hydrocarbon Receptor), and GADD45 (Growth Arrest and DNA Damage-inducible 45) family members, have emerged as potential targets for the regulation of the activation/suppression balance of immune cells. This review offers a perspective on well-characterized as well as emergent negative immune regulatory molecules in the context of autoimmune inflammatory diseases. PMID:22819828

  4. Mind Molecules

    PubMed Central

    Snyder, Solomon H.

    2011-01-01

    Scientific styles vary tremendously. For me, research is largely about the unfettered pursuit of novel ideas and experiments that can test multiple ideas in a day, not a year, an approach that I learned from my mentor Julius “Julie” Axelrod. This focus on creative conceptualizations has been my métier since working in the summers during medical school at the National Institutes of Health, during my two years in the Axelrod laboratory, and throughout my forty-five years at Johns Hopkins University School of Medicine. Equally important has been the “high” that emerges from brainstorming with my students. Nothing can compare with the eureka moments when, together, we sense new insights and, better yet, when high-risk, high-payoff experiments succeed. Although I have studied many different questions over the years, a common theme emerges: simple biochemical approaches to understanding molecular messengers, usually small molecules. Equally important has been identifying, purifying, and cloning the messengers' relevant biosynthetic, degradative, or target proteins, at all times seeking potential therapeutic relevance in the form of drugs. In the interests of brevity, this Reflections article is highly selective, and, with a few exceptions, literature citations are only of findings of our laboratory that illustrate notable themes. PMID:21543333

  5. Relative Sizes of Organic Molecules

    NASA Technical Reports Server (NTRS)

    2000-01-01

    This computer graphic depicts the relative complexity of crystallizing large proteins in order to study their structures through x-ray crystallography. Insulin is a vital protein whose structure has several subtle points that scientists are still trying to determine. Large molecules such as insuline are complex with structures that are comparatively difficult to understand. For comparison, a sugar molecule (which many people have grown as hard crystals in science glass) and a water molecule are shown. These images were produced with the Macmolecule program. Photo credit: NASA/Marshall Space Flight Center (MSFC)

  6. Relative Sizes of Organic Molecules

    NASA Technical Reports Server (NTRS)

    2000-01-01

    This computer graphic depicts the relative complexity of crystallizing large proteins in order to study their structures through x-ray crystallography. Insulin is a vital protein whose structure has several subtle points that scientists are still trying to determine. Large molecules such as insuline are complex with structures that are comparatively difficult to understand. For comparison, a sugar molecule (which many people have grown as hard crystals in science glass) and a water molecule are shown. These images were produced with the Macmolecule program. Photo credit: NASA/Marshall Space Flight Center (MSFC)

  7. Variational two-electron reduced density matrix theory for many-electron atoms and molecules: Implementation of the spin- and symmetry-adapted T{sub 2} condition through first-order semidefinite programming

    SciTech Connect

    Mazziotti, David A.

    2005-09-15

    The energy and properties of a many-electron atom or molecule may be directly computed from a variational optimization of a two-electron reduced density matrix (2RDM) that is constrained to represent many-electron quantum systems. In this paper we implement a variational 2RDM method with a representability constraint, known as the T{sub 2} condition. The optimization of the 2RDM is performed with a first-order algorithm for semidefinite programming [D. A. Mazziotti, Phys. Rev. Lett. 93, 213001 (2004)] which, because of its lower computational cost in comparison to second-order methods, allows the treatment of larger basis sets. We also derive and implement a spin- and symmetry-adapted formulation of the T{sub 2} condition that significantly decreases the size of the largest block in the T{sub 2} matrix. The T{sub 2} condition, originally derived by Erdahl [Int. J. Quantum Chem. 13, 697 (1978)], was recently applied via a second-order algorithm to atoms and molecules [Z. Zhao et al., J. Chem. Phys. 120, 2095 (2004)]. While these calculations were restricted to molecules at equilibrium geometries in minimal basis sets, we apply the 2RDM method with the T{sub 2} condition to compute the electronic energies of molecules in both minimal and nonminimal basis sets at equilibrium as well as nonequilibrium geometries. Accurate potential energies curves are produced for BH, HF, and N{sub 2}. Results are compared with the 2RDM method without the T{sub 2} condition as well as several wave-function methods.

  8. Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease

    PubMed Central

    Flies, Andrew S.; Blackburn, Nicholas B.; Lyons, Alan Bruce; Hayball, John D.; Woods, Gregory M.

    2017-01-01

    Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii) facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY) ligand-binding motif and the CTLA-4 (GVYVKM) inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs

  9. Comparative Analysis of Immune Checkpoint Molecules and Their Potential Role in the Transmissible Tasmanian Devil Facial Tumor Disease.

    PubMed

    Flies, Andrew S; Blackburn, Nicholas B; Lyons, Alan Bruce; Hayball, John D; Woods, Gregory M

    2017-01-01

    Immune checkpoint molecules function as a system of checks and balances that enhance or inhibit immune responses to infectious agents, foreign tissues, and cancerous cells. Immunotherapies that target immune checkpoint molecules, particularly the inhibitory molecules programmed cell death 1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have revolutionized human oncology in recent years, yet little is known about these key immune signaling molecules in species other than primates and rodents. The Tasmanian devil facial tumor disease is caused by transmissible cancers that have resulted in a massive decline in the wild Tasmanian devil population. We have recently demonstrated that the inhibitory checkpoint molecule PD-L1 is upregulated on Tasmanian devil (Sarcophilus harrisii) facial tumor cells in response to the interferon-gamma cytokine. As this could play a role in immune evasion by tumor cells, we performed a thorough comparative analysis of checkpoint molecule protein sequences among Tasmanian devils and eight other species. We report that many of the key signaling motifs and ligand-binding sites in the checkpoint molecules are highly conserved across the estimated 162 million years of evolution since the last common ancestor of placental and non-placental mammals. Specifically, we discovered that the CTLA-4 (MYPPPY) ligand-binding motif and the CTLA-4 (GVYVKM) inhibitory domain are completely conserved across all nine species used in our comparative analysis, suggesting that the function of CTLA-4 is likely conserved in these species. We also found that cysteine residues for intra- and intermolecular disulfide bonds were also highly conserved. For instance, all 20 cysteine residues involved in disulfide bonds in the human 4-1BB molecule were also present in devil 4-1BB. Although many key sequences were conserved, we have also identified immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs

  10. A fitting program for molecules with two equivalent methyl tops and C2v point-group symmetry at equilibrium: Application to existing microwave, millimeter, and sub-millimeter wave measurements of acetone

    NASA Astrophysics Data System (ADS)

    Ilyushin, Vadim V.; Hougen, Jon. T.

    2013-07-01

    A program, called PAM_C2v_2tops, for fitting the high-resolution torsion-rotation spectra of molecules with two equivalent methyl rotors and C2v symmetry at equilibrium is described and applied to the spectrum of acetone [(CH3)2CO]. The G36 permutation-inversion group-theoretical considerations used in the design of the program are presented followed by a description of the structure of the program, which uses the principal axis method and a two-step diagonalization procedure. The program was used to carry out a weighted least-squares fit of 1720 microwave, millimeter-wave, and sub-millimeter-wave line frequencies of acetone that are available in the literature. The weighted standard deviation of 0.94 obtained here for a joint fit of rotational lines belonging to the ground, the lower torsional fundamental, and the higher torsional fundamental states of acetone represents significant progress in comparison with previous fitting attempts, especially for the excited torsional states.

  11. Physics of Molecules

    NASA Astrophysics Data System (ADS)

    Williams, D.; Murdin, P.

    2000-11-01

    Many varieties of molecule have been detected in the Milky Way and in other galaxies. The processes by which these molecules are formed and destroyed are now broadly understood (see INTERSTELLAR CHEMISTRY). These molecules are important components of galaxies in two ways. Firstly, radiation emitted by molecules enables us to trace the presence of diffuse gas, to infer its physical properties and ...

  12. Autonomous DNA-Molecule Computing

    NASA Astrophysics Data System (ADS)

    Komiya, Ken; Rose, John A.; Yamamura, Masayuki

    DNA molecules autonomously change their forms from the single strand to the double helix by specific binding between complementary sequences according to the Watson-Crick base pairing rule. This paring rule allows us to control connections among molecules and to construct various structures by sequence design. Further, the motion of constructed structures can also be designed by considering sequential bindings. Recently, the feasibility to utilize the programmed DNA structural change for information processing was studied. In the present paper, we report an efficient synthetic chain reaction based on autonomous binding of DNA to realize a computing system, which enable us to implement computational intelligence in vitro.

  13. Cell Wall Invertase Promotes Fruit Set under Heat Stress by Suppressing ROS-Independent Cell Death1[OPEN

    PubMed Central

    2016-01-01

    Reduced cell wall invertase (CWIN) activity has been shown to be associated with poor seed and fruit set under abiotic stress. Here, we examined whether genetically increasing native CWIN activity would sustain fruit set under long-term moderate heat stress (LMHS), an important factor limiting crop production, by using transgenic tomato (Solanum lycopersicum) with its CWIN inhibitor gene silenced and focusing on ovaries and fruits at 2 d before and after pollination, respectively. We found that the increase of CWIN activity suppressed LMHS-induced programmed cell death in fruits. Surprisingly, measurement of the contents of H2O2 and malondialdehyde and the activities of a cohort of antioxidant enzymes revealed that the CWIN-mediated inhibition on programmed cell death is exerted in a reactive oxygen species-independent manner. Elevation of CWIN activity sustained Suc import into fruits and increased activities of hexokinase and fructokinase in the ovaries in response to LMHS. Compared to the wild type, the CWIN-elevated transgenic plants exhibited higher transcript levels of heat shock protein genes Hsp90 and Hsp100 in ovaries and HspII17.6 in fruits under LMHS, which corresponded to a lower transcript level of a negative auxin responsive factor IAA9 but a higher expression of the auxin biosynthesis gene ToFZY6 in fruits at 2 d after pollination. Collectively, the data indicate that CWIN enhances fruit set under LMHS through suppression of programmed cell death in a reactive oxygen species-independent manner that could involve enhanced Suc import and catabolism, HSP expression, and auxin response and biosynthesis. PMID:27462084

  14. Conserved water molecules in bacterial serine hydroxymethyltransferases.

    PubMed

    Milano, Teresa; Di Salvo, Martino Luigi; Angelaccio, Sebastiana; Pascarella, Stefano

    2015-10-01

    Water molecules occurring in the interior of protein structures often are endowed with key structural and functional roles. We report the results of a systematic analysis of conserved water molecules in bacterial serine hydroxymethyltransferases (SHMTs). SHMTs are an important group of pyridoxal-5'-phosphate-dependent enzymes that catalyze the reversible conversion of l-serine and tetrahydropteroylglutamate to glycine and 5,10-methylenetetrahydropteroylglutamate. The approach utilized in this study relies on two programs, ProACT2 and WatCH. The first software is able to categorize water molecules in a protein crystallographic structure as buried, positioned in clefts or at the surface. The other program finds, in a set of superposed homologous proteins, water molecules that occur approximately in equivalent position in each of the considered structures. These groups of molecules are referred to as 'clusters' and represent structurally conserved water molecules. Several conserved clusters of buried or cleft water molecules were found in the set of 11 bacterial SHMTs we took into account for this work. The majority of these clusters were not described previously. Possible structural and functional roles for the conserved water molecules are envisaged. This work provides a map of the conserved water molecules helpful for deciphering SHMT mechanism and for rational design of molecular engineering experiments.

  15. Blockade of Programmed Death 1 Augments the Ability of Human T Cells Engineered to Target NY-ESO-1 to Control Tumor Growth after Adoptive Transfer.

    PubMed

    Moon, Edmund K; Ranganathan, Raghuveer; Eruslanov, Evgeniy; Kim, Soyeon; Newick, Kheng; O'Brien, Shaun; Lo, Albert; Liu, Xiaojun; Zhao, Yangbing; Albelda, Steven M

    2016-01-15

    Tumor-infiltrating lymphocytes (TILs) become hypofunctional, although the mechanisms are not clear. Our goal was to generate a model of human tumor-induced TIL hypofunction to study mechanisms and to test anti-human therapeutics. We transduced human T cells with a published, optimized T-cell receptor (TCR) that is directed to a peptide within the cancer testis antigen, NY-ESO-1. After demonstrating antigen-specific in vitro activity, these cells were used to target a human lung cancer line that expressed NY-ESO-1 in the appropriate HLA context growing in immunodeficient mice. The ability of anti-PD1 antibody to augment efficacy was tested. Injection of transgenic T cells had some antitumor activity, but did not eliminate the tumors. The injected T cells became profoundly hypofunctional accompanied by upregulation of PD1, Tim3, and Lag3 with coexpression of multiple inhibitory receptors in a high percentage of cells. This model allowed us to test reagents targeted specifically to human T cells. We found that injections of an anti-PD1 antibody in combination with T cells led to decreased TIL hypofunction and augmented the efficacy of the adoptively transferred T cells. This model offers a platform for preclinical testing of adjuvant immunotherapeutics targeted to human T cells prior to transition to the bedside. Because the model employs engineering of human T cells with a TCR clone instead of a CAR, it allows for study of the biology of tumor-reactive TILs that signal through an endogenous TCR. The lessons learned from TCR-engineered TILs can thus be applied to tumor-reactive TILs. ©2015 American Association for Cancer Research.

  16. a Fitting Program for Molecules with Two Equivalent Tops and C_{2V} Point-Group Symmetry at Equilibrium: Application to Existing Microwave, Millimeter, and Sub-Millimeter Wave Measurements of Acetone

    NASA Astrophysics Data System (ADS)

    Ilyushin, Vadim V.; Hougen, Jon T.

    2013-06-01

    We will present a new theoretical tool, a program called PAM-C2v-2tops, for analysis of the high-resolution torsion-rotation spectra of molecules with two equivalent methyl rotors and C_{2V} symmetry at equilibrium. The new tool belongs to the broad class of effective Hamiltonians, is based on Longuet-Higgins' group theoretical ideas and uses G_{36} permutation-inversion group-theoretical considerations, the principal axis method and a two-step diagonalization procedure. The program was used to carry out a weighted least-squares fit of 1720 microwave, millimeter-wave, and sub-millimeter-wave line frequencies of acetone [(CH_3)_2CO] that are available in the literature. The weighted root-mean-square deviation of 0.93 obtained for a joint fit of the microwave lines belonging to the ground, the lower torsional fundamental, and the higher torsional fundamental states of acetone represents significant progress in comparison with previous fitting attempts, especially for the excited torsional states.

  17. Singlet Oxygen-Induced Membrane Disruption and Serpin-Protease Balance in Vacuolar-Driven Cell Death1[OPEN

    PubMed Central

    Carmieli, Raanan; Mor, Avishai; Fluhr, Robert

    2016-01-01

    Singlet oxygen plays a role in cellular stress either by providing direct toxicity or through signaling to initiate death programs. It was therefore of interest to examine cell death, as occurs in Arabidopsis, due to differentially localized singlet oxygen photosensitizers. The photosensitizers rose bengal (RB) and acridine orange (AO) were localized to the plasmalemma and vacuole, respectively. Their photoactivation led to cell death as measured by ion leakage. Cell death could be inhibited by the singlet oxygen scavenger histidine in treatments with AO but not with RB. In the case of AO treatment, the vacuolar membrane was observed to disintegrate. Concomitantly, a complex was formed between a vacuolar cell-death protease, RESPONSIVE TO DESSICATION-21 and its cognate cytoplasmic protease inhibitor ATSERPIN1. In the case of RB treatment, the tonoplast remained intact and no complex was formed. Over-expression of AtSerpin1 repressed cell death, only under AO photodynamic treatment. Interestingly, acute water stress showed accumulation of singlet oxygen as determined by fluorescence of Singlet Oxygen Sensor Green, by electron paramagnetic resonance spectroscopy and the induction of singlet oxygen marker genes. Cell death by acute water stress was inhibited by the singlet oxygen scavenger histidine and was accompanied by vacuolar collapse and the appearance of serpin-protease complex. Over-expression of AtSerpin1 also attenuated cell death under this mode of cell stress. Thus, acute water stress damage shows parallels to vacuole-mediated cell death where the generation of singlet oxygen may play a role. PMID:26884487

  18. The status of molecules

    SciTech Connect

    Barnes, T. :

    1994-10-01

    This report summarizes the experimental and theoretical status of hadronic molecules, which are weakly-bound states of two or more hadrons. We begin with a brief history of the subject and discuss a few good candidates, and then abstract some signatures for molecules which may be of interest in the classification of possible molecule states. Next we argue that a more general understanding of 2 {yields} 2 hadron-hadron scattering amplitudes will be crucial for molecule searches, and discuss some of our recent work in this area. We conclude with a discussion of a few more recent molecule candidates (notably the f{sub o}(1710)) which are not well established as molecules but satisfy some of the expected signatures.

  19. [Endothelial cell adhesion molecules].

    PubMed

    Ivanov, A N; Norkin, I A; Puchin'ian, D M; Shirokov, V Iu; Zhdanova, O Iu

    2014-01-01

    The review presents current data concerning the functional role of endothelial cell adhesion molecules belonging to different structural families: integrins, selectins, cadherins, and the immunoglobulin super-family. In this manuscript the regulatory mechanisms and factors of adhesion molecules expression and distribution on the surface of endothelial cells are discussed. The data presented reveal the importance of adhesion molecules in the regulation of structural and functional state of endothelial cells in normal conditions and in pathology. Particular attention is paid to the importance of these molecules in the processes of physiological and pathological angiogenesis, regulation of permeability of the endothelial barrier and cell transmigration.

  20. Final Report: Cooling Molecules with Laser Light

    SciTech Connect

    Di Rosa, Michael D.

    2012-05-08

    Certain diatomic molecules are disposed to laser cooling in the way successfully applied to certain atoms and that ushered in a revolution in ultracold atomic physics, an identification first made at Los Alamos and which took root during this program. Despite their manipulation into numerous achievements, atoms are nonetheless mundane denizens of the quantum world. Molecules, on the other hand, with their internal degrees of freedom and rich dynamical interplay, provide considerably more complexity. Two main goals of this program were to demonstrate the feasibility of laser-cooling molecules to the same temperatures as laser-cooled atoms and introduce a means for collecting laser-cooled molecules into dense ensembles, a foundational start of studies and applications of ultracold matter without equivalence in atomic systems.

  1. Chemical Recycling of Molecules in Cometary Comae

    NASA Astrophysics Data System (ADS)

    Boice, Daniel C.; Kawakita, Hideyo; Shinnaka, Yoshiharu; Kobayashi, Hitomi

    2015-08-01

    Modeling is essential to understand the important physical and chemical processes that occur in cometary comae, especially the relationship between native and sibling molecules, such as, HCN and CN. Photochemistry is a major source of ions and electrons that further initiate key gas-phase reactions, leading to the plethora of molecules and atoms observed in comets. The effects of photoelectrons that react via impacts are important to the overall ionization in the inner coma. We have found that many molecules undergo protonation reactions with primarily water, followed by electron recombination resulting in the original molecules in a vibrationally excited state. These excited molecules spontaneously emit photons back to the ground state. We identify this series of reactions as chemical “recycling.” We discuss the importance of this mechanism for HCN, NH3, and water in comets. We also identify other relevant processes in the collision-dominated, inner coma of a comet within a global modeling framework to better understand observations and in situ measurements of cometary species, especially relationships between native and sibling molecules for the Rosetta Mission to Comet 67P/Churyumov-Gerasimenko.Acknowledgements: We appreciate support from the NSF Planetary Astronomy Program under Grant No. 0908529. This program is partially supported by the MEXT Supported Program for the Strategic Research Foundation at Private Universities, 2014-2018.

  2. Enzymatic DNA molecules

    NASA Technical Reports Server (NTRS)

    Joyce, Gerald F. (Inventor); Breaker, Ronald R. (Inventor)

    1998-01-01

    The present invention discloses deoxyribonucleic acid enzymes--catalytic or enzymatic DNA molecules--capable of cleaving nucleic acid sequences or molecules, particularly RNA, in a site-specific manner, as well as compositions including same. Methods of making and using the disclosed enzymes and compositions are also disclosed.

  3. Molecules between the Stars.

    ERIC Educational Resources Information Center

    Verschuur, Gerrit L.

    1987-01-01

    Provides a listing of molecules discovered to date in the vast interstellar clouds of dust and gas. Emphasizes the recent discoveries of organic molecules. Discusses molecular spectral lines, MASERs (microwave amplification by stimulated emission of radiation), molecular clouds, and star birth. (TW)

  4. Molecules between the Stars.

    ERIC Educational Resources Information Center

    Verschuur, Gerrit L.

    1987-01-01

    Provides a listing of molecules discovered to date in the vast interstellar clouds of dust and gas. Emphasizes the recent discoveries of organic molecules. Discusses molecular spectral lines, MASERs (microwave amplification by stimulated emission of radiation), molecular clouds, and star birth. (TW)

  5. Porous organic molecules

    NASA Astrophysics Data System (ADS)

    Holst, James R.; Trewin, Abbie; Cooper, Andrew I.

    2010-11-01

    Most synthetic materials that show molecular-scale porosity consist of one-, two- or three-dimensional networks. Porous metal-organic frameworks in particular have attracted a lot of recent attention. By contrast, discrete molecules tend to pack efficiently in the solid state, leaving as little empty space as possible, which leads to non-porous materials. This Perspective discusses recent developments with discrete organic molecules that are porous in the solid state. Such molecules, which may be either crystalline or amorphous, can be categorized as either intrinsically porous (containing permanent covalent cavities) or extrinsically porous (inefficiently packed). We focus on the possible advantages of organic molecules over inorganic or hybrid systems in terms of molecular solubility, choice of components and functionalities, and structural mobility and responsiveness in non-covalent extended solids. We also highlight the potential for 'undiscovered' porous systems among the large number of cage-like organic molecules that are already known.

  6. Single molecule electronic devices.

    PubMed

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

    2011-04-12

    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. Dynamics of Activated Molecules

    SciTech Connect

    Mullin, Amy S.

    2016-11-16

    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.

  8. Heavy exotic molecules

    NASA Astrophysics Data System (ADS)

    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+- 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.

  9. Heavy exotic molecules

    NASA Astrophysics Data System (ADS)

    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.

  10. Of Molecules and Models.

    ERIC Educational Resources Information Center

    Brinner, Bonnie

    1992-01-01

    Presents an activity in which models help students visualize both the DNA process and transcription. After constructing DNA, RNA messenger, and RNA transfer molecules; students model cells, protein synthesis, codons, and RNA movement. (MDH)

  11. Single-Molecule Enzymology

    SciTech Connect

    Xie, Xiaoliang; Lu, H PETER.

    1999-06-04

    Viewing a movie of an enzyme molecule made from molecular dynamics (MD) simulation, we see incredible details of molecular motions, be it a change of the conformation or the action of a chemical reaction.

  12. Of Molecules and Models.

    ERIC Educational Resources Information Center

    Brinner, Bonnie

    1992-01-01

    Presents an activity in which models help students visualize both the DNA process and transcription. After constructing DNA, RNA messenger, and RNA transfer molecules; students model cells, protein synthesis, codons, and RNA movement. (MDH)

  13. Polyatomic molecule vibrations

    NASA Technical Reports Server (NTRS)

    1976-01-01

    Polyatomic molecule vibrations are analyzed as harmonic vibrations along normal coordinates. The energy eigenvalues are found for linear and nonlinear symmetric triatomic molecules for valence bond models of the potential function with arbitrary coupling coefficients; such models can usually be fitted to observed energy levels with reasonably good accuracy. Approximate normal coordinates for the H2O molecule are discussed. Degenerate vibrational modes such as occur in CO2 are analyzed and expressions for Fermi resonance between close-lying states of the same symmetry are developed. The bending modes of linear triatomic molecules are expressed in terms of Laguerre polynomials in cylindrical coordinates as well as in terms of Hermite polynomials in Cartesian coordinates. The effects of large-amplitude bending such as occur in the C3 molecule are analyzed, along with anharmonic effects, which split the usually degenerate bending mode energy levels. Finally, the vibrational frequencies, degeneracies, and symmetry properties of XY3, X2Y2, and XY4 type molecules are discussed.

  14. Computing Fluxes Of Molecules On And Near A Spacecraft

    NASA Technical Reports Server (NTRS)

    Ehlers, H. K.; Rios, E. R.; Hakes, C. L.; Bui, B. D.

    1996-01-01

    Molecular Flux (MOLFLUX) computer code is versatile program used to compute following conditions on and near spacecraft: fluxes of molecules to, and deposition of molecules on, surfaces; densities and column densities of molecules in surrounding space, and return fluxes of molecules to surfaces caused by both collisions of molecules with ambient atmosphere and by self-scattering. User has option to modify spacecraft configurations and sources of contamination and to choose which critical surfaces to examine. Written in FORTRAN and C language. Three machine versions available: VAX version (MSC-22260), HP version (MSC-22565), and Cray version (MSC-22566).

  15. Computing Fluxes Of Molecules On And Near A Spacecraft

    NASA Technical Reports Server (NTRS)

    Ehlers, H. K.; Rios, E. R.; Hakes, C. L.; Bui, B. D.

    1996-01-01

    Molecular Flux (MOLFLUX) computer code is versatile program used to compute following conditions on and near spacecraft: fluxes of molecules to, and deposition of molecules on, surfaces; densities and column densities of molecules in surrounding space, and return fluxes of molecules to surfaces caused by both collisions of molecules with ambient atmosphere and by self-scattering. User has option to modify spacecraft configurations and sources of contamination and to choose which critical surfaces to examine. Written in FORTRAN and C language. Three machine versions available: VAX version (MSC-22260), HP version (MSC-22565), and Cray version (MSC-22566).

  16. Understanding ultracold polar molecules

    NASA Astrophysics Data System (ADS)

    Julienne, Paul

    2009-05-01

    The successful production of a dense sample of ultracold ground state KRb polar molecules [1] opens the door to a new era of research with dipolar gases and lattices of such species. This feat was achieved by first associating a K and a Rb atom to make a weakly bound Feshbach molecule and then coherently transferring the population to the ground vibrational level of the molecule. This talk focuses on theoretical issues associated with making and using ultracold polar molecules, using KRb as an example [2]. Full understanding of this species and the processes by which it is made requires taking advantage of accurate molecular potentials [3], ab initio calculations [4], and the properties of the long-range potential. A highly accurate model is available for KRb for all bound states below the ground state separated atom limit and could be constructed for other species. The next step is to develop an understanding of the interactions between polar molecules, and their control in the ultracold domain. Understanding long-range interactions and threshold resonances will be crucial for future work. [1] K.-K. Ni, et al, Science 322, 231(2008). [2] P. S. Julienne, arXiv:0812:1233. [3] Pashov et al., Phys. Rev. A76, 022511 (2007). [4] S. Kotochigova, et al., arXiv:0901.1486.

  17. The defender against apoptotic cell death 1 gene is required for tissue growth and efficient N-glycosylation in Drosophila melanogaster.

    PubMed

    Zhang, Yifan; Cui, Chang; Lai, Zhi-Chun

    2016-12-01

    How organ growth is regulated in multicellular organisms is a long-standing question in developmental biology. It is known that coordination of cell apoptosis and proliferation is critical in cell number and overall organ size control, while how these processes are regulated is still under investigation. In this study, we found that functional loss of a gene in Drosophila, named Drosophila defender against apoptotic cell death 1 (dDad1), leads to a reduction of tissue growth due to increased apoptosis and lack of cell proliferation. The dDad1 protein, an orthologue of mammalian Dad1, was found to be crucial for protein N-glycosylation in developing tissues. Our study demonstrated that loss of dDad1 function activates JNK signaling and blocking the JNK pathway in dDad1 knock-down tissues suppresses cell apoptosis and partially restores organ size. In addition, reduction of dDad1 triggers ER stress and activates unfolded protein response (UPR) signaling, prior to the activation of JNK signaling. Furthermore, Perk-Atf4 signaling, one branch of UPR pathways, appears to play a dual role in inducing cell apoptosis and mediating compensatory cell proliferation in this dDad1 knock-down model. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Positronium ions and molecules

    NASA Technical Reports Server (NTRS)

    Ho, Y. K.

    1990-01-01

    Recent theoretical studies on positronium ions and molecules are discussed. A positronium ion is a three particle system consisting of two electrons in singlet spin state, and a positron. Recent studies include calculations of its binding energy, positron annihilation rate, and investigations of its doubly excited resonant states. A positronium molecule is a four body system consisting of two positrons and two electrons in an overall singlet spin state. The recent calculations of its binding energy against the dissociation into two positronium atoms, and studies of auto-detaching states in positronium molecules are discussed. These auto-dissociating states, which are believed to be part of the Rydberg series as a result of a positron attaching to a negatively charged positronium ion, Ps-, would appear as resonances in Ps-Ps scattering.

  19. Single-Molecule Bioelectronics

    PubMed Central

    Rosenstein, Jacob K.; Lemay, Serge G.; Shepard, Kenneth L.

    2014-01-01

    Experimental techniques which interface single biomolecules directly with microelectronic systems are increasingly being used in a wide range of powerful applications, from fundamental studies of biomolecules to ultra-sensitive assays. Here we review several technologies which can perform electronic measurements of single molecules in solution: ion channels, nanopore sensors, carbon nanotube field-effect transistors, electron tunneling gaps, and redox cycling. We discuss the shared features among these techniques that enable them to resolve individual molecules, and discuss their limitations. Recordings from each of these methods all rely on similar electronic instrumentation, and we discuss the relevant circuit implementations and potential for scaling these single-molecule bioelectronic interfaces to high-throughput arrayed sensing platforms. PMID:25529538

  20. MOLECULES IN {eta} CARINAE

    SciTech Connect

    Loinard, Laurent; Menten, Karl M.; Guesten, Rolf; Zapata, Luis A.; Rodriguez, Luis F.

    2012-04-10

    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.

  1. Molecules as Automata

    NASA Astrophysics Data System (ADS)

    Cardelli, Luca

    Molecular biology investigates the structure and function of biochemical systems starting from their basic building blocks: macromolecules. A macromolecule is a large, complex molecule (a protein or a nucleic acid) that usually has inner mutable state and external activity. Informal explanations of biochemical events trace individual macromolecules through their state changes and their interaction histories: a macromolecule is endowed with an identity that is retained through its transformations, even through changes in molecular energy and mass. A macromolecule, therefore, is qualitatively different from the small molecules of inorganic chemistry. Such molecules are stateless: in the standard notation for chemical reactions they are seemingly created and destroyed, and their atomic structure is used mainly for the bookkeeping required by the conservation of mass.

  2. Photochemistry of interstellar molecules

    NASA Technical Reports Server (NTRS)

    Stief, L. J.

    1971-01-01

    The photochemistry of two diatomic and eight polyatomic molecules is discussed quantitatively. For an interstellar molecule, the lifetime against photodecomposition depends upon the absorption cross section, the quantum yield or probability of dissociation following photon absorption, and the interstellar radiation field. The constant energy density of Habing is used for the unobserved regions of interstellar radiation field, and the field in obscuring clouds is estimated by combining the constant flux with the observed interstellar extinction curve covering the visible and ultraviolet regions. Lifetimes against photodecomposition in the unobscured regions and as a function of increasing optical thickness in obscuring clouds are calculated for the ten species. The results show that, except for CO, all the molecules have comparable lifetimes of less than one hundred years. Thus they can exist only in dense clouds and can never have been exposed to the unobscured radiation. The calculations further show that the lifetimes in clouds of moderate opacity are of the order of one million years.

  3. Single molecule diffraction.

    PubMed

    Spence, J C H; Doak, R B

    2004-05-14

    For solving the atomic structure of organic molecules such as small proteins which are difficult to crystallize, the use of a jet of doped liquid helium droplets traversing a continuous high energy electron beam is proposed as a means of obtaining electron diffraction patterns (serial crystallography). Organic molecules (such as small proteins) within the droplet (and within a vitreous ice jacket) may be aligned by use of a polarized laser beam. Iterative methods for solving the phase problem are indicated. Comparisons with a related plan for pulsed x-ray diffraction from single proteins in a molecular beam are provided.

  4. DNA: An Extensible Molecule

    NASA Astrophysics Data System (ADS)

    Cluzel, Philippe; Lebrun, Anne; Heller, Christoph; Lavery, Richard; Viovy, Jean-Louis; Chatenay, Didier; Caron, Francois

    1996-02-01

    The force-displacement response of a single duplex DNA molecule was measured. The force saturates at a plateau around 70 piconewtons, which ends when the DNA has been stretched about 1.7 times its contour length. This behavior reveals a highly cooperative transition to a state here termed S-DNA. Addition of an intercalator suppresses this transition. Molecular modeling of the process also yields a force plateau and suggests a structure for the extended form. These results may shed light on biological processes involving DNA extension and open the route for mechanical studies on individual molecules in a previously unexplored range.

  5. Enzyme molecules as nanomotors.

    PubMed

    Sengupta, Samudra; Dey, Krishna K; Muddana, Hari S; Tabouillot, Tristan; Ibele, Michael E; Butler, Peter J; Sen, Ayusman

    2013-01-30

    Using fluorescence correlation spectroscopy, we show that the diffusive movements of catalase enzyme molecules increase in the presence of the substrate, hydrogen peroxide, in a concentration-dependent manner. Employing a microfluidic device to generate a substrate concentration gradient, we show that both catalase and urease enzyme molecules spread toward areas of higher substrate concentration, a form of chemotaxis at the molecular scale. Using glucose oxidase and glucose to generate a hydrogen peroxide gradient, we induce the migration of catalase toward glucose oxidase, thereby showing that chemically interconnected enzymes can be drawn together.

  6. Diversity in Biological Molecules

    ERIC Educational Resources Information Center

    Newbury, H. John

    2010-01-01

    One of the striking characteristics of fundamental biological processes, such as genetic inheritance, development and primary metabolism, is the limited amount of variation in the molecules involved. Natural selective pressures act strongly on these core processes and individuals carrying mutations and producing slightly sub-optimal versions of…

  7. Mighty Molecule Models

    ERIC Educational Resources Information Center

    Brown, Tom; Rushton, Greg; Bencomo, Marie

    2008-01-01

    As part of the SMATHematics Project: The Wonder of Science, The Power of Mathematics--a collaborative partnership between Kennesaw State University and two local school districts, fifth graders had the opportunity to puzzle out chemical formulas of propane, methanol, and other important molecules. In addition, they explored properties that…

  8. Diversity in Biological Molecules

    ERIC Educational Resources Information Center

    Newbury, H. John

    2010-01-01

    One of the striking characteristics of fundamental biological processes, such as genetic inheritance, development and primary metabolism, is the limited amount of variation in the molecules involved. Natural selective pressures act strongly on these core processes and individuals carrying mutations and producing slightly sub-optimal versions of…

  9. Mighty Molecule Models

    ERIC Educational Resources Information Center

    Brown, Tom; Rushton, Greg; Bencomo, Marie

    2008-01-01

    As part of the SMATHematics Project: The Wonder of Science, The Power of Mathematics--a collaborative partnership between Kennesaw State University and two local school districts, fifth graders had the opportunity to puzzle out chemical formulas of propane, methanol, and other important molecules. In addition, they explored properties that…

  10. Disentangling DNA molecules

    NASA Astrophysics Data System (ADS)

    Vologodskii, Alexander

    2016-09-01

    The widespread circular form of DNA molecules inside cells creates very serious topological problems during replication. Due to the helical structure of the double helix the parental strands of circular DNA form a link of very high order, and yet they have to be unlinked before the cell division. DNA topoisomerases, the enzymes that catalyze passing of one DNA segment through another, solve this problem in principle. However, it is very difficult to remove all entanglements between the replicated DNA molecules due to huge length of DNA comparing to the cell size. One strategy that nature uses to overcome this problem is to create the topoisomerases that can dramatically reduce the fraction of linked circular DNA molecules relative to the corresponding fraction at thermodynamic equilibrium. This striking property of the enzymes means that the enzymes that interact with DNA only locally can access their topology, a global property of circular DNA molecules. This review considers the experimental studies of the phenomenon and analyzes the theoretical models that have been suggested in attempts to explain it. We describe here how various models of enzyme action can be investigated computationally. There is no doubt at the moment that we understand basic principles governing enzyme action. Still, there are essential quantitative discrepancies between the experimental data and the theoretical predictions. We consider how these discrepancies can be overcome.

  11. Single molecules: Thermodynamic limits

    NASA Astrophysics Data System (ADS)

    Liphardt, Jan

    2012-09-01

    Technologies aimed at single-molecule resolution of non-equilibrium systems increasingly require sophisticated new ways of thinking about thermodynamics. An elegant extension to standard fluctuation theory grants access to the kinetic intermediate states of these systems -- as DNA-pulling experiments now demonstrate.

  12. Disentangling DNA molecules.

    PubMed

    Vologodskii, Alexander

    2016-09-01

    The widespread circular form of DNA molecules inside cells creates very serious topological problems during replication. Due to the helical structure of the double helix the parental strands of circular DNA form a link of very high order, and yet they have to be unlinked before the cell division. DNA topoisomerases, the enzymes that catalyze passing of one DNA segment through another, solve this problem in principle. However, it is very difficult to remove all entanglements between the replicated DNA molecules due to huge length of DNA comparing to the cell size. One strategy that nature uses to overcome this problem is to create the topoisomerases that can dramatically reduce the fraction of linked circular DNA molecules relative to the corresponding fraction at thermodynamic equilibrium. This striking property of the enzymes means that the enzymes that interact with DNA only locally can access their topology, a global property of circular DNA molecules. This review considers the experimental studies of the phenomenon and analyzes the theoretical models that have been suggested in attempts to explain it. We describe here how various models of enzyme action can be investigated computationally. There is no doubt at the moment that we understand basic principles governing enzyme action. Still, there are essential quantitative discrepancies between the experimental data and the theoretical predictions. We consider how these discrepancies can be overcome. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Sweeping molecules with light

    NASA Astrophysics Data System (ADS)

    Hutzler, Nicholas R.

    2017-03-01

    Many areas of physics—precision measurements, quantum information, and physical chemistry, to name a few—are starting to benefit from the enormous advantages offered by cold and ultracold polar molecules. Molecules have more states, more interactions, and more chemical properties compared to atoms, which make them exciting to study but difficult to tame. In particular, the powerful techniques of atomic laser cooling cannot be naïvely applied to molecules due to their complicated structure. Developments over the past few years have made directly laser cooled and trapped molecules a reality, and now much effort is focused on making these samples larger, denser, and colder—an important step to realizing many of their exciting applications. A careful experimental and numerical study by Truppe et al (2017 New J. Phys. 19 022001) demonstrates a significant improvement and advance in understanding of one of the most limiting steps in laser cooling and trapping of molecules—slowing them from a molecular beam to a near-standstill, with small enough kinetic energy that they can be loaded into a trap.

  14. Three new 'nonterrestrial' molecules

    NASA Astrophysics Data System (ADS)

    Thaddeus, P.; Guelin, M.; Linke, R. A.

    1981-05-01

    Eight new interstellar lines have been detected from three molecules not previously observed spectroscopically in space or in the laboratory. One is a linear or nearly linear molecule with microwave constants B0 equals 21,337.15 plus or minus 0.06 MHz, D0 equals 21.4 plus or minus 1.5 kHz. This is the thioformyl ion HCS(plus), first identified because B0 and D0 are close to those calculated, and now confirmed by laboratory detection of one of the present lines (Gudeman et al.). The second molecule, also linear or nearly so, has microwave constants B0 equals 10,691,406 plus or minus 0.043 MHz, D0 equals 1.84 plus or minus 0.91 kHz close to those expected for the isoelectronic systems HOCO(plus) and HOCN; a choice between the two cannot be made on the basis of the available astronomical data. The existence of a third molecule is deduced from an unidentified line at 85,338 MHz that has been found in many sources, is fairly intense in several, and may be self-absorbed in Sgr B2.

  15. Algebraic theory of molecules

    NASA Technical Reports Server (NTRS)

    Iachello, Franco

    1995-01-01

    An algebraic formulation of quantum mechanics is presented. In this formulation, operators of interest are expanded onto elements of an algebra, G. For bound state problems in nu dimensions the algebra G is taken to be U(nu + 1). Applications to the structure of molecules are presented.

  16. OMG: Open Molecule Generator.

    PubMed

    Peironcely, Julio E; Rojas-Chertó, Miguel; Fichera, Davide; Reijmers, Theo; Coulier, Leon; Faulon, Jean-Loup; Hankemeier, Thomas

    2012-09-17

    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.

  17. OMG: Open Molecule Generator

    PubMed Central

    2012-01-01

    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. PMID:22985496

  18. Bacterial invasion reconstructed molecule by molecule

    SciTech Connect

    Werner, James H

    2009-01-01

    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 point of

  19. A toy model for a diatomic molecule

    NASA Astrophysics Data System (ADS)

    Hecker Denschlag, Johannes

    2016-08-01

    We introduce a toy model for a diatomic molecule which is based on coupling electronic and nuclear spins to a rigid rotor. Despite its simplicity, the model can be used scientifically to analyze and understand complex molecular hyperfine spectra. In addition, the model has educational value as a number of fundamental symmetries and conservation laws of the molecule can be studied. Because of its simple structure, the model can be readily implemented as a computer program with comparatively short computing times on the order of a few seconds.

  20. Small molecule inhibitors of ebola virus infection.

    PubMed

    Picazo, Edwige; Giordanetto, Fabrizio

    2015-02-01

    Ebola viruses are extremely virulent and highly transmissible. They are responsible for sporadic outbreaks of severe hemorrhagic fevers with human mortality rates of up to 90%. No prophylactic or therapeutic treatments in the form of vaccine, biologicals or small molecule, currently exist. Yet, a wealth of antiviral research on ebola virus is being generated and potential inhibitors have been identified in biological screening and medicinal chemistry programs. Here, we detail the state-of-the-art in small molecule inhibitors of ebola virus infection, with >60 examples, including approved drugs, compounds currently in clinical trials, and more exploratory leads, and summarize the associated in vitro and in vivo evidence for their effectiveness.

  1. Computer Modelling of Biological Molecules: Free Resources on the Internet.

    ERIC Educational Resources Information Center

    Millar, Neil

    1996-01-01

    Describes a three-dimensional computer modeling system for biological molecules which is suitable for sixth-form teaching. Consists of the modeling program "RasMol" together with structure files of proteins, DNA, and small biological molecules. Describes how the whole system can be downloaded from various sites on the Internet.…

  2. Computer Modelling of Biological Molecules: Free Resources on the Internet.

    ERIC Educational Resources Information Center

    Millar, Neil

    1996-01-01

    Describes a three-dimensional computer modeling system for biological molecules which is suitable for sixth-form teaching. Consists of the modeling program "RasMol" together with structure files of proteins, DNA, and small biological molecules. Describes how the whole system can be downloaded from various sites on the Internet.…

  3. Calculating Henry’s Constants of Charged Molecules Using SPARC

    EPA Science Inventory

    SPARC Performs Automated Reasoning in Chemistry is a computer program designed to model physical and chemical properties of molecules solely based on thier chemical structure. SPARC uses a toolbox of mechanistic perturbation models to model intermolecular interactions. SPARC has ...

  4. Calculating Henry’s Constants of Charged Molecules Using SPARC

    EPA Science Inventory

    SPARC Performs Automated Reasoning in Chemistry is a computer program designed to model physical and chemical properties of molecules solely based on thier chemical structure. SPARC uses a toolbox of mechanistic perturbation models to model intermolecular interactions. SPARC has ...

  5. Molecules in Magnetic Fields

    NASA Astrophysics Data System (ADS)

    Berdyugina, Svetlana

    2015-08-01

    Molecules probe cool matter in the Universe and various astrophysical objects. Their ability to sense magnetic fields provides new insights into magnetic properties of these objects. During the past fifteen years we have carried out a theoretical study of molecular magnetic effects such as the Zeeman, Paschen-Back and Hanle effects and their applications for inferring magnetic structures and spatial inhomogeneities on the Sun, cool stars, brown dwarfs, and exoplanets from molecular spectro-polarimetry (e.g., Berdyugina 2011). Here, we present an overview of this study and compare our theoretical predictions with recent laboratory measurements of magnetic properties of some molecules. We present also a new web-based tool to compute molecular magnetic effects and polarized spectra which is supported by the ERC Advanced Grant HotMol.

  6. Single-molecule electrometry

    NASA Astrophysics Data System (ADS)

    Ruggeri, Francesca; Zosel, Franziska; Mutter, Natalie; Różycka, Mirosława; Wojtas, Magdalena; Ożyhar, Andrzej; Schuler, Benjamin; Krishnan, Madhavi

    2017-05-01

    Mass and electrical charge are fundamental properties of biological macromolecules. Although molecular mass has long been determined with atomic precision, a direct and precise determination of molecular charge remains an outstanding challenge. Here we report high-precision (<1e) measurements of the electrical charge of molecules such as nucleic acids, and globular and disordered proteins in solution. The measurement is based on parallel external field-free trapping of single macromolecules, permits the estimation of a dielectric coefficient of the molecular interior and can be performed in real time. Further, we demonstrate the direct detection of single amino acid substitution and chemical modifications in proteins. As the electrical charge of a macromolecule strongly depends on its three-dimensional conformation, this kind of high-precision electrometry offers an approach to probe the structure, fluctuations and interactions of a single molecule in solution.

  7. Strange skyrmion molecules

    NASA Astrophysics Data System (ADS)

    Kopeliovich, Vladimir B.; Stern, Boris E.

    1997-05-01

    Composed skyrmions with B=2, strangeness content close to 0.5 and the binding energy of several tens of Mev are described. These skyrmions are obtained starting from the system of two B=1 hedgehogs located in different SU(2) subgroups of SU(3) and have the mass and baryon number distribution of molecular (dipole) type. The quantization of zero modes of skyrmion molecules and physics consequences of their existence are discussed.

  8. Strange skyrmion molecules

    SciTech Connect

    Kopeliovich, Vladimir B.; Stern, Boris E.

    1997-05-20

    Composed skyrmions with B=2, strangeness content close to 0.5 and the binding energy of several tens of Mev are described. These skyrmions are obtained starting from the system of two B=1 hedgehogs located in different SU(2) subgroups of SU(3) and have the mass and baryon number distribution of molecular (dipole) type. The quantization of zero modes of skyrmion molecules and physics consequences of their existence are discussed.

  9. Characterization of dinaphthosulfoxide molecule

    NASA Astrophysics Data System (ADS)

    Uluçam, Gühergül; Okan, S. Erol; Aktaş, Şaban; Öğretmen, Gül Penbe

    2015-12-01

    Dinaphthosulfoxide has been synthesized, and confirmed by the experimental methods. The geometrical optimization of the two isomers of the molecule in their ground state was studied using density functional theory. Then, NMR and IR spectra were calculated for the optimized configurations. Analyzing the hydroxyl features in the NMR data and that of sulfoxide in IR spectra, the experimental observables are found to be in agreement with the properties of the syn isomer.

  10. Single Molecule Mechanochemistry

    NASA Astrophysics Data System (ADS)

    Li, Shaowei; Zhang, Yanxing; Ho, Wilson; Wu, Ruqian; Ruqian Wu, Yanxing Zhang Team; Wilson Ho, Shaowei Li Team

    Mechanical forces can be used to trigger chemical reactions through bending and stretching of chemical bonds. Using the reciprocating movement of the tip of a scanning tunneling microscope (STM), mechanical energy can be provided to a single molecule sandwiched between the tip and substrate. When the mechanical pulse center was moved to the outer ring feature of a CO molecule, the reaction rate was significantly increased compared with bare Cu surface and over Au atoms. First, DFT calculations show that the presence of CO makes the Cu cavity more attractive toward H2 Second, H2 prefers the horizontal adsorption geometry in the Cu-Cu and Au-Cu cavities and no hybridization occurs between the antibonding states of H2 and states of Cu atoms. While H2 loses electrons from its bonding state in all three cavities, the filling of its anti-bonding state only occurs in the CO-Cu cavity. Both make the CO-Cu cavity much more effectively to chop the H2 molecule. Work was supported by the National Science Foundation Center for Chemical Innovation on Chemistry at the Space-Time Limit (CaSTL) under Grant No. CHE-1414466.

  11. Photonic Molecule Lasers Revisited

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

    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.

  12. Model molecules mimicking asphaltenes.

    PubMed

    Sjöblom, Johan; Simon, Sébastien; Xu, Zhenghe

    2015-04-01

    Asphalthenes are typically defined as the fraction of petroleum insoluble in n-alkanes (typically heptane, but also hexane or pentane) but soluble in toluene. This fraction causes problems of emulsion formation and deposition/precipitation during crude oil production, processing and transport. From the definition it follows that asphaltenes are not a homogeneous fraction but is composed of molecules polydisperse in molecular weight, structure and functionalities. Their complexity makes the understanding of their properties difficult. Proper model molecules with well-defined structures which can resemble the properties of real asphaltenes can help to improve this understanding. Over the last ten years different research groups have proposed different asphaltene model molecules and studied them to determine how well they can mimic the properties of asphaltenes and determine the mechanisms behind the properties of asphaltenes. This article reviews the properties of the different classes of model compounds proposed and present their properties by comparison with fractionated asphaltenes. After presenting the interest of developing model asphaltenes, the composition and properties of asphaltenes are presented, followed by the presentation of approaches and accomplishments of different schools working on asphaltene model compounds. The presentation of bulk and interfacial properties of perylene-based model asphaltene compounds developed by Sjöblom et al. is the subject of the next part. Finally the emulsion-stabilization properties of fractionated asphaltenes and model asphaltene compounds is presented and discussed.

  13. Negative ions of polyatomic molecules.

    PubMed

    Christophorou, L G

    1980-06-01

    In this paper general concepts relating to, and recent advances in, the study of negative ions of polyatomic molecules area discussed with emphasis on halocarbons. The topics dealt with in the paper are as follows: basic electron attachment processes, modes of electron capture by molecules, short-lived transient negative ions, dissociative electron attachment to ground-state molecules and to "hot" molecules (effects of temperature on electron attachment), parent negative ions, effect of density, nature, and state of the medium on electron attachment, electron attachment to electronically excited molecules, the binding of attached electrons to molecules ("electron affinity"), and the basic and the applied significance of negative-ion studies.

  14. Watching single molecules dance

    NASA Astrophysics Data System (ADS)

    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

  15. Molecules in crystals

    NASA Astrophysics Data System (ADS)

    Spackman, Mark A.

    2013-04-01

    Hirshfeld surface analysis has developed from the serendipitous discovery of a novel partitioning of the crystal electron density into discrete molecular fragments, to a suite of computational tools used widely for the identification, analysis and discussion of intermolecular interactions in molecular crystals. The relationship between the Hirshfeld surface and very early ideas on the internal structure of crystals is outlined, and applications of Hirshfeld surface analysis are presented for three molecules of historical importance in the development of modern x-ray crystallography: hexamethylbenzene, hexamethylenetetramine and diketopiperazine.

  16. Advancing Biological Understanding and Therapeutics Discovery with Small Molecule Probes

    PubMed Central

    Schreiber, Stuart L.; Kotz, Joanne D.; Li, Min; Aubé, Jeffrey; Austin, Christopher P.; Reed, John C.; Rosen, Hugh; White, E. Lucile; Sklar, Larry A.; Lindsley, Craig W.; Alexander, Benjamin R.; Bittker, Joshua A.; Clemons, Paul A.; de Souza, Andrea; Foley, Michael A.; Palmer, Michelle; Shamji, Alykhan F.; Wawer, Mathias J.; McManus, Owen; Wu, Meng; Zou, Beiyan; Yu, Haibo; Golden, Jennifer E.; Schoenen, Frank J.; Simeonov, Anton; Jadhav, Ajit; Jackson, Michael R.; Pinkerton, Anthony B.; Chung, Thomas D.Y.; Griffin, Patrick R.; Cravatt, Benjamin F.; Hodder, Peter S.; Roush, William R.; Roberts, Edward; Chung, Dong-Hoon; Jonsson, Colleen B.; Noah, James W.; Severson, William E.; Ananthan, Subramaniam; Edwards, Bruce; Oprea, Tudor I.; Conn, P. Jeffrey; Hopkins, Corey R.; Wood, Michael R.; Stauffer, Shaun R.; Emmitte, Kyle A.

    2015-01-01

    Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the U.S. National Institutes of Health launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines, but also highlight the need to innovate the science of therapeutic discovery. PMID:26046436

  17. Ultra-cold molecule production.

    SciTech Connect

    Ramirez-Serrano, Jamie; Chandler, David W.; Strecker, Kevin; Rahn, Larry A.

    2005-12-01

    The production of Ultra-cold molecules is a goal of many laboratories through out the world. Here we are pursuing a unique technique that utilizes the kinematics of atomic and molecular collisions to achieve the goal of producing substantial numbers of sub Kelvin molecules confined in a trap. Here a trap is defined as an apparatus that spatially localizes, in a known location in the laboratory, a sample of molecules whose temperature is below one degree absolute Kelvin. Further, the storage time for the molecules must be sufficient to measure and possibly further cool the molecules. We utilize a technique unique to Sandia to form cold molecules from near mass degenerate collisions between atoms and molecules. This report describes the progress we have made using this novel technique and the further progress towards trapping molecules we have cooled.

  18. Dihydrino molecule identification

    SciTech Connect

    Mills, R.L.; Good, W.R. ); Shaubach, R.M. )

    1994-01-01

    Three sets of heat production and [open quotes]ash[close quotes] identification data are presented. An exothermic reaction is reported wherein the electrons of hydrogen and deuterium atoms are stimulated to relax to quantized potential energy levels below that of the [open quotes]ground state[close quotes] via electrochemical reactants K[sup +] and K[sup +]; Pd[sup 2+] and Li[sup +]; or Pd and O[sub 2] of redox energy resonant with the energy hole that stimulates this transition. Calorimetry of pulsed current and continuous electrolysis of aqueous potassium carbonate (K[sup +]/K[sup +] electrocatalytic couple) at a nickel cathode were performed. The excess output power of 41 W exceeded by a factor >8 the total input power given by the product of the electrolysis voltage and current. The product of the exothermic reaction is atoms having electrons of energy below the ground state, which are predicted to form molecules. The predicted molecules were identified by their lack of reactivity with oxygen, by separation from molecular deuterium by cryofiltration, and by mass spectroscopic analysis. 15 refs., 12 figs., 9 tabs.

  19. Covalent Chemistry beyond Molecules.

    PubMed

    Jiang, Juncong; Zhao, Yingbo; Yaghi, Omar M

    2016-03-16

    Linking molecular building units by covalent bonds to make crystalline extended structures has given rise to metal-organic frameworks (MOFs) and covalent organic frameworks (COFs), thus bringing the precision and versatility of covalent chemistry beyond discrete molecules to extended structures. The key advance in this regard has been the development of strategies to overcome the "crystallization problem", which is usually encountered when attempting to link molecular building units into covalent solids. Currently, numerous MOFs and COFs are made as crystalline materials in which the large size of the constituent units provides for open frameworks. The molecular units thus reticulated become part of a new environment where they have (a) lower degrees of freedom because they are fixed into position within the framework; (b) well-defined spatial arrangements where their properties are influenced by the intricacies of the pores; and (c) ordered patterns onto which functional groups can be covalently attached to produce chemical complexity. The notion of covalent chemistry beyond molecules is further strengthened by the fact that covalent reactions can be carried out on such frameworks, with full retention of their crystallinity and porosity. MOFs are exemplars of how this chemistry has led to porosity with designed metrics and functionality, chemically-rich sequences of information within their frameworks, and well-defined mesoscopic constructs in which nanoMOFs enclose inorganic nanocrystals and give them new levels of spatial definition, stability, and functionality.

  20. Molecules Best Paper Award 2013.

    PubMed

    McPhee, Derek J

    2013-02-05

    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.

  1. Molecules in the Spotlight

    SciTech Connect

    Cryan, James

    2010-01-26

    SLAC has just unveiled the world's first X-ray laser, the LCLS. This machine produces pulses of X-rays that are ten billion times brighter than those from conventional sources. One of the goals of this machine is to make movies of chemical reactions, including reactions necessary for life and reactions that might power new energy technologies. This public lecture will show the first results from the LCLS. As a first target, we have chosen nitrogen gas, the main component of the air we breathe. Using the unprecedented power of the LCLS X-rays as a blasting torch, we have created new forms of this molecule and with unique electronic arrangements. Please share with us the first insights from this new technology.

  2. Biochips - Can molecules compute?

    NASA Astrophysics Data System (ADS)

    Tucker, J. B.

    1984-02-01

    In recent years the possibility has been considered to build 'biochip' computers, in which the silicon transistors of present machines would be replaced by large organic molecules or genetically engineered proteins. Two major advantages of such biochips over current devices would be related to vastly increased densities of computing elements, and entirely new styles of data processing, suited to such high-level tasks as pattern recognition and context-dependent analysis. The limitations of the semiconductor chip with respect to the density of elementary units due to size considerations and heat development could be overcome by making use of molecular switches. Attention is given to soliton switching, soliton logic, bulk molecular devices, analog biochips, 'intelligent' switches based on the employment of enzymes, robot vision, questions of biochip fabrication, protein engineering, and a strategy for the development of biochips.

  3. Fiber-mesh photonic molecule

    NASA Astrophysics Data System (ADS)

    Mishra, Subodha; Satpathy, Sashi

    2008-03-01

    Analogous to the photonic crystal, we introduce the concept of a fiber-mesh photonic molecule made up of optical fibers and study its transmission characteristics. We consider a specific example of a photonic molecule, inspired by the well-known C60 molecule, with the arms of the molecule formed out of single-moded optical fibers. The transmittance consists of sharp peaks determined by the pole structure of the scattering matrix in the complex energy plane. A molecule can be designed to control the positions and the widths of the transmission peaks, opening up the possibility of building new photonic devices such as high quality band-pass filters.

  4. Source of polarized hydrogen molecules

    NASA Astrophysics Data System (ADS)

    Toporkov, D. K.; Gramolin, A. V.; Nikolenko, D. M.; Rachek, I. A.; Sadykov, R. Sh.; Shestakov, Yu. V.; Yurchenko, A. V.; Zevakov, S. A.

    2017-10-01

    A novel source of polarized hydrogen and deuterium molecules has been tested. The use of sextupole superconducting magnets allows us to select molecules with the nuclear spin projection -1 for hydrogen and -2 for deuterium. The measured beam intensity of polarized hydrogen molecules for the nozzle temperature range of 6.5-30 K and a gas flow rate up to 5 ṡ 10-2 Torr ṡ l / s is presented. The measured flux of polarized hydrogen molecules of ≈ 3 ṡ 1012 mol / s is in reasonable agreement with estimations. The obtained results can be used as a basis for the development of a high-intensity source of polarized molecules.

  5. The Submillimeter-wave Rotational Spectra of Interstellar Molecules

    NASA Technical Reports Server (NTRS)

    Herbst, Eric; DeLucia, Frank C.; Butler, R. A. H.; Winnewisser, M.; Winnewisser, G.; Fuchs, U.; Groner, P.; Sastry, K. V. L. N.

    2002-01-01

    We discuss past and recent progress in our long-term laboratory program concerning the submillimeter-wave rotational spectroscopy of known and likely interstellar molecules, especially those associated with regions of high-mass star formation. Our program on the use of spectroscopy to study rotationally inelastic collisions of interstellar interest is also briefly mentioned.

  6. Discovery of RNA Binding Small Molecules Using Small Molecule Microarrays.

    PubMed

    Connelly, Colleen M; Abulwerdi, Fardokht A; Schneekloth, John S

    2017-01-01

    New methods to identify RNA-binding small molecules open yet unexplored opportunities for the pharmacological modulation of RNA-driven biology and disease states. One such approach is the use of small molecule microarrays (SMMs). Typically, SMMs are generated by spatially arraying and covalently linking a library of small molecules to a glass surface. Next, incubation of the arrays with a fluorescently labeled RNA reveals binding interactions that are detected upon slide imaging. The relative ease with which SMMs are manufactured enables the screening of multiple oligonucleotides in parallel against tens of thousands of small molecules, providing information about both binding and selectivity of identified RNA-small molecule interactions. This approach is useful for screening a broad variety of structurally and functionally diverse RNAs. Here, we present a general method for the preparation and use of SMMs to rapidly identify small molecules that selectively bind to an RNA of interest.

  7. Geranyl diphosphate synthase molecules, and nucleic acid molecules encoding same

    DOEpatents

    Croteau, Rodney Bruce; Burke, Charles Cullen

    2008-06-24

    In one aspect, the present invention provides isolated nucleic acid molecules that each encode a geranyl diphosphate synthase protein, wherein each isolated nucleic acid molecule hybridizes to a nucleic acid molecule consisting of the sequence set forth in SEQ ID NO:1 under conditions of 5.times.SSC at 45.degree. C. for one hour. The present invention also provides isolated geranyl diphosphate synthase proteins, and methods for altering the level of expression of geranyl diphosphate synthase protein in a host cell.

  8. Organic Molecules in Meteorites

    NASA Astrophysics Data System (ADS)

    Martins, Zita

    2015-08-01

    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 (<30%) consists of a rich organic inventory of soluble organic compounds, including key compounds important in terrestrial biochemistry [2-4]. Different carbonaceous meteorites contain soluble organic molecules with different abundances and distributions, which may reflect the extension of aqueous alteration or thermal metamorphism on the meteorite parent bodies. Extensive aqueous alteration on the meteorite parent body may result on 1) the decomposition of α-amino acids [5, 6]; 2) synthesis of β- and γ-amino acids [2, 6-9]; 3) higher relative abundances of alkylated polycyclic aromatic hydrocarbons (PAHs) [6, 10]; and 4) higher L-enantiomer excess (Lee) value of isovaline [6, 11, 12].The soluble organic content of carbonaceous meteorites may also have a contribution from Fischer-Tropsch/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

  9. Electron-excited molecule interactions

    SciTech Connect

    Christophorou, L.G. Tennessee Univ., Knoxville, TN . Dept. of Physics)

    1991-01-01

    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.

  10. Atmospheric trace molecule spectroscopy

    NASA Technical Reports Server (NTRS)

    Farmer, C. B.

    1982-01-01

    The Spacelab investigation entitled Atmospheric Trace Molecule Spectroscopy (ATMOS) is designed to obtain fundamental information related to the chemistry and physics of the Earth's upper atmosphere using the techniques of infrared absorption spectroscopy. There are two principal objectives to be met. The first is the determination, on a global scale, of the compositional structure of the upper atmosphere and its spatial variability. The establishment of this variability represents the first step toward determining the characteristic residence times for the upper atmospheric constituents; the magnitudes of their sources and sinks; and, ultimately, an understanding of their effects on the stability of the stratosphere. The second objective is to provide the high-resolution, calibrated spectral information which is essential for the detailed design of advanced instrumentation for subsequent global monitoring of specific species found to be critical to atmospheric stability. This information will be disseminated in the form of a three dimensional atlas of solar absorption spectra obtained over a range of latitudes, longitudes, and altitudes.

  11. Single molecule tracking

    DOEpatents

    Shera, E. Brooks

    1988-01-01

    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.

  12. Electrochromic Graphene Molecules

    DOE PAGES

    Ji, Zhiqiang; Doorn, Stephen K.; Sykora, Milan

    2015-03-13

    Polyclic aromatic hydrocarbons, also called Graphene Molecules (GMs), with chemical composition C132H36(COOH)2 were synthesized in-situ on the surface of transparent nanocrystaline indium tin oxide (nc-ITO) electrodes. Their electronic structure was studied electrochemically and spectro-electrochemically. Variations in the potential applied onto the nc-ITO/GM electrodes induce only small changes in the observed current but they produce dramatic changes in the absorption of the GMs, which are associated with their oxidation and reduction. Analysis of the absorption changes using modified Nernst equation is used to determine standard potentials associated with the individual charge transfer processes. For the GMs prepared here these were foundmore » to be E1,ox 0 = 0.77± 0.01 V and E2,ox 0 = 1.24 ± 0.02 V vs. NHE for the first and second oxidation and E1,red 0 = -1.50 ± 0.04 V for the first reduction. The charge transfer processes are found to be non-ideal. The non-ideality factors associated with the oxidation and reduction processes suggest presence of strong interactions between the GM redox centers. Under the conditions of potential cycling GMs show rapid (seconds) color change with high contrast and stability. An electrochromic application is demonstrated wherein the GMs are used as the optically active component.« less

  13. Single molecule tracking

    DOEpatents

    Shera, E.B.

    1987-10-07

    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. Photons 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. 3 figs.

  14. Towards single molecule DNA sequencing

    NASA Astrophysics Data System (ADS)

    Liu, Hao

    Single molecule DNA Sequencing technology has been a hot research topic in the recent decades because it holds the promise to sequence a human genome in a fast and affordable way, which will eventually make personalized medicine possible. Single molecule differentiation and DNA translocation control are the two main challenges in all single molecule DNA sequencing methods. In this thesis, I will first introduce DNA sequencing technology development and its application, and then explain the performance and limitation of prior art in detail. Following that, I will show a single molecule DNA base differentiation result obtained in recognition tunneling experiments. Furthermore, I will explain the assembly of a nanofluidic platform for single strand DNA translocation, which holds the promised to be integrated into a single molecule DNA sequencing instrument for DNA translocation control. Taken together, my dissertation research demonstrated the potential of using recognition tunneling techniques to serve as a general readout system for single molecule DNA sequencing application.

  15. Water Molecule Hops on Ceres

    NASA Image and Video Library

    2016-12-15

    This graphic shows a theoretical path of a water molecule on Ceres. Some water molecules fall into cold, dark craters at high latitudes called "cold traps," where very little of the ice turns into vapor, even over the course of a billion years. Other water molecules that do not land in cold traps are lost to space as they hop around the dwarf planet. http://photojournal.jpl.nasa.gov/catalog/PIA21083

  16. Aromatic molecules as spintronic devices

    SciTech Connect

    Ojeda, J. H.; Orellana, P. A.; Laroze, D.

    2014-03-14

    In this paper, we study the spin-dependent electron transport through aromatic molecular chains attached to two semi-infinite leads. We model this system taking into account different geometrical configurations which are all characterized by a tight binding Hamiltonian. Based on the Green's function approach with a Landauer formalism, we find spin-dependent transport in short aromatic molecules by applying external magnetic fields. Additionally, we find that the magnetoresistance of aromatic molecules can reach different values, which are dependent on the variations in the applied magnetic field, length of the molecules, and the interactions between the contacts and the aromatic molecule.

  17. Vibrational autoionization in polyatomic molecules.

    PubMed

    Pratt, S T

    2005-01-01

    The vibrationally autoionizing Rydberg states of small polyatomic molecules provide a fascinating laboratory in which to study fundamental nonadiabatic processes. In this review, recent results on the vibrational mode dependence of vibrational autoionization are discussed. In general, autoionization rates depend strongly on the character of the normal mode driving the process and on the electronic character of the Rydberg electron. Although quantitative calculations based on multichannel quantum defect theory are available for some polyatomic molecules, including H3, only qualitative information exists for most molecules. This review shows how qualitative information, such as Walsh diagrams along different normal coordinates of the molecule, can provide insight into the vibrational autoionization rates.

  18. Electrical Transport through Organic Molecules

    NASA Astrophysics Data System (ADS)

    Lau, C. N.; Chang, Shun-Chi; Williams, Stan

    2003-03-01

    We investigate electrical transport properties of single organic molecules using electromigration break junctions[1]. A self-assembled monolayer of various organic molecules such as 1,4-di(phenylethynyl-4'-methanethiol)benzene was grown on narrow metal wires, and single or a few molecules were incorporated into the junctions which were created by applying a large voltage and breaking the wires. The transport properties of these molecules were then measured at low temperatures. Latest experimental results will be discussed. [1] Park, J. et al, Nature, 417, 722 (2002); Liang W. et al, Nature, 417, 725 (2002).

  19. Electrochromic Graphene Molecules

    SciTech Connect

    Ji, Zhiqiang; Doorn, Stephen K.; Sykora, Milan

    2015-03-13

    Polyclic aromatic hydrocarbons, also called Graphene Molecules (GMs), with chemical composition C132H36(COOH)2 were synthesized in-situ on the surface of transparent nanocrystaline indium tin oxide (nc-ITO) electrodes. Their electronic structure was studied electrochemically and spectro-electrochemically. Variations in the potential applied onto the nc-ITO/GM electrodes induce only small changes in the observed current but they produce dramatic changes in the absorption of the GMs, which are associated with their oxidation and reduction. Analysis of the absorption changes using modified Nernst equation is used to determine standard potentials associated with the individual charge transfer processes. For the GMs prepared here these were found to be E1,ox 0 = 0.77± 0.01 V and E2,ox 0 = 1.24 ± 0.02 V vs. NHE for the first and second oxidation and E1,red 0 = -1.50 ± 0.04 V for the first reduction. The charge transfer processes are found to be non-ideal. The non-ideality factors associated with the oxidation and reduction processes suggest presence of strong interactions between the GM redox centers. Under the conditions of potential cycling GMs show rapid (seconds) color change with high contrast and stability. An electrochromic application is demonstrated wherein the GMs are used as the optically active component.

  20. Computing Fluxes Of Molecules On And Near A Spacecraft

    NASA Technical Reports Server (NTRS)

    Ehlers, H. K.; Rios, E. R.; Hakes, C. L.; Rodriguez, R. T.

    1995-01-01

    Molecular Flux (MOLFLUX) computer code versatile program used to compute following environmental effects induced by spacecraft: fluxes of molecules to, and deposition of molecules on, surfaces; densities and column densities of molecules in surrounding space, and return fluxes of molecules to surfaces caused by both collisions of molecules with ambient atmosphere and by self-scattering. Includes capability to predict buildup in density of ambient gas in front of surfaces exposed to ram conditions by specifying ambient flux rates for all species impinging on surfaces. Surface chemical reactions represented as rates of emission from surfaces. User has option to modify spacecraft configurations and sources of contamination, and to choose which critical surfaces to examine. Written in FORTRAN and C language.

  1. Computing Fluxes Of Molecules On And Near A Spacecraft

    NASA Technical Reports Server (NTRS)

    Ehlers, H. K.; Rios, E. R.; Hakes, C. L.; Rodriguez, R. T.

    1995-01-01

    Molecular Flux (MOLFLUX) computer code versatile program used to compute following environmental effects induced by spacecraft: fluxes of molecules to, and deposition of molecules on, surfaces; densities and column densities of molecules in surrounding space, and return fluxes of molecules to surfaces caused by both collisions of molecules with ambient atmosphere and by self-scattering. Includes capability to predict buildup in density of ambient gas in front of surfaces exposed to ram conditions by specifying ambient flux rates for all species impinging on surfaces. Surface chemical reactions represented as rates of emission from surfaces. User has option to modify spacecraft configurations and sources of contamination, and to choose which critical surfaces to examine. Written in FORTRAN and C language.

  2. Ultrafast Imaging of Electronic Motion in Atoms and Molecules

    DTIC Science & Technology

    2016-01-12

    AFRL-AFOSR-VA-TR-2016-0045 Ultrafast Imaging of Electronic Motion in Atoms and Molecules Martin Centurion UNIVERSITY OF NEBRSKA Final Report 01/12...Ultrafast Imaging of Electronic Motion in Atoms and Molecules 5a. CONTRACT NUMBER 5b. GRANT NUMBER FA9550-12-1-0149 5c. PROGRAM ELEMENT NUMBER 6...Institution name University of Nebraska - Lincoln Grant/Contract Title The full title of the funded effort. Ultrafast Imaging of Electronic Motion in

  3. Micro-Kelvin cold molecules.

    SciTech Connect

    Strecker, Kevin E.; Chandler, David W.

    2009-10-01

    We have developed a novel experimental technique for direct production of cold molecules using a combination of techniques from atomic optical and molecular physics and physical chemistry. The ability to produce samples of cold molecules has application in a broad spectrum of technical fields high-resolution spectroscopy, remote sensing, quantum computing, materials simulation, and understanding fundamental chemical dynamics. Researchers around the world are currently exploring many techniques for producing samples of cold molecules, but to-date these attempts have offered only limited success achieving milli-Kelvin temperatures with low densities. This Laboratory Directed Research and Development project is to develops a new experimental technique for producing micro-Kelvin temperature molecules via collisions with laser cooled samples of trapped atoms. The technique relies on near mass degenerate collisions between the molecule of interest and a laser cooled (micro-Kelvin) atom. A subset of collisions will transfer all (nearly all) of the kinetic energy from the 'hot' molecule, cooling the molecule at the expense of heating the atom. Further collisions with the remaining laser cooled atoms will thermally equilibrate the molecules to the micro-Kelvin temperature of the laser-cooled atoms.

  4. Loosely-Bound Diatomic Molecules.

    ERIC Educational Resources Information Center

    Balfour, W. J.

    1979-01-01

    Discusses concept of covalent bonding as related to homonuclear diatomic molecules. Article draws attention to the existence of bound rare gas and alkaline earth diatomic molecules. Summarizes their molecular parameters and offers spectroscopic data. Strength and variation with distance of interatomic attractive forces is given. (Author/SA)

  5. Featured Molecules: Sucrose and Vanillin

    NASA Astrophysics Data System (ADS)

    Coleman, William F.; Wildman, Randall J.

    2003-04-01

    The WebWare molecules of the month for April relate to the sense of taste. Apple Fool, the JCE Classroom Activity, mentions sucrose and vanillin and their use as flavorings. Fully manipulable (Chime) versions of these and other molecules are available at Only@JCE Online.

  6. Loosely-Bound Diatomic Molecules.

    ERIC Educational Resources Information Center

    Balfour, W. J.

    1979-01-01

    Discusses concept of covalent bonding as related to homonuclear diatomic molecules. Article draws attention to the existence of bound rare gas and alkaline earth diatomic molecules. Summarizes their molecular parameters and offers spectroscopic data. Strength and variation with distance of interatomic attractive forces is given. (Author/SA)

  7. Triatomic molecules laser-cooled

    NASA Astrophysics Data System (ADS)

    2017-06-01

    Molecules containing three atoms have been laser-cooled to ultracold temperatures for the first time. John Doyle and colleagues at Harvard University in the US used a technique called Sisyphus cooling to chill an ensemble of about a million strontium-monohydroxide molecules to 750 μK.

  8. Enzyme molecules in solitary confinement.

    PubMed

    Liebherr, Raphaela B; Gorris, Hans H

    2014-09-12

    Large arrays of homogeneous microwells each defining a femtoliter volume are a versatile platform for monitoring the substrate turnover of many individual enzyme molecules in parallel. The high degree of parallelization enables the analysis of a statistically representative enzyme population. Enclosing individual enzyme molecules in microwells does not require any surface immobilization step and enables the kinetic investigation of enzymes free in solution. This review describes various microwell array formats and explores their applications for the detection and investigation of single enzyme molecules. The development of new fabrication techniques and sensitive detection methods drives the field of single molecule enzymology. Here, we introduce recent progress in single enzyme molecule analysis in microwell arrays and discuss the challenges and opportunities.

  9. Molecule-hugging graphene nanopores.

    PubMed

    Garaj, Slaven; Liu, Song; Golovchenko, Jene A; Branton, Daniel

    2013-07-23

    It has recently been recognized that solid-state nanopores in single-atomic-layer graphene membranes can be used to electronically detect and characterize single long charged polymer molecules. We have now fabricated nanopores in single-layer graphene that are closely matched to the diameter of a double-stranded DNA molecule. Ionic current signals during electrophoretically driven translocation of DNA through these nanopores were experimentally explored and theoretically modeled. Our experiments show that these nanopores have unusually high sensitivity (0.65 nA/Å) to extremely small changes in the translocating molecule's outer diameter. Such atomically short graphene nanopores can also resolve nanoscale-spaced molecular structures along the length of a polymer, but do so with greatest sensitivity only when the pore and molecule diameters are closely matched. Modeling confirms that our most closely matched pores have an inherent resolution of ≤ 0.6 nm along the length of the molecule.

  10. An optical conveyor for molecules.

    PubMed

    Weinert, Franz M; Braun, Dieter

    2009-12-01

    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.

  11. Magnetoassociation of KRb Feshbach molecules

    NASA Astrophysics Data System (ADS)

    Cumby, Tyler; Perreault, John; Shewmon, Ruth; Jin, Deborah

    2010-03-01

    I will discuss experiments in which we study the creation of ^40K^87Rb Feshbach molecules via magnetoassociation. We measure the molecule number as a function of the magnetic-field sweep rate through the interspecies Feshbach resonance and explore the dependence of association on the initial atom gas conditions. This study of the Feshbach molecule creation process may be relevant to the production of ultracold polar molecules, where magnetoassociated Feshbach molecules can be a crucial first step [1].[4pt] [1] K.-K. Ni, S. Ospelkaus, M. H. G. de Miranda, A. Peer, B. Neyenhuis, J. J. Zirbel, S. Kotochigova, P. S. Julienne, D. S. Jin, and J. Ye, Science, 2008, 322, 231-235.

  12. Magnetoassociation of KRb Feshbach molecules

    NASA Astrophysics Data System (ADS)

    Cumby, Tyler; Perreault, John; Shewmon, Ruth; Jin, Deborah

    2010-03-01

    I will discuss experiments in which we study the creation of ^40K^87Rb Feshbach molecules via magnetoassociation. We measure the molecule number as a function of the magnetic-field sweep rate through the interspecies Feshbach resonance and explore the dependence of association on the initial atom gas conditions. This study of the Feshbach molecule creation process may be relevant to the production of ultracold polar molecules, where magnetoassociated Feshbach molecules can be a crucial first step [1].[4pt] [1] K.-K. Ni, S. Ospelkaus, M. H. G. de Miranda, A. Peer, B. Neyenhuis, J. J. Zirbel, S. Kotochigova, P. S. Julienne, D. S. Jin, and J. Ye, Science, 2008, 322, 231- 235.

  13. Highly Parallel Translation of DNA Sequences into Small Molecules

    PubMed Central

    Weisinger, Rebecca M.; Wrenn, S. Jarrett; Harbury, Pehr B.

    2012-01-01

    A large body of in vitro evolution work establishes the utility of biopolymer libraries comprising 1010 to 1015 distinct molecules for the discovery of nanomolar-affinity ligands to proteins.[1], [2], [3], [4], [5] Small-molecule libraries of comparable complexity will likely provide nanomolar-affinity small-molecule ligands.[6], [7] Unlike biopolymers, small molecules can offer the advantages of cell permeability, low immunogenicity, metabolic stability, rapid diffusion and inexpensive mass production. It is thought that such desirable in vivo behavior is correlated with the physical properties of small molecules, specifically a limited number of hydrogen bond donors and acceptors, a defined range of hydrophobicity, and most importantly, molecular weights less than 500 Daltons.[8] Creating a collection of 1010 to 1015 small molecules that meet these criteria requires the use of hundreds to thousands of diversity elements per step in a combinatorial synthesis of three to five steps. With this goal in mind, we have reported a set of mesofluidic devices that enable DNA-programmed combinatorial chemistry in a highly parallel 384-well plate format. Here, we demonstrate that these devices can translate DNA genes encoding 384 diversity elements per coding position into corresponding small-molecule gene products. This robust and efficient procedure yields small molecule-DNA conjugates suitable for in vitro evolution experiments. PMID:22479303

  14. Ab initio calculations of the photoionization of diatomic molecules

    NASA Astrophysics Data System (ADS)

    Lefebvre-Brion, Helene; Raşeev, Georges

    2003-01-01

    A review is presented of the calculation of photoionization spectra, particularly in the spectral range where electron autoionization of diatomic molecules takes place. In addition to some interesting results obtained over years that compare favourably with experiment, the emphasis here is put on the relation between the methods developed for the calculation of observables associated with the continuum energy spectrum of the electrons and the Alchemy system of programs. This system of programs serves as a basis for initial and intermediate calculations. The examples presented show that diatomic molecules not only in gas phase but also oriented in space or physisorbed at surfaces may be studied readily.

  15. Single Molecule Electronics and Devices

    PubMed Central

    Tsutsui, Makusu; Taniguchi, Masateru

    2012-01-01

    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

  16. Adhesion molecules in vernal keratoconjunctivitis

    PubMed Central

    El-Asrar, A.; Geboes, K.; Al-Kharashi, S.; Tabbara, K.; Missotten, L.; Desmet, V.

    1997-01-01

    AIMS/BACKGROUND—Adhesion molecules play a key role in the selective recruitment of different leucocyte population to inflammatory sites. The purpose of the present study was to investigate the presence and distribution of adhesion molecules in the conjunctiva of patients with vernal keratoconjunctivitis (VKC).
METHODS—The presence and distribution of adhesion molecules were studied in 14 conjunctival biopsy specimens from seven patients with active VKC and in four normal conjunctival biopsy specimens. We used a panel of specific monoclonal antibodies (mAbs) directed against intercellular adhesion molecule-1 (ICAM-1), intercellular adhesion molecule-3 (ICAM-3), lymphocyte function associated antigen-1 (LFA-1), very late activation antigen-4 (VLA-4), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leucocyte adhesion molecule-1 (ELAM-1). In addition, a panel of mAbs were used to characterise the composition of the inflammatory infiltrate.
RESULTS—In the normal conjunctiva, ICAM-1 was expressed on the vascular endothelium only, LFA-1 and ICAM-3 on epithelial and stromal mononuclear cells , and VLA-4 on stromal mononuclear cells. The expression of VCAM-1 and ELAM-1 was absent. The number of cells expressing adhesion molecules was found to be markedly increased in all VKC specimens. This was concurrent with a heavy inflammatory infiltrate. Strong ICAM-1 expression was induced on the basal epithelial cells, and vascular endothelial cells. Furthermore, ICAM-1 was expressed on stromal mononuclear cells. LFA-1 and ICAM-3 were expressed on the majority of epithelial and stromal infiltrating mononuclear cells. VLA-4 expression was noted on stromal mononuclear cells. Compared with controls, VKC specimens showed significantly more ICAM-3+, LFA-1+, and VLA-4+ cells. VCAM-1 and ELAM-1 were induced on the vascular endothelial cells.
CONCLUSIONS—Increased expression of adhesion molecules may play an important role in the pathogenesis of VKC.

 PMID

  17. Resolving metal-molecule interfaces at single-molecule junctions

    NASA Astrophysics Data System (ADS)

    Komoto, Yuki; Fujii, Shintaro; Nakamura, Hisao; Tada, Tomofumi; Nishino, Tomoaki; Kiguchi, Manabu

    2016-05-01

    Electronic and structural detail at the electrode-molecule interface have a significant influence on charge transport across molecular junctions. Despite the decisive role of the metal-molecule interface, a complete electronic and structural characterization of the interface remains a challenge. This is in no small part due to current experimental limitations. Here, we present a comprehensive approach to obtain a detailed description of the metal-molecule interface in single-molecule junctions, based on current-voltage (I-V) measurements. Contrary to conventional conductance studies, this I-V approach provides a correlated statistical description of both, the degree of electronic coupling across the metal-molecule interface, and the energy alignment between the conduction orbital and the Fermi level of the electrode. This exhaustive statistical approach was employed to study single-molecule junctions of 1,4-benzenediamine (BDA), 1,4-butanediamine (C4DA), and 1,4-benzenedithiol (BDT). A single interfacial configuration was observed for both BDA and C4DA junctions, while three different interfacial arrangements were resolved for BDT. This multiplicity is due to different molecular adsorption sites on the Au surface namely on-top, hollow, and bridge. Furthermore, C4DA junctions present a fluctuating I-V curve arising from the greater conformational freedom of the saturated alkyl chain, in sharp contrast with the rigid aromatic backbone of both BDA and BDT.

  18. Resolving metal-molecule interfaces at single-molecule junctions

    PubMed Central

    Komoto, Yuki; Fujii, Shintaro; Nakamura, Hisao; Tada, Tomofumi; Nishino, Tomoaki; Kiguchi, Manabu

    2016-01-01

    Electronic and structural detail at the electrode-molecule interface have a significant influence on charge transport across molecular junctions. Despite the decisive role of the metal-molecule interface, a complete electronic and structural characterization of the interface remains a challenge. This is in no small part due to current experimental limitations. Here, we present a comprehensive approach to obtain a detailed description of the metal-molecule interface in single-molecule junctions, based on current-voltage (I-V) measurements. Contrary to conventional conductance studies, this I-V approach provides a correlated statistical description of both, the degree of electronic coupling across the metal-molecule interface, and the energy alignment between the conduction orbital and the Fermi level of the electrode. This exhaustive statistical approach was employed to study single-molecule junctions of 1,4-benzenediamine (BDA), 1,4-butanediamine (C4DA), and 1,4-benzenedithiol (BDT). A single interfacial configuration was observed for both BDA and C4DA junctions, while three different interfacial arrangements were resolved for BDT. This multiplicity is due to different molecular adsorption sites on the Au surface namely on-top, hollow, and bridge. Furthermore, C4DA junctions present a fluctuating I-V curve arising from the greater conformational freedom of the saturated alkyl chain, in sharp contrast with the rigid aromatic backbone of both BDA and BDT. PMID:27221947

  19. Quantum transport through aromatic molecules

    SciTech Connect

    Ojeda, J. H.; Rey-González, R. R.; Laroze, D.

    2013-12-07

    In this paper, we study the electronic transport properties through aromatic molecules connected to two semi-infinite leads. The molecules are in different geometrical configurations including arrays. Using a nearest neighbor tight-binding approach, the transport properties are analyzed into a Green's function technique within a real-space renormalization scheme. We calculate the transmission probability and the Current-Voltage characteristics as a function of a molecule-leads coupling parameter. Our results show different transport regimes for these systems, exhibiting metal-semiconductor-insulator transitions and the possibility to employ them in molecular devices.

  20. The Chloroplastic Protein THF1 Interacts with the Coiled-Coil Domain of the Disease Resistance Protein N′ and Regulates Light-Dependent Cell Death1[OPEN

    PubMed Central

    Sekine, Ken-Taro; Wallon, Thérèse; Sugiwaka, Yuji; Kobayashi, Kappei

    2016-01-01

    One branch of plant immunity is mediated through nucleotide-binding/Leu-rich repeat (NB-LRR) family proteins that recognize specific effectors encoded by pathogens. Members of the I2-like family constitute a well-conserved subgroup of NB-LRRs from Solanaceae possessing a coiled-coil (CC) domain at their N termini. We show here that the CC domains of several I2-like proteins are able to induce a hypersensitive response (HR), a form of programmed cell death associated with disease resistance. Using yeast two-hybrid screens, we identified the chloroplastic protein Thylakoid Formation1 (THF1) as an interacting partner for several I2-like CC domains. Co-immunoprecipitations and bimolecular fluorescence complementation assays confirmed that THF1 and I2-like CC domains interact in planta and that these interactions take place in the cytosol. Several HR-inducing I2-like CC domains have a negative effect on the accumulation of THF1, suggesting that the latter is destabilized by active CC domains. To confirm this model, we investigated N′, which recognizes the coat protein of most Tobamoviruses, as a prototypical member of the I2-like family. Transient expression and gene silencing data indicated that THF1 functions as a negative regulator of cell death and that activation of full-length N′ results in the destabilization of THF1. Consistent with the known function of THF1 in maintaining chloroplast homeostasis, we show that the HR induced by N′ is light-dependent. Together, our results define, to our knowledge, novel molecular mechanisms linking light and chloroplasts to the induction of cell death by a subgroup of NB-LRR proteins. PMID:26951433

  1. Observations of molecules in comets

    NASA Technical Reports Server (NTRS)

    Feldman, P. D.

    1987-01-01

    Ultraviolet and visible spectroscopy of comets has identified a large number of species in the coma, most of which appear to be the photodissociation and photoionization products of the 'parent' molecules evaporated directly from the cometary nucleus. Analyses of cometary spectra support the icy conglomerate model of the nucleus with H2O as the dominant ice species. Two molecules detected in the ultraviolet, CO and S2, are of particular interest to the study of the cosmogonic evolution of cometary grains. CO appears to be a highly variable constituent from comet to comet, while S2, first observed in comet IRAS-Araki-Alcock in 1983, is found in no other celestial source. Both of these molecules appear to be parent molecules.

  2. Molecule-hugging graphene nanopores

    PubMed Central

    Garaj, Slaven; Liu, Song; Golovchenko, Jene A.; Branton, Daniel

    2013-01-01

    It has recently been recognized that solid-state nanopores in single-atomic-layer graphene membranes can be used to electronically detect and characterize single long charged polymer molecules. We have now fabricated nanopores in single-layer graphene that are closely matched to the diameter of a double-stranded DNA molecule. Ionic current signals during electrophoretically driven translocation of DNA through these nanopores were experimentally explored and theoretically modeled. Our experiments show that these nanopores have unusually high sensitivity (0.65 nA/Å) to extremely small changes in the translocating molecule’s outer diameter. Such atomically short graphene nanopores can also resolve nanoscale-spaced molecular structures along the length of a polymer, but do so with greatest sensitivity only when the pore and molecule diameters are closely matched. Modeling confirms that our most closely matched pores have an inherent resolution of ≤0.6 nm along the length of the molecule. PMID:23836648

  3. Fluorescence Microscopy of Single Molecules

    ERIC Educational Resources Information Center

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

    2004-01-01

    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.

  4. Fluorescence Microscopy of Single Molecules

    ERIC Educational Resources Information Center

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

    2004-01-01

    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.

  5. Moving Molecules and Mothball Madness.

    ERIC Educational Resources Information Center

    Strain, John

    1993-01-01

    Describes concrete demonstrations on the states of matter. In the first demonstration, students represent molecules; and, in the second demonstration, moth balls are heated to produce a change of state. (PR)

  6. Cell adhesion molecules and sleep.

    PubMed

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

    2017-03-01

    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.

  7. Quantum Transport Through Heterocyclic Molecules

    NASA Astrophysics Data System (ADS)

    Maiti, Santanu K.; Karmakar, S. N.

    We explore electron transport properties in molecular wires made of heterocyclic molecules (pyrrole, furan and thiophene) by using the Green's function technique. Parametric calculations are given based on the tight-binding model to describe the electron transport in these wires. It is observed that the transport properties are significantly influenced by (a) the heteroatoms in the heterocyclic molecules and (b) the molecule-to-electrodes coupling strength. Conductance (g) shows sharp resonance peaks associated with the molecular energy levels in the limit of weak molecular coupling, while they get broadened in the strong molecular coupling limit. These resonances get shifted with the change of the heteroatoms in these heterocyclic molecules. All the essential features of the electron transfer through these molecular wires become much more clearly visible from the study of our current-voltage (I-V) characteristics, and they provide several key information in the study of molecular transport.

  8. Moving Molecules and Mothball Madness.

    ERIC Educational Resources Information Center

    Strain, John

    1993-01-01

    Describes concrete demonstrations on the states of matter. In the first demonstration, students represent molecules; and, in the second demonstration, moth balls are heated to produce a change of state. (PR)

  9. Electrostatic trapping of ammonia molecules

    PubMed

    Bethlem; Berden; Crompvoets; Jongma; van Roij AJ; Meijer

    2000-08-03

    The ability to cool and slow atoms with light for subsequent trapping allows investigations of the properties and interactions of the trapped atoms in unprecedented detail. By contrast, the complex structure of molecules prohibits this type of manipulation, but magnetic trapping of calcium hydride molecules thermalized in ultra-cold buffer gas and optical trapping of caesium dimers generated from ultra-cold caesium atoms have been reported. However, these methods depend on the target molecules being paramagnetic or able to form through the association of atoms amenable to laser cooling, respectively, thus restricting the range of species that can be studied. Here we describe the slowing of an adiabatically cooled beam of deuterated ammonia molecules by time-varying inhomogeneous electric fields and subsequent loading into an electrostatic trap. We are able to trap state-selected ammonia molecules with a density of 10(6) cm(-3) in a volume of 0.25 cm3 at temperatures below 0.35 K. We observe pronounced density oscillations caused by the rapid switching of the electric fields during loading of the trap. Our findings illustrate that polar molecules can be efficiently cooled and trapped, thus providing an opportunity to study collisions and collective quantum effects in a wide range of ultra-cold molecular systems.

  10. [Adhesion molecules and diabetes mellitus].

    PubMed

    Urso, C; Hopps, E; Caimi, G

    2010-01-01

    Adhesion molecules play a significant role in leukocyte migration across the endothelium and are also involved in regulating immune system. It is shown that diabetic patients have an increase of soluble adhesion molecules (sICAM-1, sICAM-2, sVCAM-1, sE-selectin, sL-selectin, sP-selectin) considered an integral part of inflammatory state. This inflammation is responsible for the increased cardiovascular risk of these patients. There is a close link between hyperglycemia, oxidative stress, coagulopathy and inflammation and between these factors and the vascular damage. Various studies have showed the potential role of adhesion molecules in the pathogenesis of diabetic vasculopathy. They promote leukocyte recruitment, which is one of the initial steps in the genesis of atherosclerotic plaque. Adhesion molecules are also involved in the pathogenesis of diabetes mellitus type 1; sICAM-1 would have a particular immunomodulatory role in the process of destroying beta-cells and could be used as a subclinical marker of insulitis. Plasma levels of soluble adhesion molecules correlate with hyperglycemia, insulin resistance, dyslipidemia and obesity; they are associated with the development of nephropathy, retinopathy, myocardial infarction, stroke and obliterant peripheral arterial disease in diabetic type 1 and 2. Given the role of these molecules in endothelial dysfunction genesis and tissue damage associated with diabetes, they could constitute a therapeutic target for the prevention of genesis and progression of chronic complications of diabetic disease.

  11. Electronic control inside a molecule : towards single molecule devices

    NASA Astrophysics Data System (ADS)

    Lastapis, Mathieu; Fukuma, Yurie; Boland, John

    2006-03-01

    The chimerical single molecule engineering has been proven to be accessible through the use of scanning tunnelling microscopy (STM) [1]. In this field, one particularly attractive area is the study of single molecules adsorbed on semiconductor surfaces. It has been recently demonstrated that a spatial fine control of the molecular dynamics is possible through the use of tunnelling current [2]. In order to improve the electronic control of a single molecule, we are currently investigating a promising system: CaF2 on Si(111). This system has been extensively studied as a model system to deposit insulator on silicon. Here we are using this system to electronically decouple the molecule from the substrate. I will present LT STM experiments on atomically thick CaF islands on Si(111). The measured electronic properties of these islands demonstrate their potential as ideal templates to study single molecules. Finally I will present some preliminary results on N-HBC [3] adsorbed on a CaF island. [1] G. Binnig and H. Rohrer, ``In touch with atoms'', Rev. Mod. Phys. 71, S324-S330 (1999) [2] M. Lastapis et al, Science, 308, 1000 (2005) [3] S.Draper et al, JACS, 126, 8694 (2004)

  12. Temperature dependence of charge transport in conjugated single molecule junctions

    NASA Astrophysics Data System (ADS)

    Huisman, Eek; Kamenetska, Masha; Venkataraman, Latha

    2011-03-01

    Over the last decade, the break junction technique using a scanning tunneling microscope geometry has proven to be an important tool to understand electron transport through single molecule junctions. Here, we use this technique to probe transport through junctions at temperatures ranging from 5K to 300K. We study three amine-terminated (-NH2) conjugated molecules: a benzene, a biphenyl and a terphenyl derivative. We find that amine groups bind selectively to undercoordinate gold atoms gold all the way down to 5K, yielding single molecule junctions with well-defined conductances. Furthermore, we find that the conductance of a single molecule junction increases with temperature and we present a mechanism for this temperature dependent transport result. Funded by a Rubicon Grant from The Netherlands Organisation for Scientific Research (NWO) and the NSEC program of NSF under grant # CHE-0641523.

  13. Formation and dissociation of dust molecules in dusty plasma

    NASA Astrophysics Data System (ADS)

    Yan, Jia; Feng, Fan; Liu, Fucheng; Dong, Lifang; He, Yafeng

    2016-09-01

    Dust molecules are observed in a dusty plasma experiment. By using measurements with high spatial resolution, the formation and dissociation of the dust molecules are studied. The ion cloud in the wake of an upper dust grain attracts the lower dust grain nearby. When the interparticle distance between the upper dust grain and the lower one is less than a critical value, the two dust grains would form a dust molecule. The upper dust grain always leads the lower one as they travel. When the interparticle distance between them is larger than the critical value, the dust molecule would dissociate. Project supported by the National Natural Science Foundation of China (Grant Nos. 11205044 and 11405042), the Natural Science Foundation of Hebei Province, China (Grant Nos. A2011201006 and A2012201015), the Research Foundation of Education Bureau of Hebei Province, China (Grant No. Y2012009), the Program for Young Principal Investigators of Hebei Province, China, and the Midwest Universities Comprehensive Strength Promotion Project, China.

  14. Signaling Molecules and Pulp Regeneration.

    PubMed

    Schmalz, Gottfried; Widbiller, Matthias; Galler, Kerstin M

    2017-09-01

    Signaling molecules play an essential role in tissue engineering because they regulate regenerative processes. Evidence exists from animal studies that single molecules such as members of the transforming growth factor beta superfamily and factors that induce the growth of blood vessels (vascular endothelial growth factor), nerves (brain-derived neurotrophic factor), or fibroblasts (fibroblast growth factor) may induce reparative dentin formation. Mainly the formation of atubular dentin (osteodentin) has been described after the application of single molecules or combinations of recombinant growth factors on healthy exposed pulps or in pulp regeneration. Generally, such preparations have not received regulatory approval on the market so far. Only the use of granulocyte colony-stimulating factors together with cell transplantation is presently tested clinically. Besides approaches with only 1 or few combined molecules, the exploitation of tissue-derived growth factors depicts a third promising way in dental pulp tissue engineering. Preparations such as platelet-rich plasma or platelet-rich fibrin provide a multitude of endogenous signaling molecules, and special regulatory approval for the market does not seem necessary. Furthermore, dentin is a perfect reservoir of signaling molecules that can be mobilized by treatment with demineralizing agents such as EDTA. This conditions the dentin surface and allows for contact differentiation of pulp stem cells into odontoblastlike cells, protects dentin from resorption, and enhances cell growth as well as attachment to dentin. By ultrasonic activation, signaling molecules can be further released from EDTA pretreated dentin into saline, thus avoiding cytotoxic EDTA in the final preparation. The use of dentin-derived growth factors offers a number of advantages because they are locally available and presumably are most fit to induce signaling processes in dental pulp. However, better characterization and standardization of the

  15. Raman Optical Activity Spectra for Large Molecules through Molecules-in-Molecules Fragment-Based Approach.

    PubMed

    Jovan Jose, K V; Raghavachari, Krishnan

    2016-02-09

    We present an efficient method for the calculation of the Raman optical activity (ROA) spectra for large molecules through the molecules-in-molecules (MIM) fragment-based method. The relevant higher energy derivatives from smaller fragments are used to build the property tensors of the parent molecule to enable the extension of the MIM method for evaluating ROA spectra (MIM-ROA). Two factors were found to be particularly important in yielding accurate results. First, the link-atom tensor components are projected back onto the corresponding host and supporting atoms through the Jacobian projection method, yielding a mathematically rigorous method. Second, the long-range interactions between fragments are taken into account by using a less computationally expensive lower level of theory. The performance of the MIM-ROA model is calibrated on the enantiomeric pairs of 10 carbohydrate benchmark molecules, with strong intramolecular interactions. The vibrational frequencies and ROA intensities are accurately reproduced relative to the full, unfragmented, results for these systems. In addition, the MIM-ROA method is employed to predict the ROA spectra of d-maltose, α-D-cyclodextrin, and cryptophane-A, yielding spectra in excellent agreement with experiment. The accuracy and performance of the benchmark systems validate the MIM-ROA model for exploring ROA spectra of large molecules.

  16. JSME: a free molecule editor in JavaScript.

    PubMed

    Bienfait, Bruno; Ertl, Peter

    2013-01-01

    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 http://peter-ertl.com/jsme/

  17. JSME: a free molecule editor in JavaScript

    PubMed Central

    2013-01-01

    Background 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. Summary 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. Conclusions 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 http://peter-ertl.com/jsme/ PMID:23694746

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

    PubMed

    Ertl, Peter; Rohde, Bernhard

    2012-07-06

    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. 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. 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 data sets, including PubChem, ChEMBL and ZINC databases using

  19. Electrical conduction through DNA molecule.

    PubMed

    Abdalla, S

    2011-09-01

    Several disorder parameters, inside the DNA molecule, lead to localization of charge carriers inside potential wells in the lowest unoccupied and highest occupied molecular orbits (LUMO and HOMO) which affects drastically the electrical conduction through the molecule, and demonstrates that the band carriers play an essential role in the conduction mechanism. So, a model is presented to shed light on the role of electrons of the LUMO in the electrical conduction through the DNA molecule. DC-, AC-conductivity and dielectric permittivity experimental data are well fitted with the presented model giving evidence that the free carriers in the LUMO and HOMO are responsible to make the DNA molecule conductor, insulator or semiconductor. The obtained results show that the localized charge carriers in the DNA molecule are characterized by four different types of relaxation phenomena which are thermally activated by corresponding four activation energies at 0.56 eV, 0.33 eV, 0.24 eV, and 0.05 eV respectively. Moreover, the calculations after the model, at room temperature, show that the time of the relaxation times of the current carriers are in the order of 5 × 10(-2)s, 1.74 × 10(-4)s, 5 × 10(-7)s, and 1.6 × 10(-10)s, respectively.

  20. Partial Dynamical Symmetry in Molecules

    NASA Astrophysics Data System (ADS)

    Ping, Jia-Lun; Chen, Jin-Quan

    1997-03-01

    It is shown that any Hamiltonian involving only one- and two-bond interactions for a molecule withnbonds and having a point groupPas its symmetry group may have theSn⊃Ppartial dynamical symmetry, i.e., the Hamiltonian can be solved analytically for a part of the states, called the unique states. For example, theXY6molecule has theS6⊃Ohpartial dynamical symmetry. The model of Iachello and Oss forncoupled anharmonic oscillators is revisited in terms of the partial dynamical symmetry. The energies are obtained analytically for the nine unique levels of theXY6molecule and the structures of the eigenstates are disclosed for the first time, while for non-unique states they are obtained by diagonalizing the Hamiltonian in theS6⊃Ohsymmetry adapted basis with greatly reduced dimension.

  1. Interstellar molecules and dense clouds.

    NASA Technical Reports Server (NTRS)

    Rank, D. M.; Townes, C. H.; Welch, W. J.

    1971-01-01

    Current knowledge of the interstellar medium is discussed on the basis of recent published studies. The subjects considered include optical identification of interstellar molecules, radio molecular lines, interstellar clouds, isotopic abundances, formation and disappearance of interstellar molecules, and interstellar probing techniques. Diagrams are plotted for the distribution of galactic sources exhibiting molecular lines, for hydrogen molecule, hydrogen atom and electron abundances due to ionization, for the densities, velocities and temperature of NH3 in the direction of Sagitarius B2, for the lower rotational energy levels of H2CO, and for temporal spectral variations in masing H2O clouds of the radio source W49. Future applications of the maser and of molecular microscopy in this field are visualized.

  2. Small Molecule Fluoride Toxicity Agonists

    PubMed Central

    Nelson1, James W.; Plummer, Mark S.; Blount, Kenneth F.; Ames, Tyler D.; Breaker, Ronald R.

    2015-01-01

    SUMMARY Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch-reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. PMID:25910244

  3. Small Molecule CXCR3 Antagonists.

    PubMed

    Andrews, Stephen P; Cox, Rhona J

    2016-04-14

    Chemokines and their receptors are known to play important roles in disease. More than 40 chemokine ligands and 20 chemokine receptors have been identified, but, to date, only two small molecule chemokine receptor antagonists have been approved by the FDA. The chemokine receptor CXCR3 was identified in 1996, and nearly 20 years later, new areas of CXCR3 disease biology continue to emerge. Several classes of small molecule CXCR3 antagonists have been developed, and two have shown efficacy in preclinical models of inflammatory disease. However, only one CXCR3 antagonist has been evaluated in clinical trials, and there remain many opportunities to further investigate known classes of CXCR3 antagonists and to identify new chemotypes. This Perspective reviews the known CXCR3 antagonists and considers future opportunities for the development of small molecules for clinical evaluation.

  4. Guidance molecules in lung cancer

    PubMed Central

    Nasarre, Patrick; Potiron, Vincent; Drabkin, Harry

    2010-01-01

    Guidance molecules were first described in the nervous system to control axon outgrowth direction. They are also widely expressed outside the nervous system where they control cell migration, tissue development and establishment of the vascular network. In addition, they are involved in cancer development, tumor angiogenesis and metastasis. This review is primarily focused on their functions in lung cancer and their involvement in lung development is also presented. Five guidance molecule families and their corresponding receptors are described, including the semaphorins/neuropilins/plexins, ephrins and Eph receptors, netrin/DCC/UNC5, Slit/Robo and Notch/Delta. In addition, the possibility to target these molecules as a therapeutic approach in cancer is discussed. PMID:20139699

  5. Small molecule fluoride toxicity agonists.

    PubMed

    Nelson, James W; Plummer, Mark S; Blount, Kenneth F; Ames, Tyler D; Breaker, Ronald R

    2015-04-23

    Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here, we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride.

  6. Single molecule imaging of protein molecules in nanopores.

    PubMed

    Ma, Changbei; Yeung, Edward S

    2010-01-15

    The interactions between single protein molecules and nanoporous polycarbonate membranes were investigated at the single molecule level. Entrapment of proteins was shown to be size selective and was dependent on the membrane pore diameter. A pore size that is only slightly larger than the maximum dimension of the proteins was inadequate for intrusion into the pores. For a given protein, the number of molecules found at a given depth decreased as the pore size decreased. In addition, as the depth increased, for a given size pore, the number of molecules decreased rapidly. The depth-dependent histograms nicely fit a one-dimensional diffusion model. However, a highly restricted motion was observed even when the pore diameter was 10 times the size of the protein, resulting in anomalously small diffusion coefficients. We also demonstrated the subtle differences in depth distribution among BSA and hemoglobin that have nearly the same molecular weight but slightly different molecular shapes. These results give unique insights into the detailed mechanism of size-exclusion chromatography and membrane filtration.

  7. Single-molecule nanopore enzymology

    PubMed Central

    Wloka, Carsten; Maglia, Giovanni

    2017-01-01

    Biological nanopores are a class of membrane proteins that open nanoscale water-conduits in biological membranes. When they are reconstituted in artificial membranes and a bias voltage is applied across the membrane, the ionic current passing through individual nanopores can be used to monitor chemical reactions, to recognize individual molecules and, of most interest, to sequence DNA. More recently, proteins and enzymes have started being analysed with nanopores. Monitoring enzymatic reactions with nanopores, i.e. nanopore enzymology, has the unique advantage that it allows long-timescale observations of native proteins at the single-molecule level. Here we describe the approaches and challenges in nanopore enzymology. PMID:28630164

  8. Phase structure of soliton molecules

    SciTech Connect

    Hause, A.; Hartwig, H.; Seifert, B.; Stolz, H.; Boehm, M.; Mitschke, F.

    2007-06-15

    Temporal optical soliton molecules were recently demonstrated; they potentially allow further increase of data rates in optical telecommunication. Their binding mechanism relies on the internal phases, but these have not been experimentally accessible so far. Conventional frequency-resolved optical gating techniques are not suited for measurement of their phase profile: Their algorithms fail to converge due to zeros both in their temporal and their spectral profile. We show that the VAMPIRE (very advanced method of phase and intensity retrieval of E-fields) method performs reliably. With VAMPIRE the phase profile of soliton molecules has been measured, and further insight into the mechanism is obtained.

  9. Phase structure of soliton molecules

    NASA Astrophysics Data System (ADS)

    Hause, A.; Hartwig, H.; Seifert, B.; Stolz, H.; Böhm, M.; Mitschke, F.

    2007-06-01

    Temporal optical soliton molecules were recently demonstrated; they potentially allow further increase of data rates in optical telecommunication. Their binding mechanism relies on the internal phases, but these have not been experimentally accessible so far. Conventional frequency-resolved optical gating techniques are not suited for measurement of their phase profile: Their algorithms fail to converge due to zeros both in their temporal and their spectral profile. We show that the VAMPIRE (very advanced method of phase and intensity retrieval of E -fields) method performs reliably. With VAMPIRE the phase profile of soliton molecules has been measured, and further insight into the mechanism is obtained.

  10. ''Stueckelberg Interferometry'' with Ultracold Molecules

    SciTech Connect

    Mark, M.; Kraemer, T.; Waldburger, P.; Herbig, J.; Naegerl, H.-C.; Chin, C.; Grimm, R.

    2007-09-14

    We report on the realization of a time-domain 'Stueckelberg interferometer', which is based on the internal-state structure of ultracold Feshbach molecules. Two subsequent passages through a weak avoided crossing between two different orbital angular momentum states in combination with a variable hold time lead to high-contrast population oscillations. This allows for a precise determination of the energy difference between the two molecular states. We demonstrate a high degree of control over the interferometer dynamics. The interferometric scheme provides new possibilities for precision measurements with ultracold molecules.

  11. Piezoresistivity in single DNA molecules

    PubMed Central

    Bruot, Christopher; Palma, Julio L.; Xiang, Limin; Mujica, Vladimiro; Ratner, Mark A.; Tao, Nongjian

    2015-01-01

    Piezoresistivity is a fundamental property of materials that has found many device applications. Here we report piezoresistivity in double helical DNA molecules. By studying the dependence of molecular conductance and piezoresistivity of single DNA molecules with different sequences and lengths, and performing molecular orbital calculations, we show that the piezoresistivity of DNA is caused by force-induced changes in the π–π electronic coupling between neighbouring bases, and in the activation energy of hole hopping. We describe the results in terms of thermal activated hopping model together with the ladder-based mechanical model for DNA proposed by de Gennes. PMID:26337293

  12. Orbital molecules in electronic materials

    SciTech Connect

    Attfield, J. Paul

    2015-04-01

    Orbital molecules are made up of coupled orbital states on several metal ions within an orbitally ordered (and sometimes also charge-ordered) solid such as a transition metal oxide. Spin-singlet dimers are known in many materials, but recent discoveries of more exotic species such as 18-electron heptamers in AlV{sub 2}O{sub 4} and magnetic 3-atom trimerons in magnetite (Fe{sub 3}O{sub 4}) have shown that orbital molecules constitute a general new class of quantum electronic states in solids.

  13. Quantum Monte Carlo for Molecules.

    DTIC Science & Technology

    1984-11-01

    AD-A148 159 QUANTUM MONTE CARLO FOR MOLECULES(U) CALIFORNIA UNIV Y BERKELEY LAWRENCE BERKELEY LAB W A LESTER ET AL. Si NOV 84 NOSUi4-83-F-Oifi...ORG. REPORT NUMBER 00 QUANTUM MONTE CARLO FOR MOLECULES ’Ids 7. AUTHOR(e) S. CONTRACT Or GRANT NUMER(e) William A. Lester, Jr. and Peter J. Reynolds...unlimited. ..’.- • p. . ° 18I- SUPPLEMENTARY NOTES IS. KEY WORDS (Cent/Rue an "Worse aide If noeesean d entlt by block fmamabr) Quantum Monte Carlo importance

  14. Nonadiabatic reaction of energetic molecules.

    PubMed

    Bhattacharya, Atanu; Guo, Yuanqing; Bernstein, Elliot R

    2010-12-21

    Energetic materials store a large amount of chemical energy that can be readily converted into mechanical energy via decomposition. A number of different ignition processes such as sparks, shocks, heat, or arcs can initiate the excited electronic state decomposition of energetic materials. Experiments have demonstrated the essential role of excited electronic state decomposition in the energy conversion process. A full understanding of the mechanisms for the decomposition of energetic materials from excited electronic states will require the investigation and analysis of the specific topography of the excited electronic potential energy surfaces (PESs) of these molecules. The crossing of multidimensional electronic PESs creates a funnel-like topography, known as conical intersections (CIs). CIs are well established as a controlling factor in the excited electronic state decomposition of polyatomic molecules. This Account summarizes our current understanding of the nonadiabatic unimolecular chemistry of energetic materials through CIs and presents the essential role of CIs in the determination of decomposition pathways of these energetic systems. Because of the involvement of more than one PES, a decomposition process involving CIs is an electronically nonadiabatic mechanism. Based on our experimental observations and theoretical calculations, we find that a nonadiabatic reaction through CIs dominates the initial decomposition process of energetic materials from excited electronic states. Although the nonadiabatic behavior of some polyatomic molecules has been well studied, the role of nonadiabatic reactions in the excited electronic state decomposition of energetic molecules has not been well investigated. We use both nanosecond energy-resolved and femtosecond time-resolved spectroscopic techniques to determine the decomposition mechanism and dynamics of energetic species experimentally. Subsequently, we employ multiconfigurational methodologies (such as, CASSCF

  15. Small Molecules Target Carcinogenic Proteins

    NASA Astrophysics Data System (ADS)

    Gradinaru, Claudiu

    2009-03-01

    An ingenious cellular mechanism of effecting protein localization is prenylation: the covalent attachment of a hydrophobic prenyl group to a protein that facilitates protein association with cell membranes. Fluorescence microscopy was used to investigate whether the oncogenic Stat3 protein can undergo artificial prenylation via high-affinity prenylated small-molecule binding agents and thus be rendered inactive by localization at the plasma membrane instead of nucleus. The measurements were performed on a home-built instrument capable of recording simultaneously several optical parameters (lifetime, polarization, color, etc) and with single-molecule sensitivity. A pH-invariant fluorescein derivative with double moiety was designed to bridge a prenyl group and a small peptide that binds Stat3 with high affinity. Confocal fluorescence images show effective localization of the ligand to the membrane of liposomes. Stat3 predominantly localizes at the membrane only in the presence of the prenylated ligand. Single-molecule FRET (fluorescence resonance energy transfer) between donor-labeled prenylated agents and acceptor-labeled, surface tethered Stat3 protein is used to determine the dynamic heterogeneity of the protein-ligand interaction and follow individual binding-unbinding events in real time. The data indicates that molecules can effect protein localization, validating a therapeutic design that influences protein activity via induced localization.

  16. Nucleic Acids as Information Molecules.

    ERIC Educational Resources Information Center

    McInerney, Joseph D.

    1996-01-01

    Presents an activity that aims at enabling students to recognize that DNA and RNA are information molecules whose function is to store, copy, and make available the information in biological systems, without feeling overwhelmed by the specialized vocabulary and the minutia of the central dogma. (JRH)

  17. Eckart frames for planar molecules

    NASA Astrophysics Data System (ADS)

    Wei, Hua

    2003-04-01

    Explicit analytic expressions of Eckart frames for planar molecules in Radau, Jacobi and bond coordinates have been presented. The orientation of the frame axis system with respect to the molecular plane at equilibrium is specified by an angle θ1e.

  18. Ultrafast dynamics of single molecules.

    PubMed

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

    2014-04-21

    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.

  19. Nanodevices for Single Molecule Studies

    NASA Astrophysics Data System (ADS)

    Craighead, H. G.; Stavis, S. M.; Samiee, K. T.

    During the last two decades, biotechnology research has resulted in progress in fields as diverse as the life sciences, agriculture and healthcare. While existing technology enables the analysis of a variety of biological systems, new tools are needed for increasing the efficiency of current methods, and for developing new ones altogether. Interest has grown in single molecule analysis for these reasons.

  20. Nucleic Acids as Information Molecules.

    ERIC Educational Resources Information Center

    McInerney, Joseph D.

    1996-01-01

    Presents an activity that aims at enabling students to recognize that DNA and RNA are information molecules whose function is to store, copy, and make available the information in biological systems, without feeling overwhelmed by the specialized vocabulary and the minutia of the central dogma. (JRH)

  1. Designing a small molecule erythropoietin mimetic.

    PubMed

    Guarnieri, Frank

    2015-01-01

    led to the creation of an in vitro active molecule. The combination of changing functional groups to enable good pharmacokinetics, while not changing the key intrinsic symmetry properties were never seriously pursued at Locus and the program died. Investigations into how red blood cells are created have occupied many prominent researchers for the entire twentieth century. In the second half of the century EPO was discovered and by the end of the century it became a blockbuster commercial product that launched the biotech revolution.

  2. Size selective hydrophobic adsorbent for organic molecules

    NASA Technical Reports Server (NTRS)

    Sharma, Pramod K. (Inventor); Hickey, Gregory S. (Inventor)

    1997-01-01

    The present invention relates to an adsorbent formed by the pyrolysis of a hydrophobic silica with a pore size greater than 5 .ANG., such as SILICALITE.TM., with a molecular sieving polymer precursor such as polyfurfuryl alcohol, polyacrylonitrile, polyvinylidene chloride, phenol-formaldehyde resin, polyvinylidene difluoride and mixtures thereof. Polyfurfuryl alcohol is the most preferred. The adsorbent produced by the pyrolysis has a silicon to carbon mole ratio of between about 10:1 and 1:3, and preferably about 2:1 to 1:2, most preferably 1:1. The pyrolysis is performed as a ramped temperature program between about 100.degree. and 800.degree. C., and preferably between about 100.degree. and 600.degree. C. The present invention also relates to a method for selectively adsorbing organic molecules having a molecular size (mean molecular diameter) of between about 3 and 6 .ANG. comprising contacting a vapor containing the small organic molecules to be adsorbed with the adsorbent composition of the present invention.

  3. HLA molecules in autoimmune diseases.

    PubMed

    Braun, W E

    1992-06-01

    The association of certain autoimmune diseases with HLA molecules is being refined through the use of sequence-specific oligonucleotide probes and amino acid sequencing, together with continuing elucidation of the functional features of HLA molecules derived from the milestone description by Bjorkman of the HLA molecular structure. The association of insulin-dependent diabetes mellitus and HLA began with weak associations of Class I antigens (B8 and B15) and progressed to Class II antigens (DR3 and DR4), then to subtypes of DR4 (Dw4, 10, and 14), and now to DQ molecules including the absence of aspartic acid at position 57 of the DQ beta chain and the presence of arginine at position 52 of the DQ alpha chain. In rheumatoid arthritis (RA) the HLA antigen association remains with certain Class II molecules of the DR series (DR4 and DR1) that share amino acid sequences with a restricted number of other DR antigens seen in RA, as well as a segment of the gp 110 protein of the Epstein-Barr virus. Although ankylosing spondylitis has a strong association with the Class I antigen B27, that association is not explained by any of the B27 subtypes defined by monoclonal antibodies, by the eight variable amino acids in B27 subtypes, or by the two unique amino acids on B27. The remarkable antibody cross-reactivity among lymphocytes bearing B27, a synthetic peptide sequence (63-84) of B27, and the 188-193 sequence of K. pneumoniae nitrogenase has provided strong support for molecular mimicry being an important mechanism in the association of HLA molecules with disease.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Quantum Monte Carlo for vibrating molecules

    SciTech Connect

    Brown, W.R. |

    1996-08-01

    Quantum Monte Carlo (QMC) has successfully computed the total electronic energies of atoms and molecules. The main goal of this work is to use correlation function quantum Monte Carlo (CFQMC) to compute the vibrational state energies of molecules given a potential energy surface (PES). In CFQMC, an ensemble of random walkers simulate the diffusion and branching processes of the imaginary-time time dependent Schroedinger equation in order to evaluate the matrix elements. The program QMCVIB was written to perform multi-state VMC and CFQMC calculations and employed for several calculations of the H{sub 2}O and C{sub 3} vibrational states, using 7 PES`s, 3 trial wavefunction forms, two methods of non-linear basis function parameter optimization, and on both serial and parallel computers. In order to construct accurate trial wavefunctions different wavefunctions forms were required for H{sub 2}O and C{sub 3}. In order to construct accurate trial wavefunctions for C{sub 3}, the non-linear parameters were optimized with respect to the sum of the energies of several low-lying vibrational states. In order to stabilize the statistical error estimates for C{sub 3} the Monte Carlo data was collected into blocks. Accurate vibrational state energies were computed using both serial and parallel QMCVIB programs. Comparison of vibrational state energies computed from the three C{sub 3} PES`s suggested that a non-linear equilibrium geometry PES is the most accurate and that discrete potential representations may be used to conveniently determine vibrational state energies.

  5. Expression of immune checkpoint molecules of T cell immunoglobulin and mucin protein 3/galectin-9 for NK cell suppression in human gastrointestinal stromal tumors.

    PubMed

    Komita, Hideo; Koido, Shigeo; Hayashi, Kazumi; Kan, Shin; Ito, Masaki; Kamata, Yuko; Suzuki, Masafumi; Homma, Sadamu

    2015-10-01

    Monoclonal antibody therapy for immune checkpoint blockade has achieved promising results for several types of malignant tumors. For the future treatment of gastrointestinal stromal tumors (GISTs) by immune checkpoint blockade, expression of immune checkpoint-related molecules that suppress antitumor immunity in GISTs was examined. Infiltration of immune cell types into 19 GIST tissues was analyzed by immunohistochemistry, and expression of T cell immunoglobulin and mucin protein 3 (Tim-3) and programmed cell death-1 (PD-1) in the infiltrated immune cells was examined by immunofluorescence microscopy. The expression status of galectin-9 in the GIST tumor cells was also determined by immunohistochemistry. All the GIST tissues showed CD8+ T cell infiltration and 8 showed CD56+ natural killer (NK) cell infiltration, and the numbers of infiltrated CD8+ T and NK cells were strongly correlated. However, these CD8+ T and NK cells were CD69-negative inactivated cells. Tim-3 was expressed in the infiltrated NK cells in 6/8 (75%) of the GIST tissues. Expression of galectin-9, a ligand of Tim-3, was observed in 13/19 (68.4%) GIST tissues and all of the GIST tissues with Tim-3+ NK cell infiltration showed positive galectin-9 expression. No PD-1 expression in the infiltrated NK cells and neither Tim-3 nor PD-1 expression was observed in the infiltrated CD8+ T cells. Interaction between Tim-3 in infiltrated NK cells and galectin-9 in tumor cells may be involved in an immune checkpoint mechanism for suppression of antitumor immunity in GISTs. Blockade of the Tim-3/galectin-9 pathway may become a new strategy for GIST treatment.

  6. Photoabsorption and photodissociation of molecules important in the interstellar medium

    NASA Technical Reports Server (NTRS)

    Lee, L. C.

    1986-01-01

    In the period from May 15, 1985 to May 14, 1986, the photoabsorption and photodissociation cross sections of the interstellar radical of SO and the interstellar molecules of HCl, H2CO, and CH3CN were measured and the results were reported in scientific papers. In the meantime, a windowless apparatus is used to measure the photoabsorption and photodissociation cross sections of CO in the 90-105 nm region. The optical data obtained in this research program are needed for the determination of the formation and destruction rates of molecules and radicals in the interstellar medium. Accomplishments in this research period are summarized below.

  7. Atoms and Molecules. Physical Science in Action[TM]. Schlessinger Science Library. [Videotape].

    ERIC Educational Resources Information Center

    2000

    There are more than 20 million known substances in the universe, and they are all made of the same basic ingredients--atoms and molecules. In this fun and engaging program, kids will learn about the three main subatomic particles--protons, neutrons and electrons--as well as the forces that keep atoms and molecules together. They'll discover how…

  8. Atoms and Molecules. Physical Science in Action[TM]. Schlessinger Science Library. [Videotape].

    ERIC Educational Resources Information Center

    2000

    There are more than 20 million known substances in the universe, and they are all made of the same basic ingredients--atoms and molecules. In this fun and engaging program, kids will learn about the three main subatomic particles--protons, neutrons and electrons--as well as the forces that keep atoms and molecules together. They'll discover how…

  9. Dissociation energy of molecules in dense gases

    NASA Technical Reports Server (NTRS)

    Kunc, J. A.

    1992-01-01

    A general approach is presented for calculating the reduction of the dissociation energy of diatomic molecules immersed in a dense (n = less than 10 exp 22/cu cm) gas of molecules and atoms. The dissociation energy of a molecule in a dense gas differs from that of the molecule in vacuum because the intermolecular forces change the intramolecular dynamics of the molecule, and, consequently, the energy of the molecular bond.

  10. Improved spatial separation of neutral molecules

    NASA Astrophysics Data System (ADS)

    Kienitz, Jens S.; Długołecki, Karol; Trippel, Sebastian; Küpper, Jochen

    2017-07-01

    We have developed and experimentally demonstrated an improved electrostatic deflector for the spatial separation of molecules according to their dipole-moment-to-mass ratio. The device features a very open structure that allows for significantly stronger electric fields as well as for stronger deflection without molecules crashing into the device itself. We have demonstrated its performance using the prototypical carbonyl sulfide molecule and we discuss opportunities regarding improved quantum-state-selectivity for complex molecules and the deflection of unpolar molecules.

  11. Dissociation energy of molecules in dense gases

    NASA Technical Reports Server (NTRS)

    Kunc, J. A.

    1992-01-01

    A general approach is presented for calculating the reduction of the dissociation energy of diatomic molecules immersed in a dense (n = less than 10 exp 22/cu cm) gas of molecules and atoms. The dissociation energy of a molecule in a dense gas differs from that of the molecule in vacuum because the intermolecular forces change the intramolecular dynamics of the molecule, and, consequently, the energy of the molecular bond.

  12. SEM (Symmetry Equivalent Molecules): a web-based GUI to generate and visualize the macromolecules

    PubMed Central

    Hussain, A. S. Z.; Kumar, Ch. Kiran; Rajesh, C. K.; Sheik, S. S.; Sekar, K.

    2003-01-01

    SEM, Symmetry Equivalent Molecules, is a web-based graphical user interface to generate and visualize the symmetry equivalent molecules (proteins and nucleic acids). In addition, the program allows the users to save the three-dimensional atomic coordinates of the symmetry equivalent molecules in the local machine. The widely recognized graphics program RasMol has been deployed to visualize the reference (input atomic coordinates) and the symmetry equivalent molecules. This program is written using CGI/Perl scripts and has been interfaced with all the three-dimensional structures (solved using X-ray crystallography) available in the Protein Data Bank. The program, SEM, can be accessed over the World Wide Web interface at http://dicsoft2.physics.iisc.ernet.in/sem/ or http://144.16.71.11/sem/. PMID:12824326

  13. DRAW: Molecule Drawing Program Version 2.00

    DTIC Science & Technology

    1989-07-01

    MP199 PLOT SETLAB DORTEP HELP MV PLOTS SETTRM DRAW HQRII NAAPSE PLTXY SETVEC DRELIM INFO NAARC PRIME SIMBOL EDIT DRCRD NACICI PROJ SPARE EDITAD LA50...MM MOVES MV MYORTEP MYPRELIM NORM NUMBUR PiXES PLOTS PLTXY PRIME PROJ RADIAL - 68 - SUBROUTINES Page B-3 RDBYTE SCRIBE SEARC SIMBOL SPARE STOR TABLE...LAP500 DORTEP DRELIM SEAKC SIMBOL GIPRD LCLEAN WRITE VTLINE - 70- SUBROUT INES Page B-5 COMMON: DENSTY DISPLY COMMON: DEVICE DRAWII NAPRIN COMMON: DISPLY

  14. Positron scattering from simple molecules

    NASA Astrophysics Data System (ADS)

    Singh, Suvam; Dutta, Sangita; Naghma, Rahla; Antony, Bobby

    2017-07-01

    A modified version of spherical complex optical potential formalism is employed to calculate the positron scattering cross sections over a wide energy range from near positronium formation threshold to 5000 eV. In the present study, the interaction potential of the positron-target scattering system is developed under an optical potential framework for the calculation of positron scattering total cross sections for CH4, CO, CO2, H2, N2O and NO molecules. The results obtained are in good agreement with most of the available experimental and theoretical values in terms of its shape and magnitude. A characteristic increase in cross section is observed for all the molecules near the positronium formation threshold, which signifies the emergence of positronium formation along with other inelastic channels.

  15. Small Molecules-Big Data.

    PubMed

    Császár, Attila G; Furtenbacher, Tibor; Árendás, Péter

    2016-11-17

    Quantum mechanics builds large-scale graphs (networks): the vertices are the discrete energy levels the quantum system possesses, and the edges are the (quantum-mechanically allowed) transitions. Parts of the complete quantum mechanical networks can be probed experimentally via high-resolution, energy-resolved spectroscopic techniques. The complete rovibronic line list information for a given molecule can only be obtained through sophisticated quantum-chemical computations. Experiments as well as computations yield what we call spectroscopic networks (SN). First-principles SNs of even small, three to five atomic molecules can be huge, qualifying for the big data description. Besides helping to interpret high-resolution spectra, the network-theoretical view offers several ideas for improving the accuracy and robustness of the increasingly important information systems containing line-by-line spectroscopic data. For example, the smallest number of measurements necessary to perform to obtain the complete list of energy levels is given by the minimum-weight spanning tree of the SN and network clustering studies may call attention to "weakest links" of a spectroscopic database. A present-day application of spectroscopic networks is within the MARVEL (Measured Active Rotational-Vibrational Energy Levels) approach, whereby the transitions information on a measured SN is turned into experimental energy levels via a weighted linear least-squares refinement. MARVEL has been used successfully for 15 molecules and allowed to validate most of the transitions measured and come up with energy levels with well-defined and realistic uncertainties. Accurate knowledge of the energy levels with computed transition intensities allows the realistic prediction of spectra under many different circumstances, e.g., for widely different temperatures. Detailed knowledge of the energy level structure of a molecule coming from a MARVEL analysis is important for a considerable number of modeling

  16. Racemic fluids of hard molecules

    NASA Astrophysics Data System (ADS)

    Vatamanu, J.; Cann, N. M.

    2001-05-01

    The structure in four racemic fluids is explored using two integral equation theories: the reference interaction site method (RISM) [D. Chandler and H. C. Andersen, J. Chem. Phys. 57, 1930 (1972)] and the diagrammatically correct theory of Chandler, Silbey, and Ladanyi (CSL) [D. Chandler, R. Silbey, and B. M. Ladanyi, Mol. Phys. 46, 1335 (1982)]. Discrimination is measured by comparison of site pair distributions for sites on identical molecules with the corresponding distributions for sites on mirror-image molecules. We find that discrimination is largest for distributions between the smallest sites in the molecules. Between racemates, those consisting of more asymmetrical chiral molecules (i.e., with a bigger range of site sizes and bond lengths) show the largest discrimination. The indirect correlation function is shown to be nondiscriminating in racemates. Further, exact relationships between like-like and like-unlike differences in the other pair functions have been obtained. From these, the importance of the bridge functions in discrimination is evident. The CSL theory always satisfies the exact relationships, even with approximate bridge diagrams. RISM theory cannot satisfy these exact limits regardless of density and closure relation. We have found that RISM theory predicts qualitatively incorrect pair distributions at low densities, but that the difference in the distributions is more accurate. All bridge diagrams which contribute to O(ρo) have been enumerated and evaluated. Inclusion of these diagrams into the CSL theory leads to exact results at low density. However, we find that the inclusion of the ρo diagrams has dramatically improved the quality of the CSL theory at all densities.

  17. Electron interactions with polar molecules

    SciTech Connect

    Garrett, W.R.

    1981-01-01

    A description is given of a number of the features of discrete and continuous spectra of electrons interacting with polar molecules. Attention is focused on the extent to which theoretical predictions concerning cross sections, resonances, and bound states are strongly influenced by the various approximations that are so ubiquitous in the treatment of such problems. Similarly, threshold scattering and photodetachment processes are examined for the case of weakly bound dipole states whose higher members overlap the continuum.

  18. Intensity calculations of HCN molecules

    NASA Astrophysics Data System (ADS)

    Yasmin, Kausar

    2006-10-01

    Accurate spectroscopic data of HCN are required for many astronomical calculations and modeling. HCN molecules are present in the atmosphere of carbon stars and in galactic centers. Ro-vibrational energy levels and intensity calculations were carried out using the full coupled cluster model and radau coordinates. Accurate ab initio calculated potential energy surface^1 and dipole moment surface^2 were used for computation. The computed values were compared with Hitran^99.^

  19. Metagenomic small molecule discovery methods

    PubMed Central

    Charlop-Powers, Zachary; Milshteyn, Aleksandr; Brady, Sean F.

    2014-01-01

    Metagenomic approaches to natural product discovery provide the means of harvesting bioactive small molecules synthesized by environmental bacteria without the requirement of first culturing these organisms. Advances in sequencing technologies and general metagenomic methods are beginning to provide the tools necessary to unlock the unexplored biosynthetic potential encoded by the genomes of uncultured environmental bacteria. Here, we highlight recent advances in sequence- and functional- based metagenomic approaches that promise to facilitate antibiotic discovery from diverse environmental microbiomes. PMID:25000402

  20. Quantum simulation with cold molecules

    NASA Astrophysics Data System (ADS)

    Rey, Ana Maria

    2014-03-01

    Recent experimental developments on cooling, trapping, manipulating and loading ultra-cold ground state molecules in an optical lattice have opened the door for the exploration of quantum magnetism and the observation of complex quantum dynamics. In this talk I will discuss recent developments towards the implementation of controllable spin lattice models in polar molecules with the spin degrees of freedom encoded in rotational states. The spin-spin couplings are generated by direct dipolar interactions and can be fully controlled by dc electromagnetic fields and microwaves. The spin models realized in this way are long range, anisotropic and can even feature direction-dependent spin interactions. They can emulate Hamiltonians ranging from the Heisenberg spin model, to Hamiltonians with symmetry protected topological phases to Hamiltonians without solid state counterpart. At JILA we have been able to realize for the first time a lattice spin model with fermionic KRb molecules pinned in a 3D lattice. We observe clear manifestation of dipolar exchange interactions in Ramsey spectroscopy even at substantially less than unit lattice filling. I will describe the new theoretical methods that we developed to model the spin dynamics and show that those reproduce the experimental observations. Even though so far the spin dynamics has been restricted to pinned molecules, in part to prevent chemical reactions, I will finish by presenting theoretical calculations supported by experimental measurement at JILA that demonstrate that the continuous quantum Zeno mechanism can actually suppress loss in this highly reactive system. This finding opens the exciting possibility of observing itinerant quantum magnetism in near term experiments. This work is supported by ARO, ARO-DARPA-OLE, NSF-PFC and NSF-PIF

  1. Optical highlighter molecules in neurobiology

    PubMed Central

    Datta, Sandeep Robert; Patterson, George H.

    2011-01-01

    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. PMID:22129781

  2. Optical highlighter molecules in neurobiology.

    PubMed

    Datta, Sandeep Robert; Patterson, George H

    2012-02-01

    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.

  3. Simple molecules as complex systems

    PubMed Central

    Furtenbacher, Tibor; Árendás, Péter; Mellau, Georg; Császár, Attila G.

    2014-01-01

    For individual molecules quantum mechanics (QM) offers a simple, natural and elegant way to build large-scale complex networks: quantized energy levels are the nodes, allowed transitions among the levels are the links, and transition intensities supply the weights. QM networks are intrinsic properties of molecules and they are characterized experimentally via spectroscopy; thus, realizations of QM networks are called spectroscopic networks (SN). As demonstrated for the rovibrational states of H216O, the molecule governing the greenhouse effect on earth through hundreds of millions of its spectroscopic transitions (links), both the measured and first-principles computed one-photon absorption SNs containing experimentally accessible transitions appear to have heavy-tailed degree distributions. The proposed novel view of high-resolution spectroscopy and the observed degree distributions have important implications: appearance of a core of highly interconnected hubs among the nodes, a generally disassortative connection preference, considerable robustness and error tolerance, and an “ultra-small-world” property. The network-theoretical view of spectroscopy offers a data reduction facility via a minimum-weight spanning tree approach, which can assist high-resolution spectroscopists to improve the efficiency of the assignment of their measured spectra. PMID:24722221

  4. A single-molecule diode

    PubMed Central

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

    2005-01-01

    We have designed and synthesized a molecular rod that consists of two weakly coupled electronic π -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. The individual molecules were immobilized by sulfur–gold bonds between both electrodes of a mechanically controlled break junction, and their electronic transport properties have been investigated. The results indeed show diode-like current–voltage characteristics. In contrast to that, control experiments with symmetric molecular rods consisting of two identical π -systems did not show significant asymmetries in the transport properties. To investigate the underlying transport mechanism, phenomenological arguments are combined with calculations based on density functional theory. The theoretical analysis suggests that the bias dependence of the polarizability of the molecule feeds back into the current leading to an asymmetric shape of the current–voltage characteristics, similar to the phenomena in a semiconductor diode. PMID:15956208

  5. A single-molecule diode.

    PubMed

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

    2005-06-21

    We have designed and synthesized a molecular rod that consists of two weakly coupled electronic pi -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. The individual molecules were immobilized by sulfur-gold bonds between both electrodes of a mechanically controlled break junction, and their electronic transport properties have been investigated. The results indeed show diode-like current-voltage characteristics. In contrast to that, control experiments with symmetric molecular rods consisting of two identical pi-systems did not show significant asymmetries in the transport properties. To investigate the underlying transport mechanism, phenomenological arguments are combined with calculations based on density functional theory. The theoretical analysis suggests that the bias dependence of the polarizability of the molecule feeds back into the current leading to an asymmetric shape of the current-voltage characteristics, similar to the phenomena in a semiconductor diode.

  6. Molecules as Drives and Witnesses of Star Formation

    NASA Astrophysics Data System (ADS)

    Shustov, B. M.

    2017-07-01

    The progress in understanding the role of molecules in star formation is discussed. After very brief introduction which we note in that no star formation would be possible without molecules at the dawn of the Universe and that molecules are important drivers and witnesses of star formation in the current epoch, we consider observational technologies and emphasize the prospective role of UV observations. Special attention is paid to possibilities of UV spectroscopy with coming space observatory Spektr-UF (World Space Observatory - Ultraviolet; WSO-UV). Only one example (observations of CO-dark clouds) from vast scientific program of the WSO-UV is mentioned. Also very briefly disclosed is a model approach to study complex evolution of very young (prestellar) object focusing on chemical (molecular) evolution.

  7. Water molecules orientation in surface layer

    NASA Astrophysics Data System (ADS)

    Klingo, V. V.

    2000-08-01

    The water molecules orientation has been investigated theoretically in the water surface layer. The surface molecule orientation is determined by the direction of a molecule dipole moment in relation to outward normal to the water surface. Entropy expressions of the superficial molecules in statistical meaning and from thermodynamical approach to a liquid surface tension have been found. The molecules share directed opposite to the outward normal that is hydrogen protons inside is equal 51.6%. 48.4% water molecules are directed along to surface outward normal that is by oxygen inside. A potential jump at the water surface layer amounts about 0.2 volts.

  8. Mechanobiology of Short DNA Molecules: A Single Molecule Perspective

    NASA Astrophysics Data System (ADS)

    Raghunathan, Krishnan

    Mechanical properties of DNA are known to play a significant role in several biological processes like wrapping of DNA around histones and looping. Most of these cellular events occur on a DNA length scale of a few hundred basepairs. Single molecule methods have been highly successful in directly investigating heterogeneity in different biomolecular systems and serve as ideal tools to study the mechanical properties of DNA. However, their use in studying DNA of contour lengths less than a kilobase are fraught with experimental difficulties. The research presented in this thesis explores the behavior of short stretches of DNA (≤ 500bp) using existing and novel single molecule methods. We have quantified the variation in persistence lengths between sequences having different elasticity using a constant force axial optical tweezers. Our experiments have also revealed that this difference in persistence lengths manifests itself as a difference in looping lifetimes of lac repressor, in sequences having the aforementioned constructs as the intervening sequence between the operator sites. We have also developed a system to probe DNA dynamics in vivo. We have found that the active processes in the cell have distinct effects on dynamics of DNA and eliminating the active processes causes a 'phase transition' like behavior in the inside the cell. We are currently extending this technique to understand DNA dynamics inside bacterial systems. Our results provide vital insights into mechanical properties of DNA and the effect of athermal fluctuations on DNA dynamics.

  9. Computational Design of Druglike Small Molecule Plk1 PBD Inhibitors

    NASA Astrophysics Data System (ADS)

    Vanadia, Sean

    2012-02-01

    Polo-like Kinase 1 (Plk1) participates in regulation of the cell cycle and is often overexpressed in cancers. Inhibition of Plk1 was found to suppress cancer development. Most known kinase inhibitors interact with highly conserved ATP binding sites of the kinases. This makes the design of Plk1-specific inhibitors difficult. However, Plk1 has another active site, the Polo-Box Domain (PBD). PBD is not present in other kinases that were studied here. In this research, the PBD site of Plk1 was used as a target for designing small molecules that could potentially bind Plk1. A previously designed small molecule, Purpurogallin (PPG), was found to bind only the PBD of Plk1 and a highly similar site of LYN kinase, but no other kinases. The PPG structure was used as a template to design new putative Plk1-specific inhibitors. Druglike properties of the new molecules were evaluated with the Osiris Property Explorer program. Interactions of the molecules with Plk1, LYN, and eight other kinases were studied using the Argus Lab docking program. Further search for Plk1-specific inhibitors that could potentially target cancers with overexpressed Plk1 is discussed.

  10. Small Molecule Organic Optoelectronic Devices

    NASA Astrophysics Data System (ADS)

    Bakken, Nathan

    Organic optoelectronics include a class of devices synthesized from carbon containing 'small molecule' thin films without long range order crystalline or polymer structure. Novel properties such as low modulus and flexibility as well as excellent device performance such as photon emission approaching 100% internal quantum efficiency have accelerated research in this area substantially. While optoelectronic organic light emitting devices have already realized commercial application, challenges to obtain extended lifetime for the high energy visible spectrum and the ability to reproduce natural white light with a simple architecture have limited the value of this technology for some display and lighting applications. In this research, novel materials discovered from a systematic analysis of empirical device data are shown to produce high quality white light through combination of monomer and excimer emission from a single molecule: platinum(II) bis(methyl-imidazolyl)toluene chloride (Pt-17). Illumination quality achieved Commission Internationale de L'Eclairage (CIE) chromaticity coordinates (x = 0.31, y = 0.38) and color rendering index (CRI) > 75. Further optimization of a device containing Pt-17 resulted in a maximum forward viewing power efficiency of 37.8 lm/W on a plain glass substrate. In addition, accelerated aging tests suggest high energy blue emission from a halogen-free cyclometalated platinum complex could demonstrate degradation rates comparable to known stable emitters. Finally, a buckling based metrology is applied to characterize the mechanical properties of small molecule organic thin films towards understanding the deposition kinetics responsible for an elastic modulus that is both temperature and thickness dependent. These results could contribute to the viability of organic electronic technology in potentially flexible display and lighting applications. The results also provide insight to organic film growth kinetics responsible for optical

  11. XUV ionization of aligned molecules

    SciTech Connect

    Kelkensberg, F.; Siu, W.; Gademann, G.; Rouzee, A.; Vrakking, M. J. J.; Johnsson, P.; Lucchini, M.; Lucchese, R. R.

    2011-11-15

    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.

  12. Exploring Nanophotovoltaic Molecules using STM

    NASA Astrophysics Data System (ADS)

    Tao, Chenggang; Sun, Jibin; Zhang, Xiaowei; Yamachika, R.; Wegner, D.; Bahri, Y.; Samsonidze, G.; Louie, S.; Tilly, T.; Segalman, R.; Crommie, M.

    2009-03-01

    Composite molecular solar cells are a promising and exciting alternative to traditional silicon or gallium arsenide solar cells, but the power conversion efficiency remains low. In order to further increase this efficiency, a deeper understanding of the microscopic mechanisms at work in organic solar cells is needed. Using scanning tunneling microscopy and spectroscopy we have investigated nanophotovoltaic molecules that combine both donor and acceptor elements. Submolecular spectral resolution reveals the energy level alignment within these composite molecular structures. This information should be useful for understanding the energy conversion pathways within molecular solar cells, and for developing higher efficiency solar cell materials.

  13. Quantum Monte Carlo for Molecules.

    DTIC Science & Technology

    1986-12-01

    AD-Ml?? Ml SITNEt MNOTE CARLO FOR OLEC ILES U) CALIFORNIA INEZY 1/ BERWLEY LRIWENCE BERKELEY LAB NI A LESTER ET AL UKLff~j~~lD61 DEC 66 MSW14-6 .3...SUMMARY REPORT 4. PERFORMING ORG. REPORT NUMBER S QUANTUM MONTE CARLO FOR MOLECULES ___ IU . AUTHOR(@) S. CONTRACT OR GRANT NUMSKR(.) S William A...DISTRIGUTION STATIEMEN4T (at the abstract entered in Block 20. it different from Report) - Quantum Monte Carlo importance functions molchuiner eqaio

  14. Are solar UV-B- and UV-A-dependent gene expression and metabolite accumulation in Arabidopsis mediated by the stress response regulator RADICAL-INDUCED CELL DEATH1?

    PubMed

    Morales, Luis O; Brosché, Mikael; Vainonen, Julia P; Sipari, Nina; Lindfors, Anders V; Strid, Åke; Aphalo, Pedro J

    2015-05-01

    Wavelengths in the ultraviolet (UV) region of the solar spectrum, UV-B (280-315 nm) and UV-A (315-400 nm), are key environmental signals modifying several aspects of plant physiology. Despite significant advances in the understanding of plant responses to UV-B and the identification of signalling components involved, there is limited information on the molecular mechanisms that control UV-B signalling in plants under natural sunlight. Here, we aimed to corroborate the previous suggested role for RADICAL-INDUCED CELL DEATH1 (RCD1) in UV-B signalling under full spectrum sunlight. Wild-type Arabidopsis thaliana and the rcd1-1 mutant were used in an experimental design outdoors where UV-B and UV-A irradiances were manipulated using plastic films, and gene expression, PYRIDOXINE BIOSYNTHESIS1 (PDX1) accumulation and metabolite profiles were analysed in the leaves. At the level of transcription, RCD1 was not directly involved in the solar UV-B regulation of genes with functions in UV acclimation, hormone signalling and stress-related markers. Furthermore, RCD1 had no role on PDX1 accumulation but modulated the UV-B induction of flavonoid accumulation in leaves of Arabidopsis exposed to solar UV. We conclude that RCD1 does not play an active role in UV-B signalling but rather modulates UV-B responses under full spectrum sunlight. © 2014 John Wiley & Sons Ltd.

  15. Molecules in Studio v. 1.0

    SciTech Connect

    Walker, La Tonya; Malczynski, Leonard

    2016-04-22

    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.

  16. Is JPC = 3-+ molecule possible?

    NASA Astrophysics Data System (ADS)

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

    2015-02-01

    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

  17. Attosecond Electron Dynamics in Molecules.

    PubMed

    Nisoli, Mauro; Decleva, Piero; Calegari, Francesca; Palacios, Alicia; Martín, Fernando

    2017-08-23

    Advances in attosecond science have led to a wealth of important discoveries in atomic, molecular, and solid-state physics and are progressively directing their footsteps toward problems of chemical interest. Relevant technical achievements in the generation and application of extreme-ultraviolet subfemtosecond pulses, the introduction of experimental techniques able to follow in time the electron dynamics in quantum systems, and the development of sophisticated theoretical methods for the interpretation of the outcomes of such experiments have raised a continuous growing interest in attosecond phenomena, as demonstrated by the vast literature on the subject. In this review, after introducing the physical mechanisms at the basis of attosecond pulse generation and attosecond technology and describing the theoretical tools that complement experimental research in this field, we will concentrate on the application of attosecond methods to the investigation of ultrafast processes in molecules, with emphasis in molecules of chemical and biological interest. The measurement and control of electronic motion in complex molecular structures is a formidable challenge, for both theory and experiment, but will indubitably have a tremendous impact on chemistry in the years to come.

  18. Exotic negative molecules in AMS

    NASA Astrophysics Data System (ADS)

    Golser, Robin; Gnaser, Hubert; Kutschera, Walter; Priller, Alfred; Steier, Peter; Wallner, Anton

    2007-06-01

    "The techniques and equipment developed for AMS studies are well suited for identifying exotic negative ions". With this sentence begins a pioneering paper by Roy Middleton and Jeff Klein (M&K) on small doubly-charged negative carbon clusters [Nucl. Instr. and Meth. B 123 (1997) 532]. M&K were the first to utilize Accelerator Mass Spectrometry to prove the existence of these clusters and a number of other exotic molecules. We review M&K's efforts and show how their work is being continued at other laboratories. The latest developments are: (1) the discovery of long-lived molecular hydrogen anions H2-,D2-and (2) the unambiguous identification of the smallest doubly-charged negative molecule (LiF3)2-. In particular we show new experimental data for D3-, and for (LiF3)2-, and we try to answer the question why M&K's search for this di-anion was unsuccessful.

  19. Organic Molecules in Protoplanetary Disks

    NASA Astrophysics Data System (ADS)

    Gibb, Erika; Horne, David; Shenoy, Sachindev; Blake, Daniel; van Brunt, Kari; Brittain, Sean; Rettig, Terrence

    2008-08-01

    We propose to use NIRSPEC to search for organic molecules in circumstellar disks toward nearly edge-on T Tauri stars. The feasibility of this study has been recently illustrated by the NIRSPEC detection of HCN toward two edge-on T Tauri stars, GV Tau (Gibb et al. 2007) and IRS 46 (Lahuis et al. 2006), and Spitzer detections of C_2H_2, HCN, and CO_2 toward IRS 46 (Lahuis et al. 2006) and AA Tau (Carr & Najita 2008). We have selected 10 molecules that are predicted to be abundant based on chemical models, observations of high and low mass star forming regions, and comet comae. We will investigate compositional variations among the T Tauri population and compare that to comets and chemical models of disk chemistry. Through this, we can explore the chemistry occurring in the planet-forming regions of protoplanetary disks and investigate the evolution of organic volatiles, which can help establish the mechanism and timescale for planet formation.

  20. Spin squeezing a cold molecule

    NASA Astrophysics Data System (ADS)

    Bhattacharya, M.

    2015-12-01

    In this article we present a concrete proposal for spin squeezing the cold ground-state polar paramagnetic molecule OH, a system currently under fine control in the laboratory. In contrast to existing work, we consider a single, noninteracting molecule with angular momentum greater than 1 /2 . Starting from an experimentally relevant effective Hamiltonian, we identify an adiabatic regime where different combinations of static electric and magnetic fields can be used to realize the single-axis twisting Hamiltonian of Kitagawa and Ueda [M. Kitagawa and M. Ueda, Phys. Rev. A 47, 5138 (1993), 10.1103/PhysRevA.47.5138], the uniform field Hamiltonian proposed by Law et al. [C. K. Law, H. T. Ng, and P. T. Leung, Phys. Rev. A 63, 055601 (2001), 10.1103/PhysRevA.63.055601], and a model of field propagation in a Kerr medium considered by Agarwal and Puri [G. S. Agarwal and R. R. Puri, Phys. Rev. A 39, 2969 (1989), 10.1103/PhysRevA.39.2969]. We then consider the situation in which nonadiabatic effects are quite large and show that the effective Hamiltonian supports spin squeezing even in this case. We provide analytical expressions as well as numerical calculations, including optimization of field strengths and accounting for the effects of field misalignment. Our results have consequences for applications such as precision spectroscopy, techniques such as magnetometry, and stereochemical effects such as the orientation-to-alignment transition.

  1. Characterization of Interstellar Organic Molecules

    NASA Astrophysics Data System (ADS)

    Gençaǧa, Deniz; Carbon, Duane F.; Knuth, Kevin H.

    2008-11-01

    Understanding the origins of life has been one of the greatest dreams throughout history. It is now known that star-forming regions contain complex organic molecules, known as Polycyclic Aromatic Hydrocarbons (PAHs), each of which has particular infrared spectral characteristics. By understanding which PAH species are found in specific star-forming regions, we can better understand the biochemistry that takes place in interstellar clouds. Identifying and classifying PAHs is not an easy task: we can only observe a single superposition of PAH spectra at any given astrophysical site, with the PAH species perhaps numbering in the hundreds or even thousands. This is a challenging source separation problem since we have only one observation composed of numerous mixed sources. However, it is made easier with the help of a library of hundreds of PAH spectra. In order to separate PAH molecules from their mixture, we need to identify the specific species and their unique concentrations that would provide the given mixture. We develop a Bayesian approach for this problem where sources are separated from their mixture by Metropolis Hastings algorithm. Separated PAH concentrations are provided with their error bars, illustrating the uncertainties involved in the estimation process. The approach is demonstrated on synthetic spectral mixtures using spectral resolutions from the Infrared Space Observatory (ISO). Performance of the method is tested for different noise levels.

  2. Electronic spectroscopy of diatomic molecules

    NASA Technical Reports Server (NTRS)

    Partridge, Harry; Langhoff, Stephen R.; Bauschlicher, Charles W., Jr.

    1994-01-01

    This article provides an overview of the principal computational approaches and their accuracy for the study of electronic spectroscopy of diatomic molecules. We include a number of examples from our work that illustrate the range of application. We show how full configuration interaction benchmark calculations were instrumental in improving the understanding of the computational requirements for obtaining accurate results for diatomic spectroscopy. With this understanding it is now possible to compute radiative lifetimes accurate to within 10% for systems involving first- and second-row atoms. We consider the determination of the infrared vibrational transition probabilities for the ground states of SiO and NO, based on a globally accurate dipole moment function. We show how we were able to assign the a(sup "5)II state of CO as the upper state in the recently observed emission bands of CO in an Ar matrix. We next discuss the assignment of the photoelectron detachment spectra of NO and the alkali oxide negative ions. We then present several examples illustrating the state-of-the-art in determining radiative lifetimes for valence-valence and valence-Rydberg transitions. We next compare the molecular spectroscopy of the valence isoelectronic B2, Al2, and AlB molecules. The final examples consider systems involving transition metal atoms, which illustrate the difficulty in describing states with different numbers of d electrons.

  3. Characterization of Interstellar Organic Molecules

    SciTech Connect

    Gencaga, Deniz; Knuth, Kevin H.; Carbon, Duane F.

    2008-11-06

    Understanding the origins of life has been one of the greatest dreams throughout history. It is now known that star-forming regions contain complex organic molecules, known as Polycyclic Aromatic Hydrocarbons (PAHs), each of which has particular infrared spectral characteristics. By understanding which PAH species are found in specific star-forming regions, we can better understand the biochemistry that takes place in interstellar clouds. Identifying and classifying PAHs is not an easy task: we can only observe a single superposition of PAH spectra at any given astrophysical site, with the PAH species perhaps numbering in the hundreds or even thousands. This is a challenging source separation problem since we have only one observation composed of numerous mixed sources. However, it is made easier with the help of a library of hundreds of PAH spectra. In order to separate PAH molecules from their mixture, we need to identify the specific species and their unique concentrations that would provide the given mixture. We develop a Bayesian approach for this problem where sources are separated from their mixture by Metropolis Hastings algorithm. Separated PAH concentrations are provided with their error bars, illustrating the uncertainties involved in the estimation process. The approach is demonstrated on synthetic spectral mixtures using spectral resolutions from the Infrared Space Observatory (ISO). Performance of the method is tested for different noise levels.

  4. Time scales for molecule formation by ion-molecule reactions

    NASA Technical Reports Server (NTRS)

    Langer, W. D.; Glassgold, A. E.

    1976-01-01

    Analytical solutions are obtained for nonlinear differential equations governing the time-dependence of molecular abundances in interstellar clouds. Three gas-phase reaction schemes are considered separately for the regions where each dominates. The particular case of CO, and closely related members of the Oh and CH families of molecules, is studied for given values of temperature, density, and the radiation field. Nonlinear effects and couplings with particular ions are found to be important. The time scales for CO formation range from 100,000 to a few million years, depending on the chemistry and regime. The time required for essentially complete conversion of C(+) to CO in the region where the H3(+) chemistry dominates is several million years. Because this time is longer than or comparable to dynamical time scales for dense interstellar clouds, steady-state abundances may not be observed in such clouds.

  5. Time scales for molecule formation by ion-molecule reactions

    NASA Technical Reports Server (NTRS)

    Langer, W. D.; Glassgold, A. E.

    1976-01-01

    Analytical solutions are obtained for nonlinear differential equations governing the time-dependence of molecular abundances in interstellar clouds. Three gas-phase reaction schemes are considered separately for the regions where each dominates. The particular case of CO, and closely related members of the Oh and CH families of molecules, is studied for given values of temperature, density, and the radiation field. Nonlinear effects and couplings with particular ions are found to be important. The time scales for CO formation range from 100,000 to a few million years, depending on the chemistry and regime. The time required for essentially complete conversion of C(+) to CO in the region where the H3(+) chemistry dominates is several million years. Because this time is longer than or comparable to dynamical time scales for dense interstellar clouds, steady-state abundances may not be observed in such clouds.

  6. Single-molecule dataset (SMD): a generalized storage format for raw and processed single-molecule data.

    PubMed

    Greenfeld, Max; van de Meent, Jan-Willem; Pavlichin, Dmitri S; Mabuchi, Hideo; Wiggins, Chris H; Gonzalez, Ruben L; Herschlag, Daniel

    2015-01-16

    Single-molecule techniques have emerged as incisive approaches for addressing a wide range of questions arising in contemporary biological research [Trends Biochem Sci 38:30-37, 2013; Nat Rev Genet 14:9-22, 2013; Curr Opin Struct Biol 2014, 28C:112-121; Annu Rev Biophys 43:19-39, 2014]. The analysis and interpretation of raw single-molecule data benefits greatly from the ongoing development of sophisticated statistical analysis tools that enable accurate inference at the low signal-to-noise ratios frequently associated with these measurements. While a number of groups have released analysis toolkits as open source software [J Phys Chem B 114:5386-5403, 2010; Biophys J 79:1915-1927, 2000; Biophys J 91:1941-1951, 2006; Biophys J 79:1928-1944, 2000; Biophys J 86:4015-4029, 2004; Biophys J 97:3196-3205, 2009; PLoS One 7:e30024, 2012; BMC Bioinformatics 288 11(8):S2, 2010; Biophys J 106:1327-1337, 2014; Proc Int Conf Mach Learn 28:361-369, 2013], it remains difficult to compare analysis for experiments performed in different labs due to a lack of standardization. Here we propose a standardized single-molecule dataset (SMD) file format. SMD is designed to accommodate a wide variety of computer programming languages, single-molecule techniques, and analysis strategies. To facilitate adoption of this format we have made two existing data analysis packages that are used for single-molecule analysis compatible with this format. Adoption of a common, standard data file format for sharing raw single-molecule data and analysis outcomes is a critical step for the emerging and powerful single-molecule field, which will benefit both sophisticated users and non-specialists by allowing standardized, transparent, and reproducible analysis practices.

  7. Hydrophobic Porous Material Adsorbs Small Organic Molecules

    NASA Technical Reports Server (NTRS)

    Sharma, Pramod K.; Hickey, Gregory S.

    1994-01-01

    Composite molecular-sieve material has pore structure designed specifically for preferential adsorption of organic molecules for sizes ranging from 3 to 6 angstrom. Design based on principle that contaminant molecules become strongly bound to surface of adsorbent when size of contaminant molecules is nearly same as that of pores in adsorbent. Material used to remove small organic contaminant molecules from vacuum systems or from enclosed gaseous environments like closed-loop life-support systems.

  8. Visualization of large elongated DNA molecules.

    PubMed

    Lee, Jinyong; Kim, Yongkyun; Lee, Seonghyun; Jo, Kyubong

    2015-09-01

    Long and linear DNA molecules are the mainstream single-molecule analytes for a variety of biochemical analysis within microfluidic devices, including functionalized surfaces and nanostructures. However, for biochemical analysis, large DNA molecules have to be unraveled, elongated, and visualized to obtain biochemical and genomic information. To date, elongated DNA molecules have been exploited in the development of a number of genome analysis systems as well as for the study of polymer physics due to the advantage of direct visualization of single DNA molecule. Moreover, each single DNA molecule provides individual information, which makes it useful for stochastic event analysis. Therefore, numerous studies of enzymatic random motions have been performed on a large elongated DNA molecule. In this review, we introduce mechanisms to elongate DNA molecules using microfluidics and nanostructures in the beginning. Secondly, we discuss how elongated DNA molecules have been utilized to obtain biochemical and genomic information by direct visualization of DNA molecules. Finally, we reviewed the approaches used to study the interaction of proteins and large DNA molecules. Although DNA-protein interactions have been investigated for many decades, it is noticeable that there have been significant achievements for the last five years. Therefore, we focus mainly on recent developments for monitoring enzymatic activity on large elongated DNA molecules.

  9. Ultrafast electron diffraction from aligned molecules

    SciTech Connect

    Centurion, Martin

    2015-08-17

    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.

  10. Tuberculosis Therapy Modifies the Cytokine Profile, Maturation State, and Expression of Inhibitory Molecules on Mycobacterium tuberculosis-Specific CD4+ T-Cells

    PubMed Central

    Saharia, Kapil K.; Petrovas, Constantinos; Ferrando-Martinez, Sara; Leal, Manuel; Luque, Rafael; Ive, Prudence; Luetkemeyer, Anne; Havlir, Diane; Koup, Richard A.

    2016-01-01

    Background Little is known about the expression of inhibitory molecules cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed-death-1 (PD-1) on Mycobacterium tuberculosis (Mtb)-specific CD4 T-cells and how their expression is impacted by TB treatment. Methods Cryopreserved PBMCs from HIV-TB co-infected and TB mono-infected patients with untreated and treated tuberculosis (TB) disease were stimulated for six hours with PPD and stained. Using polychromatic flow cytometry, we characterized the differentiation state, cytokine profile, and inhibitory molecule expression on PPD-specific CD4 T-cells. Results In our HIV-TB co-infected cohort, TB treatment increased the proportion of PPD-specific CD4 T-cells co-producing IFN-γ+IL-2+TNF-α+ and IFN-γ+IL-2+ (p = 0.0004 and p = 0.0002, respectively) while decreasing the proportion of PPD-specific CD4 T-cells co-producing IFN-γ+MIP1-β+TNF-α+ and IFN-γ+MIP1-β+. The proportion of PPD-specific CD4 T-cells expressing an effector memory phenotype decreased (63.6% vs 51.6%, p = 0.0015) while the proportion expressing a central memory phenotype increased (7.8% vs. 21.7%, p = 0.001) following TB treatment. TB treatment reduced the proportion of PPD-specific CD4 T-cells expressing CTLA-4 (72.4% vs. 44.3%, p = 0.0005) and PD-1 (34.5% vs. 29.2%, p = 0.03). Similar trends were noted in our TB mono-infected cohort. Conclusion TB treatment alters the functional profile of Mtb-specific CD4 T-cells reflecting shifts towards a less differentiated maturational profile and decreases PD-1 and CTLA-4 expression. These could serve as markers of reduced mycobacterial burden. Further study is warranted. PMID:27367521

  11. Programmed Organic Synthesis

    ERIC Educational Resources Information Center

    Heusler, Karl

    1975-01-01

    Describes recent attempts to program computers to map synthetic routes to organic compounds. The computer is provided with structural information for many molecules and reaction descriptions; when a target compound is specified, the computer lists possible precursors, thus indicating possible synthetic routes. (MLH)

  12. A single-molecule diode

    NASA Astrophysics Data System (ADS)

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

    2005-06-01

    We have designed and synthesized a molecular rod that consists of two weakly coupled electronic π -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. The individual molecules were immobilized by sulfur-gold bonds between both electrodes of a mechanically controlled break junction, and their electronic transport properties have been investigated. The results indeed show diode-like current-voltage characteristics. In contrast to that, control experiments with symmetric molecular rods consisting of two identical π -systems did not show significant asymmetries in the transport properties. To investigate the underlying transport mechanism, phenomenological arguments are combined with calculations based on density functional theory. The theoretical analysis suggests that the bias dependence of the polarizability of the molecule feeds back into the current leading to an asymmetric shape of the current-voltage characteristics, similar to the phenomena in a semiconductor diode. Author contributions: F.E., H.B.W., and M.M. designed research; M.E., R.O., M.K., M.F., F.E., H.B.W., and M.M. performed research; M.E., R.O., M.K., M.F., C.v.H., F.W., F.E., H.B.W., and M.M. contributed new reagents/analytic tools; M.E., R.O., M.K., C.v.H., F.E., H.B.W., and M.M. analyzed data; and F.E., H.B.W., and M.M. wrote the paper.This paper was submitted directly (Track II) to the PNAS office.Abbreviations: A, acceptor; D, donor; MCB, mechanically controlled break junction.Data deposition: The atomic coordinates have been deposited in the Cambridge Structural Database, Cambridge Crystallographic Data Centre, Cambridge CB2 1EZ, United Kingdom (CSD reference no. 241632).

  13. Behavior of atypical amphiphilic molecules

    NASA Astrophysics Data System (ADS)

    Ko, John

    1997-08-01

    The physical behavior of several atypical amphiphilic molecules was studied in various environments including micelles, model bilayer membranes, and emulsions. The molecules under investigation were nor-chenodeoxycholic acid (nor-CDCA), ursodeoxycholic acid (UDCA), sphingosine (Sp), sphingosine hydrochloride (SpċHCl), and tetrahydrolipstatin (THL). The bile acids, nor-CDCA and UDCA, were studied using 13C-Nuclear Magnetic Resonance ([13C) -NMR) in micelles of taurocholate and in bilayers of phosphatidylcholine. The pK a values of the bile acids in each environment were determined by [13C) -NMR and are as follows: 6.08 ±.03 for nor-CDCA and 6.27 ±.01 for UDCA in micelles, and 7.04 ± 12 for nor-CDCA and 6.89 ±.05 for UDCA in vesicles. Using line shape analysis, the transbilayer movement rate at 36oC for nor-CDCA and UDCA was calculated to be 580 sec--1 and 409 sec-1, respectively. [13C) -NMR titration of Sp gave pK a values of 9.09 ±.02 in micelles and 9.69 ±.21 in bilayers. Differential scanning calorimetry (DSC) and X-ray diffraction were used to establish the Spċwater and SpċHClċwater phase diagrams. Anhydrous and hydrated samples ranging from 5- 90% water were analyzed. The DSC thermograms traced out the transition temperatures of each molecule while the X- ray diffraction patterns revealed their chain and crystalline lattice packing structures. In general, sphingosine exists as a hydrated crystal with β packing phase below 43oC and melts into an Lα phase. Sphingosine hydrochloride, however, exists as a gel phase (L_beta or /beta/sp') below 42oC that swells to 61% hydration. At low water concentrations (0-64%), a lamellar liquid crystal phase (L_alpha) is formed above the chain melting transition of 42oC. At medium concentration (65%), a Hexagonal I phase is present, and at high water concentrations (66-90%), a micellar phase is present. THL, a specific inhibitor of lipases, was analyzed with [ 13C) -NMR to study its behavior in various environments

  14. Laboratory studies of astrophysical molecules

    NASA Astrophysics Data System (ADS)

    Wang, Haiyan

    There is growing evidence that the molecules necessary for the evolution of life on earth arrived from the interstellar medium. The study of these molecules is therefore of great current interest. Two major types of signals from interstellar space, so-called unidentified interstellar infrared emission bands and the diffuse interstellar absorption bands, have intrigued and puzzled astrochemists for decades. This work has been concentrated on how to contribute to an understanding of the origins of these perplexing signals from space and help identify other molecules that may exist in outer space. Matrix isolation spectroscopy (infrared and ultraviolet-visible) combined with theoretical calculations has been employed throughout this research. Fourier transform infrared absorption spectroscopic measurements, aided by theoretical calculations and 13 C-isotope shifts, have led to the identification of eight heretofore unknown C n S m clusters: C 2 S, C 6 S, C 7 S, C 7 S 2 , C 9 S 2 , C 11 S 2 , C 13 S 2 , and C 15 S 2 . Infrared absorption studies of xenon polycarbon clusters aid in understanding the special electronic structure and reactivity of carbon clusters, which might be associated with the formation mechanism of Buckyball (C 60 ). Reaction of C3 with benzene and ammonia might be involved in the formation of more complex molecular structures, including polycyclic aromatic hydrocarbons (PAHs) and biomolecules such as the amino acids. High resolution vibrational and electronic spectra of neutral dibenzo [b,def]chrysene and its ions in 12 K argon matrices have been recorded. Spectral assignments were supported by high level theoretical calculations. A mixture of the neutral and ionic infrared spectra of dibenzo[b,def]chrysene resembles the unidentified IR bands in the reflection nebula NGC 7023. Anharmonic frequency calculations for neutral and cationic naphthalene, phenanthrene and anthracene using density functional theory have been carried out for the first time

  15. Special Issue: "Molecules against Alzheimer".

    PubMed

    Decker, Michael; Muñoz-Torrero, Diego

    2016-12-16

    This Special Issue, entitled "Molecules against Alzheimer", gathers a number of original articles, short communications, and review articles on recent research efforts toward the development of novel drug candidates, diagnostic agents and therapeutic approaches for Alzheimer's disease (AD), the most prevalent neurodegenerative disorder and a leading cause of death worldwide. This Special Issue contains many interesting examples describing the design, synthesis, and pharmacological profiling of novel compounds that hit one or several key biological targets, such as cholinesterases, β-amyloid formation or aggregation, monoamine oxidase B, oxidative stress, biometal dyshomeostasis, mitochondrial dysfunction, serotonin and/or melatonin systems, the Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase, or nuclear erythroid 2-related factor. The development of novel AD diagnostic agents based on tau protein imaging and the use of lithium or intranasal insulin for the prevention or the symptomatic treatment of AD is also covered in some articles of the Special Issue.

  16. Laser optogalvanic spectroscopy of molecules

    NASA Technical Reports Server (NTRS)

    Webster, C. R.; Rettner, C. T.

    1983-01-01

    In laser optogalvanic (LOG) spectroscopy, a tunable laser is used to probe the spectral characteristics of atomic or molecular species within an electrical discharge in a low pressure gas. Optogalvanic signals arise when the impedance of the discharge changes in response to the absorption of laser radiation. The technique may, therefore, be referred to as impedance spectroscopy. This change in impedance may be monitored as a change in the voltage across the discharge tube. LOG spectra are recorded by scanning the wavelength of a chopped CW dye laser while monitoring the discharge voltage with a lock-in amplifier. LOG signals are obtained if the laser wavelength matches a transition in a species present in the discharge (or flame), and if the absorption of energy in the laser beam alters the impedance of the discharge. Infrared LOG spectroscopy of molecules has been demonstrated and may prove to be the most productive application in the field of optogalvanic techniques.

  17. Electrokinetic concentration of charged molecules

    DOEpatents

    Singh, Anup K.; Neyer, David W.; Schoeniger, Joseph S.; Garguilo, Michael G.

    2002-01-01

    A method for separating and concentrating charged species from uncharged or neutral species regardless of size differential. The method uses reversible electric field induced retention of charged species, that can include molecules and molecular aggregates such as dimers, polymers, multimers, colloids, micelles, and liposomes, in volumes and on surfaces of porous materials. The retained charged species are subsequently quantitatively removed from the porous material by a pressure driven flow that passes through the retention volume and is independent of direction thus, a multi-directional flow field is not required. Uncharged species pass through the system unimpeded thus effecting a complete separation of charged and uncharged species and making possible concentration factors greater than 1000-fold.

  18. Nonadiabatic calculations on hydrogen molecule

    NASA Astrophysics Data System (ADS)

    Komasa, Jacek; Pachucki, Krzysztof

    Since its infancy quantum mechanics has treated hydrogen molecule as a test bed. Contemporary spectroscopy is able to supply the dissociation energy (D0) of H2 with the accuracy of 3 . 7 .10-4cm-1 , while current theoretical predictions are 10-3cm-1 in error. Both the uncertainties are already smaller than the quantum electrodynamic (QED) effects contributing to D0, which poses a particular challenge to theoreticians. Undoubtedly, in order to increase the predictive power of theory one has to not only account for the multitude of the tiny relativistic and QED effects but, especially, significantly increase precision of the largest component of D0--the nonrelativistic contribution. We approach the problem of solving the Schroedinger equation, equipped with new methodology, with the target precision of D0 set at the level of 10-7cm-1 .

  19. Small-molecule arginase inhibitors.

    PubMed

    Ivanenkov, Yan A; Chufarova, Nina V

    2014-01-01

    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.

  20. Photoluminescence of a Plasmonic Molecule.

    PubMed

    Huang, Da; Byers, Chad P; Wang, Lin-Yung; Hoggard, Anneli; Hoener, Ben; Dominguez-Medina, Sergio; Chen, Sishan; Chang, Wei-Shun; Landes, Christy F; Link, Stephan

    2015-07-28

    Photoluminescent Au nanoparticles are appealing for biosensing and bioimaging applications because of their non-photobleaching and non-photoblinking emission. The mechanism of one-photon photoluminescence from plasmonic nanostructures is still heavily debated though. Here, we report on the one-photon photoluminescence of strongly coupled 50 nm Au nanosphere dimers, the simplest plasmonic molecule. We observe emission from coupled plasmonic modes as revealed by single-particle photoluminescence spectra in comparison to correlated dark-field scattering spectroscopy. The photoluminescence quantum yield of the dimers is found to be surprisingly similar to the constituent monomers, suggesting that the increased local electric field of the dimer plays a minor role, in contradiction to several proposed mechanisms. Aided by electromagnetic simulations of scattering and absorption spectra, we conclude that our data are instead consistent with a multistep mechanism that involves the emission due to radiative decay of surface plasmons generated from excited electron-hole pairs following interband absorption.

  1. Helminth-derived immunomodulatory molecules.

    PubMed

    Adisakwattana, Poom; Saunders, Sean P; Nel, Hendrik J; Fallon, Padraic G

    2009-01-01

    Infection of man with parasitic helminths leads to potent activation and modulation of the host immune response. This modulation of immunity by helminth infections may have bystander effects in altering, either suppressing or exacerbating, unrelated inflammatory processes. Various ongoing clinical trials are testing the therapeutic application of helminth infection of patients with inflammatory diseases, including inflammatory bowel disease and allergic disorders. Rather than the use of live helminth infection, with the potential for side effects, an alternative approach is to identify the immune modulatory molecules (IM) produced by helminths that can alter immune functions. In this review, we will focus on characterized helminth-derived IMs that may have potential to be developed as novel therapeutics for inflammatory diseases.

  2. Nanometer Resolution Imaging by SIngle Molecule Switching

    SciTech Connect

    Hu, Dehong; Orr, Galya

    2010-04-02

    The fluorescence intensity of single molecules can change dramatically even under constant laser excitation. The phenomenon is frequently called "blinking" and involves molecules switching between high and low intensity states.[1-3] In additional to spontaneous blinking, the fluorescence of some special fluorophores, such as cyanine dyes and photoactivatable fluorescent proteins, can be switched on and off by choice using a second laser. Recent single-molecule spectroscopy investigations have shed light on mechanisms of single molecule blinking and photoswitching. This ability to controllably switch single molecules led to the invention of a novel fluorescence microscopy with nanometer spatial resolution well beyond the diffraction limit.

  3. Electrorheological crystallization of proteins and other molecules

    DOEpatents

    Craig, G.D.; Rupp, B.

    1996-06-11

    An electrorheological crystalline mass of a molecule is formed by dispersing the molecule in a dispersion fluid and subjecting the molecule dispersion to a uniform electrical field for a period of time during which time an electrorheological crystalline mass is formed. Molecules that may be used to form an electrorheological crystalline mass include any organic or inorganic molecule which has a permanent dipole and/or which is capable of becoming an induced dipole in the presence of an electric field. The molecules used to form the electrorheological crystalline mass are preferably macromolecules, such as biomolecules, such as proteins, nucleic acids, carbohydrates, lipoproteins and viruses. Molecules are crystallized by a method in which an electric field is maintained for a period of time after the electrorheological crystalline mass has formed during which time at least some of the molecules making up the electrorheological crystalline mass form a crystal lattice. The three dimensional structure of a molecule is determined by a method in which an electrorheological crystalline mass of the molecule is formed, an X-ray diffraction pattern of the electrorheological crystalline mass is obtained and the three dimensional structure of the molecule is calculated from the X-ray diffraction pattern. 4 figs.

  4. Production and application of translationally cold molecules

    NASA Astrophysics Data System (ADS)

    Bethlem, Hendrick L.; Meijer, Gerard

    Inspired by the spectacular successes in the field of cold atoms, there is currently great interest in cold molecules. Cooling molecules is useful for various fundamental physics studies and gives access to an exotic regime in chemistry where the wave property of the molecules becomes important. Although cooling molecules has turned out to be considerably more difficult than cooling atoms, a number of methods to produce samples of cold molecules have been demonstrated over the last few years. This paper aims to review the application of cold molecules and the methods to produce them. Emphasis is put on the deceleration of polar molecules using time-varying electric fields. The operation principle of the array of electrodes that is used to decelerate polar molecules is described in analogy with, and using terminology from, charged-particle accelerators. It is shown that, by applying an appropriately timed high voltage burst, molecules can be decelerated while the phase-space density, i.e. the number of molecules per position-velocity interval, remains constant. In this way the high density and low temperature in the moving frame of a pulsed molecular beam can be transferred to the laboratory frame. Experiments on metastable CO in states that are either repelled by or attracted to high electric fields are presented. Loading of slow molecules into traps and storage rings is discussed.

  5. Electrorheological crystallization of proteins and other molecules

    DOEpatents

    Craig, George D.; Rupp, Bernhard

    1996-01-01

    An electrorheological crystalline mass of a molecule is formed by dispersing the molecule in a dispersion fluid and subjecting the molecule dispersion to a uniform electrical field for a period of time during which time an electrorheological crystalline mass is formed. Molecules that may be used to form an electrorheological crystalline mass include any organic or inorganic molecule which has a permanent dipole and/or which is capable of becoming an induced dipole in the presence of an electric field. The molecules used to form the electrorheological crystalline mass are preferably macromolecules, such as biomolecules, such as proteins, nucleic acids, carbohydrates, lipoproteins and viruses. Molecules are crystallized by a method in which an electric field is maintained for a period of time after the electrorheological crystalline mass has formed during which time at least some of the molecules making up the electrorheological crystalline mass form a crystal lattice. The three dimensional structure of a molecule is determined by a method in which an electrorheological crystalline mass of the molecule is formed, an x-ray diffraction pattern of the electrorheological crystalline mass is obtained and the three dimensional structure of the molecule is calculated from the x-ray diffraction pattern.

  6. Observation of pendular butterfly Rydberg molecules.

    PubMed

    Niederprüm, Thomas; Thomas, Oliver; Eichert, Tanita; Lippe, Carsten; Pérez-Ríos, Jesús; Greene, Chris H; Ott, Herwig

    2016-10-05

    Engineering molecules with a tunable bond length and defined quantum states lies at the heart of quantum chemistry. The unconventional binding mechanism of Rydberg molecules makes them a promising candidate to implement such tunable molecules. A very peculiar type of Rydberg molecules are the so-called butterfly molecules, which are bound by a shape resonance in the electron-perturber scattering. Here we report the observation of these exotic molecules and employ their exceptional properties to engineer their bond length, vibrational state, angular momentum and orientation in a small electric field. Combining the variable bond length with their giant dipole moment of several hundred Debye, we observe counter-intuitive molecules which locate the average electron position beyond the internuclear distance.

  7. High-harmonic spectroscopy of aligned molecules

    NASA Astrophysics Data System (ADS)

    Yun, Hyeok; Yun, Sang Jae; Lee, Gae Hwang; Nam, Chang Hee

    2017-01-01

    High harmonics emitted from aligned molecules driven by intense femtosecond laser pulses provide the opportunity to explore the structural information of molecules. The field-free molecular alignment technique is an expedient tool for investigating the structural characteristics of linear molecules. The underlying physics of field-free alignment, showing the characteristic revival structure specific to molecular species, is clearly explained from the quantum-phase analysis of molecular rotational states. The anisotropic nature of molecules is shown from the harmonic polarization measurement performed with spatial interferometry. The multi-orbital characteristics of molecules are investigated using high-harmonic spectroscopy, applied to molecules of N2 and CO2. In the latter case the two-dimensional high-harmonic spectroscopy, implemented using a two-color laser field, is applied to distinguish harmonics from different orbitals. Molecular high-harmonic spectroscopy will open a new route to investigate ultrafast dynamics of molecules.

  8. Observation of pendular butterfly Rydberg molecules

    NASA Astrophysics Data System (ADS)

    Niederprüm, Thomas; Thomas, Oliver; Eichert, Tanita; Lippe, Carsten; Pérez-Ríos, Jesús; Greene, Chris H.; Ott, Herwig

    2016-10-01

    Engineering molecules with a tunable bond length and defined quantum states lies at the heart of quantum chemistry. The unconventional binding mechanism of Rydberg molecules makes them a promising candidate to implement such tunable molecules. A very peculiar type of Rydberg molecules are the so-called butterfly molecules, which are bound by a shape resonance in the electron-perturber scattering. Here we report the observation of these exotic molecules and employ their exceptional properties to engineer their bond length, vibrational state, angular momentum and orientation in a small electric field. Combining the variable bond length with their giant dipole moment of several hundred Debye, we observe counter-intuitive molecules which locate the average electron position beyond the internuclear distance.

  9. Observation of pendular butterfly Rydberg molecules

    PubMed Central

    Niederprüm, Thomas; Thomas, Oliver; Eichert, Tanita; Lippe, Carsten; Pérez-Ríos, Jesús; Greene, Chris H.; Ott, Herwig

    2016-01-01

    Engineering molecules with a tunable bond length and defined quantum states lies at the heart of quantum chemistry. The unconventional binding mechanism of Rydberg molecules makes them a promising candidate to implement such tunable molecules. A very peculiar type of Rydberg molecules are the so-called butterfly molecules, which are bound by a shape resonance in the electron–perturber scattering. Here we report the observation of these exotic molecules and employ their exceptional properties to engineer their bond length, vibrational state, angular momentum and orientation in a small electric field. Combining the variable bond length with their giant dipole moment of several hundred Debye, we observe counter-intuitive molecules which locate the average electron position beyond the internuclear distance. PMID:27703143

  10. Deformation of DNA molecules by hydrodynamic focusing

    NASA Astrophysics Data System (ADS)

    Wong, Pak Kin; Lee, Yi-Kuen; Ho, Chih-Ming

    2003-12-01

    The motion of a DNA molecule in a solvent flow reflects the deformation of a nano/microscale flexible mass spring structure by the forces exerted by the fluid molecules. The dynamics of individual molecules can reveal both fundamental properties of the DNA and basic understanding of the complex rheological properties of long-chain molecules. In this study, we report the dynamics of isolated DNA molecules under homogeneous extensional flow. Hydrodynamic focusing generates homogeneous extensional flow with uniform velocity in the transverse direction. The deformation of individual DNA molecules in the flow was visualized with video fluorescence microscopy. A coil stretch transition was observed when the Deborah number (De) is larger than 0.8. With a sudden stopping of the flow, the DNA molecule relaxes and recoils. The longest relaxation time of T2 DNA was determined to be 0.63 s when scaling viscosity to 0.9 cP.

  11. Methods and applications in single molecule electronics

    NASA Astrophysics Data System (ADS)

    Hihath, Joshua

    In recent years it has become possible to measure charge transport in a single molecule contacted to two metal electrodes. However, a thorough understanding of how a molecule behaves while contacted to two electrodes and how it interacts with its environment is still lacking. This thesis demonstrates various experimental methods for understanding and controlling charge transport in a single molecule junction and the application of these methods to various molecular systems to help elucidate the conduction mechanisms invoked. First, the conductance of DNA is examined in a controlled environment while varying the length, sequence, base-pair matching, bias, temperature, and electrochemical gate of the molecule. These studies show that the conductance of DNA is extremely sensitive to changes in length, sequence, and base-matching, but not as sensitive to temperature and electrochemical gate. Despite the variety of experimental methods applied, the subtleties of the conduction mechanism remain uncertain, and as such necessitate the development of additional tools for understanding the behavior of a single molecule junction. Next, the Conductance Screening Tool for Molecules (CSTM) is described. This is a new tool capable of creating 1000's of single molecules junctions in a matter of minutes. This tool has been used to study the conductance of alkanedithiols, molecules in an array, and single amino acid residues. This system allows for greater speed and flexibility in determining the conductance of a single molecule junction, and provides a capability for performing large-scale systematic studies of molecular systems to determine the conduction mechanism. Finally, an additional experimental method capable of extracting information about the interaction between a molecule and its environment is developed. Here, electron-phonon interactions in a single molecule contacted to two electrodes are studied. This method allows one to obtain a specific, chemical signature of a

  12. PREFACE: Processes in Isotopes and Molecules

    NASA Astrophysics Data System (ADS)

    Bogdan, Diana; Tosa, Valer

    2009-07-01

    These Proceedings present some of the Invited Lectures and Contributed Papers of the International Conference 'Processes in Isotopes and Molecules' (PIM), held in Cluj-Napoca, Romania, 24-26 September 2009. The PIM conference, started in 1999 as a local event, is now an international conference organized every two years by the National Institute for R&D of Isotopic and Molecular Technologies in Cluj-Napoca, the capital city of Transylvania, Romania. The meetings are attended by researchers in the field of atomic and molecular physics as well as those developing new materials and technologies. The scientific subjects are at the cross-roads of three fundamental research areas: physics, chemistry, and biology. The papers here are grouped according to the five conference topics: T1 - Molecular and biomolecular systems T2 - Modern techniques and technologies T3 - Environmental molecular processes T4 - Hydrogen and renewable sources of energy T5 - Nanostructured materials and nanocomposites We gratefully acknowledge the contribution of our colleagues from the Scientific Committee and Program Committee who contributed their time, energy and expertise to the refereeing process. Finally, we would like to thank people from IOP Publishing for their friendly advice and prompt help during the editing process, as well as for their efforts making the Journal of Physics: Conference Series available to the scientific community. Diana Bogdan and Valer Tosa National Institute for R&D Isotopic and Molecular Technologies, Cluj-Napoca

  13. Single-molecule dynamics in nanofabricated traps

    NASA Astrophysics Data System (ADS)

    Cohen, Adam

    2009-03-01

    The Anti-Brownian Electrokinetic trap (ABEL trap) provides a means to immobilize a single fluorescent molecule in solution, without surface attachment chemistry. The ABEL trap works by tracking the Brownian motion of a single molecule, and applying feedback electric fields to induce an electrokinetic motion that approximately cancels the Brownian motion. We present a new design for the ABEL trap that allows smaller molecules to be trapped and more information to be extracted from the dynamics of a single molecule than was previously possible. In particular, we present strategies for extracting dynamically fluctuating mobilities and diffusion coefficients, as a means to probe dynamic changes in molecular charge and shape. If one trapped molecule is good, many trapped molecules are better. An array of single molecules in solution, each immobilized without surface attachment chemistry, provides an ideal test-bed for single-molecule analyses of intramolecular dynamics and intermolecular interactions. We present a technology for creating such an array, using a fused silica plate with nanofabricated dimples and a removable cover for sealing single molecules within the dimples. With this device one can watch the shape fluctuations of single molecules of DNA or study cooperative interactions in weakly associating protein complexes.

  14. NMR studies of electrostatic potential distribution around biologically important molecules.

    PubMed Central

    Likhtenshtein, G I; Adin, I; Novoselsky, A; Shames, A; Vaisbuch, I; Glaser, R

    1999-01-01

    A new experimental approach has been developed to study the distribution of local electrostatic potential around specific protons in biologically important molecules. The approach is the development of a method denoted as "spin label/spin probe," which was proposed by one of us (. Mol. Biol. 6:498-507). The proposed method is based upon the quantitative measurement of the contribution of differently charged nitroxide probes to the spin lattice relaxation rate (1/T1) of protons in the molecule of interest, followed by calculation of local electrostatic potential using the classical Debye equation. In parallel, the theoretical calculation of potential distribution with the use of the MacSpartan Plus 1.0 program has been performed. Application of the method to solutions of simple organic molecules (aliphatic and aromatic alcohols, aliphatic carboxylates (propionate anion), and protonated ethyl amine and imidazole) allowed us to estimate the effective potential around the molecules under investigation. These were found to be in good agreement with theoretically expected values. This technique was then applied to zwitterionic amino acids bearing neutral and charged side chains (glycine, lysine, histidine, and aspartic acid). The reliability of the general approach is proved by the data presented in this paper. Application of this new methodology can afford insight into the biochemical significance of electrostatic effects in biological systems. PMID:10388770

  15. Coinhibitory molecule PD-1 as a therapeutic target in the microenvironment of Multiple Myeloma.

    PubMed

    Atanackovic, Djordje; Luetkens, Tim; Steinbach, Mary; Kröger, Nicolaus

    2017-09-06

    Immunological dysfunction in the microenvironment of multiple myeloma is a potential target for immune-mediated therapies. The programmed death 1 (PD-1) receptor is expressed on the surface of exhausted T and B cells and its ligand PD-L1 is expressed on tumor cells and inhibits T-cell-mediated apoptosis. Inhibiting such "checkpoint" by monoclonal antibodies recently has been shown high activity in solid tumors and malignant lymphomas. In patients with multiple myeloma PD-L1 is overexpressed on myeloma cells and PD1 on T-cells suggesting an active role of PD- 1/PD-L1 in the immunosuppressive microenvironment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Open source software and web services for designing therapeutic molecules.

    PubMed

    Singla, Deepak; Dhanda, Sandeep Kumar; Chauhan, Jagat Singh; Bhardwaj, Anshu; Brahmachari, Samir K; Raghava, Gajendra P S

    2013-01-01

    Despite the tremendous progress in the field of drug designing, discovering a new drug molecule is still a challenging task. Drug discovery and development is a costly, time consuming and complex process that requires millions of dollar and 10-15 years to bring new drug molecules in the market. This huge investment and long-term process are attributed to high failure rate, complexity of the problem and strict regulatory rules, in addition to other factors. Given the availability of 'big' data with ever improving computing power, it is now possible to model systems which is expected to provide time and cost effectiveness to drug discovery process. Computer Aided Drug Designing (CADD) has emerged as a fast alternative method to bring down the cost involved in discovering a new drug. In past, numerous computer programs have been developed across the globe to assist the researchers working in the field of drug discovery. Broadly, these programs can be classified in three categories, freeware, shareware and commercial software. In this review, we have described freeware or open-source software that are commonly used for designing therapeutic molecules. Major emphasis will be on software and web services in the field of chemo- or pharmaco-informatics that includes in silico tools used for computing molecular descriptors, inhibitors designing against drug targets, building QSAR models, and ADMET properties.

  17. Geochemical Origin of Biological Molecules

    NASA Astrophysics Data System (ADS)

    Bassez, Marie-Paule

    2013-04-01

    A model for the geochemical origin of biological molecules is presented. Rocks such as peridotites and basalts, which contain ferromagnesian minerals, evolve in the presence of water. Their hydrolysis is an exothermic reaction which generates heat and a release of H2 and of minerals with modified structures. The hydrogen reacts with the CO2 embedded inside the rock or with the CO2 of the environment to form CO in an hydrothermal process. With the N2 of the environment, and with an activation source arising from cosmic radiation, ferromagnesian rocks might evolve towards the abiotic formation of biological molecules, such as peptide like macromolecules which produce amino acids after acid hydrolysis. The reactions concerned are described. The production of hydrothermal CO is discussed in geological sites containing ferromagnesian silicate minerals and the low intensity of the Earth's magnetic field during Paleoarchaean Era is also discussed. It is concluded that excitation sources arising from cosmic radiation were much more abundant during Paleoarchaean Era and that macromolecular structures of biological relevance might consequently form during Archaean Eon, as a product of the chemical evolution of the rocks and of their mineral contents. This synthesis of abiotically formed biological molecules is consecutively discussed for meteorites and other planets such as Mars. This model for the geochemical origin of biological molecules has first been proposed in 2008 in the context of reactions involving catalysers such as kaolinite [Bassez 2008a] and then presented in conferences and articles [Bassez 2008b, 2009, 2012; Bassez et al. 2009a to 2012b]. BASSEZ M.P. 2008a Synthèse prébiotique dans les conditions hydrothermales, CNRIUT'08, Lyon 29-30/05/2008, Conf. and open access article:http://liris.cnrs.fr/~cnriut08/actes/ 29 mai 11h-12h40. BASSEZ M.P. 2008b Prebiotic synthesis under hydrothermal conditions, ISSOL'08, P2-6, Firenze-Italy, 24-29/08/2008. Poster at the

  18. NMR studies of oriented molecules

    SciTech Connect

    Sinton, S.W.

    1981-11-01

    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 (..delta..M = +-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. Single Molecule Studies of Chromatin

    SciTech Connect

    Jeans, C; Thelen, M P; Noy, A

    2006-02-06

    In eukaryotic cells, DNA is packaged as chromatin, a highly ordered structure formed through the wrapping of the DNA around histone proteins, and further packed through interactions with a number of other proteins. In order for processes such as DNA replication, DNA repair, and transcription to occur, the structure of chromatin must be remodeled such that the necessary enzymes can access the DNA. A number of remodeling enzymes have been described, but our understanding of the remodeling process is hindered by a lack of knowledge of the fine structure of chromatin, and how this structure is modulated in the living cell. We have carried out single molecule experiments using atomic force microscopy (AFM) to study the packaging arrangements in chromatin from a variety of cell types. Comparison of the structures observed reveals differences which can be explained in terms of the cell type and its transcriptional activity. During the course of this project, sample preparation and AFM techniques were developed and optimized. Several opportunities for follow-up work are outlined which could provide further insight into the dynamic structural rearrangements of chromatin.

  20. Proteasome Activation by Small Molecules.

    PubMed

    Leestemaker, Yves; de Jong, Annemieke; Witting, Katharina F; Penning, Renske; Schuurman, Karianne; Rodenko, Boris; Zaal, Esther A; van de Kooij, Bert; Laufer, Stefan; Heck, Albert J R; Borst, Jannie; Scheper, Wiep; Berkers, Celia R; Ovaa, Huib

    2017-06-22

    Drugs that increase 26S proteasome activity have potential therapeutic applications in the treatment of neurodegenerative diseases. A chemical genetics screen of over 2,750 compounds using a proteasome activity probe as a readout in a high-throughput live-cell fluorescence-activated cell sorting-based assay revealed more than ten compounds that increase proteasome activity, with the p38 MAPK inhibitor PD169316 being one of the most potent ones. Genetic and chemical inhibition of either p38 MAPK, its upstream regulators, ASK1 and MKK6, and downstream target, MK2, enhance proteasome activity. Chemical activation of the 26S proteasome increases PROTAC-mediated and ubiquitin-dependent protein degradation and decreases the levels of both overexpressed and endogenous α-synuclein, without affecting the overall protein turnover. In addition, survival of cells overexpressing toxic α-synuclein assemblies is increased in the presence of p38 MAPK inhibitors. These findings highlight the potential of activation of 26S proteasome activity and that this can be achieved through multiple mechanisms by distinct molecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Cochleates bridged by drug molecules.

    PubMed

    Syed, Uwais M; Woo, Amy F; Plakogiannis, Fotios; Jin, Tuo; Zhu, Hua

    2008-11-03

    A new type of cochleate, able to microencapsulate water-soluble cationic drugs or peptides into its inter-lipid bi-layer space, was formed through interaction between negatively charged lipids and drugs or peptides acting as the inter-bi-layer bridges instead of multi-cationic metal ions. This new type of cochleate opened up to form large liposomes when treated with EDTA, suggesting that cationic organic molecules can be extracted from these cochleates in a way similar to multivalent metal ions from metal ion-bridged cochleates. Cochleates can be produced in sub-micron size using a method known as "hydrogel isolated cochleation" or simply by increasing the ratio of multivalent cationic peptides over negatively charged liposomes. When nanometer-sized cochleates and liposomes containing the same fluorescent labeled lipid component were incubated with human fibroblasts cells under identical conditions, cells exposed to cochleates showed bright fluorescent cell surfaces, whereas those incubated with liposomes did not. This result suggests that cochleates' edges made them fuse with the cell surfaces as compared to edge free liposomes. This mechanism of cochleates' fusion with cell membrane was supported by a bactericidal activity assay using tobramycin cochleates, which act by inhibiting intracellular ribosomes. Tobramycin bridged cochleates in nanometer size showed improved antibacterial activity than the drug's solution.

  2. Broadband single-molecule excitation spectroscopy

    PubMed Central

    Piatkowski, Lukasz; Gellings, Esther; van Hulst, Niek F.

    2016-01-01

    Over the past 25 years, single-molecule spectroscopy has developed into a widely used tool in multiple disciplines of science. The diversity of routinely recorded emission spectra does underpin the strength of the single-molecule approach in resolving the heterogeneity and dynamics, otherwise hidden in the ensemble. In early cryogenic studies single molecules were identified by their distinct excitation spectra, yet measuring excitation spectra at room temperature remains challenging. Here we present a broadband Fourier approach that allows rapid recording of excitation spectra of individual molecules under ambient conditions and that is robust against blinking and bleaching. Applying the method we show that the excitation spectra of individual molecules exhibit an extreme distribution of solvatochromic shifts and distinct spectral shapes. Importantly, we demonstrate that the sensitivity and speed of the broadband technique is comparable to that of emission spectroscopy putting both techniques side-by-side in single-molecule spectroscopy. PMID:26794035

  3. Analyzing single-molecule manipulation experiments.

    PubMed

    Calderon, Christopher P; Harris, Nolan C; Kiang, Ching-Hwa; Cox, Dennis D

    2009-01-01

    Single-molecule manipulation studies can provide quantitative information about the physical properties of complex biological molecules without ensemble artifacts obscuring the measurements. We demonstrate computational techniques which aim at more fully utilizing the wealth of information contained in noisy experimental time series. The "noise" comes from multiple sources e.g., inherent thermal motion, instrument measurement error, etc. The primary focus of this paper is a methodology that uses time domain based methods to extract the effective molecular friction from single-molecule pulling data. We studied molecules composed of eight tandem repeat titin I27 domains, but the modeling approaches have applicability to other single-molecule mechanical studies. The merits and challenges associated with applying such a computational approach to existing single-molecule manipulation data are also discussed. Copyright (c) 2009 John Wiley & Sons, Ltd.

  4. Aggregated Gas Molecules: Toxic to Protein?

    PubMed Central

    Zhang, Meng; Zuo, Guanghong; Chen, Jixiu; Gao, Yi; Fang, Haiping

    2013-01-01

    The biological toxicity of high levels of breathing gases has been known for centuries, but the mechanism remains elusive. Earlier work mainly focused on the influences of dispersed gas molecules dissolved in water on biomolecules. However, recent studies confirmed the existence of aggregated gas molecules at the water-solid interface. In this paper, we have investigated the binding preference of aggregated gas molecules on proteins with molecular dynamics simulations, using nitrogen (N2) gas and the Src-homology 3 (SH3) domain as the model system. Aggregated N2 molecules were strongly bound by the active sites of the SH3 domain, which could impair the activity of the protein. In contrast, dispersed N2 molecules did not specifically interact with the SH3 domain. These observations extend our understanding of the possible toxicity of aggregates of gas molecules in the function of proteins. PMID:23588597

  5. The entropy of a complex molecule

    NASA Astrophysics Data System (ADS)

    Faure, Gérôme; Delgado-Buscalioni, Rafael; Español, Pep

    2017-06-01

    Entropy is a central concept in the theory of coarse-graining. Through Einstein's formula, it provides the equilibrium probability distribution of the coarse-grained variables used to describe the system of interest. We study with molecular dynamics simulations the equilibrium probability distribution of thermal blobs representing at a coarse-grained level star polymer molecules in melt. Thermal blobs are characterized by the positions and momenta of the centers of mass, and internal energies of the molecules. We show that the entropy of the level of description of thermal blobs can be very well approximated as the sum of the thermodynamic entropy of each single molecule considered as isolated thermodynamic systems. The entropy of a single molecule depends on the intrinsic energy, involving only contributions from the atoms that make the molecule and not from the interactions with atoms of other molecules.

  6. Ballistic electron spectroscopy of individual buried molecules

    NASA Astrophysics Data System (ADS)

    Kirczenow, George

    2007-01-01

    A theoretical study is presented of the ballistic electron emission spectra (BEES) of individual insulating and conducting organic molecules chemisorbed on a silicon substrate and buried under a thin gold film. It is predicted that ballistic electrons injected into the gold film from a scanning tunneling microscope tip should be transmitted so weakly to the silicon substrate by alkane molecules of moderate length (decane, hexane) and their thiolates that individual buried molecules of this type will be difficult to detect in BEES experiments. However, resonant transmission by molecules containing unsaturated C-C bonds or aromatic rings is predicted to be strong enough for BEES spectra of individual buried molecules of these types to be measured. Calculated BEES spectra of molecules of both types are presented and the effects of some simple interstitial and substitutional gold defects that may occur in molecular films are also briefly discussed.

  7. Mechanics and imaging of single DNA molecules.

    PubMed

    Hegner, M; Grange, W

    2002-01-01

    We review recent experiments that have revealed mechanical properties of single DNA molecules using advanced manipulation and force sensing techniques(scanning force microscopy (SFM), optical or magnetic tweezers, microneedles). From such measurements, intrinsic relevant parameters (persistence length, stretch modulus) as well as their dependence on external parameters (non-physiological conditions, coating with binding agents or proteins) are obtained on a single-molecule level. In addition, imaging of DNA molecules using SFM is presented.

  8. Small-Molecule Carbohydrate-Based Immunostimulants.

    PubMed

    Marzabadi, Cecilia H; Franck, Richard W

    2017-02-03

    In this review, we discuss small-molecule, carbohydrate-based immunostimulants that target Toll-like receptor 4 (TLR-4) and cluster of differentiation 1D (CD1d) receptors. The design and use of these molecules in immunotherapy as well as results from their use in clinical trials are described. How these molecules work and their utilization as vaccine adjuvants are also discussed. Future applications and extensions for the use of these analogues as therapeutic agents will be outlined.

  9. Polarizing beam splitter for dipolar molecules

    SciTech Connect

    Dutta, O.; Jaeaeskelaeinen, M.; Meystre, P.

    2005-05-15

    We propose a coherent beam splitter for polarized heteronuclear molecules based on a stimulated Raman adiabatic passage scheme that uses a tripod linkage of electrotranslational molecular states. We show that for strongly polarized molecules the rotational dynamics imposes significantly larger Rabi frequencies than would otherwise be expected, but within this limitation, a full transfer of the molecules to two counterpropagating ground-state wave packets is possible.

  10. Production and Trapping of Ultracold Polar Molecules

    SciTech Connect

    David, DeMille

    2015-04-21

    We report a set of experiments aimed at the production and trapping of ultracold polar molecules. We begin with samples of laser-cooled and trapped Rb and Cs atoms, and bind them together to form polar RbCs molecules. The binding is accomplished via photoassociation, which uses a laser to catalyze the sticking process. We report results from investigation of a new pathway for photoassociation that can produce molecules in their absolute ground state of vibrational and rotational motion. We also report preliminary observations of collisions between these ground-state molecules and co-trapped atoms.

  11. The Arrangement of Information in DNA Molecules

    PubMed Central

    Thomas, Charles A.

    1966-01-01

    The anatomy of DNA molecules isolated from mature bacteriophage is reviewed. These molecules are linear, duplex DNA consisting mainly of uninterrupted polynucleotide chains. Certain phage (T5 and PB) contain four specifically located interruptions. While the nucleotide sequence of most of these molecules is unique (T5, T3, T7, λ), some are circular permutations of each other (T2, T4, P22). Partial degradation of these DNA molecules by exonuclease III predisposes some of them to form circles upon annealing, but indicating they are terminally redundant. PMID:5967428

  12. Rovibrational cooling of molecules by optical pumping.

    PubMed

    Manai, I; Horchani, R; Lignier, H; Pillet, P; Comparat, D; Fioretti, A; Allegrini, M

    2012-11-02

    We demonstrate rotational and vibrational cooling of cesium dimers by optical pumping techniques. We use two laser sources exciting all the populated rovibrational states, except a target state that thus behaves like a dark state where molecules pile up thanks to absorption-spontaneous emission cycles. We are able to accumulate photoassociated cold Cs(2) molecules in their absolute ground state (v = 0, J = 0) with up to 40% efficiency. Given its simplicity, the method could be extended to other molecules and molecular beams. It also opens up general perspectives in laser cooling the external degrees of freedom of molecules.

  13. Second virial coefficients for chain molecules

    SciTech Connect

    Bokis, C.P.; Donohue, M.D. . Dept. of Chemical Engineering); Hall, C.K. . Dept. of Chemical Engineering)

    1994-01-01

    The importance of having accurate second virial coefficients in phase equilibrium calculations, especially for the calculation of dew points, is discussed. The square-well potentials results in a simple but inaccurate equation for the second virial coefficient for small, spherical molecules such as argon. Here, the authors present a new equation for the second virial coefficient of both spherical molecules and chain molecules which is written in a form similar to that for the square-well potential. This new equation is accurate in comparison to Monte Carlo simulation data on second virial coefficients for square-well chain molecules and with second virial coefficients obtained from experiments on n-alkanes.

  14. Ultracold Molecules: Physics in the Quantum Regime

    SciTech Connect

    Doyle, John

    2014-11-17

    Our research encompasses approaches to the trapping of diatomic molecules at low temperature plus the cooling and detection of polyatomic molecules in the kelvin temperature regime. We have cooled and trapped CaF and/or CaH molecules, loaded directly from a molecular beam. As part of this work, we are continuing to develop an important trapping technique, optical loading from a buffer-gas beam. This method was invented in our lab. We are also studying cold polyatomic molecules and their interactions with cold atoms.

  15. Double photoionization of hydrocarbons and aromatic molecules

    NASA Astrophysics Data System (ADS)

    Wehlitz, R.

    2016-11-01

    This article reviews the recent progress in the field of double photoionization of hydrocarbons and aromatic molecules using synchrotron radiation. First I will describe the importance of carbon-based molecules, which are all around us and are literally part of our life. They exhibit intriguing properties some of which can be probed via double photoionization, i.e., the simultaneous emission of two electrons. Furthermore, I will discuss the different mechanisms that can lead to a doubly charged organic molecule and will highlight those findings by comparing them with the results for atoms and other (simple) molecules. Finally, I will give an outlook on future directions on this subject.

  16. Negative refraction in Möbius molecules

    NASA Astrophysics Data System (ADS)

    Fang, Y. N.; Shen, Yao; Ai, Qing; Sun, C. P.

    2016-10-01

    We theoretically show the negative refraction existing in Möbius molecules. The negative refractive index is induced by the nontrivial topology of the molecules. With the Möbius boundary condition, the effective electromagnetic fields felt by the electron in a Möbius ring is spatially inhomogeneous. In this regard, the DN symmetry is broken in Möbius molecules and thus the magnetic response is induced through the effective magnetic field. Our findings provide an alternative architecture for negative refractive index materials based on the nontrivial topology of Möbius molecules.

  17. Circularly Polarized Luminescence from Simple Organic Molecules.

    PubMed

    Sánchez-Carnerero, Esther M; Agarrabeitia, Antonia R; Moreno, Florencio; Maroto, Beatriz L; Muller, Gilles; Ortiz, María J; de la Moya, Santiago

    2015-09-21

    This article aims to show the identity of "circularly polarized luminescent active simple organic molecules" as a new concept in organic chemistry due to the potential interest of these molecules, as availed by the exponentially growing number of research articles related to them. In particular, it describes and highlights the interest and difficulty in developing chiral simple (small and non-aggregated) organic molecules able to emit left- or right-circularly polarized light efficiently, the efforts realized up to now to reach this challenging objective, and the most significant milestones achieved to date. General guidelines for the preparation of these interesting molecules are also presented.

  18. Submillimeter Spectroscopy of Hydride Molecules

    NASA Astrophysics Data System (ADS)

    Phillips, T. G.

    1998-05-01

    Simple hydride molecules are of great importance in astrophysics and astrochemistry. Physically they dominate the cooling of dense, warm phases of the ISM, such as the cores and disks of YSOs. Chemically they are often stable end points of chemical reactions, or may represent important intermediate stages of the reaction chains, which can be used to test the validity of the process. Through the efforts of astronomers, physicists, chemists, and laboratory spectroscopists we have an approximate knowledge of the abundance of some of the important species, but a great deal of new effort will be required to achieve the comprehensive and accurate data set needed to determine the energy balance and firmly establish the chemical pathways. Due to the low moment of inertia, the hydrides rotate rapidly and so have their fundamental spectral lines in the submillimeter. Depending on the cloud geometry and temperature profile they may be observed in emission or absorption. Species such as HCl, HF, OH, CH, CH(+) , NH_2, NH_3, H_2O, H_2S, H_3O(+) and even H_3(+) have been detected, but this is just a fraction of the available set. Also, most deduced abundances are not nearly sufficiently well known to draw definitive conclusions about the chemical processes. For example, the most important coolant for many regions, H_2O, has a possible range of deduced abundance of a factor of 1000. The very low submillimeter opacity at the South Pole site will be a significant factor in providing a new capabilty for interstellar hydride spectroscopy. The new species and lines made available in this way will be discussed.

  19. Theoretical spectra of floppy molecules

    NASA Astrophysics Data System (ADS)

    Chen, Hua

    2000-09-01

    Detailed studies of the vibrational dynamics of floppy molecules are presented. Six-D bound-state calculations of the vibrations of rigid water dimer based on several anisotropic site potentials (ASP) are presented. A new sequential diagonalization truncation approach was used to diagonalize the angular part of the Hamiltonian. Symmetrized angular basis and a potential optimized discrete variable representation for intermonomer distance coordinate were used in the calculations. The converged results differ significantly from the results presented by Leforestier et al. [J. Chem. Phys. 106 , 8527 (1997)]. It was demonstrated that ASP-S potential yields more accurate tunneling splittings than other ASP potentials used. Fully coupled 4D quantum mechanical calculations were performed for carbon dioxide dimer using the potential energy surface given by Bukowski et al [J. Chem. Phys., 110, 3785 (1999)]. The intermolecular vibrational frequencies and symmetry adapted force constants were estimated and compared with experiments. The inter-conversion tunneling dynamics was studied using the calculated virtual tunneling splittings. Symmetrized Radau coordinates and the sequential diagonalization truncation approach were formulated for acetylene. A 6D calculation was performed with 5 DVR points for each stretch coordinate, and an angular basis that is capable of converging the angular part of the Hamiltonian to 30 cm-1 for internal energies up to 14000 cm-1. The probability at vinylidene configuration were evaluated. It was found that the eigenstates begin to extend to vinylidene configuration from about 10000 cm-1, and the ra, coordinate is closely related to the vibrational dynamics at high energy. Finally, a direct product DVR was defined for coupled angular momentum operators, and the SDT approach were formulated. They were applied in solving the angular part of the Hamiltonian for carbon dioxide dimer problem. The results show the method is capable of giving very accurate

  20. Halogen bonds in biological molecules

    PubMed Central

    Auffinger, Pascal; Hays, Franklin A.; Westhof, Eric; Ho, P. Shing

    2004-01-01

    Short oxygen–halogen interactions have been known in organic chemistry since the 1950s and recently have been exploited in the design of supramolecular assemblies. The present survey of protein and nucleic acid structures reveals similar halogen bonds as potentially stabilizing inter- and intramolecular interactions that can affect ligand binding and molecular folding. A halogen bond in biomolecules can be defined as a short CX···OY interaction (CX is a carbon-bonded chlorine, bromine, or iodine, and OY is a carbonyl, hydroxyl, charged carboxylate, or phosphate group), where the X···O distance is less than or equal to the sums of the respective van der Waals radii (3.27 Å for Cl···O, 3.37Å for Br···O, and 3.50 Å for I···O) and can conform to the geometry seen in small molecules, with the CX···O angle ≈165° (consistent with a strong directional polarization of the halogen) and the X···OY angle ≈120°. Alternative geometries can be imposed by the more complex environment found in biomolecules, depending on which of the two types of donor systems are involved in the interaction: (i) the lone pair electrons of oxygen (and, to a lesser extent, nitrogen and sulfur) atoms or (ii) the delocalized π -electrons of peptide bonds or carboxylate or amide groups. Thus, the specific geometry and diversity of the interacting partners of halogen bonds offer new and versatile tools for the design of ligands as drugs and materials in nanotechnology. PMID:15557000

  1. Completed Optimised Structure of Threonine Molecule by Fuzzy Logic Modelling

    NASA Astrophysics Data System (ADS)

    Sahiner, Ahmet; Ucun, Fatih; Kapusuz, Gulden; Yilmaz, Nurullah

    2016-04-01

    In this study we applied the fuzzy logic approach in order to model the energy depending on the two torsion angles for the threonine (C4H9NO3) molecule. The model is set up according to theoretical results obtained by the density functional theory (B3LYP) with a 6-31 G(d) basic set on a Gausian program. We aimed to determine the best torsion angle values providing the energy of the molecule minimum by a fuzzy logic approach and to compare them with the density functional theory results. It was concluded that the fuzzy logic approach gives information about the untested data and its best value which are expensive and time-consuming to obtain by other methods and experimentation.

  2. Fungal quorum sensing molecules: Role in fungal morphogenesis and pathogenicity.

    PubMed

    Wongsuk, Thanwa; Pumeesat, Potjaman; Luplertlop, Natthanej

    2016-05-01

    When microorganisms live together in high numbers, they need to communicate with each other. To achieve cell-cell communication, microorganisms secrete molecules called quorum-sensing molecules (QSMs) that control their biological activities and behaviors. Fungi secrete QSMs such as farnesol, tyrosol, phenylethanol, and tryptophol. The role of QSMs in fungi has been widely studied in both yeasts and filamentous fungi, for example in Candida albicans, C. dubliniensis, Aspergillus niger, A. nidulans, and Fusarium graminearum. QSMs impact fungal morphogenesis (yeast-to-hypha formation) and also play a role in the germination of macroconidia. QSMs cause fungal cells to initiate programmed cell death, or apoptosis, and play a role in fungal pathogenicity. Several types of QSMs are produced during stages of biofilm development to control cell population or morphology in biofilm communities. This review article emphasizes the role of fungal QSMs, especially in fungal morphogenesis, biofilm formation, and pathogenicity. Information about QSMs may lead to improved measures for controlling fungal infection.

  3. Quantum Phases of Atom-Molecule Mixtures of Fermionic Atoms

    NASA Astrophysics Data System (ADS)

    Lopez, Nicolas; Tsai, Shan-Wen

    2009-11-01

    Cold atom experiments have observed atom-molecule mixtures by tuning the interactions between particles.footnotetextM.L. Olsen, J. D. Perreault, T. D. Cumby, and D. S. Jin, Phys. Rev. A 80, 030701(R) (2009) We study many particle interactions by examaning a simple model that describes the destruction of fermionic atom pairs to form single bosonic molecules and vice versa. A set of functional Renomalization Group equationsfootnotetextR. Shankar, Rev. Mod. Phys., Vol 66 No. 1, January 1994^,footnotetextS.W. Tsai, A.H. Castro Neto, R. Shankar, D.K. Campbell, Phys. Rev. B 72, 054531 (2005) describing these processes are set up and solved numerically. The Self Energy of the fermions are attained as a function of frequency and we search for frequency dependent instabilities that could denote a transition from a disordered liquid to a BCS phase. (Financial support from NSF DMR-084781 and UC-Lab Fees Research Program.)

  4. Minimizing Pulling Geometry Errors in Atomic Force Microscope Single Molecule Force Spectroscopy

    PubMed Central

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

    2008-01-01

    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. PMID:18641069

  5. Carbon Nanotube Biosensors for Space Molecule Detection and Clinical Molecular Diagnostics

    NASA Technical Reports Server (NTRS)

    Han, Jie

    2001-01-01

    Both space molecule detection and clinical molecule diagnostics need to develop ultra sensitive biosensors for detection of less than attomole molecules such as amino acids for DNA. However all the electrode sensor systems including those fabricated from the existing carbon nanotubes, have a background level of nA (nanoAmp). This has limited DNA or other molecule detection to nA level or molecules whose concentration is, much higher than attomole level. A program has been created by NASA and NCI (National Cancer Institute) to exploit the possibility of carbon nanotube based biosensors to solve this problem for both's interest. In this talk, I will present our effort on the evaluation and novel design of carbon nanotubes as electrode biosensors with strategies to minimize background currents while maximizing signal intensity.The fabrication of nanotube electrode arrays, immobilization of molecular probes on nanotube electrodes and in vitro biosensor testing will also be discussed.

  6. Minimizing pulling geometry errors in atomic force microscope single molecule force spectroscopy.

    PubMed

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

    2008-10-01

    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.

  7. Carbon Nanotube Biosensors for Space Molecule Detection and Clinical Molecular Diagnostics

    NASA Technical Reports Server (NTRS)

    Han, Jie

    2001-01-01

    Both space molecule detection and clinical molecule diagnostics need to develop ultra sensitive biosensors for detection of less than attomole molecules such as amino acids for DNA. However all the electrode sensor systems including those fabricated from the existing carbon nanotubes, have a background level of nA (nanoAmp). This has limited DNA or other molecule detection to nA level or molecules whose concentration is, much higher than attomole level. A program has been created by NASA and NCI (National Cancer Institute) to exploit the possibility of carbon nanotube based biosensors to solve this problem for both's interest. In this talk, I will present our effort on the evaluation and novel design of carbon nanotubes as electrode biosensors with strategies to minimize background currents while maximizing signal intensity.The fabrication of nanotube electrode arrays, immobilization of molecular probes on nanotube electrodes and in vitro biosensor testing will also be discussed.

  8. Plasmonic Aptamer-Gold Nanoparticle Sensors for Small Molecule Fingerprint Identification

    DTIC Science & Technology

    2014-08-01

    AFRL-RH-WP-TR-2014-0107 PLASMONIC APTAMER -GOLD NANOPARTICLE SENSORS FOR SMALL MOLECULE FINGERPRINT IDENTIFICATION Jorge Chávez Grant Slusher...Plasmonic Aptamer -Gold Nanoparticle Sensors for Small Molecule Fingerprint Identification 5a. CONTRACT NUMBER N/A 5b. GRANT NUMBER 5c. PROGRAM...The utilization of the plasmonic response of aptamer -gold nanoparticle conjugates (Apt-AuNPs) to design cross- reactive arrays for fingerprint

  9. Laser cooling of a diatomic molecule.

    PubMed

    Shuman, E S; Barry, J F; Demille, D

    2010-10-14

    It has been roughly three decades since laser cooling techniques produced ultracold atoms, leading to rapid advances in a wide array of fields. Laser cooling has not yet been extended to molecules because of their complex internal structure. However, this complexity makes molecules potentially useful for a wide range of applications. For example, heteronuclear molecules possess permanent electric dipole moments that lead to long-range, tunable, anisotropic dipole-dipole interactions. The combination of the dipole-dipole interaction and the precise control over molecular degrees of freedom possible at ultracold temperatures makes ultracold molecules attractive candidates for use in quantum simulations of condensed-matter systems and in quantum computation. Also, ultracold molecules could provide unique opportunities for studying chemical dynamics and for tests of fundamental symmetries. Here we experimentally demonstrate laser cooling of the polar molecule strontium monofluoride (SrF). Using an optical cycling scheme requiring only three lasers, we have observed both Sisyphus and Doppler cooling forces that reduce the transverse temperature of a SrF molecular beam substantially, to a few millikelvin or less. At present, the only technique for producing ultracold molecules is to bind together ultracold alkali atoms through Feshbach resonance or photoassociation. However, proposed applications for ultracold molecules require a variety of molecular energy-level structures (for example unpaired electronic spin, Omega doublets and so on). Our method provides an alternative route to ultracold molecules. In particular, it bridges the gap between ultracold (submillikelvin) temperatures and the ∼1-K temperatures attainable with directly cooled molecules (for example with cryogenic buffer-gas cooling or decelerated supersonic beams). Ultimately, our technique should allow the production of large samples of molecules at ultracold temperatures for species that are chemically

  10. Water: a responsive small molecule.

    PubMed

    Shultz, Mary Jane; Vu, Tuan Hoang; Meyer, Bryce; Bisson, Patrick

    2012-01-17

    Unique among small molecules, water forms a nearly tetrahedral yet flexible hydrogen-bond network. In addition to its flexibility, this network is dynamic: bonds are formed or broken on a picosecond time scale. These unique features make probing the local structure of water challenging. Despite the challenges, there is intense interest in developing a picture of the local water structure due to water's fundamental importance in many fields of chemistry. Understanding changes in the local network structure of water near solutes likely holds the key to unlock problems from analyzing parameters that determine the three dimensional structure of proteins to modeling the fate of volatile materials released into the atmosphere. Pictures of the local structure of water are heavily influenced by what is known about the structure of ice. In hexagonal I(h) ice, the most stable form of solid water under ordinary conditions, water has an equal number of donor and acceptor bonds; a kind of symmetry. This symmetric tetrahedral coordination is only approximately preserved in the liquid. The most obvious manifestation of this altered tetrahedral bonding is the greater density in the liquid compared with the solid. Formation of an interface or addition of solutes further modifies the local bonding in water. Because the O-H stretching frequency is sensitive to the environment, vibrational spectroscopy provides an excellent probe for the hydrogen-bond structure in water. In this Account, we examine both local interactions between water and small solutes and longer range interactions at the aqueous surface. Locally, the results suggest that water is not a symmetric donor or acceptor, but rather has a propensity to act as an acceptor. In interactions with hydrocarbons, action is centered at the water oxygen. For soluble inorganic salts, interaction is greater with the cation than the anion. The vibrational spectrum of the surface of salt solutions is altered compared with that of neat

  11. Decelerating and Trapping Large Polar Molecules.

    PubMed

    Patterson, David

    2016-11-18

    Manipulating the motion of large polyatomic molecules, such as benzonitrile (C6 H5 CN), presents significant difficulties compared to the manipulation of diatomic molecules. Although recent impressive results have demonstrated manipulation, trapping, and cooling of molecules as large as CH3 F, no general technique for trapping such molecules has been demonstrated, and cold neutral molecules larger than 5 atoms have not been trapped (M. Zeppenfeld, B. G. U. Englert, R. Glöckner, A. Prehn, M. Mielenz, C. Sommer, L. D. van Buuren, M. Motsch, G. Rempe, Nature 2012, 491, 570-573). In particular, extending Stark deceleration and electrostatic trapping to such species remains challenging. Here, we propose to combine a novel "asymmetric doublet state" Stark decelerator with recently demonstrated slow, cold, buffer-gas-cooled beams of closed-shell volatile molecules to realize a general system for decelerating and trapping samples of a broad range of volatile neutral polar prolate asymmetric top molecules. The technique is applicable to most stable volatile molecules in the 100-500 AMU range, and would be capable of producing trapped samples in a single rotational state and at a motional temperature of hundreds of mK. Such samples would immediately allow for spectroscopy of unprecedented resolution, and extensions would allow for further cooling and direct observation of slow intramolecular processes such as vibrational relaxation and Hertz-level tunneling dynamics.

  12. Nanoscience: Single-molecule instant replay

    NASA Astrophysics Data System (ADS)

    Camillone, Nicholas

    2016-11-01

    A nanoscale imaging method that uses ultrashort light pulses to initiate and follow the motion of a single molecule adsorbed on a solid surface opens a window onto the physical and chemical dynamics of molecules on surfaces. See Letter p.263

  13. Small Molecules in the Cone Snail Arsenal.

    PubMed

    Neves, Jorge L B; Lin, Zhenjian; Imperial, Julita S; Antunes, Agostinho; Vasconcelos, Vitor; Olivera, Baldomero M; Schmidt, Eric W

    2015-10-16

    Cone snails are renowned for producing peptide-based venom, containing conopeptides and conotoxins, to capture their prey. A novel small-molecule guanine derivative with unprecedented features, genuanine, was isolated from the venom of two cone snail species. Genuanine causes paralysis in mice, indicating that small molecules and not just polypeptides may contribute to the activity of cone snail venom.

  14. Single-molecule studies of DNA mechanics.

    PubMed

    Bustamante, C; Smith, S B; Liphardt, J; Smith, D

    2000-06-01

    During the past decade, physical techniques such as optical tweezers and atomic force microscopy were used to study the mechanical properties of DNA at the single-molecule level. Knowledge of DNA's stretching and twisting properties now permits these single-molecule techniques to be used in the study of biological processes such as DNA replication and transcription.

  15. How organic molecules can control electronic devices.

    PubMed

    Vilan, Ayelet; Cahen, David

    2002-01-01

    This article examines a somewhat counter-intuitive approach to molecular-based electronic devices. Control over the electronic energy levels at the surfaces of conventional semiconductors and metals is achieved by assembling on the solid surfaces, poorly organized, partial monolayers (MLs) of molecules instead of the more commonly used ideal ones. Once those surfaces become interfaces, these layers exert electrostatic rather than electrodynamic control over the resulting devices, based on both electrical monopole and dipole effects of the molecules. Thus electronic transport devices, incorporating molecules, can be constructed without current flow through the molecules. This is illustrated for a gallium arsenide (GaAs) sensor as well as for gold-silicon (Au-Si) and Au-GaAs diodes. Incorporating molecules into solid interfaces becomes possible, using a 'soft' electrical contacting procedure, so as not to damage the molecules. Because there are only a few molecular restrictions, this approach opens up possibilities for the use of more complex (including biologically active) molecules as it circumvents requirements for ideal MLs and for molecules that can tolerate actual electron transport through them.

  16. Near-field single molecule spectroscopy

    SciTech Connect

    Xie, X.S.; Dunn, R.C.

    1995-02-01

    The high spatial resolution and sensitivity of near-field fluorescence microscopy allows one to study spectroscopic and dynamical properties of individual molecules at room temperature. Time-resolved experiments which probe the dynamical behavior of single molecules are discussed. Ground rules for applying near-field spectroscopy and the effect of the aluminum coated near-field probe on spectroscopic measurements are presented.

  17. Polymer physics experiments with single DNA molecules

    NASA Astrophysics Data System (ADS)

    Smith, Douglas E.

    1999-11-01

    Bacteriophage DNA molecules were taken as a model flexible polymer chain for the experimental study of polymer dynamics at the single molecule level. Video fluorescence microscopy was used to directly observe the conformational dynamics of fluorescently labeled molecules, optical tweezers were used to manipulate individual molecules, and micro-fabricated flow cells were used to apply controlled hydrodynamic strain to molecules. These techniques constitute a powerful new experimental approach in the study of basic polymer physics questions. I have used these techniques to study the diffusion and relaxation of isolated and entangled polymer molecules and the hydrodynamic deformation of polymers in elongational and shear flows. These studies revealed a rich, and previously unobserved, ``molecular individualism'' in the dynamical behavior of single molecules. Individual measurements on ensembles of identical molecules allowed the average conformation to be determined as well as the underlying probability distributions for molecular conformation. Scaling laws, that predict the dependence of properties on chain length and concentration, were also tested. The basic assumptions of the reptation model were directly confirmed by visualizing the dynamics of entangled chains.

  18. The Distribution of Solubilized Molecules among Micelles.

    ERIC Educational Resources Information Center

    Miller, Dennis J.

    1978-01-01

    Conflicting views have been put forward on the derivation of the distribution of solubilized molecules among micelles. This stems from failure to consider the arrangement of the solubilized molecules in the micelles. In the treatment presented enthalpy effects are ignored as they are not amenable to a simple general theory. (Author/BB)

  19. The Distribution of Solubilized Molecules among Micelles.

    ERIC Educational Resources Information Center

    Miller, Dennis J.

    1978-01-01

    Conflicting views have been put forward on the derivation of the distribution of solubilized molecules among micelles. This stems from failure to consider the arrangement of the solubilized molecules in the micelles. In the treatment presented enthalpy effects are ignored as they are not amenable to a simple general theory. (Author/BB)

  20. Tumor suppressor molecules and methods of use

    DOEpatents

    Welch, Peter J.; Barber, Jack R.

    2004-09-07

    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.

  1. Interstellar molecules and the origin of life.

    NASA Technical Reports Server (NTRS)

    Buhl, D.; Ponnamperuma, C.

    1971-01-01

    Synopsis of the various views expressed at the conference held at NASA Ames Research Center in February 1971 on the relationship of interstellar molecules to the origin of life, intended to provide a basis for future discussion and work in this area. The topics covered include: a summary of molecules discovered, the interstellar environment, laboratory measurements, chemical evolution, and exobiology.

  2. The symmetry of single-molecule conduction.

    PubMed

    Solomon, Gemma C; Gagliardi, Alessio; Pecchia, Alessandro; Frauenheim, Thomas; Di Carlo, Aldo; Reimers, Jeffrey R; Hush, Noel S

    2006-11-14

    We introduce the conductance point group which defines the symmetry of single-molecule conduction within the nonequilibrium Green's function formalism. It is shown, either rigorously or to within a very good approximation, to correspond to a molecular-conductance point group defined purely in terms of the properties of the conducting molecule. This enables single-molecule conductivity to be described in terms of key qualitative chemical descriptors that are independent of the nature of the molecule-conductor interfaces. We apply this to demonstrate how symmetry controls the conduction through 1,4-benzenedithiol chemisorbed to gold electrodes as an example system, listing also the molecular-conductance point groups for a range of molecules commonly used in molecular electronics research.

  3. Single molecule junction conductance and binding geometry

    NASA Astrophysics Data System (ADS)

    Kamenetska, Maria

    This Thesis addresses the fundamental problem of controlling transport through a metal-organic interface by studying electronic and mechanical properties of single organic molecule-metal junctions. Using a Scanning Tunneling Microscope (STM) we image, probe energy-level alignment and perform STM-based break junction (BJ) measurements on molecules bound to a gold surface. Using Scanning Tunneling Microscope-based break-junction (STM-BJ) techniques, we explore the effect of binding geometry on single-molecule conductance by varying the structure of the molecules, metal-molecule binding chemistry and by applying sub-nanometer manipulation control to the junction. These experiments are performed both in ambient conditions and in ultra high vacuum (UHV) at cryogenic temperatures. First, using STM imaging and scanning tunneling spectroscopy (STS) measurements we explore binding configurations and electronic properties of an amine-terminated benzene derivative on gold. We find that details of metal-molecule binding affect energy-level alignment at the interface. Next, using the STM-BJ technique, we form and rupture metal-molecule-metal junctions ˜104 times to obtain conductance-vs-extension curves and extract most likely conductance values for each molecule. With these measurements, we demonstrated that the control of junction conductance is possible through a choice of metal-molecule binding chemistry and sub-nanometer positioning. First, we show that molecules terminated with amines, sulfides and phosphines bind selectively on gold and therefore demonstrate constant conductance levels even as the junction is elongated and the metal-molecule attachment point is modified. Such well-defined conductance is also obtained with paracyclophane molecules which bind to gold directly through the pi system. Next, we are able to create metal-molecule-metal junctions with more than one reproducible conductance signatures that can be accessed by changing junction geometry. In the

  4. Electronic and thermal properties of Biphenyl molecules

    NASA Astrophysics Data System (ADS)

    Medina, F. G.; Ojeda, J. H.; Duque, C. A.; Laroze, D.

    2015-11-01

    Transport properties of a single Biphenyl molecule coupled to two contacts are studied. We characterise this system by a tight-binding Hamiltonian. Based on the non-equilibrium Green's functions technique with a Landauer-Büttiker formalism the transmission probability, current and thermoelectrical power are obtained. We show that the Biphenyl molecule may have semiconductor behavior for certain values of the electrode-molecule-electrode junctions and different values of the angle between the two rings of the molecule. In addition, the density of states (DOS) is calculated to compare the bandwidths with the profile of the transmission probability. DOS allows us to explain the asymmetric shape with respect to the molecule's Fermi energy.

  5. Superresolution Imaging using Single-Molecule Localization

    PubMed Central

    Patterson, George; Davidson, Michael; Manley, Suliana; Lippincott-Schwartz, Jennifer

    2013-01-01

    Superresolution imaging is a rapidly emerging new field of microscopy that dramatically improves the spatial resolution of light microscopy by over an order of magnitude (∼10–20-nm resolution), allowing biological processes to be described at the molecular scale. Here, we discuss a form of superresolution microscopy based on the controlled activation and sampling of sparse subsets of photoconvertible fluorescent molecules. In this single-molecule based imaging approach, a wide variety of probes have proved valuable, ranging from genetically encodable photoactivatable fluorescent proteins to photoswitchable cyanine dyes. These have been used in diverse applications of superresolution imaging: from three-dimensional, multicolor molecule localization to tracking of nanometric structures and molecules in living cells. Single-molecule-based superresolution imaging thus offers exciting possibilities for obtaining molecular-scale information on biological events occurring at variable timescales. PMID:20055680

  6. Quantum transport of the single metallocene molecule

    NASA Astrophysics Data System (ADS)

    Yu, Jing-Xin; Chang, Jing; Wei, Rong-Kai; Liu, Xiu-Ying; Li, Xiao-Dong

    2016-10-01

    The Quantum transport of three single metallocene molecule is investigated by performing theoretical calculations using the non-equilibrium Green's function method combined with density functional theory. We find that the three metallocen molecules structure become stretched along the transport direction, the distance between two Cp rings longer than the other theory and experiment results. The lager conductance is found in nickelocene molecule, the main transmission channel is the electron coupling between molecule and the electrodes is through the Ni dxz and dyz orbitals and the s, dxz, dyz of gold. This is also confirmed by the highest occupied molecular orbital resonance at Fermi level. In addition, negative differential resistance effect is found in the ferrocene, cobaltocene molecules, this is also closely related with the evolution of the transmission spectrum under applied bias.

  7. Biological signaling by small inorganic molecules.

    PubMed

    Basudhar, Debashree; Ridnour, Lisa A; Cheng, Robert; Kesarwala, Aparna H; Heinecke, Julie; Wink, David A

    2016-01-01

    Small redox active molecules such as reactive nitrogen and oxygen species and hydrogen sulfide have emerged as important biological mediators that are involved in various physiological and pathophysiological processes. Advancement in understanding of cellular mechanisms that tightly regulate both generation and reactivity of these molecules is central to improved management of various disease states including cancer and cardiovascular dysfunction. Imbalance in the production of redox active molecules can lead to damage of critical cellular components such as cell membranes, proteins and DNA and thus may trigger the onset of disease. These small inorganic molecules react independently as well as in a concerted manner to mediate physiological responses. This review provides a general overview of the redox biology of these key molecules, their diverse chemistry relevant to physiological processes and their interrelated nature in cellular signaling.

  8. Single molecule sensing with carbon nanotube devices

    NASA Astrophysics Data System (ADS)

    Choi, Yongki; Sims, Patrick C.; Olsen, Tivoli J.; Iftikhar, Mariam; Corso, Brad L.; Gul, O. Tolga; Weiss, Gregory A.; Collins, Philip G.

    2013-09-01

    Nanoscale electronic devices like field-effect transistors have long promised to provide sensitive, label-free detection of biomolecules. In particular, single-walled carbon nanotubes have the requisite sensitivity to detect single molecule events and sufficient bandwidth to directly monitor single molecule dynamics in real time. Recent measurements have demonstrated this premise by monitoring the dynamic, single-molecule processivity of three different enzymes: lysozyme, protein Kinase A, and the Klenow fragment of DNA polymerase I. In each case, recordings resolved detailed trajectories of tens of thousands of individual chemical events and provided excellent statistics for single-molecule events. This electronic technique has a temporal resolution approaching 1 microsecond, which provides a new window for observing brief, intermediate transition states. In addition, the devices are indefinitely stable, so that the same molecule can be observed for minutes and hours. The extended recordings provide new insights into rare events like transitions to chemically-inactive conformations.

  9. Chemical principles of single-molecule electronics

    NASA Astrophysics Data System (ADS)

    Su, Timothy A.; Neupane, Madhav; Steigerwald, Michael L.; Venkataraman, Latha; Nuckolls, Colin

    2016-03-01

    The field of single-molecule electronics harnesses expertise from engineering, physics and chemistry to realize circuit elements at the limit of miniaturization; it is a subfield of nanoelectronics in which the electronic components are single molecules. In this Review, we survey the field from a chemical perspective and discuss the structure-property relationships of the three components that form a single-molecule junction: the anchor, the electrode and the molecular bridge. The spatial orientation and electronic coupling between each component profoundly affect the conductance properties and functions of the single-molecule device. We describe the design principles of the anchor group, the influence of the electronic configuration of the electrode and the effect of manipulating the structure of the molecular backbone and of its substituent groups. We discuss single-molecule conductance switches as well as the phenomenon of quantum interference and then trace their fundamental roots back to chemical principles.

  10. Circumstellar and interstellar synthesis of organic molecules.

    PubMed

    Tielens, A G; Charnley, S B

    1997-06-01

    We review the formation and evolution of complex circumstellar and interstellar molecules. A number of promising chemical routes are discussed which may lead to the formation of polycyclic aromatic hydrocarbon molecules, fullerenes, and unsaturated hydrocarbon chains in the outflows from stars. Some of the problems with these chemical schemes are pointed out as well. We also review the role of grains in the formation of complex molecules in interstellar molecular clouds. This starts with the formation of simple molecules in an ice grain mantle. UV photolysis and/or thermal polymerization can convert some of these simple molecules into more complex polymeric structures. Some of these species may be released to the gas phase, particularly in the warm regions around newly formed stars. Methanol and formaldehyde seem to play an important role in this drive towards molecular complexity and their chemistry is traced in some detail.

  11. Extracting Models in Single Molecule Experiments

    NASA Astrophysics Data System (ADS)

    Presse, Steve

    2013-03-01

    Single molecule experiments can now monitor the journey of a protein from its assembly near a ribosome to its proteolytic demise. Ideally all single molecule data should be self-explanatory. However data originating from single molecule experiments is particularly challenging to interpret on account of fluctuations and noise at such small scales. Realistically, basic understanding comes from models carefully extracted from the noisy data. Statistical mechanics, and maximum entropy in particular, provide a powerful framework for accomplishing this task in a principled fashion. Here I will discuss our work in extracting conformational memory from single molecule force spectroscopy experiments on large biomolecules. One clear advantage of this method is that we let the data tend towards the correct model, we do not fit the data. I will show that the dynamical model of the single molecule dynamics which emerges from this analysis is often more textured and complex than could otherwise come from fitting the data to a pre-conceived model.

  12. The Origins and Evolution of Molecules in Icy Solids

    NASA Technical Reports Server (NTRS)

    Hudson, Reggie L.; Moore, Marla H.

    2010-01-01

    Astronomical observations of the past few decades have revealed the existence of a variety of molecules in extraterrestrial ices. These molecules include H2O, CO, and CO2, and organics such as CH4, CH30H, and C2H6. Some ices are dominated by polar molecules, while non-polar species appear to dominate others. Observations, mainly in the radio and IR regions, have allowed the inference of other solid-phase molecules whose formation remains difficult to explain by gas-phase chemistry alone. Several laboratory research groups have reported on extensive experiments on the solid-phase reaction chemistry of icy materials, generally as initiated by either ionizing radiation or vacuum-UV photons. These experiments not only permit molecular identifications to be made from astronomical observations, but also allow predictions of yet unidentified molecules. This laboratory approach has evolved over more than 30 years with much of the earliest work focusing on complex mixtures thought to represent either cometary or interstellar ices. Although those early experiments documented a rich solid-state photo- and radiation chemistry, they revealed few details of reactions for particular molecules, partly due to the multi-component nature of the samples. Since then, model systems have been examined that allow the chemistry of individual species and specific reactions to be probed. Reactions involving most of the smaller astronomical molecules have now been studied and specific processes identified. Current laboratory work suggests that a variety of reactions occur in extraterrestrial ices, including acid-base processes, radical dimerizations, proton transfers, oxidations, reductions, and isomerizations. This workshop presentation will focus on chemical reactions relevant to solar system and interstellar ices. While most of the work will be drawn from that to which the speaker has contributed, results from other laboratories also will be included. Suggestions for future studies will be

  13. Laser-induced Coulomb explosion of 1,4-diiodobenzene molecules: Studies of isolated molecules and molecules in helium nanodroplets

    NASA Astrophysics Data System (ADS)

    Christiansen, Lars; Nielsen, Jens H.; Christensen, Lauge; Shepperson, Benjamin; Pentlehner, Dominik; Stapelfeldt, Henrik

    2016-02-01

    Coulomb explosion of 1,4-diiodobenzene molecules, isolated or embedded in helium nanodroplets, is induced by irradiation with an intense femtosecond laser pulse. The recoiling ion fragments are probed by time-of-flight measurements and two-dimensional velocity map imaging. Correlation analysis of the emission directions of I+ ions recoiling from each end of the molecules reveals significant deviation from axial recoil, i.e., where the I+ ions leave strictly along the I-I symmetry axis. For isolated molecules, the relative angular distribution of the I+ ions is centered at 180∘, corresponding to perfect axial recoil, but with a full width at half maximum of 30∘. For molecules inside He droplets, the width of the distribution increases to 45∘. These results provide a direct measure of the accuracy of Coulomb explosion as a probe of the spatial orientation of molecules, which is particularly relevant in connection with laser-induced molecular alignment and orientation. In addition, our studies show how it is possible to identify fragmentation pathways of the Coulomb explosion for the isolated 1,4-diiodobenzene molecules. Finally, for the 1,4-diiodobenzene molecules in He droplets, it is shown that the angular correlation between fragments from the Coulomb explosion is preserved after they have interacted with the He environment.

  14. Attachment of second harmonic-active moiety to molecules for detection of molecules at interfaces

    DOEpatents

    Salafsky, Joshua S.; Eisenthal, Kenneth B.

    2005-10-11

    This invention provides methods of detecting molecules at an interface, which comprise labeling the molecules with a second harmonic-active moiety and detecting the labeled molecules at the interface using a surface selective technique. The invention also provides methods for detecting a molecule in a medium and for determining the orientation of a molecular species within a planar surface using a second harmonic-active moiety and a surface selective technique.

  15. Search for complex organic molecules in space

    NASA Astrophysics Data System (ADS)

    Ohishi, Masatoshi

    2016-07-01

    It was 1969 when the first organic molecule in space, H2CO, was discovered. Since then many organic molecules were discovered by using the NRAO 11 m (upgraded later to 12 m), Nobeyama 45 m, IRAM 30 m, and other highly sensitive radio telescopes as a result of close collaboration between radio astronomers and microwave spectroscopists. It is noteworthy that many famous organic molecules such as CH3OH, C2H5OH, (CH3)2O and CH3NH2 were detected by 1975. Organic molecules were found in so-called hot cores where molecules were thought to form on cold dust surfaces and then to evaporate by the UV photons emitted from the central star. These days organic molecules are known to exist not only in hot cores but in hot corinos (a warm, compact molecular clump found in the inner envelope of a class 0 protostar) and even protoplanetary disks. As was described above, major organic molecules were known since 1970s. It was very natural that astronomers considered a relationship between organic molecules in space and the origin of life. Several astronomers challenged to detect glycine and other prebiotic molecules without success. ALMA is expected to detect such important materials to further consider the gexogenous deliveryh hypothesis. In this paper I summarize the history in searching for complex organic molecules together with difficulties in observing very weak signals from larger species. The awfully long list of references at the end of this article may be the most useful part for readers who want to feel the exciting discovery stories.

  16. Spectroscopic and dynamical studies of highly energized small polyatomic molecules

    SciTech Connect

    Field, R.W.; Silbey, R.J.

    1993-12-01

    The authors have initiated a program to perform spectroscopic and dynamic studies of small molecules. Large amplitude motions in excited acetylene were discussed along with plans to record the dispersed fluorescence (DF) and the stimulated emission pumping (SEP) spectra. SEP spectra were reported for the formyl radical. A Fourier transform spectrometer was discussed with respect to its ability to probe the structure of radicals. This instrument is capable of performing studies using various techniques such as magnetic rotation spectroscopy and sub-Doppler sideband-OODR Zeman (SOODRZ) spectroscopy.

  17. Electron-driven excitations and dissociation of molecules

    SciTech Connect

    Miller, Greg; Orel, Ann E.

    2015-02-13

    This program studied how energy is interchanged in electron and photon collisions with molecules leading to ex-citation and dissociation. Modern ab initio techniques, both for the photoionization and electron scattering, and the subsequent nuclear dynamics studies, are used to accurately treat these problems. This work addresses vibrational ex-citation and dissociative attachment following electron impact, and the dynamics following inner shell photoionzation. These problems are ones for which a full multi-dimensional treatment of the nuclear dynamics is essential and where non-adiabatic effects are expected to be important.

  18. CHEMICAL ACTIVATION OF MOLECULES BY METALS: EXPERIMENTAL STUDIES OF ELECTRON DISTRIBUTIONS AND BONDING

    SciTech Connect

    LICHTENBERGER, DENNIS L.

    2002-03-26

    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.

  19. [< Early stimulation > programs evaluation].

    PubMed

    Bonnier, C

    2007-09-01

    Early intervention include educational and neuroprotection strategies. Early educational strategies are based on the cerebral plasticity concept. Neuroprotection, initially reserved for molecules preventing cell death phenomena, can be extended now to all actions promoting harmonious development and preventing handicaps, and include organisational, therapeutic and environmental aspects. Early stimulation programs have been first devised in United States for vulnerable children who belong to an unfavorable socio-economic category ; positive effects were recorded in school failure rates and social problems ; programs have also been launched in several countries for premature infants and infants with a low birth weight, population exposed to a high risk of deficiencies. The programs are targetted either to the child, or to the parents, or combined to provide assistance for both the child and the parents. The programs given the best evaluation are NIDCAP Program in Sweden (Newborn Individualized Developmental Care and Assessment Program), intended for babies < 1500 g in neonatal intensive care units, then a longitudinal, multisite program, known as IHDP (Infant Health and Development Program). It was launched in United States for infants < 37 weeks or < 2500 g. Results show that combined parent-child programs are the most useful. Effects on parent- child relationships and on child's cognitive development are especially effective if stimulation is maintained and when mothers have a low level of education.

  20. A quantum gas of polar molecules

    NASA Astrophysics Data System (ADS)

    Ni, Kang-Kuen

    Ultracold polar molecular gases promise new directions and exciting applications in precision measurements, ultracold chemistry, electric-field controlled collisions, dipolar quantum gases, and quantum information sciences. This thesis presents experimental realization of a near quantum degenerate gas of polar molecules, where the phase-space density of the gas achieved is more than 10 orders of magnitude higher than previous results. The near quantum degenerate gas of polar molecules is created using two coherent steps. First, atoms in an ultracold gas mixture are converted into extremely weakly bound molecules near a Fano-Feshbach resonance. Second, the weakly bound molecules are transferred to the ro-vibronic ground state using a coherent two-photon Raman technique. The fact that these ground-state molecules are polar is confirmed with a spectroscopic measurement of the permanent electric dipole moment. Finally, manipulation of the molecular hyperfine state is demonstrated; this allows molecules to be populated in a single quantum state, in particular, the lowest energy state. With an ultracold gas of molecules, full control of molecular internal state, and electric field as a new handle, ultracold molecular collisions, including ultracold chemical reactions and dipolar collisions, are studied.

  1. Optically active quantum-dot molecules.

    PubMed

    Shlykov, Alexander I; Baimuratov, Anvar S; Baranov, Alexander V; Fedorov, Anatoly V; Rukhlenko, Ivan D

    2017-02-20

    Chiral molecules made of coupled achiral semiconductor nanocrystals, also known as quantum dots, show great promise for photonic applications owing to their prospective uses as configurable building blocks for optically active structures, materials, and devices. Here we present a simple model of optically active quantum-dot molecules, in which each of the quantum dots is assigned a dipole moment associated with the fundamental interband transition between the size-quantized states of its confined charge carriers. This model is used to analytically calculate the rotatory strengths of optical transitions occurring upon the excitation of chiral dimers, trimers, and tetramers of general configurations. The rotatory strengths of such quantum-dot molecules are found to exceed the typical rotatory strengths of chiral molecules by five to six orders of magnitude. We also study how the optical activity of quantum-dot molecules shows up in their circular dichroism spectra when the energy gap between the molecular states is much smaller than the states' lifetime, and maximize the strengths of the circular dichroism peaks by optimizing orientations of the quantum dots in the molecules. Our analytical results provide clear design guidelines for quantum-dot molecules and can prove useful in engineering optically active quantum-dot supercrystals and photonic devices.

  2. Symmetry calculation for molecules and transition states.

    PubMed

    Vandewiele, Nick M; Van de Vijver, Ruben; Van Geem, Kevin M; Reyniers, Marie-Françoise; Marin, Guy B

    2015-01-30

    The symmetry of molecules and transition states of elementary reactions is an essential property with important implications for computational chemistry. The automated identification of symmetry by computers is a very useful tool for many applications, but often relies on the availability of three-dimensional coordinates of the atoms in the molecule and hence becomes less useful when these coordinates are a priori unavailable. This article presents a new algorithm that identifies symmetry of molecules and transition states based on an augmented graph representation of the corresponding structures, in which both topology and the presence of stereocenters are accounted for. The automorphism group order of the graph associated with the molecule or transition state is used as a starting point. A novel concept of label-stereoisomers, that is, stereoisomers that arise after labeling homomorph substituents in the original molecule so that they become distinguishable, is introduced and used to obtain the symmetry number. The algorithm is characterized by its generic nature and avoids the use of heuristic rules that would limit the applicability. The calculated symmetry numbers are in agreement with expected values for a large and diverse set of structures, ranging from asymmetric, small molecules such as fluorochlorobromomethane to highly symmetric structures found in drug discovery assays. The new algorithm opens up new possibilities for the fast screening of the degree of symmetry of large sets of molecules.

  3. Controlling polar molecules in optical lattices

    SciTech Connect

    Kotochigova, S.; Tiesinga, E.

    2006-04-15

    We theoretically investigate the interaction of polar molecules with optical lattices and microwave fields. We demonstrate the existence of frequency windows in the optical domain where the complex internal structure of the molecule does not influence the trapping potential of the lattice. In such frequency windows the Franck-Condon factors are so small that near-resonant interaction of vibrational levels of the molecule with the lattice fields have a negligible contribution to the polarizability, and light-induced decoherences are kept to a minimum. In addition, we show that microwave fields can induce a tunable dipole-dipole interaction between ground-state rotationally symmetric (J=0) molecules. A combination of a carefully chosen lattice frequency and microwave-controlled interaction between molecules will enable trapping of polar molecules in a lattice and possibly realize molecular quantum logic gates. Our results are based on ab initio relativistic electronic structure calculations of the polar KRb and RbCs molecules combined with calculations of their rovibrational motion.

  4. Trapping and manipulating single molecules of DNA

    NASA Astrophysics Data System (ADS)

    Shon, Min Ju

    This thesis presents the development and application of nanoscale techniques to trap and manipulate biomolecules, with a focus on DNA. These methods combine single-molecule microscopy and nano- and micro-fabrication to study biophysical properties of DNA and proteins. The Dimple Machine is a lab-on-a-chip device that can isolate and confine a small number of molecules from a bulk solution. It traps molecules in nanofabricated chambers, or "dimples", and the trapped molecules are then studied on a fluorescence microscope at the single-molecule level. The sampling of bulk solution by dimples is representative, reproducible, and automated, enabling highthroughput single-molecule experiments. The device was applied to study hybridization of oligonucleotides, particularly in the context of reaction thermodynamics and kinetics in nanoconfinement. The DNA Pulley is a system to study protein binding and the local mechanical properties of DNA. A molecule of DNA is tethered to a surface on one end, and a superparamagnetic bead is attached to the other. A magnet pulls the DNA taut, and a silicon nitride knife with a nanoscale blade scans the DNA along its contour. Information on the local properties of the DNA is extracted by tracking the bead with nanometer precision in a white-light microscope. The system can detect proteins bound to DNA and localize their recognition sites, as shown with a model protein, EcoRI restriction enzyme. Progress on the measurements of nano-mechanical properties of DNA is included.

  5. Potentiometric Sensing of the Organic Molecules

    NASA Astrophysics Data System (ADS)

    Wang, Yantian; Jain, Vijay; Lee, Harriman; Levon, Kalle; Rafailovich, Miriam; Sokolov, Jonathan

    2006-03-01

    A prototype detector was constructed for the detection of complex biomolecules, such as viruses and complete chromosomes. The technology is based on ref. [1], where the technique was demonstrated for small molecules. A monolayer of 11-mercapto-1-undocanol (thiol) is co-absorbed with the organic molecules on a gold plated electrode. The thiolated molecules self assemble into a highly organized crystalline film chemically anchored to the surface. The bio-molecules which are not attached and can then be removed by washing in water, leaving behind templated regions, or cavities in the monolayer with specific size and shape. The electrochemical response between the modified electrode and the Ag/AgCl reference electrode was measured by the potentiometer. When the electrode was exposed to the solution containing the template molecules, in a concentration as low as 10-6M, a sharp potential response was observed, while very slight response was observed when exposed to other kind of molecules. This was attributed to the selective absorption of the molecules onto the electrode. Reference: [1]. Zhou Y., Yu B., Shiu E., Levon K., Anal. Chem. 2004, 76, 2689.

  6. Single Molecule Spectroscopy of Electron Transfer

    SciTech Connect

    Michael Holman; Ling Zang; Ruchuan Liu; David M. Adams

    2009-10-20

    The objectives of this research are threefold: (1) to develop methods for the study electron transfer processes at the single molecule level, (2) to develop a series of modifiable and structurally well defined molecular and nanoparticle systems suitable for detailed single molecule/particle and bulk spectroscopic investigation, (3) to relate experiment to theory in order to elucidate the dependence of electron transfer processes on molecular and electronic structure, coupling and reorganization energies. We have begun the systematic development of single molecule spectroscopy (SMS) of electron transfer and summaries of recent studies are shown. There is a tremendous need for experiments designed to probe the discrete electronic and molecular dynamic fluctuations of single molecules near electrodes and at nanoparticle surfaces. Single molecule spectroscopy (SMS) has emerged as a powerful method to measure properties of individual molecules which would normally be obscured in ensemble-averaged measurement. Fluctuations in the fluorescence time trajectories contain detailed molecular level statistical and dynamical information of the system. The full distribution of a molecular property is revealed in the stochastic fluctuations, giving information about the range of possible behaviors that lead to the ensemble average. In the case of electron transfer, this level of understanding is particularly important to the field of molecular and nanoscale electronics: from a device-design standpoint, understanding and controlling this picture of the overall range of possible behaviors will likely prove to be as important as designing ia the ideal behavior of any given molecule.

  7. Line broadening of confined CO gas: from molecule-wall to molecule-molecule collisions with pressure.

    PubMed

    Hartmann, J-M; Boulet, C; Auwera, J Vander; El Hamzaoui, H; Capoen, B; Bouazaoui, M

    2014-02-14

    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.

  8. Giant molecules composed of polar molecules and atoms in mixed dimensions

    NASA Astrophysics Data System (ADS)

    Qi, Ran; Tan, Shina

    2014-05-01

    Two or three polar molecules, confined to one or two dimensions, can form stable bound states with a single atom living in three dimensions, if the molecule and the atom can interact resonantly such that their mixed dimensional scattering length is large. We call these bound states ``giant molecules'' since it's a molecule composed of smaller molecules and atoms. We study their properties using techniques including exact numerical solution, exact qunatum diffusion Monte Carlo (QMC), Born-Oppenheimer approximation (BOA), and semiclassical approximation. These bound states have a hierarchical structure reminiscent of the celestial systems.

  9. Single molecule microscopy and spectroscopy: concluding remarks.

    PubMed

    van Hulst, Niek F

    2015-01-01

    Chemistry is all about molecules: control, synthesis, interaction and reaction of molecules. All too easily on a blackboard, one draws molecules, their structures and dynamics, to create an insightful picture. The dream is to see these molecules in reality. This is exactly what "Single Molecule Detection" provides: a look at molecules in action at ambient conditions; a breakthrough technology in chemistry, physics and biology. Within the realms of the Royal Society of Chemistry, the Faraday Discussion on "Single Molecule Microscopy and Spectroscopy" was a very appropriate topic for presentation, deliberation and debate. Undoubtedly, the Faraday Discussions have a splendid reputation in stimulating scientific debates along the traditions set by Michael Faraday. Interestingly, back in the 1830's, Faraday himself pursued an experiment that led to the idea that atoms in a compound were joined by an electrical component. He placed two opposite electrodes in a solution of water containing a dissolved compound, and observed that one of the elements of the compound accumulated on one electrode, while the other was deposited on the opposite electrode. Although Faraday was deeply opposed to atomism, he had to recognize that electrical forces were responsible for the joining of atoms. Probably a direct view on the atoms or molecules in his experiment would have convinced him. As such, Michael Faraday might have liked the gathering at Burlington House in September 2015 (). Surely, with the questioning eyes of his bust on the 1st floor corridor, the non-believer Michael Faraday has incited each passer-by to enter into discussion and search for deeper answers at the level of single molecules. In these concluding remarks, highlights of the presented papers and discussions are summarized, complemented by a conclusion on future perspectives.

  10. Decay behaviors of the Pc hadronic molecules

    NASA Astrophysics Data System (ADS)

    Lin, Yong-Hui; Shen, Chao-Wei; Guo, Feng-Kun; Zou, Bing-Song

    2017-06-01

    The Pc(4380 ) and Pc(4450 ) states observed recently by the LHCb experiment were proposed to be either D ¯Σc* or D¯*Σc bound states. We analyze the decay behaviors of two such types of hadronic molecules within the effective Lagrangian framework. With branching ratios of ten possible decay channels calculated, it is found that the two types of hadronic molecules have distinguishable decay patterns. While the D ¯Σc* molecule decays dominantly to the D¯*Λc channel with a branching ratio by 2 orders of magnitude larger than to D ¯Λc, the D¯*Σc molecule decays to these two channels with a difference of less than a factor of 2. Our results show that the total decay width of Pc(4380 ) as the spin-parity-3/2- D ¯Σc* molecule is about a factor of 2 larger than the corresponding value for the D¯*Σc molecule. It suggests that the assignment of the D ¯Σc* molecule for Pc(4380 ) is more favorable than the D¯*Σc molecule. In addition, Pc(4450 ) seems to be a D¯*Σc molecule with JP=5/2+ in our scheme. Based on these partial decay widths of the Pc states, we estimate the cross sections for the reactions γ p →J /ψ p and π p →J /ψ p through the s-channel Pc states. The forthcoming γ p experiment at JLAB and the π p experiment at JPARC should be able to pin down the nature of these Pc states.

  11. Life at the Single Molecule Level

    SciTech Connect

    Xie, Xiaoliang Sunny

    2011-03-04

    In a living cell, gene expression—the transcription of DNA to messenger RNA followed by translation to protein—occurs stochastically, as a consequence of the low copy number of DNA and mRNA molecules involved. Can one monitor these processes in a living cell in real time? How do cells with identical genes exhibit different phenotypes? Recent advances in single-molecule imaging in living bacterial cells allow these questions to be answered at the molecular level in a quantitative manner. It was found that rare events of single molecules can have important biological consequences.

  12. Affibody molecules as engineered protein drugs

    PubMed Central

    Frejd, Fredrik Y; Kim, Kyu-Tae

    2017-01-01

    Affibody molecules can be used as tools for molecular recognition in diagnostic and therapeutic applications. There are several preclinical studies reported on diagnostic and therapeutic use of this molecular class of alternative scaffolds, and early clinical evidence is now beginning to accumulate that suggests the Affibody molecules to be efficacious and safe in man. The small size and ease of engineering make Affibody molecules suitable for use in multispecific constructs where AffiMabs is one such that offers the option to potentiate antibodies for use in complex disease. PMID:28336959

  13. Exploring biology with small organic molecules.

    PubMed

    Stockwell, Brent R

    2004-12-16

    Small organic molecules have proven to be invaluable tools for investigating biological systems, but there is still much to learn from their use. To discover and to use more effectively new chemical tools to understand biology, strategies are needed that allow us to systematically explore 'biological-activity space'. Such strategies involve analysing both protein binding of, and phenotypic responses to, small organic molecules. The mapping of biological-activity space using small molecules is akin to mapping the stars--uncharted territory is explored using a system of coordinates that describes where each new feature lies.

  14. H2 molecules and the intercloud medium

    NASA Technical Reports Server (NTRS)

    Hill, J. K.; Hollenbach, D. J.

    1976-01-01

    The paper discusses expected column densities of H2 in the intercloud medium and the possible use of molecules as indicators of intercloud physical conditions. Molecule formation by the H(-) process and on graphite grains is treated, and it is shown that the Barlow-Silk hypothesis of a 1-eV semichemical hydrogen-graphite bond leads to a large enhancement of the intercloud molecule-formation rate. Rotational-excitation calculations are presented for both cloud and intercloud conditions which show, in agreement with Jura (1975), that the presently observed optically thin H2 absorption components are more likely to originate in cold clouds than in the intercloud medium.

  15. Engineering discrete stacks of aromatic molecules.

    PubMed

    Klosterman, Jeremy K; Yamauchi, Yoshihiro; Fujita, Makoto

    2009-06-01

    Intrigued by transannular interactions occurring in stacked aromatic molecules, chemists have long endeavored to engineer discrete stacks of specific lengths and orientation. The maturation of self-assembly methodologies has shifted the focus away from utilizing covalent scaffolds to harnessing non-covalent interactions such as ionic interactions, hydrogen bonds, metal-ligand interactions, and aromatic interactions. Aromatic molecules often assemble into ill-defined, infinite aggregates and thus multiple self-assembly techniques must be combined to achieve the desired stack size and conformations. This critical review briefly highlights covalent scaffolds of stack aromatics before focusing on modern self-assembly based strategies for engineering discrete stacks of aromatic molecules (149 references).

  16. Porous hydrocarbon networks of pyramidal molecules

    NASA Astrophysics Data System (ADS)

    Sorimachi, Jun-ya; Okada, Susumu

    2017-06-01

    Using the density functional theory with generalized gradient approximation, we theoretically design porous hydrocarbon networks by assembling pyramidal hydrocarbon molecules with S = 1/2 radical spin. Our calculation showed that the porous hydrocarbon networks have either metallic or semiconducting electronic properties depending on the mutual arrangement of the pyramidal molecules in the networks. Furthermore, owing to the radical spin on the pyramidal molecules, the porous hydrocarbon network exhibits magnetic spin ordering with various spin configurations for metastable states, because the polarized electron spin forms a Kagome lattice and prefers singlet spin-spin coupling.

  17. Circularly Polarized Luminescence from Simple Organic Molecules

    PubMed Central

    Sánchez-Carnerero, Esther M.; Agarrabeitia, Antonia R.; Moreno, Florencio; Maroto, Beatriz L.; Muller, Gilles; Ortiz, María J.

    2015-01-01

    This article aims to show the identity of “CPL-active simple organic molecules” as a new concept in Organic Chemistry due to the potential interest of these molecules, as availed by the exponentially growing number of research articles related to them. In particular, it describes and highlights the interest and difficulty in developing chiral simple (small and nonaggregated) organic molecules able to emit left- or right-circularly polarized light efficiently, the efforts realized up to now to reach this challenging objective, and the most significant milestones achieved to date. General guidelines for the preparation of these interesting molecules are also presented. PMID:26136234

  18. Probing Intermolecular Coupled Vibrations between Two Molecules

    NASA Astrophysics Data System (ADS)

    Han, Zhumin; Czap, Gregory; Xu, Chen; Chiang, Chi-lun; Yuan, Dingwang; Wu, Ruqian; Ho, W.

    2017-01-01

    Intermolecular interactions can induce energy shifts and coupling of molecular vibrations. However, the detection of intermolecular coupled vibrations has not been reported at the single molecule level. Here we detected an intermolecular coupled vibration between two CO molecules, one on the surface and another on the tip within the gap of a subkelvin scanning tunneling microscope, and analyzed the results by density functional calculations. We attribute the evolution of the energy and intensity of this coupled vibration as a function of tip-sample distance to the tilting and orbital alignment of the two CO molecules.

  19. Absorption and fluorescence of single molecules.

    PubMed

    Butter, J Y P; Hecht, B; Crenshaw, B R; Weder, C

    2006-10-21

    Simultaneous detection of single molecules by absorption and fluorescence is demonstrated using confocal microscopy at cryogenic temperature. Dynamical processes such as blinking and spectral jumping of single emitters are observed in both detection channels. The relative magnitude of fluorescence and absorption varies between molecules. In particular, we observe molecules that do not emit detectable Stokes-shifted fluorescence but show a strong absorption signal. The fact that coherent resonant scattering underlies the absorption process is demonstrated by a correlation between small linewidth and large absorption amplitude.

  20. Exploring biology with small organic molecules

    PubMed Central

    Stockwell, Brent R.

    2011-01-01

    Small organic molecules have proven to be invaluable tools for investigating biological systems, but there is still much to learn from their use. To discover and to use more effectively new chemical tools to understand biology, strategies are needed that allow us to systematically explore ‘biological-activity space’. Such strategies involve analysing both protein binding of, and phenotypic responses to, small organic molecules. The mapping of biological-activity space using small molecules is akin to mapping the stars — uncharted territory is explored using a system of coordinates that describes where each new feature lies. PMID:15602550

  1. Molecular Programming with DNA

    NASA Astrophysics Data System (ADS)

    Winfree, Erik

    2009-05-01

    Information can be stored in molecules and processed by molecular reactions. Molecular information processing is at the heart of all biological systems; might it soon also be at the heart of non-biological synthetic chemical systems? Perhaps yes. One technological approach comes from DNA nanotechnology and DNA computing, where DNA is used as a non-biological informational polymer that can be rationally designed to create a rich class of molecular systems -- for example, DNA molecules that self-assemble precisely, that fold into complex nanoscale objects, that act as mechanical actuators and molecular motors, and that make decisions based on digital and analog logic. I will argue that to fully exploit their design potential, we will need to invent programming languages for specifying the behavior of information-based molecular systems, to create theoretical tools for understanding and analyzing the behavior of molecular programs, to develop compilers that automate the design of molecules with the desired behaviors, and to expand experimental techniques so that the implementation and debugging of complex molecular systems becomes as commonplace and practical as computer programming.

  2. Stochastic Models of Molecule Formation on Dust

    NASA Technical Reports Server (NTRS)

    Charnley, Steven; Wirstroem, Eva

    2011-01-01

    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

  3. Dynamics of molecules in extreme rotational states

    PubMed Central

    Yuan, Liwei; Teitelbaum, Samuel W.; Robinson, Allison; Mullin, Amy S.

    2011-01-01

    We have constructed an optical centrifuge with a pulse energy that is more than 2 orders of magnitude larger than previously reported instruments. This high pulse energy enables us to create large enough number densities of molecules in extreme rotational states to perform high-resolution state-resolved transient IR absorption measurements. Here we report the first studies of energy transfer dynamics involving molecules in extreme rotational states. In these studies, the optical centrifuge drives CO2 molecules into states with J ∼ 220 and we use transient IR probing to monitor the subsequent rotational, translational, and vibrational energy flow dynamics. The results reported here provide the first molecular insights into the relaxation of molecules with rotational energy that is comparable to that of a chemical bond.

  4. Laser Spectroscopy of Atoms and Molecules.

    ERIC Educational Resources Information Center

    Schawlow, Arthur L.

    1978-01-01

    Surveys new laser techniques and a variety of spectroscopic experiments that can be used to detect, measure and study very small numbers of atoms on molecules. The range of applicability of these techniques is also included. (HM)

  5. SINGLE MOLECULE ENZYMOLOGY FINDS ITS STRIDE.

    PubMed

    Perkel, Jeffrey

    2015-10-01

    More techniques aimed at probing the nature of single molecules are being developed and advanced in biophysics labs. Jeffrey Perkel takes a look at the scientists leading the charge into the micro-world.

  6. Single-Molecule Studies in Live Cells.

    PubMed

    Yu, Ji

    2016-05-27

    Live-cell single-molecule experiments are now widely used to study complex biological processes such as signal transduction, self-assembly, active trafficking, and gene regulation. These experiments' increased popularity results in part from rapid methodological developments that have significantly lowered the technical barriers to performing them. Another important advance is the development of novel statistical algorithms, which, by modeling the stochastic behaviors of single molecules, can be used to extract systemic parameters describing the in vivo biochemistry or super-resolution localization of biological molecules within their physiological environment. This review discusses recent advances in experimental and computational strategies for live-cell single-molecule studies, as well as a selected subset of biological studies that have utilized these new technologies.

  7. Biological mechanisms, one molecule at a time.

    PubMed

    Tinoco, Ignacio; Gonzalez, Ruben L

    2011-06-15

    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.

  8. Biological mechanisms, one molecule at a time

    PubMed Central

    Tinoco, Ignacio; Gonzalez, Ruben L.

    2011-01-01

    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

  9. Stretching p -wave molecules by transverse confinements

    NASA Astrophysics Data System (ADS)

    Zhou, Lihong; Cui, Xiaoling

    2017-09-01

    We revisit the confinement-induced p -wave resonance in quasi-one-dimensional (quasi-1D) atomic gases and study the induced molecules near resonance. We derive the reduced 1D interaction parameters and show that they can well predict the binding energy of shallow molecules in quasi-1D system. Importantly, these shallow molecules are found to be much more spatially extended compared to those in three dimensions (3D) without transverse confinement. Our results strongly indicate that a p -wave interacting atomic gas can be much more stable in quasi-1D near the induced p -wave resonance, where most weight of the molecule lies outside the short-range regime and thus the atom loss could be suppressed.

  10. Large molecules in diffuse interstellar clouds

    NASA Technical Reports Server (NTRS)

    Lepp, S.; Dalgarno, A.; Van Dishoeck, E. F.; Black, J. H.

    1988-01-01

    The effects of the presence of a substantial component of large molecules on the chemistry of diffuse molecular clouds are explored, and detailed models of the zeta Persei and zeta Ophiuchi clouds are constructed. The major consequence is a reduction in the abundances of singly charged atomic species. The long-standing discrepancy between cloud densities inferred from rotational and fine-structure level populations and from the ionization balance can be resolved by postulating a fractional abundance of large molecules of 1 x 10 to the -7th for zeta Persei and 6 x 10 to the -7th for zeta Ophiuchi. If the large molecules are polycyclic aromatic hydrocarbons (PAH) containing about 50 carbon atoms, they contain 1 percent of the carbon in zeta Persei and 7 percent in zeta Ophiuchi. Other consequences of the possible presence of PAH molecules are discussed.

  11. Electron affinities of atoms, molecules and radicals

    NASA Astrophysics Data System (ADS)

    Christodoulides, A. A.; McCorkle, D. L.; Christophorou, L. G.

    The theoretical, semiempirical and experimental methods employed to determine electron affinities (EAs) of atoms, molecules and radicals, and summarize the EA data obtained by these methods were reviewed. The detailed processes underlying the principles of the experimental methods are discussed very briefly. It is, nonetheless, instructive to recapitulate the definition of EA and those of the related quantities, namely, the vertical detachment energy, VDE, and the vertical attachment energy, VAE. The EA of an atom is defined as the difference in total energy between the ground state of the neutral atom (plus the electron at rest at infinity) and its negative ion. The EA of a molecule is defined as the difference in energy between the neutral molecule plus an electron at rest at infinity and the molecular negative ion when both, the neutral molecules and the negative ion, are in their ground electronic, vibrational and rotational states.

  12. Synaptic Cell Adhesion Molecules in Alzheimer's Disease

    PubMed Central

    Leshchyns'ka, Iryna

    2016-01-01

    Alzheimer's disease (AD) is a neurodegenerative brain disorder associated with the loss of synapses between neurons in the brain. Synaptic cell adhesion molecules are cell surface glycoproteins which are expressed at the synaptic plasma membranes of neurons. These proteins play key roles in formation and maintenance of synapses and regulation of synaptic plasticity. Genetic studies and biochemical analysis of the human brain tissue, cerebrospinal fluid, and sera from AD patients indicate that levels and function of synaptic cell adhesion molecules are affected in AD. Synaptic cell adhesion molecules interact with Aβ, a peptide accumulating in AD brains, which affects their expression and synaptic localization. Synaptic cell adhesion molecules also regulate the production of Aβ via interaction with the key enzymes involved in Aβ formation. Aβ-dependent changes in synaptic adhesion affect the function and integrity of synapses suggesting that alterations in synaptic adhesion play key roles in the disruption of neuronal networks in AD. PMID:27242933

  13. Macronuclear gene-sized molecules of hypotrichs.

    PubMed Central

    Hoffman, D C; Anderson, R C; DuBois, M L; Prescott, D M

    1995-01-01

    The macronuclear genome of hypotrichous ciliates consists of DNA molecules of gene-sized length. A macronuclear DNA molecule contains a single coding region. We have analyzed the many hypotrich macronuclear DNA sequences sequenced by us and others. No highly conserved promoter sequences nor replication initiation sequences have been identified in the 5' nor in the 3' non-translated regions, suggesting that promoter function in hypotrichs may differ from other eukaryotes. The macronuclear genes are intron-poor; approximately 19% of the genes sequenced to date have one to three introns. Not all macronuclear DNA molecules may be transcribed; some macronuclear molecules may not have any coding function. Codon bias in hypotrichs is different in many respects from other ciliates and from other eukaryotes. PMID:7753617

  14. Novel electrostatic trap for cold polar molecules

    NASA Astrophysics Data System (ADS)

    Xu, Xue-Yan; Ma, Hui; Yin, Jian-Ping

    2007-12-01

    We propose a novel scheme in which cold polar molecules are trapped by an electrostatic field generated by the combination of a pair of parallel transparent electrodes (i.e., two infinite transparent plates) and a ring electrode (i.e., a ring wire). The spatial distributions of the electrostatic fields from the above charged wire and the charged plates and the corresponding Stark potentials for cold CO molecules are calculated; the dependences of the trap centre position on the geometric parameters of the electrode are analysed. We also discuss the loading process of cold molecules from a cold molecular beam into our trap. This study shows that the proposed scheme is not only simple and convenient to trap, manipulate and control cold polar molecules in weak-field-seeking states, but also provides an opportunity to study cold collisions and collective quantum effects in a variety of cold molecular systems, etc.

  15. Single molecule fluorescence and force microscopy.

    PubMed

    Schütz, G J; Hinterdorfer, P

    2002-12-01

    The investigation of biomolecules has entered a new age since the development of methodologies capable of studies at the level of single molecules. In biology, most molecules show a complex dynamical behavior, with individual motions and transitions between different states occurring highly correlated in space and time within an arrangement of various elements. Recent advances in the development of new microscopy techniques with sensitivity at the single molecule have gained access to essentially new types of information obtainable from imaging biomolecular samples. These methodologies are described here in terms of their applicability to the in vivo detection and visualization of molecular processes on surfaces, membranes, and cells. First examples of single molecule microscopy on cell membranes revealed new basic insight into the lateral organization of the plasma membrane, providing the captivating perspective of an ultra-sensitive methodology as a general tool to study local processes and heterogeneities in living cells.

  16. Electronic Structure of Small Lanthanide Containing Molecules

    NASA Astrophysics Data System (ADS)

    Kafader, Jared O.; Ray, Manisha; Topolski, Josey E.; Chick Jarrold, Caroline

    2016-06-01

    Lanthanide-based materials have unusual electronic properties because of the high number of electronic degrees of freedom arising from partial occupation of 4f orbitals, which make these materials optimal for their utilization in many applications including electronics and catalysis. Electronic spectroscopy of small lanthanide molecules helps us understand the role of these 4f electrons, which are generally considered core-like because of orbital contraction, but are energetically similar to valence electrons. The spectroscopy of small lanthanide-containing molecules is relatively unexplored and to broaden this understanding we have completed the characterization of small cerium, praseodymium, and europium molecules using photoelectron spectroscopy coupled with DFT calculations. The characterization of PrO, EuH, EuO/EuOH, and CexOy molecules have allowed for the determination of their electron affinity, the assignment of numerous anion to neutral state transitions, modeling of anion/neutral structures and electron orbital occupation.

  17. Protein mechanics: from single molecules to functional biomaterials.

    PubMed

    Li, Hongbin; Cao, Yi

    2010-10-19

    multidomain elastomeric proteins, and the design of novel elastomeric proteins that exhibit stimuli-responsive mechanical properties. Moving forward, we are now exploring the use of these artificial elastomeric proteins as building blocks of protein-based biomaterials. Ultimately, we would like to rationally tailor mechanical properties of elastomeric protein-based materials by programming the molecular sequence, and thus nanomechanical properties, of elastomeric proteins at the single-molecule level. This step would help bridge the gap between single protein mechanics and material biomechanics, revealing how the mechanical properties of individual elastomeric proteins are translated into the properties of macroscopic materials.

  18. [Chemoinformatics and virtual screening of molecules for therapeutic use].

    PubMed

    Vayer, Philippe; Arrault, Alban; Lesur, Brigitte; Bertrand, Marc; Walther, Bernard

    2009-10-01

    Successful identification of new chemical entities with drug-like properties in pharmaceutical and academic research groups involves an early screen and the use of a large number of public and proprietary chemical libraries. Before applying high-throughput experimental screening approaches, virtual screening strategies have been put in place in order to sort and filter this massive amount of compounds and data available at these very early stages. Chemoinformatic tools have a crucial role in this selection process and enable therapeutic chemists to focus very early on promising candidates. Virtual screening has conventionally been based either on models of the target or the ligand (molecule), but today these models include biopharmaceutical filters addressing right from the start of the project the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of the molecules. Above all, chemoinformatic tools help chemists understand better the chemical diversity they can work with, especially when comparing chemical libraries. This paper will focus on exemples of the day-to-day use of chemoinformatics in screening programs. A large part will be dedicated to new tools (chemographic and pharmacographic approaches) being developed for the representation and analysis of chemical diversity, but also for combining chemical and biological information to expedite research programs.

  19. Novel Small-Molecule Antibacterial Agents

    DTIC Science & Technology

    2014-07-01

    of Papers published in peer-reviewed journals: Number of Papers published in non peer-reviewed journals: Novel Small-Molecule Antibacterial Agents...Release; Distribution Unlimited Novel Small-Molecule Antibacterial Agents The views, opinions and/or findings contained in this report are those of...half life of ~31 days. (a) Papers published in peer-reviewed journals (N/A for none) Enter List of papers submitted or published that acknowledge ARO

  20. Trapping and Cooling of Polar Molecules

    DTIC Science & Technology

    2013-02-27

    force via radiative cycling in SrF molecules. We demonstrated the ability to create an effective cycling transition in SrF molecules, using only 2-3... Zeeman sublevels). With two lasers, we demonstrated up to 100 photon scattering events with loss too small to observe (ɝ%). The number of scattered...scattering. In the course of these measurements, we understood that the dark Zeeman and vibrational sublevels in the ground state of our cycling