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Sample records for molecule programmed death-1

  1. Costimulatory molecule programmed death-1 in the cytotoxic response during chronic hepatitis C.

    PubMed

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

    2009-11-01

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

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

    PubMed

    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

    2016-05-01

    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. PMID:26916881

  4. 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. PMID:26250412

  5. The Efficacy and Safety of Programmed Cell Death 1 and Programmed Cell Death 1 Ligand Inhibitors for Advanced Melanoma

    PubMed Central

    Guan, Xiuwen; Wang, Haijuan; Ma, Fei; Qian, Haili; Yi, Zongbi; Xu, Binghe

    2016-01-01

    Abstract The purpose of this study was to investigate the efficacy and safety of programmed cell death 1 (PD-1) and programmed cell death 1 ligand (PD-L1) inhibitors using a meta-analysis of present trials for advanced melanoma. A fully recursive literature search of the primary electronic databases for available trials was performed. The objective response rate (ORR) and the median progression-free survival (PFS) of clinical responses were considered the main endpoints to evaluate the efficacy, whereas Grade 3–4 adverse effects (AEs) were analyzed to evaluate safety. The ORR of PD-1 and PD-L1 inhibitors was 30% (95% CI: 25–35%). No significant difference in the ORR was observed after the comparisons of low-dose, median-dose, and high-dose cohorts. In addition, the rate of Grade 3–4 AEs was 9% (95% CI: 6–12%). According to the 3 randomized controlled trials that compared PD-1 inhibitors with chemotherapy, the difference between these 2 groups was found to be statistically significant with respect to the ORR, PFS and the incidence of Grade 3–4 AEs; that is, the relative risk (RR) of the ORR was 3.42 (95% CI: 2.49–4.69, P < 0.001), the hazard ratio (HR) of the PFS was 0.50 (95% CI: 0.44–0.58, P < 0.001), and the RR of Grade 3–4 AEs was 0.45 (95% CI: 0.31–0.65, P < 0.001). According to a meta-analysis of limited concurrent studies, PD-1 and PD-L1 inhibitors appear to be associated with improved response rates, superior response durability and tolerable toxicity in patients with advanced melanoma. PMID:26986169

  6. Analysis of Programmed Death-1 in Patients with Psoriatic Arthritis.

    PubMed

    Peled, Michael; Strazza, Marianne; Azoulay-Alfaguter, Inbar; Silverman, Gregg J; Scher, Jose U; Mor, Adam

    2015-08-01

    Programmed death-1 (PD-1) is an inhibitory co-receptor that is highly expressed in T lymphocytes that has been shown to downregulate inflammatory responses in several inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis. Yet, the role of PD-1 in psoriatic arthritis (PsA) has not been studied. In order to fill this gap, we measured the expression levels of PD-1 in peripheral T cells from patients with active disease. Twenty patients and fifteen age-matched healthy control subjects were recruited. The percentage of CD3(+)PD-1(+) T cells was measured by flow cytometry. Despite normal concentration of peripheral T cells, the expression levels of PD-1 were significantly higher in patients compared to healthy controls. Interestingly, among the patients, the expression levels inversely correlated with disease activity measured by disease activity scores (DAS28). PD-1 expression levels strongly correlated with the number of tender and swollen joints, but not with C-reactive protein (CRP) levels or psoriasis area and severity index (PASI). Functionally, in vitro ligation of PD-1 receptor in PsA T cells inhibited interleukin-2 (IL-2) secretion, Akt phosphorylation, and Rap1 activation. These findings suggest that PD-1 might serve as a biomarker for disease activity in PsA and highlight the need for additional studies in order to establish the role of PD-1 in PsA pathogenesis. PMID:25663558

  7. New-onset toxicity with programmed death-1 inhibitor rechallenge.

    PubMed

    Ludlow, Steven P; Andrews, Stephanie; Pasikhova, Yanina; Hill, Eboné

    2016-06-01

    Immunotherapy has become a mainstay in the treatment of metastatic melanoma. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors and programmed death-1 (PD-1) inhibitors, which have been added more recently, represent two of the main classes of immunomodulating agents. PD-1 inhibitors are well tolerated and are known to have a decreased rate of occurrence of adverse effects compared with CTLA-4 inhibitors. However, the risk remains for serious immune-mediated adverse reactions. Given their long half and extended efficacy, treatment with a CTLA-4 inhibitor before use of a PD-1 inhibitor may increase the risk of adverse effects. In addition, caution should be exercised when rechallenging grade 3 or 4 adverse effects with the same agent or a different agent of the same class. The re-emergence of a previous toxicity may occur or, as found in this case, a new severe effect may arise. This article will present a case of fatal immune-related hepatoxicity in a patient treated with a CTLA-4 inhibitor, followed by treatment with a PD-1 inhibitor. The mechanisms of action and safety profiles for both classes of drugs will also be reviewed. PMID:26983078

  8. Development of amino- and dimethylcarbamate-substituted resorcinol as programmed cell death-1 (PD-1) inhibitor.

    PubMed

    Liu, An; Dong, Lei; Wei, Xiao-Li; Yang, Xiao-Hong; Xiao, Jun-Hai; Liu, Zai-Qun

    2016-06-10

    Blockading the interaction of programmed death-1 (PD-1) protein with its ligands (PD-Ls, such as PD-L1) was proved to be a pathway for suppressing the development of tumors and other degradations of biological species. Thus, finding PD-1 inhibitors situated at the convergence point of drug discovery. In addition to some monoclonal antibodies applied to treat cancers clinically, the screening of organic molecules for hindering the interaction of PD-1 with PD-L1 became an efficient strategy in the development of PD-1 inhibitors. We herein applied resorcinol and 3-hydroxythiophenol as the core to link with N,N-dimethylcarbamate and other alkyl-substituted amines to afford 13 amine-appended phenyl dimethylcarbamates (AAPDs). The test for blockading the combination of PD-1 with PD-L1 revealed that abilities of 13 AAPDs were higher than that of sulfamethizole, a successful PD-1 inhibitor. In particular, large hydrophobic substituents at amine moiety or a nitro at resorcinol skeleton enhanced the inhibitory effect of AAPD even higher than that of sulfamethoxypyridazine, another successful PD-1 inhibitor. The present results may provide valuable information for further investigation on synthetic PD-1 inhibitors. PMID:27063329

  9. 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

  10. 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

  11. Regulation of postsurgical fibrosis by the programmed death-1 inhibitory pathway.

    PubMed

    Holsti, Matthew A; Chitnis, Tanuja; Panzo, Ronald J; Bronson, Roderick T; Yagita, Hideo; Sayegh, Mohamed H; Tzianabos, Arthur O

    2004-05-01

    Surgical adhesions are a common and often severe complication of abdominal or pelvic injury that cause pelvic pain, bowel obstruction, and infertility in women. Current treatments are of limited effectiveness because little is known about the cellular and subcellular processes underlying adhesiogenesis. Recently, we showed that Th1 alpha beta CD4(+) T cells mediate the pathogenesis of adhesion formation in a rodent model of this disease process. In this study, we demonstrate that in mice these T cells home directly to the site of surgically induced adhesions and control local chemokine production in a manner dependent on the CD28 T cell costimulatory pathway. Conversely, the inhibitory programmed death-1 pathway plays a central role in limiting adhesiogenesis, as programmed death-1 blockade was associated with increased T cell infiltration, chemokine production, and a concomitant exacerbation of disease. Our results reveal for the first time that the development of postsurgical fibrosis is under the tight control of positive and negative T cell costimulation, and suggest that targeting these pathways may provide promising therapies for the prevention of adhesion formation. PMID:15100324

  12. 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. PMID:27113507

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

    PubMed Central

    Salem, Mohamed L; El-Badawy, Ahmed

    2015-01-01

    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. PMID:26483866

  14. Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice.

    PubMed

    Frebel, Helge; Nindl, Veronika; Schuepbach, Reto A; Braunschweiler, Thomas; Richter, Kirsten; Vogel, Johannes; Wagner, Carsten A; Loffing-Cueni, Dominique; Kurrer, Michael; Ludewig, Burkhard; Oxenius, Annette

    2012-12-17

    The inhibitory programmed death 1 (PD-1)-programmed death ligand 1 (PD-L1) pathway contributes to the functional down-regulation of T cell responses during persistent systemic and local virus infections. The blockade of PD-1-PD-L1-mediated inhibition is considered as a therapeutic approach to reinvigorate antiviral T cell responses. Yet previous studies reported that PD-L1-deficient mice develop fatal pathology during early systemic lymphocytic choriomeningitis virus (LCMV) infection, suggesting a host protective role of T cell down-regulation. As the exact mechanisms of pathology development remained unclear, we set out to delineate in detail the underlying pathogenesis. Mice deficient in PD-1-PD-L1 signaling or lacking PD-1 signaling in CD8 T cells succumbed to fatal CD8 T cell-mediated immunopathology early after systemic LCMV infection. In the absence of regulation via PD-1, CD8 T cells killed infected vascular endothelial cells via perforin-mediated cytolysis, thereby severely compromising vascular integrity. This resulted in systemic vascular leakage and a consequential collapse of the circulatory system. Our results indicate that the PD-1-PD-L1 pathway protects the vascular system from severe CD8 T cell-mediated damage during early systemic LCMV infection, highlighting a pivotal physiological role of T cell down-regulation and suggesting the potential development of immunopathological side effects when interfering with the PD-1-PD-L1 pathway during systemic virus infections. PMID:23230000

  15. Nivolumab, an Anti-Programmed Cell Death-1 Antibody, Induces Fulminant Type 1 Diabetes.

    PubMed

    Miyoshi, Yuka; Ogawa, Osamu; Oyama, Yu

    2016-01-01

    Programmed cell death-1 (PD-1), an immunoreceptor, is located on T cells and pro-B cells and interacts with its ligands to inhibit T cell activation and proliferation, thereby promoting immunological self-tolerance. Nivolumab, an anti-PD1 antibody, blocks PD-1 and can restore anticancer immune responses by abrogating PD-1 pathway-mediated T-cell inhibition. Autoimmune adverse events are expected with PD-1 therapy. Fulminant type 1 diabetes is the subtype of type 1 diabetes. The clinical feature is the extremely rapid progression of hyperglycemia and ketoacidosis. Here we describe a 66-year-old woman with advanced melanoma who was treated with nivolumab. After 4 months and six doses of the medicine, the patient was admitted to the hospital with complaints of nausea and vomiting. The laboratory data showed ketonuria, hyperglycemia (531 mg/dl), high anion gap metabolic acidosis, HbA1c (7.3%), and absence of insulin-secreting capacity. These data are compatible with the criteria of fulminant type 1 diabetes. The patient was diagnosed with diabetic ketoacidosis because of fulminant type 1 diabetes. The findings of this case indicated that nivolumab can cause fulminant type 1 diabetes. Diabetic ketoacidosis due to fulminant type 1 diabetes is potentially fatal condition. Thus, diabetic ketoacidosis due to fulminant type 1 diabetes should be considered in the differential diagnosis when patients treated with nivolumab complain of gastrointestinal symptoms. PMID:27297738

  16. Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).

    PubMed

    Fuller, Michael J; Callendret, Benoit; Zhu, Baogong; Freeman, Gordon J; Hasselschwert, Dana L; Satterfield, William; Sharpe, Arlene H; Dustin, Lynn B; Rice, Charles M; Grakoui, Arash; Ahmed, Rafi; Walker, Christopher M

    2013-09-10

    Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti-PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited. PMID:23980172

  17. Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice

    PubMed Central

    Frebel, Helge; Nindl, Veronika; Schuepbach, Reto A.; Braunschweiler, Thomas; Richter, Kirsten; Vogel, Johannes; Wagner, Carsten A.; Loffing-Cueni, Dominique; Kurrer, Michael; Ludewig, Burkhard

    2012-01-01

    The inhibitory programmed death 1 (PD-1)–programmed death ligand 1 (PD-L1) pathway contributes to the functional down-regulation of T cell responses during persistent systemic and local virus infections. The blockade of PD-1–PD-L1–mediated inhibition is considered as a therapeutic approach to reinvigorate antiviral T cell responses. Yet previous studies reported that PD-L1–deficient mice develop fatal pathology during early systemic lymphocytic choriomeningitis virus (LCMV) infection, suggesting a host protective role of T cell down-regulation. As the exact mechanisms of pathology development remained unclear, we set out to delineate in detail the underlying pathogenesis. Mice deficient in PD-1–PD-L1 signaling or lacking PD-1 signaling in CD8 T cells succumbed to fatal CD8 T cell–mediated immunopathology early after systemic LCMV infection. In the absence of regulation via PD-1, CD8 T cells killed infected vascular endothelial cells via perforin-mediated cytolysis, thereby severely compromising vascular integrity. This resulted in systemic vascular leakage and a consequential collapse of the circulatory system. Our results indicate that the PD-1–PD-L1 pathway protects the vascular system from severe CD8 T cell–mediated damage during early systemic LCMV infection, highlighting a pivotal physiological role of T cell down-regulation and suggesting the potential development of immunopathological side effects when interfering with the PD-1–PD-L1 pathway during systemic virus infections. PMID:23230000

  18. 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

  19. Immunological effects of the anti-programmed death-1 antibody on human peripheral blood mononuclear cells.

    PubMed

    Akiyama, Yasuto; Nonomura, Chizu; Kondou, Ryota; Miyata, Haruo; Ashizawa, Tadashi; Maeda, Chie; Mitsuya, Koichi; Hayashi, Nakamasa; Nakasu, Yoko; Yamaguchi, Ken

    2016-09-01

    Immune checkpoint antibody-mediated blockade has gained attention as a new cancer immunotherapy strategy. Accumulating evidence suggests that this therapy imparts a survival benefit to metastatic melanoma and non-small cell lung cancer patients. A substantial amount of data on immune checkpoint antibodies has been collected from clinical trials; however, the direct effect of the antibodies on human peripheral blood mononuclear cells (PBMCs) has not been exclusively investigated. In this study, we developed an anti-programmed death-1 (PD-1) antibody (with biosimilarity to nivolumab) and examined the effects of the antibody on PBMCs derived from cancer patients. Specifically, we investigated the effects of the anti-PD-1 antibody on proliferation, cytokine production, cytotoxic T lymphocytes (CTL) and regulatory T cells. These investigations yielded several important results. First, the anti-PD-1 antibody had no obvious effect on resting PBMCs; however, high levels of the anti-PD-1 antibody partly stimulated PBMC proliferation when accompanied by an anti-CD3 antibody. Second, the anti-PD-1 antibody restored the growth inhibition of anti-CD3 Ab-stimulated PBMCs mediated by PD-L1. Third, the anti-PD-1 antibody exhibited a moderate inhibitory effect on the induction of myeloid-derived suppressor cells (MDSCs) by anti-CD3 antibody stimulation. Additionally, the presence of the anti-PD-1 antibody promoted antigen-specific CTL induction, which suggests that combining anti-PD-1 antibody and conventional immunotherapy treatments may have beneficial effects. These results indicate that specific cellular immunological mechanisms are partly responsible for the antitumor effect exhibited by the anti-PD-1 antibody against advanced cancers in clinical trials. PMID:27573705

  20. 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

  1. Association of programmed death-1 gene polymorphism rs2227981 with tumor: evidence from a meta analysis

    PubMed Central

    Mamat, Umarjan; Arkinjan, Muyassar

    2015-01-01

    To investigate the association of programmed death-1 gene polymorphism rs2227981 with tumor risk. The PubMed, Medline, Ovid Medline, EMBASE, Web of Knowledge were searched. Meta-analyses were conducted using RevMan 5.2.2 software. Total six researches involving in a total of 1427 tumor patients and 1811 healthy control people were included into this meta analysis. There was no association of PD-1 gene polymorphism with total tumor risk under four genetic models. (CT+TT vs CC, OR=1.09, 95% CI=0.80-1.49, P=0.59; CT+CC vs TT, OR=0.93, 95% CI=0.52-1.66, P=0.61; TT vs CC, OR=0.99, 95% CI=0.57-1.72, P=0.97; CT vs CC, OR=1.16, 95% CI=0.80-1.70, P=0.43). The sub-group analysis shown there were a significantly difference on association of PD-1 gene polymorphism with digestive system tumor risk between tumor patients and healthy control people, except recessive model. (CT+TT vs CC, OR=1.57, 95% CI=1.20-2.07, P=0.001; TT vs CC, OR=1.67, 95% CI=1.12-2.49, P=0.01; CT vs CC, OR=1.51, 95% CI=1.13-2.01, P=0.005). Moreover, the meta analysis results shown that there were association of PD-1 gene polymorphism with tumor risk under two models for the tumor specific occurring only in women. (CT+TT vs CC, OR=0.80, 95% CI=0.67-0.95, P=0.01; TT vs CC, OR=0.61, 95% CI=0.44-0.83, P=0.002). This study suggests that PD-1 gene polymorphism rs2227981 is associated with specific tumor types, including digestive system tumor and tumor specific occurring in woman. PMID:26550254

  2. Results of clinical trials with anti-programmed death 1/programmed death ligand 1 inhibitors in lung cancer

    PubMed Central

    González-Cao, María; Barrón, Feliciano; Riso, Aldo; Rosell, Rafael

    2015-01-01

    One of the main hallmarks of cancer is the capability of evading immune destruction. In order to drive tumor progression, malignant cells are able to promote immunosuppressive mechanisms avoiding recognition and elimination. Increasing knowledge of the mechanisms of immune tolerance has led to the identification of several membrane receptors strongly implicated in this cancer feature: the immune checkpoints. Among them, programmed death 1 (PD-1) receptors and their ligands have been identified as potential targets for a new anti-cancer therapeutic approach: the use of immune-modulatory monoclonal antibodies designed to interrupt the immune escape activated by the interaction of PD-1 receptors and their ligands. Five of these antibodies are now in their late stages of clinical development and this review will summarize their up-to-date efficacy and toxicity data. PMID:26798585

  3. Predictive factors of activity of anti-programmed death-1/programmed death ligand-1 drugs: immunohistochemistry analysis

    PubMed Central

    Chakravarti, Nitin

    2015-01-01

    Anti-programmed death-1 (anti-PD1)/programmed death ligand-1 (PD-L1) therapeutic antibodies targeting regulatory pathways in T cells have recently shown to promising clinical effectiveness in several solid tumors by enhancing antitumor immune response. Immune checkpoint therapy has propelled therapeutic efforts opening a new field in cancer treatment. However, durable clinical response has been educed only in a fraction of patients, underlining the need to predictively select those patients most likely to respond, e.g., by detecting predictive biomarkers. Immunohistochemistry (IHC) detection of PD-L1 in tumor cells has been used in various trials of anti-PD-1/PD-L1 agents to try to select those patients most likely to respond. However, since there are different techniques and scoring systems, results have not been conclusive. Thus efforts are needed to develop standardized IHC assays as well as to explore additional biomarkers to evaluate and predict immune responses elicited by anti-PD-1/PD-L1 therapies. PMID:26798583

  4. Implications of Programmed Cell Death 1 Ligand 1 Heterogeneity in the Selection of Patients With Non-Small Cell Lung Cancer to Receive Immunotherapy.

    PubMed

    Mansfield, A S; Dong, H

    2016-09-01

    The use of programmed cell death 1 ligand 1 (PD-L1) as a predictive biomarker to select patients to receive programmed cell death 1 (PD-1) or PD-L1 inhibitors in non-small cell lung cancer (NSCLC) is limited by the definitions of positivity, interassay agreement, and intra- and intertumoral heterogeneity of expression. Although PD-L1 expression enriches for responses, the lack of expression does not exclude clinical benefit. PMID:26916808

  5. Negative influence of programmed death-1-ligands on the survival of esophageal cancer patients treated with chemotherapy.

    PubMed

    Tanaka, Koji; Miyata, Hiroshi; Sugimura, Keijiro; Kanemura, Takashi; Hamada-Uematsu, Mika; Mizote, Yu; Yamasaki, Makoto; Wada, Hisashi; Nakajima, Kiyokazu; Takiguchi, Shuji; Mori, Masaki; Doki, Yuichiro; Tahara, Hideaki

    2016-06-01

    The programmed death-1/programmed death-1 ligands (PD-1/PD-L) pathway plays an important role in immunological tumor evasion. However, the clinical significance of the PD-L (L1 and L2) expression in esophageal cancer treated with chemotherapy has not been fully investigated. We examined the expression of PD-L of the primary tumors obtained from 180 esophageal cancer patients who underwent radical resection with or without neoadjuvant chemotherapy (NAC) using immunohistochemical staining. The relationship between the expression patterns and clinico-pathological characteristics was examined. In the present study, 53 patients (29.4%) and 88 patients (48.3%) were classified into positive for PD-L1 and PD-L2 expression, respectively. In all the patients examined, overall survival rates of the patients with tumors positive for PD-L1 or PD-L2 were significantly worse than those with tumors negative for PD-L1 or PD-L2 (P = 0.0010 and P = 0.0237, respectively). However, subgroup analysis showed that these tendencies are only found in the patients treated with NAC, and not in those without NAC. The patients with positive PD-L1 expression had a significantly higher rate of NAC history (P = 0.0139), but those with positive PD-L2 expression did not have a significantly high rate of NAC history (P = 0.6127). There is no significant relationship between PD-L1 expression and response to chemotherapy (P = 0.3118), but patients with positive PD-L2 expression had significantly inferior responses to chemotherapy (P = 0.0034). The PD-1/PD-L pathway might be an immunological mechanism associated with the long-term effectiveness of chemotherapy in esophageal cancer patients. Further investigation into the roles of PD-1 pathway in chemotherapy could lead to the development of better treatment options for this disease. PMID:27015293

  6. 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. PMID:24038528

  7. Surgical trauma induces postoperative T-cell dysfunction in lung cancer patients through the programmed death-1 pathway.

    PubMed

    Xu, Pingbo; Zhang, Ping; Sun, Zhirong; Wang, Yun; Chen, Jiawei; Miao, Changhong

    2015-11-01

    The programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) pathway have been shown to be involved in tumor-induced and sepsis-induced immunosuppression. However, whether this pathway is involved in the surgery-induced dysfunction of T lymphocytes is not known. Here, we analyzed expression of PD-1 and PD-L1 on human peripheral mononuclear cells during the perioperative period. We found that surgery increased PD-1/PD-L1 expression on immune cells, which was correlated with the severity of surgical trauma. The count of T lymphocytes and natural killer cells reduced after surgery, probably due to the increased activity of caspase-3. Caspase-3 level was positively correlated with PD-1 expression. Profile of perioperative cytokines and hormones in plasma showed a significantly increased level of interferon-α, as well as various inflammatory cytokines and stress hormones. In ex vivo experiments, administration of anti-PD-1 antibody significantly ameliorated T-cell proliferation and partially reversed the T-cell apoptosis induced by surgical trauma. We provide evidences that surgical trauma can induce immunosuppression through the PD-1/PD-L1 pathway. This pathway could be a target for preventing postoperative cellular immunosuppression. PMID:26183035

  8. 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

  9. 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.

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

    PubMed

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

    2015-02-01

    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 (Tr(egs)). 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(+) T(reg) cell percentage. P/T mice developed systemic inflammation, which was probably induced by augmented Th1 response and low FoxP3(+) T(reg) count. The study identified a unique, previously undescribed role for PD-1 in Th1 and T(reg) differentiation, with potential implication in the development of Th1 cell-targeted therapy. PMID:25219397

  11. Programmed cell death-1 is expressed in large retinal ganglion cells and is upregulated after optic nerve crush.

    PubMed

    Wang, Wei; Chan, Ann; Qin, Yu; Kwong, Jacky M K; Caprioli, Joseph; Levinson, Ralph; Chen, Ling; Gordon, Lynn K

    2015-11-01

    Programmed cell death-1 (PD-1) is a key negative receptor inducibly expressed on T cells, B cells and dendritic cells. It was discovered on T cells undergoing classical programmed cell death. Studies showed that PD-1 ligation promotes retinal ganglion cell (RGC) death during retinal development. The purpose of this present study is to characterize PD-1 regulation in the retina after optic nerve crush (ONC). C57BL/6 mice were subjected to ONC and RGC loss was monitored by immunolabelling with RNA-binding protein with multiple splicing (Rbpms). Time course of PD-1 mRNA expression was determined by real-time PCR. PD-1 expression was detected with anti-PD-1 antibody on whole mount retinas. PD-1 staining intensity was quantitated. Colocalization of PD-1 and cleaved-caspase-3 after ONC was analyzed. Real-time PCR results demonstrated that PD-1 gene expression was significantly upregulated at day 1, 3, 7, 10 and 14 after ONC. Immunofluorescent staining revealed a dramatic increase of PD-1 expression following ONC. In both control and injured retinas, PD-1 tended to be up-expressed in a subtype of RGCs, whose somata size were significantly larger than others. Compared to control, PD-1 intensity in large RGCs was increased by 82% in the injured retina. None of the large RGCs expressed cleaved-caspase-3 at day 5 after ONC. Our work presents the first evidence of PD-1 induction in RGCs after ONC. This observation supports further investigation into the role of PD-1 expression during RGC death or survival following injury. PMID:26277582

  12. Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response.

    PubMed

    Rui, Yuxiang; Honjo, Tasuku; Chikuma, Shunsuke

    2013-10-01

    Programmed cell death 1 (PD-1) is an inhibitory coreceptor on immune cells and is essential for self-tolerance because mice genetically lacking PD-1 (PD-1(-/-)) develop spontaneous autoimmune diseases. PD-1(-/-) mice are also susceptible to severe experimental autoimmune encephalomyelitis (EAE), characterized by a massive production of effector/memory T cells against myelin autoantigen, the mechanism of which is not fully understood. We found that an increased primary response of PD-1(-/-) mice to heat-killed mycobacteria (HKMTB), an adjuvant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1(-/-) recombination activating gene (RAG)2(-/-) mice were found to drive antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1(+/+) RAG2(-/-) mice. This result suggested PD-1's involvement in the regulation of innate immune responses. Mice reconstituted with PD-1(-/-) RAG2(-/-) bone marrow and PD-1(+/+) CD4(+) T cells developed more severe EAE compared with the ones reconstituted with PD-1(+/+) RAG2(-/-) bone marrow and PD-1(+/+) CD4(+) T cells. We found that upon recognition of HKMTB, CD11b(+) macrophages from PD-1(-/-) mice produced very high levels of IL-6, which helped promote naive CD4(+) T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negatively regulates antimycobacterial responses by suppressing innate immune cells, which in turn prevents autoreactive T-cell priming and differentiation to inflammatory effector T cells. PMID:24043779

  13. Programmed death-1 pathway in host tissues ameliorates Th17/Th1-mediated experimental chronic graft-versus-host disease.

    PubMed

    Fujiwara, Hideaki; Maeda, Yoshinobu; Kobayashi, Koichiro; Nishimori, Hisakazu; Matsuoka, Ken-Ichi; Fujii, Nobuharu; Kondo, Eisei; Tanaka, Takehiro; Chen, Lieping; Azuma, Miyuki; Yagita, Hideo; Tanimoto, Mitsune

    2014-09-01

    Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the role of the programmed death-1 (PD-1) pathway in chronic GVHD using a well-defined mouse model of B10.D2 (H-2(d)) donor to BALB/c (H-2(d)) recipients. PD-1 expression on allogeneic donor T cells was upregulated continuously in chronic GVHD development, whereas PD-L1 expression in host tissues was transiently upregulated and declined to basal levels in the late posttransplant period. Blockade of the PD-1 pathway by anti-PD-1, anti-PD-L1, or anti-PD-L2 mAbs exacerbated clinical and pathologic chronic GVHD. Chimeric mice revealed that PD-L1 expression in host tissues suppressed expansion of IL-17(+)IFN-γ(+) T cells, and that PD-L1 expression on hematopoietic cells plays a role in the development of regulatory T cells only during the early transplantation period but does not affect the severity of chronic GVHD. Administration of the synthetic retinoid Am80 overcame the IL-17(+)IFN-γ(+) T cell expansion caused by PD-L1 deficiency, resulting in reduced chronic GVHD damage in PD-L1(-/-) recipients. Stimulation of the PD-1 pathway also alleviated chronic GVHD. These results suggest that the PD-1 pathway contributes to the suppression of Th17/Th1-mediated chronic GVHD and may represent a new target for the prevention or treatment of chronic GVHD. PMID:25080485

  14. Programmed Cell Death-1 Polymorphisms Decrease the Cancer Risk: A Meta-Analysis Involving Twelve Case-Control Studies

    PubMed Central

    Dong, Wenjing; Gong, Mancheng; Shi, Zhirong; Xiao, Jianjun; Zhang, Junkai; Peng, Jiewen

    2016-01-01

    Programmed cell death-1 (PD-1) plays an important inhibitory role in anti-tumor responses, so it is considered as a powerful candidate gene for individual’s genetic susceptibility to cancer. Recently, some epidemiological studies have evaluated the association between PD-1 polymorphisms and cancer risk. However, the results of the studies are conflicting. Therefore, a meta-analysis was performed. We identified all studies reporting the relationship between PD-1 polymorphisms and cancers by electronically searches. According to the inclusion criteria and the quality assessment of Newcastle-Ottawa Scale (NOS), only high quality studies were included. A total of twelve relevant studies involving 5,206 cases and 5,174 controls were recruited. For PD-1.5 (rs2227981) polymorphism, significantly decreased cancer risks were obtained among overall population, Asians subgroup and population-based subgroup both in TT vs. CC and TT vs. CT+CC genetic models. In addition, a similar result was also found in T vs. C allele for overall population. However, there were no significant associations between either PD-1.9 (rs2227982) or PD-1 rs7421861 polymorphisms and cancer risks in all genetic models and alleles. For PD-1.3 (rs11568821) polymorphism, we found different cancer susceptibilities between GA vs. GG and AA vs. AG+GG genetic models, and no associations between AA vs. GG, AA+AG vs. GG genetic models or A vs. G allele and cancer risks. In general, our results firstly indicated that PD-1.5 (rs2227981) polymorphism is associated a strongly decreased risk of cancers. Additional epidemiological studies are needed to confirm our findings. PMID:27031235

  15. Programmed Death 1 (PD-1) is involved in the development of proliferative diabetic retinopathy by mediating activation-induced apoptosis

    PubMed Central

    Fang, Mengyuan; Meng, Qianli; Wang, Liya; Zhao, Zhaoxia; Zhang, Liang; Kuang, Jian; Cui, Ying; Mai, Liping; Zhu, Jiening

    2015-01-01

    Purpose Recent studies revealed that immunological mechanisms play a prominent role in the pathogenesis of proliferative diabetic retinopathy (PDR). Given the importance of the immune response in PDR and the significance of the programmed death 1 (PD-1) pathway as an immune regulatory pathway, the aim of this study is to determine the expression and functional characteristics of the PD-1 pathway in peripheral blood lymphocytes from patients with PDR. Methods Peripheral blood lymphocytes were obtained from patients with PDR, age-matched patients with diabetes mellitus and no diabetic retinopathy (DM-NDR), and controls. The mRNA expression of PD-1 and its ligands were determined using real-time PCR. The frequencies of PD-1 and its ligands, activation-induced apoptosis, IFN-γ, and IL-4 were determined by flow cytometry. Results The PD-1 mRNA expression markedly decreased, while the frequency of PD-1+ cells increased in the PDR group compared with the DM-NDR and control groups. The expression of PD-ligand 1 (PD-L1) mRNA and PD-L1+ cells in the PDR group was lower than that in the other two groups. In the PDR group, the frequency of Annexin V+PI- and Annexin V+PI-PD-1+ cells increased, while the frequency of Annexin V+PI-PD-L1+ cells decreased. Although their expression was upregulated, the ratio of PD-1+ IFN-γ+ to PD-1+IL-4+ cells in the PDR group was not significantly different to that in the DM-NDR and control groups. Conclusions These results suggest that PD-1 is involved in the development of PDR by mediating activation-induced apoptosis. PMID:26321864

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

    PubMed Central

    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. PMID:26885204

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

    PubMed Central

    ZHANG, JIEHUA; WANG, CHIEH-MEI; ZHANG, PING; WANG, XIAOQIAN; CHEN, JIAO; YANG, JUN; LU, WANLU; ZHOU, WENJIE; YUAN, WENWEN; FENG, YUN

    2016-01-01

    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. PMID:26847035

  18. 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. PMID:26329973

  19. Variable patterns of programmed death-1 expression on fully functional memory T cells after spontaneous resolution of hepatitis C virus infection.

    PubMed

    Bowen, David G; Shoukry, Naglaa H; Grakoui, Arash; Fuller, Michael J; Cawthon, Andrew G; Dong, Christine; Hasselschwert, Dana L; Brasky, Kathleen M; Freeman, Gordon J; Seth, Nilufer P; Wucherpfennig, Kai W; Houghton, Michael; Walker, Christopher M

    2008-05-01

    The inhibitory receptor programmed death-1 (PD-1) is present on CD8(+) T cells in chronic hepatitis C virus (HCV), but expression patterns in spontaneously resolving infections are incompletely characterized. Here we report that PD-1 was usually absent on memory CD8(+) T cells from chimpanzees with resolved infections, but sustained low-level expression was sometimes observed in the absence of apparent virus replication. PD-1-positive memory T cells expanded and displayed antiviral activity upon reinfection with HCV, indicating conserved function. This animal model should facilitate studies of whether PD-1 differentially influences effector and memory T-cell function in resolved versus persistent human infections. PMID:18337576

  20. Programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and EBV-encoded RNA (EBER) expression in Hodgkin lymphoma.

    PubMed

    Paydas, Semra; Bağır, Emine; Seydaoglu, Gulsah; Ercolak, Vehbi; Ergin, Melek

    2015-09-01

    Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are new targets in cancer immunotherapy. PD-1 protein is an immune checkpoint expressed in many tumors. Epstein-Barr virus (EBV) is present in malignant Hodgkin/Reed-Sternberg (HRS) cells in approximately 40-50 % of Hodgkin lymphoma (HL). The aim of this study is to evaluate the clinical and prognostic importance of PD-1 and/or PD-L1 in HL and also to determine the association between EBV-encoded RNA (EBER) and PD-1/PD-L1. Formalin-fixed, paraffin-embedded tissue samples from 87 cases with HL were analyzed in this study. Immunohistochemical staining was performed to detect the PD-1 and PD-L1 expressions. Chromogenic in situ hybridization for EBER was performed using fluorescein-labeled oligonucleotide probes. PD-1 and PD-L1 expressions were found in 20 % of the cases. The EBER positivity was found in 40 cases (45 %). It has been found that co-expression of PD-1 and PD-L1 was associated with shorter survival although PD-1 or PD-L1 expressions were not found to be related with survival. Overall survival (OS) and disease-free survival (DFS) in cases without PD-1 and PD-L1 expressions were 135 and 107 months, respectively. OS and DFS in cases with co-expression for PD-1 and PD-L1 were 24 and 20 months, respectively, and these differences were found to be statistically significant for both OS and DFS (p = 0.002 and p = 0.003, respectively). Cox regression analysis showed that co-expression of PD-1 and PD-L1 was found to be an independent risk factor for prognosis (OR 6.9, 95 % CI 1.9-24.3). Targeting PD-1 and/or PD-L1 is meaningful due to the 20 % expression of each in HL, and we did not find an important association between PD-1 and PD-L1 and EBER expression in HL. Very poor outcome in cases with co-expression of PD-1/PD-L1 suggests new avenues to detect the new prognostic markers and also therapeutic approaches in HL. PMID:26004934

  1. Programmed death 1 expression in the peritumoral microenvironment is associated with a poorer prognosis in classical Hodgkin lymphoma.

    PubMed

    Koh, Young Wha; Jeon, Yoon Kyung; Yoon, Dok Hyun; Suh, Cheolwon; Huh, Jooryung

    2016-06-01

    Programmed cell death protein-1 (PD-1) inhibitor may be therapeutic in patients with relapsed or refractory classical Hodgkin's lymphoma (cHL). This study examined the prognostic significance of PD-1 and two PD-1 ligands (PD-L1 and PD-L2) in uniformly treated cHL. Diagnostic tissues from 109 cHL patients treated with a doxorubicin, bleomycin, vinblastine, and dacarbazine regimen were evaluated retrospectively by immunohistochemical analysis of PD-L1, PD-L2, and PD-1 expressions. The median follow-up time was 4.91 years (range, 0.17-17.33 years). Thirteen patients (11 %) expressed PD-1 protein in the peritumoral microenvironment, which was associated with poor overall survival (OS) (P = 0.017). PD-L1 or PD-L2 expression was not associated with OS. There was no correlation between PD-L1 and PD-1 expression or between PD-L2 and PD-1 expression. Multivariate analysis identified PD-1 protein as an independent prognostic factor for OS (P = 0.019). Subgroup analysis according to the Ann Arbor stage of cHL showed that PD-1 protein expression had a prognostic value in limited-stage cHL (P = 0.048). PD-1 is an independent prognostic factor in cHL and may allow the identification of a subgroup of patients with limited-stage cHL who require more intensive therapy and who may benefit from anti-PD-1 agents. PMID:26678894

  2. Mechanisms of Indirect Acute Lung Injury: A Novel Role for the Co-Inhibitory Receptor, Programmed Death-1 (PD-1)

    PubMed Central

    Monaghan, Sean F.; Thakkar, Rajan K.; Heffernan, Daithi S.; Huang, Xin; Chung, Chun-Shiang; Lomas-Neira, Joanne; Cioffi, William G.; Ayala, Alfred

    2011-01-01

    Objective To determine the contribution of PD-1 in the morbidity and mortality associated with the development of indirect-acute lung injury Summary Background Data The immune cell interaction(s) leading to indirect-acute lung injury are not completely understood. In this respect, while we have recently shown that the murine cell surface co-inhibitory receptor, Programmed Cell death receptor (PD)-1, has a role in septic morbidity/mortality that is mediated in part through the effects on the innate immune arm. However, it is not know if PD-1 has a role in the development of indirect-acute lung injury and how this may be mediated at a cellular level. Methods PD-1 −/− mice were used in a murine model of indirect-acute lung injury (hemorrhagic shock followed 24 h after with cecal ligation & puncture-septic challenge) and compared to wild type controls. Groups were initially compared for survival and subsequently for markers of pulmonary inflammation, influx of lymphocytes and neutrophils, and expression of PD-1 and its ligand, PD-L1. In addition, peripheral blood leukocytes of patients with indirect-acute lung injury were examined to assess changes in cellular PD-1 expression relative to mortality. Results PD-1 −/− mice showed improved survival compared to wild type controls. In the mouse lung, CD4+, CD11c+ and Gr-1+ cells showed increased PD-1 expression in response to indirect-acute lung injury. However, while the rise in BAL fluid protein concentrations, lung IL-6, and lung MCP-1 were similar between PD-1 −/− and wild type animals subjected to indirect acute lung injury, the PD-1 −/− animals that were subjected to shock/septic challenge had reduced CD4:CD8 ratios, TNF-α levels, MPO activity, and caspase 3 levels in the lung. Comparatively, we observed that humans, who survived their acute lung injury, had significantly lower expression of PD-1 on T cells. Conclusions PD-1 expression contributes to mortality following the induction of indirect

  3. Effects of interferon-α-transduced tumor cell vaccines and blockade of programmed cell death-1 on the growth of established tumors.

    PubMed

    Omori, R; Eguchi, J; Hiroishi, K; Ishii, S; Hiraide, A; Sakaki, M; Doi, H; Kajiwara, A; Ito, T; Kogo, M; Imawari, M

    2012-09-01

    Interferon-alpha (IFN-α) has strong antitumor effects, and IFN-α gene therapy has been used clinically against some cancers. In this study, we evaluated the efficacy of the combination of IFN-α-transduced tumor cell vaccines and programmed cell death 1 (PD-1) blockade, and investigated the mechanisms of the antitumor effects of the combined therapy. A poorly immunogenic murine colorectal cancer cell line, MC38, was transduced to overexpress IFN-α. In a therapeutic model, parental tumor-bearing mice were inoculated with MC38-IFNα cells and an anti-PD-1 antagonistic antibody. Analyses of immunohistochemistry and tumor-specific lysis were performed. The outgrowth of the established tumors was significantly reduced in mice treated with the combination of IFN-α and anti-PD-1. Immunohistochemical analyses of the therapeutic model showed marked infiltration of CD4(+) cells and CD8(+) cells in the established MC38 tumors of mice treated with both IFN-α and anti-PD-1. Significant tumor-specific cytolysis was detected when splenocytes of mice that were treated with both IFN-α and anti-PD-1 were used as effector cells. These results suggest that blockade of the PD-1 PD-ligand enhanced the Th1-type antitumor immune responses induced by IFN-α. The combination of IFN-α gene-transduced tumor cell vaccines and PD-1 blockade may be a possible candidate for a cancer vaccine for clinical trials. PMID:22790963

  4. The Expression of Programmed Death-1 in Circulating CD4+ and CD8+ T Cells during Hepatitis B Virus Infection Progression and Its Correlation with Clinical Baseline Characteristics

    PubMed Central

    Xu, Ping; Chen, Yong-Jing; Chen, Hui; Zhu, Xiao-Yan; Song, Hua-Feng; Cao, Li-Juan

    2014-01-01

    Background/Aims Programmed death-1 (PD-1) expression was investigated in CD4+ and CD8+ T cells from hepatitis B virus (HBV)-infected patients at the chronic hepatitis B (CHB) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC) stages. Methods PD-1 expression in circulating CD4+ and CD8+ T cells was detected by flow cytometry. The correlations between PD-1 expression and HBV viral load, alanine aminotransaminase (ALT) levels and aspartate aminotransferase (AST) levels were analyzed using GraphPad Prism 5.0. Results PD-1 expression in CD4+ and CD8+ T cells was significantly increased in both the CHB group and advanced-stage group (LC plus HCC). In the CHB group, PD-1 expression in both CD4+ and CD8+ T cells was positively correlated with the HBV viral load, ALT, and AST levels. However, in the LC plus HCC group, significant correlations between PD-1 expression and the clinical parameters were nearly absent. Conclusions PD-1 expression in peripheral CD4+ and CD8+ T cells is dynamic, changes with HBV infection progression, and is related to HBV viral load and liver function, especially in CHB. PD-1 expression could be utilized as a potential clinical indicator to determine the extent of virus replication and liver injury. PMID:24672661

  5. 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. PMID:27533014

  6. Mice lacking Programmed cell death-1 show a role for CD8(+) T cells in long-term immunity against blood-stage malaria.

    PubMed

    Horne-Debets, Joshua M; Karunarathne, Deshapriya S; Faleiro, Rebecca J; Poh, Chek Meng; Renia, Laurent; Wykes, Michelle N

    2016-01-01

    Even after years of experiencing malaria, caused by infection with Plasmodium species, individuals still have incomplete immunity and develop low-density parasitemia on re-infection. Previous studies using the P. chabaudi (Pch) mouse model to understand the reason for chronic malaria, found that mice with a deletion of programmed cell death-1 (PD-1KO) generate sterile immunity unlike wild type (WT) mice. Here we investigated if the mechanism underlying this defect during acute immunity also impacts on long-term immunity. We infected WT and PD-1KO mice with Pch-malaria and measured protection as well as immune responses against re-infections, 15 or 20 weeks after the original infection had cleared. WT mice showed approximately 1% parasitemia compared to sterile immunity in PD-1KO mice on re-infection. An examination of the mechanisms of immunity behind this long-term protection in PD-1KO mice showed a key role for parasite-specific CD8(+) T cells even when CD4(+) T cells and B cells responded to re-infection. These studies indicate that long-term CD8(+) T cell-meditated protection requires consideration for future malaria vaccine design, as part of a multi-cell type response. PMID:27217330

  7. Bullous pemphigoid, an autoantibody-mediated disease, is a novel immune-related adverse event in patients treated with anti-programmed cell death 1 antibodies.

    PubMed

    Hwang, Shelley J E; Carlos, Giuliana; Chou, Shaun; Wakade, Deepal; Carlino, Matteo S; Fernandez-Penas, Pablo

    2016-08-01

    Anti-programmed cell death 1 (anti-PD1) antibodies such as pembrolizumab have shown improved progression-free and overall survival in patients with advanced melanoma. Of 124 patients reviewed in Westmead Hospital from May 2012 to November 2015, treated with pembrolizumab for advanced melanoma, we encountered three cases of bullous pemphigoid (BP). We have previously reported a case of BP. In two recent cases, BP was diagnosed early and treated promptly with potent topical or oral steroid. Patients on anti-PD1 antibodies are at a higher risk of developing cutaneous immune-related adverse events such as lichenoid reactions, eczema and vitiligo. No cases of BP were encountered in the previously published cohort of 260 melanoma patients treated with BRAF inhibitors; as such, it appears that BP is associated with anti-PD1 treatment rather than metastatic melanoma. BP appears to be another immune-related adverse event, and clinicians should have a low threshold for performing cutaneous biopsies and immunofluorescence studies in patients on anti-PD1 therapies. PMID:27031539

  8. [Increased expressions of programmed death 1 (PD-1) and its ligands in peripheral CD3(+) T cells and CD19(+) B cells in patients with hepatocellular carcinoma].

    PubMed

    Liu, Wei; Chai, Lin; Liang, Junli; Lu, Zhizhong; Yang, Siwei

    2016-09-01

    Objective To investigate the changes of programmed death 1 (PD-1) and ligands, as well as interferon-γ (IFN-γ) in peripheral blood mononuclear cells (PBMCs) of patients with hepatocellular carcinoma (HCC). Methods The peripheral blood was collected from 15 early HCC patients, 13 progressive HCC patients and 12 healthy volunteers. PBMCs was isolated from the peripheral blood. The expressions of PD-1, PD-L1 and PD-L2 in PBMCs were detected by flow cytometry; the serum level of IFN-γ was determined by ELISA; the correlation of PD-1 and IFN-γ was analyzed with Pearson's correlation and One-way ANOVA. Results The expression levels of PD-1, PD-L1 and PD-L2 in CD3(+) T cells and CD19(+) B cells and serum IFN-γ level in progressive HCC patients were significantly higher than those in the healthy group and early HCC patients. The expression levels of PD-1, PD-L1 and PD-L2 in the CD3(+) T cells and CD19(+) B cells of the HCC patients were positively correlated with IFN-γ. Conclusion The expression levels of PD-1, PD-L1 and PD-L2 increase in the PBMCs of HCC patients; PD-1 and PD-L1 are correlated with IFN-γ level. PMID:27609582

  9. Mice lacking Programmed cell death-1 show a role for CD8+ T cells in long-term immunity against blood-stage malaria

    PubMed Central

    Horne-Debets, Joshua M.; Karunarathne, Deshapriya S.; Faleiro, Rebecca J.; Poh, Chek Meng; Renia, Laurent; Wykes, Michelle N.

    2016-01-01

    Even after years of experiencing malaria, caused by infection with Plasmodium species, individuals still have incomplete immunity and develop low-density parasitemia on re-infection. Previous studies using the P. chabaudi (Pch) mouse model to understand the reason for chronic malaria, found that mice with a deletion of programmed cell death-1 (PD-1KO) generate sterile immunity unlike wild type (WT) mice. Here we investigated if the mechanism underlying this defect during acute immunity also impacts on long-term immunity. We infected WT and PD-1KO mice with Pch-malaria and measured protection as well as immune responses against re-infections, 15 or 20 weeks after the original infection had cleared. WT mice showed approximately 1% parasitemia compared to sterile immunity in PD-1KO mice on re-infection. An examination of the mechanisms of immunity behind this long-term protection in PD-1KO mice showed a key role for parasite-specific CD8+ T cells even when CD4+ T cells and B cells responded to re-infection. These studies indicate that long-term CD8+ T cell-meditated protection requires consideration for future malaria vaccine design, as part of a multi-cell type response. PMID:27217330

  10. Mathematics and Molecules: Exploring Connections via Programming.

    ERIC Educational Resources Information Center

    Ploger, Don; Carlock, Margaret

    1996-01-01

    Examines the self-directed activity of two students who learned about molecular structure by writing computer programs. The programs displayed the solution of a mathematics problem, then the programs were extended to represent several classes of organic molecules. Different ways to enhance mathematical connections to chemistry education are…

  11. Interacting Alleles of the Coinhibitory Immunoreceptor Genes Cytotoxic T-Lymphocyte Antigen 4 and Programmed Cell-Death 1 Influence Risk and Features of Primary Biliary Cirrhosis

    PubMed Central

    Juran, Brian D.; Atkinson, Elizabeth J.; Schlicht, Erik M.; Fridley, Brooke L.; Petersen, Gloria M.; Lazaridis, Konstantinos N.

    2012-01-01

    Autoimmune diseases such as primary biliary cirrhosis (PBC) result from failure in the immune mechanisms that establish and maintain self-tolerance. Evidence suggests that these processes are shared among the spectrum of autoimmune syndromes and are likely genetically determined. Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell-death 1 (PDCD1) are two genes encoding coinhibitory immunoreceptors that harbor polymorphisms with demonstrated associations to multiple autoimmune disorders. We aimed to assess functional single nucleotide polymorphisms (SNPs) in these two genes for association with PBC. SNPs in CTLA4 and PDCD1 were genotyped in 351 PBC patients and 205 controls. Allele and genotype frequencies were evaluated for association with PBC and/or antimitochondrial antibody (AMA) positivity with logistic regression. Haplotypes were inferred with an expectation-maximization algorithm, and allelic interaction was analyzed by logistic regression modeling. Individual SNPs demonstrated no association to PBC. However, the GG genotype of CTLA4 49AG was significantly associated with AMA positivity among the PBC patients. Also, individual SNPs and a haplotype of CTLA4 as well as a rare genotype of the PDCD1 SNP PD1.3 were associated with orthotopic liver transplantation. As well, we identified the influence of an interaction between the putatively autoimmune-protective CTLA4 49AG:CT60 AA haplotype and autoimmune-risk PDCD1 PD1.3 A allele on development of PBC. Conclusion Our findings illustrate the complex nature of the genetically induced risk of PBC and emphasize the importance of considering definable subphenotypes of disease, such as AMA positivity, or definitive measures of disease severity/progression, like orthotopic liver transplantation, when genetic analyses are being performed. Comprehensive screening of genes involved with immune function will lead to a greater understanding of the genetic component of autoimmunity in PBC while furthering our

  12. The Expression of Programmed Death-1 on CD4+ and CD8+ T Lymphocytes in Patients with Type 2 Diabetes and Severe Sepsis

    PubMed Central

    Li, Chunsheng; Shao, Rui

    2016-01-01

    Objective To investigate the expression of Programmed death-1 (PD-1) on T lymphocytes in patients with type 2 diabetes mellitus (T2DM) and severe sepsis, we determined PD-1 expression on CD4+ and CD8+ T lymphocytes of patients with T2DM, severe sepsis, and T2DM combined with severe sepsis. Research Design and Methods This prospective and observational study included 50 healthy controls, 80 cases of T2DM without infection (T2DM group), 88 cases of severe sepsis without T2DM (SS group), and 77 cases of severe sepsis combined with T2DM (SS+T2DM group). Expression of peripheral blood PD-1+ CD4+ T cells and PD-1+ CD8+ T cells were compared between these 4 groups. Then, 28-day survival of the SS and SS+T2DM patients was assessed, and the expression of PD-1 on T cells was also compared between survivors and non-survivors. Results Percentages of PD-1+ CD4+ T cells and PD-1+ CD8+ T cells were higher in the T2DM group than in the healthy control group, and were highest in the SS and SS+T2DM groups. However, the expression of PD-1 on T cells and the mortality showed no significant difference between the SS and SS+T2DM groups. The expression of PD-1 on T cells was higher in non-survivors than survivors, but within the survivor group or non-survivor group, no difference can be detected between those with T2DM and those without T2DM. Conclusion The expression of PD-1 on T cells was increased in both T2DM and severe septic patients, but combining T2DM did not cause a further increase on the PD-1 expression in patients with severe sepsis. PMID:27459386

  13. 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

  14. Do programmed death 1 (PD-1) and its ligand (PD-L1) play a role in patients with non-clear cell renal cell carcinoma?

    PubMed

    Abbas, Mahmoud; Steffens, Sandra; Bellut, Maria; Becker, Jan U; Großhennig, Anika; Eggers, Hendrik; Wegener, Gerd; Kuczyk, Markus A; Kreipe, Hans H; Grünwald, Viktor; Schrader, Andres J; Ivanyi, Philipp

    2016-06-01

    Clinical trials targeting programmed death 1 (PD-1) and its ligand PD-L1 (PD-L1) for metastatic renal cell cancer (RCC) are ongoing. The aim of this study is to validate their roles as prognostic markers in non-clear cell (non-cc) RCC. Sixty-four non-cc RCC tissue specimens were collected from patients undergoing renal tumor surgery. Expressions of biomarkers were assessed using immunohistochemistry and compared with clinical characteristics. Survival analyses were performed with a median follow-up of 77.5 (range: 0-176) months. No significant correlations were found for PD-1(+) tumor-infiltrating mononuclear cells (TIMC) or PD-L1(+) expression and clinical attributes in patients with non-cc RCC. Kaplan-Meier analysis revealed no differences in 5- and 10-year cancer-specific survival (CSS) for PD-1(-) TIMC compared to PD-1(+) TIMC (71.4 and 63 % versus 72.2 and 61.9 %; p = 0.88). Intratumoral expression of PD-L1 did not appear to influence the 5- and 10-year CSS significantly, even though a trend was identified (68 and 53.6 % versus 80.1 and 75.7 %; p = 0.08). In multivariate analysis, neither PD-1(+) TIMC nor intratumoral PD-L1(+) expression proved to be independent predictors of CSS (p = 0.99 and p = 0.68, respectively). Our study demonstrates that PD-1(+) TIMC and intratumoral PD-L1(+) expression did not significantly impact tumor aggressiveness or clinical outcome in non-ccRCC specimens. Due to rare incidence of non-cc RCC in particular according to PD-L1 expression, further analyzes are warranted. PMID:27165272

  15. Expression of Programmed Cell Death 1 Ligands (PD-L1 and PD-L2) in Histiocytic and Dendritic Cell Disorders.

    PubMed

    Xu, Jie; Sun, Heather H; Fletcher, Christopher D M; Hornick, Jason L; Morgan, Elizabeth A; Freeman, Gordon J; Hodi, F Stephen; Pinkus, Geraldine S; Rodig, Scott J

    2016-04-01

    Programmed cell death 1 ligands 1 and 2 (PD-L1 and PD-L2) are cell surface proteins expressed by activated antigen-presenting cells and by select malignancies that bind PD-1 on T cells to inhibit immune responses. Antibodies targeting PD-1 or PD-L1 elicit antitumor immunity in a subset of patients, and clinical response correlates with PD-1 ligand expression by malignant or immune cells within the tumor microenvironment. We examined the expression of PD-1 ligands on subsets of antigen-presenting cells and 87 histiocytic and dendritic cell disorders including those that are benign, borderline, and malignant. Within reactive lymphoid tissue, strong PD-L1 is detected on most macrophages, subsets of interdigitating dendritic cells, and plasmacytoid dendritic cells, but not on follicular dendritic cells or Langerhans cells. Macrophage/dendritic cell subsets do not express discernible PD-L2. Seven of 7 cases of sarcoidosis (100%), 6 of 6 cases of histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) (100%), 2 of 11 cases of Rosai-Dorfman disease (18%), and 3 of 15 cases of Langerhans cell histiocytosis (20%) exhibited positivity for PD-L1. All cases of sarcoidosis were also positive for PD-L2. Seven of 14 histiocytic sarcomas (50%), 2 of 5 interdigitating dendritic cell sarcomas (40%), 10 of 20 follicular dendritic cell sarcomas (50%), and none of 9 blastic plasmacytoid dendritic cell neoplasms were positive for PD-L1. Eleven of 20 (55%) follicular dendritic cell sarcomas were also positive for PD-L2. PD-L1 and PD-L2 are useful new markers for identifying select histiocyte and dendritic cell disorders and reveal novel patient populations as rational candidates for immunotherapy. PMID:26752545

  16. 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

    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 (T(EM)) 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 T(EM)-phenotype cells relative to WT. Transfer of peripheral naïve CD4 T cells suggested that accumulated PD-1 KO T(EM)-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

  17. Coordination programming of photofunctional molecules.

    PubMed

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

    2013-01-01

    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. PMID:23563859

  18. 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

  19. Role of soluble programmed death-1 (sPD-1) and sPD-ligand 1 in patients with cystic echinococcosis

    PubMed Central

    LI, YANHUA; XIAO, YUNFENG; SU, MINGQUAN; ZHANG, RONG; DING, JIANBING; HAO, XIAOKE; MA, YUEYUN

    2016-01-01

    The programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) signaling pathway is a negative regulatory mechanism that inhibits T cell proliferation and cytokine production. Soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1), are also involved in regulation of the PD-1/PD-L1 signaling pathway. In the present study, the expression levels of sPD-1 and sPD-L1, as well as those of T helper (Th)1 [including interleukin (IL)-2 and interferon gamma], Th2 (including IL-4, IL-6 and IL-10) and Th17 (including interleukin 17) cell cytokines, were measured in the sera of patients with cystic echinococcosis (CE). Measurements were performed prior to and following after surgery and treatment with cyclic albendazole to investigate the effects of sPD-1 and sPD-L1 in patients with CE. Cytokine expression levels were measured using cytokine bead array and the expression levels of sPD-1 and sPD-L1 were measured using ELISA. In addition, in vitro stimulation was used to detect whether sPD-L1 has a negative regulatory effect on cytokine secretion or homeostasis. The present study observed significantly higher levels of sPD-L1 in patients with CE compared with healthy controls. Significantly elevated levels of Th2 cytokines in the sera of patients with CE were also observed. The results also suggest that there is an imbalanced expression of Th1 and Th2 cells during CE. In addition, it was demonstrated that sPD-1 and sPD-L1 are regulatory factors to the PD-1/PD-L1 signaling pathway, each having opposite effect, suggesting that they regulate the immune response to CE infection by creating a dynamic balance. In conclusion, sPD-L1 may play an important role in maintaining homeostasis in hosts with CE. PMID:26889250

  20. Expression of programmed death-1 ligand (PD-L1) in tumor-infiltrating lymphocytes is associated with favorable spinal chordoma prognosis

    PubMed Central

    Zou, Ming-Xiang; Peng, An-Bo; Lv, Guo-Hua; Wang, Xiao-Bin; Li, Jing; She, Xiao-Ling; Jiang, Yi

    2016-01-01

    Aberrant expression of programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) proteins alters human immunoresponse and promotes tumor development and progression. We assessed the expression status of PD-1 and PD-L1 in spinal chordoma tissue specimens and their association with clinicopathological characteristics of patients. Formalin-fixed paraffin-embedded tumor samples from 54 patients with spinal chordoma were collected for immunohistochemical analysis of PD-1 and PD-L1 expression. The association of the expression levels of PD-1 and PD-L1 with clinicopathological variables and survival data were statistically analyzed. Lymphocyte infiltrates were present in all 54 patient samples. Of 54 samples, 37 (68.5%) had both positive PD-1 and PD-L1 expression in tumor cell membrane. Moreover, 38 (70.4%) and 12 (22.2%) had positive PD-1 and PD-L1 expression in tumor-infiltrating lymphocytes (TILs), respectively. Tumors with positive PD-L1 expression were significantly associated with advanced stages of chordoma (p = 0.041) and TIL infiltration (p = 0.005), and had a borderline association with tumor grade (p = 0.051). However, positive tumor PD-L1 expression was not significantly associated with local recurrence-free survival (LRFS) or overall survival (OS). PD-1 expression in TILs was associated with poor LRFS (χ2 = 10.051, p = 0.002, log-rank test). Multivariate analysis showed that PD-L1 expression only in TILs was an independent predictor for LRFS (HR = 0.298, 95% CI: 0.098-0.907, p = 0.033), and OS (HR = 0.188, 95% CI: 0.051-0.687, p = 0.011) in spinal chordoma patients. In conclusion, PD-L1 expression in TILs was an independent predictor for both LRFS and OS in spinal chordoma patients. Our findings suggest that the PD-1/PD-L1 pathway may be a novel therapeutic target for the immunotherapy of chordoma. PMID:27508049

  1. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo

    PubMed Central

    Yasuda, S; Sho, M; Yamato, I; Yoshiji, H; Wakatsuki, K; Nishiwada, S; Yagita, H; Nakajima, Y

    2013-01-01

    Recent basic and clinical studies have shown that the programmed death ligand (PD-L)/PD-1 pathway has a significant role in tumour immunity, and its blockade has a therapeutic potential against several human cancers. We hypothesized that anti-angiogeneic treatment might augment the efficacy of PD-1 blockade. To this end, we evaluated combining the blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2) in a murine cancer model using Colon-26 adenocarcinoma. Interestingly, simultaneous treatment with anti-PD-1 and anti-VEGFR2 monoclonal antibodies (mAbs) inhibited tumour growth synergistically in vivo without overt toxicity. Blocking VEGFR2 inhibited tumour neovascularization significantly, as demonstrated by the reduced number of microvessels, while PD-1 blockade had no impact on tumour angiogenesis. PD-1 blockade might promote T cell infiltration into tumours and significantly enhanced local immune activation, as shown by the up-regulation of several proinflammatory cytokine expressions. Importantly, VEGFR2 blockade did not interfere with T cell infiltration and immunological activation induced by PD-1 blockade. In conclusion, simultaneous blockade of PD-1 and VEGFR2 induced a synergistic in-vivo anti-tumour effect, possibly through different mechanisms that might not be mutually exclusive. This unique therapeutic strategy may hold significant promise for future clinical application. PMID:23600839

  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. PMID:27160390

  3. 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

  4. 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

  5. Expression of programmed death-1 in primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma, cutaneous pseudo-T-cell lymphoma, and other types of cutaneous T-cell lymphoma.

    PubMed

    Cetinözman, Fatma; Jansen, Patty M; Willemze, Rein

    2012-01-01

    In this study we investigated whether programmed death-1 (PD-1) could serve as a useful diagnostic marker to differentiate between primary cutaneous CD4 small/medium-sized pleomorphic T-cell lymphoma (PCSM-TCL) and cutaneous pseudo-T-cell lymphomas on the one hand and other types of cutaneous T-cell lymphomas (CTCLs) on the other. Formalin-fixed, paraffin-embedded skin biopsies from 26 patients with PCSM-TCL or pseudo-T-cell lymphoma, including 1 patient with a lymphomatoid drug eruption, and 52 skin biopsies from other types of CTCLs were stained for PD-1. In addition, PD-1-positive cases were stained with antibodies against BCL6, CXCL13, and CD10 to determine a possible relationship with follicular helper T (TFH) cells. In all 26 cases of PCSM-TCL or pseudo-T-cell lymphoma, the medium-sized to large-sized atypical T cells consistently expressed PD-1, BCL6, and CXCL13 but not CD10. PD-1 expression was found in only 2 of 21 cases of mycosis fungoides and in only 2 of 16 cases of cutaneous peripheral T-cell lymphoma, unspecified. All 4 patients with an aggressive epidermotropic cytotoxic CD8 CTCL and all 11 cases with a primary cutaneous CD30 lymphoproliferative disorder were negative for PD-1. In conclusion, PD-1 is typically expressed by atypical cells in PCSM-TCL and pseudo-T-cell lymphoma but is not expressed or is rarely expressed in other types of CTCLs. Therefore, it may serve as a suitable adjunct in differential diagnosis. Our results demonstrate that the atypical cells in PCSM-TCL and pseudo-T-cell lymphomas share a common TFH phenotype and support the view that most cases classified nowadays as PCSM-TCL are identical to cutaneous pseudo-T-cell lymphomas described previously. PMID:21989349

  6. Roles of the programmed cell death 1, T cell immunoglobulin mucin-3, and cluster of differentiation 288 pathways in the low reactivity of invariant natural killer T cells after chronic hepatitis B virus infection.

    PubMed

    Yang, Zhixin; Lei, Yu; Chen, Chunbo; Ren, Hong; Shi, Tongdong

    2015-10-01

    One of the main responses of invariant natural killer T (iNKT) cells to antigen stimulation is the rapid production of interleukin (IL)-4 and interferon (IFN)-γ cytokines. There is a decline in the function of iNKT cells in chronic hepatitis B (CHB) patients. In this study, we explored the impact of programmed cell death 1 (PD-1), T cell immunoglobulin mucin-3 (Tim-3), and cluster of differentiation 28 (CD28) expression on iNKT cell functions in CHB patients. Flow cytometry was used to test iNKT frequencies and levels of PD-1, Tim-3, CD28, IL-4, and IFN-γ secreted by iNKT cells. An enzyme-linked immunosorbent assay (ELISA) was used to measure IL-4 and IFN-γ secretion upon α-galactosylceramide (α-GalCer) activation ex vivo. We found that the levels of expression of PD-1 and Tim-3 from iNKT cells in CHB patients were significantly higher than in healthy donors (p < 0.05), but there was lower expression of CD28 (p < 0.05) and an impaired capability to produce IL-4 and IFN-γ (p < 0.05). In vitro α-GalCer stimulation upregulated the expression of PD-1(+) iNKT cells (p < 0.05), Tim-3(+) iNKT cells (p < 0.05), and CD28(+) iNKT cells (p < 0.05). In response to combination therapies consisting of α-GalCer and anti-PDL1 monoclonal antibody (mAb) and/or anti-Tim-3 mAbs and/or anti-CD80/anti-CD28 mAbs, IL-4(+) and IFN-γ(+) iNKT cells demonstrated different degrees of growth (p < 0.05). The functional decline of iNKT cells was closely related to the decrease in CD28 expression and the increases of Tim-3 and PD-1. In addition, clinical antiviral treatment with lamivudine could partially restore the immune function of iNKT cells in CHB patients. PMID:26215444

  7. A Randomized, Double-Blind, Placebo-Controlled Assessment of BMS-936558, a Fully Human Monoclonal Antibody to Programmed Death-1 (PD-1), in Patients with Chronic Hepatitis C Virus Infection

    PubMed Central

    Gardiner, David; Lalezari, Jay; Lawitz, Eric; DiMicco, Michael; Ghalib, Rheem; Reddy, K. Rajender; Chang, Kyong-Mi; Sulkowski, Mark; Marro, Steven O’; Anderson, Jeffrey; He, Bing; Kansra, Vikram; McPhee, Fiona; Wind-Rotolo, Megan; Grasela, Dennis; Selby, Mark; Korman, Alan J.; Lowy, Israel

    2013-01-01

    Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) – a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding – was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5∶1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n = 5 each] or 10 mg/kg [n = 10]) or of placebo (n = 7). An additional 12 HCV treatment-naïve patients were randomized to receive 10 mg/kg BMS-936558 (n = 10) or placebo (n = 2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n = 1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA ≥0.5 log10 IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log10 reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4+, CD8+ and CD19+ cells, including both naïve and memory CD4+ and CD8+ subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20–24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of

  8. Programmed necrosis in inflammation: Toward identification of the effector molecules.

    PubMed

    Wallach, David; Kang, Tae-Bong; Dillon, Christopher P; Green, Douglas R

    2016-04-01

    Until recently, programmed cell death was conceived of as a single set of molecular pathways. We now know of several distinct sets of death-inducing mechanisms that lead to differing cell-death processes. In one of them--apoptosis--the dying cell affects others minimally. In contrast, programmed necrotic cell death causes release of immunostimulatory intracellular components after cell-membrane rupture. Defining the in vivo relevance of necrotic death is hampered because the molecules initiating it [such as receptor-interacting protein kinase-1 (RIPK1), RIPK3, or caspase-1] also serve other functions. Proteins that participate in late events in two forms of programmed necrosis [mixed lineage kinase domain-like protein (MLKL) in necroptosis and gasdermin-D in pyroptosis] were recently discovered, bringing us closer to identifying molecules that strictly serve in death mediation, thereby providing probes for better assessing its role in inflammation. PMID:27034377

  9. DUO: A general program for calculating spectra of diatomic molecules

    NASA Astrophysics Data System (ADS)

    Yurchenko, Sergei N.; Lodi, Lorenzo; Tennyson, Jonathan; Stolyarov, Andrey V.

    2016-05-01

    DUO is a general, user-friendly program for computing rotational, rovibrational and rovibronic spectra of diatomic molecules. DUO solves the Schrödinger equation for the motion of the nuclei not only for the simple case of uncoupled, isolated electronic states (typical for the ground state of closed-shell diatomics) but also for the general case of an arbitrary number and type of couplings between electronic states (typical for open-shell diatomics and excited states). Possible couplings include spin-orbit, angular momenta, spin-rotational and spin-spin. Corrections due to non-adiabatic effects can be accounted for by introducing the relevant couplings using so-called Born-Oppenheimer breakdown curves. DUO requires user-specified potential energy curves and, if relevant, dipole moment, coupling and correction curves. From these it computes energy levels, line positions and line intensities. Several analytic forms plus interpolation and extrapolation options are available for representation of the curves. DUO can refine potential energy and coupling curves to best reproduce reference data such as experimental energy levels or line positions. DUO is provided as a Fortran 2003 program and has been tested under a variety of operating systems.

  10. Programmed cell death 1 and Helios distinguish TCR-αβ+ double negative (CD4-CD8-) T cells that derive from self-reactive CD8 T cells1

    PubMed Central

    Rodríguez-Rodríguez, Noé; Apostolidis, Sokratis A.; Penaloza-MacMaster, Pablo; Manuel Martín Villa, José; Barouch, Dan H.; Tsokos, George C.; Crispín, José C.

    2015-01-01

    TCR-αβ+ double negative (DN; CD4-CD8-) T cells represent a poorly understood cellular subset suggested to contribute to the pathogenesis of the autoimmune disease systemic lupus erythematosus. DN T cells have been proposed to derive from CD8+ cells. However, the conditions that govern the loss of CD8 expression after antigen encounter are unknown. Here we tracked the fate of CD8 T cells from transgenic TCR mice exposed to their cognate antigens as self or in the context of infection. We demonstrate that CD8 T cells lose CD8 expression and become DN only when cognate antigen is sensed as self. This process is restricted to tissues where the antigen is present. We also show that DN T cells derived from self-reactive CD8 cells express the inhibitory molecules PD-1 and Helios. These molecules identify a subset of DN T cells in normal mice. A similar population expands when CD8 T cells from repertoires enriched in self-reactive cells (Aire-deficient) are transferred into cognate hosts. Collectively, our data suggest that a subset of DN T cells, identified by the expression of PD-1 and Helios, represent self-reactive cells. Our results provide an explanation for the origin of DN T cells and introduce CD8 loss as a process associated to self-antigen encounter. PMID:25825451

  11. A Computer Program for the Distribution of End-to-End Distances in Polymer Molecules

    ERIC Educational Resources Information Center

    Doorne, William Van; And Others

    1976-01-01

    Describes a Fortran program that illustrates how the end-to-end distances in randomly coiled polymer molecules is affected by varying the number and lengths of chains and the angles between them. (MLH)

  12. Three-Dimensional Chemical Structure Search Using the Conformational Code for Organic Molecules (CCOM) Program.

    PubMed

    Izumi, Hiroshi; Nafie, Laurence A; Dukor, Rina K

    2016-05-01

    Searching the 3D structural fragments of organic molecules is challenging because of structural differences between X-ray and theoretically calculated geometries and the conformational flexibility of substituents. The codification program called Conformational Code for Organic Molecules (CCOM) can be used to unambiguously convert 3D conformational data for various molecules to 1D data. Two deviations from Rule E-5.6 of the International Union of Pure and Applied Chemistry (IUPAC) Rules for Nomenclature of Organic Chemistry were introduced to the CCOM program for 3D fragment searching. First, the search for the highest priority atom was limited to a distance of two bonds from the center bond for dihedral angle determination. Second, for indistinguishable atoms in experimentally observed solution structures, the smallest number of atom index in the molecular model was chosen as the priority atom for dihedral angle determination. A search of the 3D conformational fragment mb_3a6c4c of mevastatin () in combination with the SMiles ARbitrary Target Specification (SMARTS) description suggested that a change in the conformation of this fragment may be the driving force for dissociation of mevastatin from its target protein. Chirality 28:370-375, 2016. © 2016 Wiley Periodicals, Inc. PMID:27040870

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

    PubMed

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

    2016-05-01

    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 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. PMID:27027267

  14. 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.

  15. 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

  16. 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

  17. A program for calculating and plotting soft-X-ray optical interaction coefficients for molecules

    NASA Astrophysics Data System (ADS)

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

    1990-05-01

    Comprehensive tables for atomic scattering factor components f1 and f2 were compiled by Henke et al. for the extended photon region of 350-10000 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 Optical Constants Grapher (OCG), 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 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 and its user's manual are available from the authors.

  18. Avogadro: Free, Open Source, Cross-Platform Computer Program for Building Molecules and Visualizing Structure

    NASA Astrophysics Data System (ADS)

    Hanwell, Marcus; Hutchison, Geoffrey

    2009-03-01

    The Avogadro project is a free, open source approach to building chemical structures. It has integrated analysis, and three-dimensional visualization capabilities. Avogadro also uses external packages to perform quantum structure calculations. The work presented here illustrates a novel approach to working with the results of quantum calculations by visualizing possible molecular orbitals and allowing the user to select orbitals of interest. The Avogadro program allows the user to prepare new jobs for various quantum codes such as GAMESS-US, Q-Chem, Gaussian and Molpro. Due to the plugin based nature of the Avogadro project many specialized options can be added, such as raytracing the electronic structure of the molecule to produce high quality output, building carbon nanotube structures, or designing solid-state structures. Avogadro is already being used by educators and researchers. Due to the free and open source nature of the project, it can be readily downloaded and used by all students in and out of the classroom. It can also be tailored to particular institutions and/or courses.

  19. 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

  20. ATIRS package: A program suite for the rovibrational analysis of infrared spectra of asymmetric top molecules

    NASA Astrophysics Data System (ADS)

    Tasinato, N.; Pietropolli Charmet, A.; Stoppa, P.

    2007-06-01

    Nowadays high-resolution infrared spectra can be recorded quite easily and therefore it has become important to assist the rovibrational analysis, especially the assignment step, that is still fraught with many problems in the presence of perturbation effects. In this article we provide a description of ATIRS, a complete software suite developed for assisting in the rotational investigation of vibrational bands of asymmetric top molecules. This package uses the Pickett's CALPGM suite for fitting transitions and predicting line positions and is composed by three stand-alone applications: (1) Visual Loomis-Wood for the assignment of spectral lines based on Loomis-Wood type diagrams; (2) Visual CALPGM, a new graphical interface to Pickett's programs SPFIT and SPCAT; (3) Visual Spectra Simulator for the simulation of spectra. The graphical interface to the CALPGM suite is developed for asymmetric rotors. The main feature of this application is to avoid the use of the parameter codes that are here replaced employing the well known parameter names or symbols. Highlighting the regular transition sequences, Visual Loomis-Wood assists in the assignment of the spectral lines. It visualizes the description of a transition and the assignment can be simply done by mouse-clicking on the diagram; moreover its display mode feature lets to check the experimental spectrum in which all the assigned lines together with their description are reported. Visual Spectra Simulator provides a simple and functionally application that, using the calculated frequencies and intensities given by SPCAT, simulates the high-resolution infrared spectrum and compare it to the experimental one. ATIRS, freely available to the spectroscopic community, is designed to be easy to use and presents a standard graphical interface; being based on the CALPGM package it can handle forbidden transitions and perturbations among many states.

  1. A computer program for a line-by-line calculation of spectra from diatomic molecules and atoms assuming a Voight line profile

    NASA Technical Reports Server (NTRS)

    Arnold, J. O.; Lyle, G. C.; Whiting, E. E.

    1969-01-01

    Computer program predicts the spectra resulting from electronic transitions of diatomic molecules and atoms in local thermodynamic equilibrium. The program produces a spectrum by accounting for the contribution of each rotational and atomic line considered.

  2. Isomer-Selective Detection of Aromatic Molecules in Temperature-Programmed Desorption for Model Catalysis.

    PubMed

    Winbauer, Andreas; Kollmannsberger, Sebastian L; Walenta, Constantin A; Schreiber, Patrick; Kiermaier, Josef; Tschurl, Martin; Heiz, Ueli

    2016-05-17

    Based on three different molecules dosed on a Pt(111) single crystal the selectivity and sensitivity of REMPI-TPD in UHV is investigated for a potential application in heterogeneous catalysis. It is shown that the two structural isomers ethylbenzene and p-xylene can be discriminated by REMPI in a standard TPD experiment. The latter is not possible for the ionization with electrons in a Q-MS. It is further demonstrated by benzene TPD studies that the sensitivity of the REMPI-TOF-MS is comparable to commercial EI-Q-MS solutions and enables the detection of less than 0.6% molecules of a monolayer. PMID:27078611

  3. 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

  4. 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. PMID:17518448

  5. 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.

  6. 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.

  7. 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.

  8. 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…

  9. 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

  10. 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

  11. Metabolic coupling of two small-molecule thiols programs the biosynthesis of lincomycin A.

    PubMed

    Zhao, Qunfei; Wang, Min; Xu, Dongxiao; Zhang, Qinglin; Liu, Wen

    2015-02-01

    Low-molecular-mass thiols in organisms are well known for their redox-relevant role in protection against various endogenous and exogenous stresses. In eukaryotes and Gram-negative bacteria, the primary thiol is glutathione (GSH), a cysteinyl-containing tripeptide. In contrast, mycothiol (MSH), a cysteinyl pseudo-disaccharide, is dominant in Gram-positive actinobacteria, including antibiotic-producing actinomycetes and pathogenic mycobacteria. MSH is equivalent to GSH, either as a cofactor or as a substrate, in numerous biochemical processes, most of which have not been characterized, largely due to the dearth of information concerning MSH-dependent proteins. Actinomycetes are able to produce another thiol, ergothioneine (EGT), a histidine betaine derivative that is widely assimilated by plants and animals for variable physiological activities. The involvement of EGT in enzymatic reactions, however, lacks any precedent. Here we report that the unprecedented coupling of two bacterial thiols, MSH and EGT, has a constructive role in the biosynthesis of lincomycin A, a sulfur-containing lincosamide (C8 sugar) antibiotic that has been widely used for half a century to treat Gram-positive bacterial infections. EGT acts as a carrier to template the molecular assembly, and MSH is the sulfur donor for lincomycin maturation after thiol exchange. These thiols function through two unusual S-glycosylations that program lincosamide transfer, activation and modification, providing the first paradigm for EGT-associated biochemical processes and for the poorly understood MSH-dependent biotransformations, a newly described model that is potentially common in the incorporation of sulfur, an element essential for life and ubiquitous in living systems. PMID:25607359

  12. Classification of drug molecules considering their IC50 values using mixed-integer linear programming based hyper-boxes method

    PubMed Central

    Armutlu, Pelin; Ozdemir, Muhittin E; Uney-Yuksektepe, Fadime; Kavakli, I Halil; Turkay, Metin

    2008-01-01

    Background A priori analysis of the activity of drugs on the target protein by computational approaches can be useful in narrowing down drug candidates for further experimental tests. Currently, there are a large number of computational methods that predict the activity of drugs on proteins. In this study, we approach the activity prediction problem as a classification problem and, we aim to improve the classification accuracy by introducing an algorithm that combines partial least squares regression with mixed-integer programming based hyper-boxes classification method, where drug molecules are classified as low active or high active regarding their binding activity (IC50 values) on target proteins. We also aim to determine the most significant molecular descriptors for the drug molecules. Results We first apply our approach by analyzing the activities of widely known inhibitor datasets including Acetylcholinesterase (ACHE), Benzodiazepine Receptor (BZR), Dihydrofolate Reductase (DHFR), Cyclooxygenase-2 (COX-2) with known IC50 values. The results at this stage proved that our approach consistently gives better classification accuracies compared to 63 other reported classification methods such as SVM, Naïve Bayes, where we were able to predict the experimentally determined IC50 values with a worst case accuracy of 96%. To further test applicability of this approach we first created dataset for Cytochrome P450 C17 inhibitors and then predicted their activities with 100% accuracy. Conclusion Our results indicate that this approach can be utilized to predict the inhibitory effects of inhibitors based on their molecular descriptors. This approach will not only enhance drug discovery process, but also save time and resources committed. PMID:18834515

  13. Defective Tapetum Cell Death 1 (DTC1) Regulates ROS Levels by Binding to Metallothionein during Tapetum Degeneration.

    PubMed

    Yi, Jakyung; Moon, Sunok; Lee, Yang-Seok; Zhu, Lu; Liang, Wanqi; Zhang, Dabing; Jung, Ki-Hong; An, Gynheung

    2016-03-01

    After meiosis, tapetal cells in the innermost anther wall layer undergo program cell death (PCD)-triggered degradation. This step is essential for microspore development and pollen wall maturation. We identified a key gene, Defective Tapetum Cell Death 1 (DTC1), that controls this degeneration by modulating the dynamics of reactive oxygen species (ROS) during rice male reproduction. Mutants defective in DTC1 exhibit phenotypes of an enlarged tapetum and middle layer with delayed degeneration, causing male sterility. The gene is preferentially expressed in the tapetal cells during early anther development. In dtc1 anthers, expression of genes encoding secretory proteases or lipid transporters is significantly reduced, while transcripts of PCD regulatory genes, e.g. UDT1, TDR1, and EAT1/DTD, are not altered. Moreover, levels of DTC1 transcripts are diminished in udt1, tdr, and eat1 anthers. These results suggest that DTC1 functions downstream of those transcription factor genes and upstream of the genes encoding secretory proteins. DTC1 protein interacts with OsMT2b, a ROS scavenger. Whereas wild-type plants accumulate large amounts of ROS in their anthers at Stage 9 of development, those levels remain low during all stages of development in dtc1 anthers. These findings indicate that DTC1 is a key regulator for tapetum PCD by inhibiting ROS-scavenging activity. PMID:26697896

  14. Defective Tapetum Cell Death 1 (DTC1) Regulates ROS Levels by Binding to Metallothionein during Tapetum Degeneration1[OPEN

    PubMed Central

    Moon, Sunok; Lee, Yang-Seok; Zhu, Lu; Jung, Ki-Hong; An, Gynheung

    2016-01-01

    After meiosis, tapetal cells in the innermost anther wall layer undergo program cell death (PCD)-triggered degradation. This step is essential for microspore development and pollen wall maturation. We identified a key gene, Defective Tapetum Cell Death 1 (DTC1), that controls this degeneration by modulating the dynamics of reactive oxygen species (ROS) during rice male reproduction. Mutants defective in DTC1 exhibit phenotypes of an enlarged tapetum and middle layer with delayed degeneration, causing male sterility. The gene is preferentially expressed in the tapetal cells during early anther development. In dtc1 anthers, expression of genes encoding secretory proteases or lipid transporters is significantly reduced, while transcripts of PCD regulatory genes, e.g. UDT1, TDR1, and EAT1/DTD, are not altered. Moreover, levels of DTC1 transcripts are diminished in udt1, tdr, and eat1 anthers. These results suggest that DTC1 functions downstream of those transcription factor genes and upstream of the genes encoding secretory proteins. DTC1 protein interacts with OsMT2b, a ROS scavenger. Whereas wild-type plants accumulate large amounts of ROS in their anthers at Stage 9 of development, those levels remain low during all stages of development in dtc1 anthers. These findings indicate that DTC1 is a key regulator for tapetum PCD by inhibiting ROS-scavenging activity. PMID:26697896

  15. Molecule nanoweaver

    DOEpatents

    Gerald, II; Rex E.; Klingler, Robert J.; Rathke, Jerome W.; Diaz, Rocio; Vukovic, Lela

    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.

  16. 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. PMID:26308749

  17. Efficient and accurate determination of the overall rotational diffusion tensor of a molecule from 15N relaxation data using computer program ROTDIF

    NASA Astrophysics Data System (ADS)

    Walker, Olivier; Varadan, Ranjani; Fushman, David

    2004-06-01

    We present a computer program ROTDIF for efficient determination of a complete rotational diffusion tensor of a molecule from NMR relaxation data. The derivation of the rotational diffusion tensor in the case of a fully anisotropic model is based on a six-dimensional search, which could be very time consuming, particularly if a grid search in the Euler angle space is involved. Here, we use an efficient Levenberg-Marquardt algorithm combined with Monte Carlo generation of initial guesses. The result is a dramatic, up to 50-fold improvement in the computational efficiency over the previous approaches [Biochemistry 38 (1999) 10225; J. Magn. Reson. 149 (2001) 214]. This method is demonstrated on a computer-generated and real protein systems. We also address the issue of sensitivity of the diffusion tensor determination from 15N relaxation measurements to experimental errors in the relaxation rates and discuss possible artifacts from applying higher-symmetry tensor model and how to recognize them.

  18. Investigation of the distribution of acidity strength in zeolites by temperature-programmed desorption of probe molecules. 2. Dealuminated Y-type zeolites

    SciTech Connect

    Karge, H.G.; Dondur, V. ); Weitkamp, J. )

    1991-01-10

    The acidity of dealuminated hydrogen forms of Y-type zeolites (Si/Al = 2.4-8.6) is determined by temperature-programmed desorption of ammonia or pyridine, which is monitored through a mass spectrometer. Four types of acidic sites are indicated by ammonia, viz., weak Broensted and/or Lewis centers and medium and strong Broensted and strong Lewis sites. In contrast, pyridine, after sample activation at 675 K, probed only two types of sites, i.e., medium and strong Broensted sites. This difference is ascribed to different accessibility of sites for the two probe molecules. From the desorption spectra (i) the fractional coverage of the various sites, (ii) the most frequent energies of activation, {anti E}{sub d}, for desorption, and (iii) the probability functions of the activation energies are derived by using a previously described method of evaluation.

  19. Interstellar molecules

    NASA Astrophysics Data System (ADS)

    Smith, D.

    1987-09-01

    Some 70 different molecular species have so far been detected variously in diffuse interstellar clouds, dense interstellar clouds, and circumstellar shells. Only simple (diatomic and triatomic) species exist in diffuse clouds because of the penetration of destructive UV radiations, whereas more complex (polyatomic) molecules survive in dense clouds as a result of the shielding against this UV radiation provided by dust grains. A current list of interstellar molecules is given together with a few other molecular species that have so far been detected only in circumstellar shells. Also listed are those interstellar species that contain rare isotopes of several elements. The gas phase ion chemistry is outlined via which the observed molecules are synthesized, and the process by which enrichment of the rare isotopes occurs in some interstellar molecules is described.

  20. 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)

  1. 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.

  2. 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. PMID:24345283

  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. Small molecule-directed specification of sclerotome-like chondroprogenitors and induction of a somitic chondrogenesis program from embryonic stem cells.

    PubMed

    Zhao, Jiangang; Li, Songhui; Trilok, Suprita; Tanaka, Makoto; Jokubaitis-Jameson, Vanta; Wang, Bei; Niwa, Hitoshi; Nakayama, Naoki

    2014-10-01

    Pluripotent embryonic stem cells (ESCs) generate rostral paraxial mesoderm-like progeny in 5-6 days of differentiation induced by Wnt3a and Noggin (Nog). We report that canonical Wnt signaling introduced either by forced expression of activated β-catenin, or the small-molecule inhibitor of Gsk3, CHIR99021, satisfied the need for Wnt3a signaling, and that the small-molecule inhibitor of BMP type I receptors, LDN193189, was able to replace Nog. Mesodermal progeny generated using such small molecules were chondrogenic in vitro, and expressed trunk paraxial mesoderm markers such as Tcf15 and Meox1, and somite markers such as Uncx, but failed to express sclerotome markers such as Pax1. Induction of the osteochondrogenically committed sclerotome from somite requires sonic hedgehog and Nog. Consistently, Pax1 and Bapx1 expression was induced when the isolated paraxial mesodermal progeny were treated with SAG1 (a hedgehog receptor agonist) and LDN193189, then Sox9 expression was induced, leading to cartilaginous nodules and particles in the presence of BMP, indicative of chondrogenesis via sclerotome specification. By contrast, treatment with TGFβ also supported chondrogenesis and stimulated Sox9 expression, but failed to induce the expression of Pax1 and Bapx1. On ectopic transplantation to immunocompromised mice, the cartilage particles developed under either condition became similarly mineralized and formed pieces of bone with marrow. Thus, the use of small molecules led to the effective generation from ESCs of paraxial mesodermal progeny, and to their further differentiation in vitro through sclerotome specification into growth plate-like chondrocytes, a mechanism resembling in vivo somitic chondrogenesis that is not recapitulated with TGFβ. PMID:25294938

  7. Distinct effects of human glioblastoma immunoregulatory molecules programmed cell death ligand-1 (PDL-1) and indoleamine 2,3-dioxygenase (IDO) on tumour-specific T cell functions.

    PubMed

    Avril, Tony; Saikali, Stéphan; Vauleon, Elodie; Jary, Anne; Hamlat, Abderrahmane; De Tayrac, Marie; Mosser, Jean; Quillien, Véronique

    2010-08-25

    Immunotherapy is a promising new treatment for patients suffering from glioma, in particular glioblastoma multiforme (GBM). However, tumour cells use different mechanisms to escape the immune responses induced by the treatment. As many other tumours, gliomas express or secrete several immunosuppressive molecules that regulate immune cell functions. In this study, we first analysed FasL, HLA-G, IDO, PDL-1 and TGF-beta1, -beta2 and -beta3 expression by transcriptomic microarray analysis in a series of 20 GBM samples and found respectively 15%, 60%, 85%, 30%, 70%, 80% and 35% of positive specimens. mRNA expression was then confirmed in 10 GBM primary cell lines and 2 immortalised cell lines U251 and U87MG. Furthermore, the protein expression of PDL-1, IDO activity and TGF-beta2 secretion were found on most of the untreated GBM primary cell lines. Remarkably, treatment with IFN-gamma increased the PDL-1 cell surface expression and the IDO activity, but reduced the TGF-beta2 secretion of GBM cell lines. We finally analysed the immunosuppressive effects of IDO, PDL-1 and TGF-beta1-3 by measuring IFN-gamma production and cell cytotoxicity activity of tumour antigen-specific T cells. PDL-1 partially affected the IFN-gamma production of antigen-specific T cells in response to GBM primary cell lines, and IDO inhibited lymphocyte proliferation induced by lectins. None of these molecules directly affected the T cell cytotoxicity function. Due to the functional role of PDL-1 and IDO molecules expressed by GBM cells, one could expect that blocking these molecules in the immunotherapy strategies would reinforce the efficiency of these treatments of GBM patients. PMID:20493562

  8. Programs.

    ERIC Educational Resources Information Center

    Community College Journal, 1996

    1996-01-01

    Includes a collection of eight short articles describing model community college programs. Discusses a literacy program, a mobile computer classroom, a support program for at-risk students, a timber-harvesting program, a multimedia presentation on successful women graduates, a career center, a collaboration with NASA, and an Israeli engineering…

  9. 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 ...

  10. 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

  11. 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.

  12. Cell-Extrinsic MHC Class I Molecule Engagement Augments Human NK Cell Education Programmed by Cell-Intrinsic MHC Class I.

    PubMed

    Boudreau, Jeanette E; Liu, Xiao-Rong; Zhao, Zeguo; Zhang, Aaron; Shultz, Leonard D; Greiner, Dale L; Dupont, Bo; Hsu, Katharine C

    2016-08-16

    The effector potential of NK cells is counterbalanced by their sensitivity to inhibition by "self" MHC class I molecules in a process called "education." In humans, interactions between inhibitory killer immunoglobulin-like receptors (KIR) and human MHC (HLA) mediate NK cell education. In HLA-B(∗)27:05(+) transgenic mice and in patients undergoing HLA-mismatched hematopoietic cell transplantation (HCT), NK cells derived from human CD34(+) stem cells were educated by HLA from both donor hematopoietic cells and host stromal cells. Furthermore, mature human KIR3DL1(+) NK cells gained reactivity after adoptive transfer to HLA-B(∗)27:05(+) mice or bone marrow chimeric mice where HLA-B(∗)27:05 was restricted to either the hematopoietic or stromal compartment. Silencing of HLA in primary NK cells diminished NK cell reactivity, while acquisition of HLA from neighboring cells increased NK cell reactivity. Altogether, these findings reveal roles for cell-extrinsic HLA in driving NK cell reactivity upward, and cell-intrinsic HLA in maintaining NK cell education. PMID:27496730

  13. Engineering biological systems with synthetic RNA molecules

    PubMed Central

    Liang, Joe C.; Bloom, Ryan J.; Smolke, Christina D.

    2011-01-01

    RNA molecules play diverse functional roles in natural biological systems. There has been growing interest in designing synthetic RNA counterparts for programming biological function. The design of synthetic RNA molecules that exhibit diverse activities, including sensing, regulatory, information processing, and scaffolding activities, has highlighted the advantages of RNA as a programmable design substrate. Recent advances in implementing these engineered RNA molecules as key control elements in synthetic genetic networks are highlighting the functional relevance of this class of synthetic elements in programming cellular behaviors. PMID:21925380

  14. Evaluation of Costimulatory Molecules in Peripheral Blood Lymphocytes of Canine Patients with Histiocytic Sarcoma

    PubMed Central

    Tagawa, Michihito; Maekawa, Naoya; Konnai, Satoru; Takagi, Satoshi

    2016-01-01

    Histiocytic sarcoma is a rapidly progressive and fatal neoplastic disease in dogs. It is unclear whether costimulatory molecules, including CD28, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and programmed death-1 (PD-1), are expressed on peripheral blood lymphocytes (PBLs) of canine patients with histiocytic sarcoma. The objective of this study was to evaluate the expression of CD28, CTLA-4, and PD-1 molecules on PBLs of patients with histiocytic sarcoma, patients with other tumors, and healthy controls. Twenty-six dogs were included in the study, with eight, ten, and eight dogs in the histiocytic sarcoma, other tumor, and healthy control groups, respectively. PBLs and serum were prospectively obtained from patients diagnosed histopathologically with histiocytic sarcoma, other tumors and healthy controls. The surface expression of CTLA-4, CD28, and PD-1 on T lymphocytes was examined using flow cytometric analysis. Serum samples were frozen at −30°C until serum interferon-γ (IFN-γ) was measured by enzyme-linked immunosorbent assay. The expression level of CTLA-4 on CD4+ lymphocytes was significantly higher in the histiocytic sarcoma group than in the control group. The expression of CTLA-4 on CD8+ lymphocytes was significantly higher in the histiocytic sarcoma group than in the other two groups. In addition, the expression of PD-1 on CD8+ lymphocytes was significantly higher in the histiocytic sarcoma group than in the control group. However, no significant differences in CD28 expressions and serum IFN-γ levels were observed. The present results provided evidence showing that the expression levels of CTLA-4 on both CD4+ and CD8+ lymphocytes and PD-1 on CD8+ lymphocytes in peripheral blood obtained from dogs with histiocytic sarcoma were upregulated. The overexpressions of CTLA 4 and PD-1 suggested that antitumor immunity may be suppressed in dogs with histiocytic sarcoma. PMID:26901565

  15. Engineering crystals of dendritic molecules

    PubMed Central

    Lukin, Oleg; Schubert, Dirk; Müller, Claudia M.; Schweizer, W. Bernd; Gramlich, Volker; Schneider, Julian; Dolgonos, Grygoriy; Shivanyuk, Alexander

    2009-01-01

    A detailed single-crystal X-ray study of conformationally flexible sulfonimide-based dendritic molecules with systematically varied molecular architectures was undertaken. Thirteen crystal structures reported in this work include 9 structures of the second-generation dendritic sulfonimides decorated with different aryl groups, 2 compounds bearing branches of both second and first generation, and 2 representatives of the first generation. Analysis of the packing patterns of 9 compounds bearing second-generation branches shows that despite their lack of strong directive functional groups there is a repeatedly reproduced intermolecular interaction mode consisting in an anchor-type packing of complementary second-generation branches of neighbouring molecules. The observed interaction tolerates a wide range of substituents in meta- and para-positions of the peripheral arylsulfonyl rings. Quantum chemical calculations of the molecule-molecule interaction energies agree at the qualitative level with the packing preferences found in the crystalline state. The calculations can therefore be used as a tool to rationalize and predict molecular structures with commensurate and non-commensurate branches for programming of different packing modes in crystal. PMID:19549870

  16. Engineering crystals of dendritic molecules.

    PubMed

    Lukin, Oleg; Schubert, Dirk; Müller, Claudia M; Schweizer, W Bernd; Gramlich, Volker; Schneider, Julian; Dolgonos, Grygoriy; Shivanyuk, Alexander

    2009-07-01

    A detailed single-crystal X-ray study of conformationally flexible sulfonimide-based dendritic molecules with systematically varied molecular architectures was undertaken. Thirteen crystal structures reported in this work include 9 structures of the second-generation dendritic sulfonimides decorated with different aryl groups, 2 compounds bearing branches of both second and first generation, and 2 representatives of the first generation. Analysis of the packing patterns of 9 compounds bearing second-generation branches shows that despite their lack of strong directive functional groups there is a repeatedly reproduced intermolecular interaction mode consisting in an anchor-type packing of complementary second-generation branches of neighbouring molecules. The observed interaction tolerates a wide range of substituents in meta- and para-positions of the peripheral arylsulfonyl rings. Quantum chemical calculations of the molecule-molecule interaction energies agree at the qualitative level with the packing preferences found in the crystalline state. The calculations can therefore be used as a tool to rationalize and predict molecular structures with commensurate and non-commensurate branches for programming of different packing modes in crystal. PMID:19549870

  17. 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.

  18. Adhesion molecules and receptors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Adhesion molecules are necessary for leukocyte trafficking and differentiation. They serve to initiate cell-cell interactions under conditions of shear, and they sustain the cell-cell and cell-matrix interactions needed for cellular locomotion. They also can serve directly as signaling molecules act...

  19. 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)

  20. 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.

  1. Parallel Molecular Dynamics Program for Molecules

    Energy Science and Technology Software Center (ESTSC)

    1995-03-07

    ParBond is a parallel classical molecular dynamics code that models bonded molecular systems, typically of an organic nature. It uses classical force fields for both non-bonded Coulombic and Van der Waals interactions and for 2-, 3-, and 4-body bonded (bond, angle, dihedral, and improper) interactions. It integrates Newton''s equation of motion for the molecular system and evaluates various thermodynamical properties of the system as it progresses.

  2. 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.

  3. Poisson's spot with molecules

    SciTech Connect

    Reisinger, Thomas; Holst, Bodil; Patel, Amil A.; Smith, Henry I.; Reingruber, Herbert; Fladischer, Katrin; Ernst, Wolfgang E.; Bracco, Gianangelo

    2009-05-15

    In the Poisson-spot experiment, waves emanating from a source are blocked by a circular obstacle. Due to their positive on-axis interference an image of the source (the Poisson spot) is observed within the geometrical shadow of the obstacle. In this paper we report the observation of Poisson's spot using a beam of neutral deuterium molecules. The wavelength independence and the weak constraints on angular alignment and position of the circular obstacle make Poisson's spot a promising candidate for applications ranging from the study of large molecule diffraction to patterning with molecules.

  4. Poisson's spot with molecules

    NASA Astrophysics Data System (ADS)

    Reisinger, Thomas; Patel, Amil A.; Reingruber, Herbert; Fladischer, Katrin; Ernst, Wolfgang E.; Bracco, Gianangelo; Smith, Henry I.; Holst, Bodil

    2009-05-01

    In the Poisson-spot experiment, waves emanating from a source are blocked by a circular obstacle. Due to their positive on-axis interference an image of the source (the Poisson spot) is observed within the geometrical shadow of the obstacle. In this paper we report the observation of Poisson’s spot using a beam of neutral deuterium molecules. The wavelength independence and the weak constraints on angular alignment and position of the circular obstacle make Poisson’s spot a promising candidate for applications ranging from the study of large molecule diffraction to patterning with molecules.

  5. Ultracold polar KRb molecules

    NASA Astrophysics Data System (ADS)

    Neyenhuis, Brian; Chotia, Amodsen; Moses, Steven; Ye, Jun; Jin, Deborah

    2011-05-01

    Ultracold polar molecules in the quantum degenerate regime open the possibility of realizing quantum gases with long-range, and spatially anisotropic, interparticle interactions. Currently, we can create a gas of ultracold fermionic ground-state KRb molecules in with a peak density of 1012 cm-3 and a temperature just 1.4 times the Fermi temperature. We will report on efforts to further cool this gas of molecules. One possibility is to evaporatively cool a spin-polarized molecular Fermi gas confined in quasi-2D, where we would rely on dipole-dipole interactions for rethermalization. We acknowledge funding from NIST, NSF, and AFOSR-MURI.

  6. 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.

  7. 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)

  8. 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.

  9. Positron binding to molecules

    NASA Astrophysics Data System (ADS)

    Danielson, J. R.

    2011-05-01

    While there is theoretical evidence that positrons can bind to atoms, calculations for molecules are much less precise. Unfortunately, there have been no measurements of positron-atom binding, due primarily to the difficulty in forming positron-atom bound states in two-body collisions. In contrast, positrons attach to molecules via Feshbach resonances (VFR) in which a vibrational mode absorbs the excess energy. Using a high-resolution positron beam, this VFR process has been studied to measure binding energies for more than 40 molecules. New measurements will be described in two areas: positron binding to relatively simple molecules, for which theoretical calculations appear to be possible; and positron binding to molecules with large permanent dipole moments, which can be compared to analogous, weakly bound electron-molecule (negative-ion) states. Binding energies range from 75 meV for CS2 (no dipole moment) to 180 meV for acetonitrile (CH3CN). Other species studied include aldehydes and ketones, which have permanent dipole moments in the range 2.5 - 3.0 debye. The measured binding energies are surprisingly large (by a factor of 10 to 100) compared to those for the analogous negative ions, and these differences will be discussed. New theoretical calculations for positron-molecule binding are in progress, and a recent result for acetonitrile will be discussed. This ability to compare theory and experiment represents a significant step in attempts to understand positron binding to matter. In collaboration with A. C. L. Jones, J. J. Gosselin, and C. M. Surko, and supported by NSF grant PHY 07-55809.

  10. 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.

  11. Poisson's Spot with Molecules

    NASA Astrophysics Data System (ADS)

    Reisinger, Thomas; Patel, Amil; Reingruber, Herbert; Fladischer, Katrin; Ernst, Wolfgang E.; Bracco, Gianangelo; Smith, Henry I.; Holst, Bodil

    2009-03-01

    In the Poisson-Spot experiment, waves emanating from a source are blocked by a circular obstacle. Due to their positive on-axis interference an image of the source (the Poisson spot) is observed within the geometrical shadow of the obstacle. The Poisson spot is the last of the classical optics experiments to be realized with neutral matter waves. In this paper we report the observation of Poisson's Spot using a beam of neutral deuterium molecules. The wavelength-independence and the weak constraints on angular alignment and position of the circular obstacle make Poisson's spot a promising candidate for applications ranging from the study of large-molecule diffraction and coherence in atom-lasers to patterning with large molecules.

  12. 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.

  13. Molecules on ice

    SciTech Connect

    Clary, D.C.

    1996-03-15

    The ozone hole that forms in the spring months over the Antarctic is thought to be produced through a network of chemical reactions catalyzed by the surfaces of ice crystals in polar stratospheric clouds (PSCs). A reaction between chlorine reservoir molecules, such as HCl + ClONO{sub 2} > HNO{sub 3} + Cl{sub 2}, is kinetically forbidden in the gas phase but proceeds quickly on the surface of ice and produces Cl{sub 2} molecules that are photodissociated by sunlight to yield the Cl atoms that destroy ozone. This destructive chain of events begins when HCl molecules stick to the ice crystals, and the mechanism for this crucial sticking process has been the subject of much debate. Recent work describes a mechanism that explains how HCl sticks to ice. This article goes on to detail research focusing surface reactions in stratospheric chemistry. 9 refs., 1 fig.

  14. 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.

  15. Molecules in η Carinae

    NASA Astrophysics Data System (ADS)

    Loinard, Laurent; Menten, Karl M.; Güsten, Rolf; Zapata, Luis A.; Rodríguez, Luis F.

    2012-04-01

    We report the detection toward η Carinae of six new molecules, CO, CN, HCO+, HCN, HNC, and N2H+, and of two of their less abundant isotopic counterparts, 13CO and H13CN. The line profiles are moderately broad (~100 km s-1), indicating that the emission originates in the dense, possibly clumpy, central arcsecond of the Homunculus Nebula. Contrary to previous claims, CO and HCO+ do not appear to be underabundant in η Carinae. On the other hand, molecules containing nitrogen or the 13C isotope of carbon are overabundant by about one order of magnitude. This demonstrates that, together with the dust responsible for the dimming of η Carinae following the Great Eruption, the molecules detected here must have formed in situ out of CNO-processed stellar material.

  16. Single-molecule bioelectronics.

    PubMed

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

    2015-01-01

    Experimental techniques that 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. In this study, we review several technologies that 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

  17. 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.

  18. Atomic branching in molecules

    NASA Astrophysics Data System (ADS)

    Estrada, Ernesto; Rodríguez-Velázquez, Juan A.; Randić, Milan

    A graph theoretic measure of extended atomic branching is defined that accounts for the effects of all atoms in the molecule, giving higher weight to the nearest neighbors. It is based on the counting of all substructures in which an atom takes part in a molecule. We prove a theorem that permits the exact calculation of this measure based on the eigenvalues and eigenvectors of the adjacency matrix of the graph representing a molecule. The definition of this measure within the context of the Hückel molecular orbital (HMO) and its calculation for benzenoid hydrocarbons are also studied. We show that the extended atomic branching can be defined using any real symmetric matrix, as well as any Hermitian (self-adjoint) matrix, which permits its calculation in topological, geometrical, and quantum chemical contexts.

  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. Towards single molecule switches.

    PubMed

    Zhang, Jia Lin; Zhong, Jian Qiang; Lin, Jia Dan; Hu, Wen Ping; Wu, Kai; Xu, Guo Qin; Wee, Andrew T S; Chen, Wei

    2015-05-21

    The concept of using single molecules as key building blocks for logic gates, diodes and transistors to perform basic functions of digital electronic devices at the molecular scale has been explored over the past decades. However, in addition to mimicking the basic functions of current silicon devices, molecules often possess unique properties that have no parallel in conventional materials and promise new hybrid devices with novel functions that cannot be achieved with equivalent solid-state devices. The most appealing example is the molecular switch. Over the past decade, molecular switches on surfaces have been intensely investigated. A variety of external stimuli such as light, electric field, temperature, tunneling electrons and even chemical stimulus have been used to activate these molecular switches between bistable or even multiple states by manipulating molecular conformations, dipole orientations, spin states, charge states and even chemical bond formation. The switching event can occur either on surfaces or in break junctions. The aim of this review is to highlight recent advances in molecular switches triggered by various external stimuli, as investigated by low-temperature scanning tunneling microscopy (LT-STM) and the break junction technique. We begin by presenting the molecular switches triggered by various external stimuli that do not provide single molecule selectivity, referred to as non-selective switching. Special focus is then given to selective single molecule switching realized using the LT-STM tip on surfaces. Single molecule switches operated by different mechanisms are reviewed and discussed. Finally, molecular switches embedded in self-assembled monolayers (SAMs) and single molecule junctions are addressed. PMID:25757483

  1. Plasmonic nanostructures: artificial molecules.

    PubMed

    Wang, Hui; Brandl, Daniel W; Nordlander, Peter; Halas, Naomi J

    2007-01-01

    This Account describes a new paradigm for the relationship between the geometry of metallic nanostructures and their optical properties. While the interaction of light with metallic nanoparticles is determined by their collective electronic or plasmon response, a compelling analogy exists between plasmon resonances of metallic nanoparticles and wave functions of simple atoms and molecules. Based on this insight, an entire family of plasmonic nanostructures, artificial molecules, has been developed whose optical properties can be understood within this picture: nanoparticles (nanoshells, nanoeggs, nanomatryushkas, nanorice), multi-nanoparticle assemblies (dimers, trimers, quadrumers), and a nanoparticle-over-metallic film, an electromagnetic analog of the spinless Anderson model. PMID:17226945

  2. Prebiologically Important Interstellar Molecules

    NASA Astrophysics Data System (ADS)

    Kuan, Y.-J.; Huang, H.-C.; Charnley, S. B.; Tseng, W.-L.; Snyder, L. E.; Ehrenfreund, P.; Kisiel, Z.; Thorwirth, S.; Bohn, R. K.; Wilson, T. L.

    2004-06-01

    Understanding the organic chemistry of molecular clouds, particularly the formation of biologically important molecules, is fundamental to the study of the processes which lead to the origin, evolution and distribution of life in the Galaxy. Determining the level of molecular complexity attainable in the clouds, and the nature of the complex organic material available to protostellar disks and the planetary systems that form from them, requires an understanding of the possible chemical pathways and is therefore a central question in astrochemistry. We have thus searched for prebiologically important molecules in the hot molecular cloud cores: Sgr B2(N-LMH), W51 e1/e2 and Orion-KL. Among the molecules searched: Pyrimidine is the unsubstituted ring analogue for three of the DNA and RNA bases. 2H-Azirine and Aziridine are azaheterocyclic compounds. And Glycine is the simplest amino acid. Detections of these interstellar organic molecular species will thus have important implications for Astrobiology. Our preliminary results indicate a tentative detection of interstellar glycine. If confirmed, this will be the first detection of an amino acid in interstellar space and will greatly strengthen the thesis that interstellar organic molecules could have played a pivotal role in the prebiotic chemistry of the early Earth.

  3. 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.

  4. The Science of Molecules

    ERIC Educational Resources Information Center

    Flory, Paul J.

    1974-01-01

    The author maintains that chemistry has a key role as the science of molecules and rejects the concept of chemistry as a branch of physics. The scope of chemistry, the philosophies underlying its practice, and the teaching of the subject also are discussed. (DT)

  5. 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…

  6. 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…

  7. 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

  8. OMG: Open Molecule Generator.

    PubMed

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

    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

  9. Building Diatomic and Triatomic Superatom Molecules.

    PubMed

    Champsaur, Anouck M; Velian, Alexandra; Paley, Daniel W; Choi, Bonnie; Roy, Xavier; Steigerwald, Michael L; Nuckolls, Colin

    2016-08-10

    In this study, we have developed a method to create Co6Se8 superatoms in which we program the metal-ligand bonds. We exclusively form the Co6Se8 core under simple reaction conditions with a facile separation of products that contain differential substitution of the core. The combination of Co2(CO)8 and PR3 with excess Se gives the differentially and directionally substituted superatoms, Co6Se8(CO)x(PR3)(6-x). The CO groups on the superatom can be exchanged quantitatively with phosphines and isonitriles. Substitution of the CO allows us to manipulate the type and length of chemical bridge between two redox-active superatomic centers in order to modulate intersuperatomic coupling. Linking two superatoms together allows us to form the simplest superatom molecule: a diatomic molecule. We extend the superatom molecule concept to link three superatoms together in a linear arrangement to form acyclic triatomic molecules. These superatom molecules have a rich electrochemical profile and chart a clear path to a whole family of superatom molecules with new and unusual collective properties. PMID:27410225

  10. 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

  11. 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.

  12. 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. (Author/JRH)

  13. Single-molecule electrophoresis

    SciTech Connect

    Castro, A.; Shera, E.B.

    1995-09-15

    A novel method for the detection and identification of single molecules in solution has been devised, computer simulated, and experimentally achieved. The technique involves the determination of electrophoretic velocities by measuring the time required for individual molecules to travel a fixed distance between two laser beams. Computer simulations of the process were performed before-hand in order to estimate the experimental feasibility of the method and to determine the optimum values for the various experimental parameters. Examples of the use of the technique for the ultrasensitive detection and identification of rhodamine-6G, a mixture of DNA restriction fragments, and a mixture of proteins in aqueous solution are presented. 20 refs., 8 figs.

  14. 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.

  15. 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.

  16. Epithelial Cell Adhesion Molecule

    PubMed Central

    Trzpis, Monika; McLaughlin, Pamela M.J.; de Leij, Lou M.F.H.; Harmsen, Martin C.

    2007-01-01

    The epithelial cell adhesion molecule (EpCAM, CD326) is a glycoprotein of ∼40 kd that was originally identified as a marker for carcinoma, attributable to its high expression on rapidly proliferating tumors of epithelial origin. Normal epithelia express EpCAM at a variable but generally lower level than carcinoma cells. In early studies, EpCAM was proposed to be a cell-cell adhesion molecule. However, recent insights revealed a more versatile role for EpCAM that is not limited only to cell adhesion but includes diverse processes such as signaling, cell migration, proliferation, and differentiation. Cell surface expression of EpCAM may actually prevent cell-cell adhesion. Here, we provide a comprehensive review of the current knowledge on EpCAM biology in relation to other cell adhesion molecules. We discuss the implications of the newly identified functions of EpCAM in view of its prognostic relevance in carcinoma, inflammatory pathophysiology, and tissue development and regeneration as well as its role in normal epithelial homeostasis. PMID:17600130

  17. 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.

  18. 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. PMID:25638443

  19. 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.

  20. Molecules in interstellar clouds

    NASA Astrophysics Data System (ADS)

    Irvine, W. M.; Hjalmarson, A.; Rydbeck, O. E. H.

    The physical conditions and chemical compositions of the gas in interstellar clouds are reviewed in light of the importance of interstellar clouds for star formation and the origin of life. The Orion A region is discussed as an example of a giant molecular cloud where massive stars are being formed, and it is pointed out that conditions in the core of the cloud, with a kinetic temperature of about 75 K and a density of 100,000-1,000,000 molecules/cu cm, may support gas phase ion-molecule chemistry. The Taurus Molecular Clouds are then considered as examples of cold, dark, relatively dense interstellar clouds which may be the birthplaces of solar-type stars and which have been found to contain the heaviest interstellar molecules yet discovered. The molecular species identified in each of these regions are tabulated, including such building blocks of biological monomers as H2O, NH3, H2CO, CO, H2S, CH3CN and H2, and more complex species such as HCOOCH3 and CH3CH2CN.

  1. 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 ...

  2. ION AND MOLECULE SENSORS USING MOLECULAR RECOGNITION IN LUMINESCENT, CONDUCTIVE POLYMERS

    EPA Science Inventory

    This program integrates three individual, highly interactive projects that will use molecular recognition strategies to develop sensor technology based on luminescent, conductive polymers that contain sites for binding specific molecules or ions in the presence of related molecul...

  3. Negative ions of polyatomic molecules.

    PubMed Central

    Christophorou, L G

    1980-01-01

    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. PMID:7428744

  4. 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

  5. Single Molecule Transcription Elongation

    PubMed Central

    Galburt, Eric A.; Grill, Stephan W.; Bustamante, Carlos

    2009-01-01

    Single molecule optical trapping assays have now been applied to a great number of macromolecular systems including DNA, RNA, cargo motors, restriction enzymes, DNA helicases, chromosome remodelers, DNA polymerases and both viral and bacterial RNA polymerases. The advantages of the technique are the ability to observe dynamic, unsynchronized molecular processes, to determine the distributions of experimental quantities and to apply force to the system while monitoring the response over time. Here, we describe the application of these powerful techniques to study the dynamics of transcription elongation by RNA polymerase II from Saccharomyces cerevisiae. PMID:19426807

  6. Leucocyte cellular adhesion molecules.

    PubMed

    Yong, K; Khwaja, A

    1990-12-01

    Leucocytes express adhesion promoting receptors which mediate cell-cell and cell-matrix interactions. These adhesive interactions are crucial to the regulation of haemopoiesis and thymocyte maturation, the direction and control of leucocyte traffic and migration through tissues, and in the development of immune and non-immune inflammatory responses. Several families of adhesion receptors have been identified (Table). The leucocyte integrin family comprises 3 alpha beta heterodimeric membrane glycoproteins which share a common beta subunit, designated CD18. The alpha subunits of each of the 3 members, lymphocyte function associated antigen-1 (LFA-1), macrophage antigen-1 (Mac-1) and p150,95 are designated CD11a, b and c respectively. These adhesion molecules play a critical part in the immune and inflammatory responses of leucocytes. The leucocyte integrin family is, in turn, part of the integrin superfamily, members of which are evolutionally, structurally and functionally related. Another Integrin subfamily found on leucocytes is the VLA group, so-called because the 'very late activation antigens' VLA-1 and VLA-2 were originally found to appear late in T-cell activation. Members of this family function mainly as extracellular matrix adhesion receptors and are found both on haemopoietic and non-haemopoietic cells. They play a part in diverse cellular functions including tissue organisation, lymphocyte recirculation and T-cell immune responses. A third integrin subfamily, the cytoadhesins, are receptors on platelets and endothelial cells which bind extracellular matrix proteins. A second family of adhesion receptors is the immunoglobulin superfamily, members of which include CD2, LFA-3 and ICAM-1, which participate in T-cell adhesive interactions, and the antigen-specific receptors of T and B cells, CD4, CD8 and the MHC Class I and II molecules. A recently recognised family of adhesion receptors is the selectins, characterised by a common lectin domain. Leucocyte

  7. 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.

  8. 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

  9. 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. PMID:26863450

  10. Polymorphisms of co-inhibitory molecules (CTLA-4/PD-1/PD-L1) and the risk of non-small cell lung cancer in a Chinese population

    PubMed Central

    Ma, Yuan; Liu, Xiuchun; Zhu, Jingyan; Li, Wanhu; Guo, Liangjun; Han, Xiao; Song, Bao; Cheng, Sensen; Jie, Liu

    2015-01-01

    Lung cancer is a leading cause of cancer-related death in China, with non-small cell lung cancer (NSCLC) comprises the most common form. Co-inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) and its ligand PD-L1, play a key roles in the physiopathological process of tumorigenesis. To investigate whether genetic variations of co-inhibitory molecules are associated with the risk of NSCLC, we analyzed polymorphisms of CTLA-4 (-318, +49), PD-1 (PD-1.1, PD-1.3, PD-1.5, PD-1.9) and PD-L1 (+8293) in a cohort of 528 NSCLC subjects and 600 healthy controls. By restriction fragment length polymorphism (RFLP) method, we found that the distributions of the CTLA-4 and PD-1 gene polymorphisms were similar between NSCLC patients and healthy controls. However, for the PD-L1 8923 A/C polymorphism, frequencies of the AC genotype and C-allele were significantly higher in NSCLC patients than in healthy controls (odds ratio [OR] =1.55; 95% confidence interval [CI] 1.13-2.13; P=0.006; OR=1.52; 95% CI 1.14-2.04; P=0.004, respectively). Stratification analysis revealed that prevalence of the 8923C allele was significantly increased in NSCLC patients who smoke compared to those non-smoking patients (OR=1.51; 95% CI 1.00-2.28; P<0.05). Moreover, NSCLC patients carrying the C-allele had higher risk of regional lymph node metastasis than those carrying the A-allele (OR=5.65; 95% CI 2.45~13.03; P<0.001). These data suggest that PD-L1+8293A>C polymorphism may play a role in the development and progression of NSCLC. PMID:26629188

  11. 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.

  12. 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.

  13. Emerging small molecule drugs.

    PubMed

    Colin, Sophie; Chinetti-Gbaguidi, Giulia; Kuivenhoven, Jan A; Staels, Bart

    2015-01-01

    Dyslipidaemia is a major risk factor for cardiovascular diseases. Pharmacological lowering of LDL-C levels using statins reduces cardiovascular risk. However, a substantial residual risk persists especially in patients with type 2 diabetes mellitus. Because of the inverse association observed in epidemiological studies of HDL-C with the risk for cardiovascular diseases, novel therapeutic strategies to raise HDL-C levels or improve HDL functionality are developed as complementary therapy for cardiovascular diseases. However, until now most therapies targeting HDL-C levels failed in clinical trials because of side effects or absence of clinical benefits. This chapter will highlight the emerging small molecules currently developed and tested in clinical trials to pharmacologically modulate HDL-C and functionality including new CETP inhibitors (anacetrapib, evacetrapib), novel PPAR agonists (K-877, CER-002, DSP-8658, INT131 and GFT505), LXR agonists (ATI-111, LXR-623, XL-652) and RVX-208. PMID:25523004

  14. Forces in molecules.

    PubMed

    Hernández-Trujillo, Jesús; Cortés-Guzmán, Fernando; Fang, De-Chai; Bader, Richard F W

    2007-01-01

    Chemistry is determined by the electrostatic forces acting within a collection of nuclei and electrons. The attraction of the nuclei for the electrons is the only attractive force in a molecule and is the force responsible for the bonding between atoms. This is the attractive force acting on the electrons in the Ehrenfest force and on the nuclei in the Feynman force, one that is countered by the repulsion between the electrons in the former and by the repulsion between the nuclei in the latter. The virial theorem relates these forces to the energy changes resulting from interactions between atoms. All bonding, as signified by the presence of a bond path, has a common origin in terms of the mechanics determined by the Ehrenfest, Feynman and virial theorems. This paper is concerned in particular with the mechanics of interaction encountered in what are classically described as 'nonbonded interactions'--are atoms that 'touch' bonded or repelling one another? PMID:17328425

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

    SciTech Connect

    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.

  16. 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.

  17. 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

  18. 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

  19. Reactions of oriented molecules.

    PubMed

    Brooks, P R

    1976-07-01

    Beams of oriented molecules have been used to directly study geometrical requirements in chemical reactions. These studies have shown that reactivity is much greater in some orientations than others and demonstrated the existence of steric effects. For some reactions portions of the orientation results are in good accord with traditional views of steric hindrance, but for others it is clear that our chemical intuition needs recalibrating. Indeed, the information gained from simultaneously orienting the reactants and observing the scattering angle of the products may lead to new insights about the detailed mechanism of certain reactions. Further work must be done to extend the scope and detail of the studies described here. More detailed information is needed on the CH(3)I reaction and the CF(3)I reaction. The effects of alkyl groups of various sizes and alkali metals of various sizes are of interest. In addition, reactions where a long-lived complex is formed should be studied to see if orientation is important. Finally, it would be of interest to apply the technique to the sort of reactions that led to our interest in the first place: the S(N)2 displacements in alkyl halides where the fascinating Walden inversion occurs. PMID:17793988

  20. Electrochromic graphene molecules.

    PubMed

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

    2015-04-28

    Polyclic aromatic hydrocarbons also called Graphene Molecules (GMs), with chemical composition C132H36(COOH)2 were synthesized in situ on the surface of transparent nanocrystalline indium tin oxide (nc-ITO) electrodes and 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 a 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 nonideal. The nonideality factors associated with the oxidation and reduction processes are attributed to 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. PMID:25768313

  1. Electrochromic Graphene Molecules

    DOE PAGESBeta

    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

  2. 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.

  3. 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.

  4. Strongly interacting ultracold polar molecules

    NASA Astrophysics Data System (ADS)

    Gadway, Bryce; Yan, Bo

    2016-08-01

    This paper reviews recent advances in the study of strongly interacting systems of dipolar molecules. Heteronuclear molecules feature large and tunable electric dipole moments, which give rise to long-range and anisotropic dipole–dipole interactions. Ultracold samples of dipolar molecules with long-range interactions offer a unique platform for quantum simulations and the study of correlated many-body physics. We provide an introduction to the physics of dipolar quantum gases, both electric and magnetic, and summarize the multipronged efforts to bring dipolar molecules into the quantum regime. We discuss in detail the recent experimental progress in realizing and studying strongly interacting systems of polar molecules trapped in optical lattices, with particular emphasis on the study of interacting spin systems and non-equilibrium quantum magnetism. Finally, we conclude with a brief discussion of the future prospects for studies of strongly interacting dipolar molecules.

  5. Adsorption kinetics of diatomic molecules.

    PubMed

    Burde, Jared T; Calbi, M Mercedes

    2014-05-01

    The adsorption dynamics of diatomic molecules on solid surfaces is examined by using a Kinetic Monte Carlo algorithm. Equilibration times at increasing loadings are obtained, and explained based on the elementary processes that lead to the formation of the adsorbed film. The ability of the molecules to change their orientation accelerates the overall uptake and leads to competitive kinetic behaviour between the different orientations. The dependence of the equilibration time on coverage follows the same decreasing trend obtained experimentally for ethane adsorption on closed-end carbon nanotube bundles. The exploration of molecule-molecule interaction effects on this trend provides relevant insights to understand the kinetic behaviour of other species, from simpler molecules to larger polyatomic molecules, adsorbing on surfaces with different binding strength. PMID:24654004

  6. 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.

  7. 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).

  8. Trapping Single Molecules by Dielectrophoresis

    NASA Astrophysics Data System (ADS)

    Hölzel, Ralph; Calander, Nils; Chiragwandi, Zackary; Willander, Magnus; Bier, Frank F.

    2005-09-01

    We have trapped single protein molecules of R-phycoerythrin in an aqueous solution by an alternating electric field. A radio frequency voltage is applied to sharp nanoelectrodes and hence produces a strong electric field gradient. The resulting dielectrophoretic forces attract freely diffusing protein molecules. Trapping takes place at the electrode tips. Switching off the field immediately releases the molecules. The electric field distribution is computed, and from this the dielectrophoretic response of the molecules is calculated using a standard polarization model. The resulting forces are compared to the impact of Brownian motion. Finally, we discuss the experimental observations on the basis of the model calculations.

  9. 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.

  10. Adhesion molecules in cutaneous inflammation.

    PubMed

    Barker, J N

    1995-01-01

    As in other organs, leukocyte adhesion molecules and their ligands play a major role in cutaneous inflammatory events both by directing leukocyte trafficking and by their effects on antigen presentation. Skin biopsies of inflamed skin from patients with diseases such as as psoriasis or atopic dermatitis reveal up-regulation of endothelial cell expression of P- and E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. Studies of evolving lesions following UVB irradiation, Mantoux reaction or application of contact allergen, demonstrate that expression of these adhesion molecules parallels leukocyte infiltration into skin. When cutaneous inflammation is widespread (e.g. in erythroderma), soluble forms of these molecules are detectable in serum. In vitro studies predict that peptide mediators are important regulatory factors for endothelial adhesion molecules. Intradermal injection of the cytokines interleukin 1, tumour necrosis factor alpha and interferon gamma into normal human skin leads to induction of endothelial adhesion molecules with concomitant infiltration of leukocytes. In addition, neuropeptides rapidly induce P-selectin translocation to the cell membrane and expression of E-selectin. Adhesion molecules also play a crucial role as accessory molecules in the presentation of antigen to T lymphocytes by Langerhans' cells. Expression of selectin ligands by Langerhans' cells is up-regulated by various inflammatory stimuli, suggesting that adhesion molecules may be important in Langerhans' cell migration. The skin, because of its accessibility, is an ideal organ in which to study expression of adhesion molecules and their relationship to inflammatory events. Inflammatory skin diseases are common and inhibition of lymphocyte accumulation in skin is likely to prove of great therapeutic benefit. PMID:7587640

  11. 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)

  12. Proregenerative Properties of ECM Molecules

    PubMed Central

    Plantman, Stefan

    2013-01-01

    After traumatic injuries to the nervous system, regrowing axons encounter a complex microenvironment where mechanisms that promote regeneration compete with inhibitory processes. Sprouting and axonal regrowth are key components of functional recovery but are often counteracted by inhibitory molecules. This review covers extracellular matrix molecules that support neuron axonal outgrowth. PMID:24195084

  13. 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.

  14. 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.

  15. Enzyme molecules in solitary confinement.

    PubMed

    Liebherr, Raphaela B; Gorris, Hans H

    2014-01-01

    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. PMID:25221867

  16. 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.

  17. 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.

  18. 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. PMID:23836648

  19. Cold molecules, collisions and reactions

    NASA Astrophysics Data System (ADS)

    Hecker Denschlag, Johannes

    2016-05-01

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

  20. 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

  1. 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.

  2. Organic heterocyclic molecules become superalkalis.

    PubMed

    Reddy, G Naaresh; Giri, Santanab

    2016-09-21

    An organic molecule which behaves like a superalkali has been designed from an aromatic heterocyclic molecule, pyrrole. Using first-principles calculation and a systematic two-step approach, we can have superalkali molecules with a low ionization energy, even lower than that of Cs. Couple cluster (CCSD) calculation reveals that a new heterocycle, C3N2(CH3)5 derived from a well-known aromatic heterocycle, pyrrole (C4H5N) has an ionization energy close to 3.0 eV. A molecular dynamics calculation on C3N2(CH3)5 reveals that the structure is dynamically stable. PMID:27530344

  3. Nonsequential double ionization of molecules

    SciTech Connect

    Prauzner-Bechcicki, Jakub S.; Sacha, Krzysztof; Zakrzewski, Jakub; Eckhardt, Bruno

    2005-03-01

    Double ionization of diatomic molecules by short linearly polarized laser pulses is analyzed. We consider the final stage of the ionization process, that is the decay of a highly excited two electron molecule, which is formed after rescattering. The saddles of the effective adiabatic potential energy close to which simultaneous escape of electrons takes place are identified. Numerical simulations of the ionization of molecules show that the process can be dominated by either sequential or nonsequential events. In order to increase the ratio of nonsequential to sequential ionizations very short laser pulses should be applied.

  4. 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

  5. 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.

  6. 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.

  7. Biomedical applications of single molecule detection

    NASA Astrophysics Data System (ADS)

    Kelso, D. M.

    1997-05-01

    The search for increased sensitivity of bio-analytical techniques has recently shifted from signal generation to detection. While enzyme amplifiers and chemiluminescent reporters developed by chemists over the last two decades gradually moved detection limits to the attomol level, it has taken engineers only a few years to reach single- molecule sensitivity with the development of new instrumentation. A number of different approaches have successfully achieved single-molecule fluorescence detection including confocal and near-field scanning optical microscopy, photon-counting cameras, fluorescence- correlation and time-gated spectroscopy. They detect labels immobilized on substrates, diffusing in solution and flowing in electro-osmotic and hydrodynamically focused streams. Biotechnology has created numerous application s for single- molecule detection. In research labs, it can dramatically increase the rate of DNA sequencing, screen libraries for products of directed evolution, and characterize compounds in drug discovery programs. In medical diagnostics, ultra- sensitive detection technologies can be used for genetic screening, detection of infectious diseases, or multi- analyte profiles. It can be applied to immunoassays as well as DNA or RNA hybridization assays.

  8. Surface chemistry of deuterated molecules

    NASA Astrophysics Data System (ADS)

    Tielens, A. G. G. M.

    1983-03-01

    The chemical composition of grain mantles is calculated in order to determine the concentration of deuterated molecules relative to their hydrogenated counterparts in grain mantles. The computation takes into account reactions involving deuterium in the gas phase and on grain surfaces. The results show that the abundance of deuterium molecules in grain mantles is much higher than expected on the basis of the cosmic abundance ratio of D to H. HDCO has a relatively high abundance in grain mantles as compared to other deuterated molecules, due to the fact that H abstraction from HDCO has a lower activation barrier than D abstraction. The infrared characteristics of the calculated grain mantles are discussed and observational tests of the model calcultions are suggested. The contribution of grain surface chemistry to the concentration of molecules in the gas phase is briefly considered.

  9. Cobalt single-molecule magnet

    NASA Astrophysics Data System (ADS)

    Yang, En-Che; Hendrickson, David N.; Wernsdorfer, Wolfgang; Nakano, Motohiro; Zakharov, Lev N.; Sommer, Roger D.; Rheingold, Arnold L.; Ledezma-Gairaud, Marisol; Christou, George

    2002-05-01

    A cobalt molecule that functions as a single-molecule magnet, [Co4(hmp)4(MeOH)4Cl4], where hmp- is the anion of hydroxymethylpyridine, is reported. The core of the molecule consists of four Co(II) cations and four hmp- oxygen atom ions at the corners of a cube. Variable-field and variable-temperature magnetization data have been analyzed to establish that the molecule has a S=6 ground state with considerable negative magnetoanisotropy. Single-ion zero-field interactions (DSz2) at each cobalt ion are the origin of the negative magnetoanisotropy. A single crystal of the compound was studied by means of a micro-superconducting quantum interference device magnetometer in the range of 0.040-1.0 K. Hysteresis was found in the magnetization versus magnetic field response of this single crystal.

  10. Spin tunneling in magnetic molecules

    NASA Astrophysics Data System (ADS)

    Kececioglu, Ersin

    In this thesis, we will focus on spin tunneling in a family of systems called magnetic molecules such as Fe8 and Mn12. This is comparatively new, in relation to other tunneling problems. Many issues are not completely solved and/or understood yet. The magnetic molecule Fe 8 has been observed to have a rich pattern of degeneracies in its magnetic spectrum. We focus on these degeneracies from several points of view. We start with the simplest anisotropy Hamiltonian to describe the Fe 8 molecule and extend our discussion to include higher order anisotropy terms. We give analytical expressions as much as we can, for the degeneracies in the semi-classical limit in both cases. We reintroduce jump instantons to the instanton formalism. Finally, we discuss the effect of the environment on the molecule. Our results, for all different models and techniques, agree well with both experimental and numerical results.

  11. 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

  12. Single-Molecule DNA Analysis

    NASA Astrophysics Data System (ADS)

    Efcavitch, J. William; Thompson, John F.

    2010-07-01

    The ability to detect single molecules of DNA or RNA has led to an extremely rich area of exploration of the single most important biomolecule in nature. In cases in which the nucleic acid molecules are tethered to a solid support, confined to a channel, or simply allowed to diffuse into a detection volume, novel techniques have been developed to manipulate the DNA and to examine properties such as structural dynamics and protein-DNA interactions. Beyond the analysis of the properties of nucleic acids themselves, single-molecule detection has enabled dramatic improvements in the throughput of DNA sequencing and holds promise for continuing progress. Both optical and nonoptical detection methods that use surfaces, nanopores, and zero-mode waveguides have been attempted, and one optically based instrument is already commercially available. The breadth of literature related to single-molecule DNA analysis is vast; this review focuses on a survey of efforts in molecular dynamics and nucleic acid sequencing.

  13. 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)

  14. 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.

  15. Collisional decoherence of polar molecules

    NASA Astrophysics Data System (ADS)

    Walter, Kai; Stickler, Benjamin A.; Hornberger, Klaus

    2016-06-01

    The quantum state of motion of a large and rotating polar molecule can lose coherence through the collisions with gas atoms. We show how the associated quantum master equation for the center of mass can be expressed in terms of the orientationally averaged differential and total scattering cross sections, for which we provide approximate analytic expressions. The master equation is then utilized to quantify collisional decoherence in a interference experiment with polar molecules.

  16. Nanochannel Based Single Molecule Recycling

    PubMed Central

    Lesoine, John F.; Venkataraman, Prahnesh A.; Maloney, Peter C.; Dumont, Mark

    2012-01-01

    We present a method for measuring the fluorescence from a single molecule hundreds of times without surface immobilization. The approach is based on the use of electroosmosis to repeatedly drive a single target molecule in a fused silica nanochannel through a stationary laser focus. Single molecule fluorescence detected during the transit time through the laser focus is used to repeatedly reverse the electrical potential controlling the flow direction. Our method does not rely on continuous observation and therefore is less susceptible to fluorescence blinking than existing fluorescence-based trapping schemes. The variation in the turnaround times can be used to measure the diffusion coefficient on a single molecule level. We demonstrate the ability to recycle both proteins and DNA in nanochannels and show that the procedure can be combined with single-pair Förster energy transfer. Nanochannel-based single molecule recycling holds promise for studying conformational dynamics on the same single molecule in solution and without surface tethering. PMID:22662745

  17. Combining single-molecule manipulation and single-molecule detection.

    PubMed

    Cordova, Juan Carlos; Das, Dibyendu Kumar; Manning, Harris W; Lang, Matthew J

    2014-10-01

    Single molecule force manipulation combined with fluorescence techniques offers much promise in revealing mechanistic details of biomolecular machinery. Here, we review force-fluorescence microscopy, which combines the best features of manipulation and detection techniques. Three of the mainstay manipulation methods (optical traps, magnetic traps and atomic force microscopy) are discussed with respect to milestones in combination developments, in addition to highlight recent contributions to the field. An overview of additional strategies is discussed, including fluorescence based force sensors for force measurement in vivo. Armed with recent exciting demonstrations of this technology, the field of combined single-molecule manipulation and single-molecule detection is poised to provide unprecedented views of molecular machinery. PMID:25255052

  18. 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.

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

    PubMed

    Jovan Jose, K V; Raghavachari, Krishnan

    2016-02-01

    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. PMID:26760444

  20. Measuring an antibody affinity distribution molecule by molecule

    SciTech Connect

    Bradbury, Andrew M; Werner, James H; Temirov, Jamshid

    2008-01-01

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

  1. 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. PMID:24689869

  2. Spectroscopic modeling of water molecule

    NASA Astrophysics Data System (ADS)

    Danylo, R. I.; Okhrimenko, B. A.

    2013-12-01

    This research is devoted to the vibrational spectroscopy inverse problem solution that gives a possibility to design a molecule and make conclusions about its geometry. The valence angle finding based on the usage of inverse spectral vibrational spectroscopy problem is a well-known task. 3N-matrix method was chosen to solve the proposed task. The usage of this method permits to make no assumptions about the molecule force field, besides it can be applied to molecules of matter in liquid state. Anharmonicity constants assessment is an important part of the valence angle finding. The reduction to zero vibrations is necessary because used matrix analytical expression were found in the harmonic approach. In order to find the single-valued inverse spectral problem of vibrational spectroscopy solution a shape parameter characterizing "mixing" of ω1 and ω2 vibrations forms must be found. The minimum of such a function Υ called a divergence parameter was found. This function characterizes method's accuracy. The valence angle assessment was reduced to the divergence parameter minimization. The β value concerning divergence parameter minimum was interpreted as the desired valence angle. The proposed method was applied for water molecule in liquid state: β = (88,8 ±1,7)° . The found angle fits the water molecule nearest surrounding tetrahedral model including hydrogen bond curvature in the first approximation.

  3. Electron Collisions with Large Molecules

    NASA Astrophysics Data System (ADS)

    McKoy, Vincent

    2006-10-01

    In recent years, interest in electron-molecule collisions has increasingly shifted to large molecules. Applications within the semiconductor industry, for example, require electron collision data for molecules such as perfluorocyclobutane, while almost all biological applications involve macromolecules such as DNA. A significant development in recent years has been the realization that slow electrons can directly damage DNA. This discovery has spurred studies of low-energy collisions with the constituents of DNA, including the bases, deoxyribose, the phosphate, and larger moieties assembled from them. In semiconductor applications, a key goal is development of electron cross section sets for plasma chemistry modeling, while biological studies are largely focused on understanding the role of localized resonances in inducing DNA strand breaks. Accurate calculations of low-energy electron collisions with polyatomic molecules are computationally demanding because of the low symmetry and inherent many-electron nature of the problem; moreover, the computational requirements scale rapidly with the size of the molecule. To pursue such studies, we have adapted our computational procedure, known as the Schwinger multichannel method, to run efficiently on highly parallel computers. In this talk, we will present some of our recent results for fluorocarbon etchants used in the semiconductor industry and for constituents of DNA and RNA. In collaboration with Carl Winstead, California Institute of Technology.

  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. Room temperature single molecule microscopes

    SciTech Connect

    Ambrose, W.P.; Goodwin, P.M.; Enderlein, G.; Semin, D.J.; Keller, R.A.

    1997-12-31

    We have developed three capabilities to image the locations of and interrogate immobilized single fluorescent molecules: near-field scanning optical, confocal scanning optical, and wide-field epi-fluorescence microscopy. Each microscopy has its own advantages. Near-field illumination can beat the diffraction limit. Confocal microscopy has high brightness and temporal resolution. Wide-field has the quickest (parallel) imaging capability. With confocal microscopy, we have verified that single fluorescent spots in our images are due to single molecules by observing photon antibunching. Using all three microscopies, we have observed that xanthene molecules dispersed on dry silica curiously exhibit intensity fluctuations on millisecond to minute time scales. We are exploring the connection between the intensity fluctuations and fluctuations in individual photophysical parameters. The fluorescence lifetimes of Rhodamine 6G on silica fluctuate. The complex nature of the intensity and lifetime fluctuations is consistent with a mechanism that perturbs more than one photophysical parameter.

  6. 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.

  7. 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.

  8. 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.

  9. Dipolar molecules in optical lattices.

    PubMed

    Sowiński, Tomasz; Dutta, Omjyoti; Hauke, Philipp; Tagliacozzo, Luca; Lewenstein, Maciej

    2012-03-16

    We study the extended Bose-Hubbard model describing an ultracold gas of dipolar molecules in an optical lattice, taking into account all on-site and nearest-neighbor interactions, including occupation-dependent tunneling and pair tunneling terms. Using exact diagonalization and the multiscale entanglement renormalization ansatz, we show that these terms can destroy insulating phases and lead to novel quantum phases. These considerable changes of the phase diagram have to be taken into account in upcoming experiments with dipolar molecules. PMID:22540482

  10. 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

  11. Piezoresistivity in single DNA molecules

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

    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.

  12. Piezoresistivity in single DNA molecules.

    PubMed

    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

  13. 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

  14. 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.

  15. Monitoring Molecules: Insights and Progress

    PubMed Central

    2015-01-01

    In August, 2014, neuroscientists and physical scientists gathered together on the campus of the University of California, Los Angeles to discuss how to monitor molecules in neuroscience. This field has seen significant growth since its inception in the 1970s. Here, the advances in this field are documented, including its advance into understanding the actions that specific neurotransmitters mediate during behavior. PMID:25514501

  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. Dialkylresorcinols as bacterial signaling molecules

    PubMed Central

    Brameyer, Sophie; Kresovic, Darko; Bode, Helge B.; Heermann, Ralf

    2015-01-01

    It is well recognized that bacteria communicate via small diffusible molecules, a process termed quorum sensing. The best understood quorum sensing systems are those that use acylated homoserine lactones (AHLs) for communication. The prototype of those systems consists of a LuxI-like AHL synthase and a cognate LuxR receptor that detects the signal. However, many proteobacteria possess LuxR receptors, yet lack any LuxI-type synthase, and thus these receptors are referred to as LuxR orphans or solos. In addition to the well-known AHLs, little is known about the signaling molecules that are sensed by LuxR solos. Here, we describe a novel cell–cell communication system in the insect and human pathogen Photorhabdus asymbiotica. We identified the LuxR homolog PauR to sense dialkylresorcinols (DARs) and cyclohexanediones (CHDs) instead of AHLs as signals. The DarABC synthesis pathway produces the molecules, and the entire system emerged as important for virulence. Moreover, we have analyzed more than 90 different Photorhabdus strains by HPLC/MS and showed that these DARs and CHDs are specific to the human pathogen P. asymbiotica. On the basis of genomic evidence, 116 other bacterial species are putative DAR producers, among them many human pathogens. Therefore, we discuss the possibility of DARs as novel and widespread bacterial signaling molecules and show that bacterial cell–cell communication goes far beyond AHL signaling in nature. PMID:25550519

  18. 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. PMID:25709041

  19. 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.

  20. 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.

  1. Structure factors for tunneling ionization rates of diatomic molecules

    SciTech Connect

    Saito, Ryoichi; Tolstikhin, Oleg I.; Madsen, Lars Bojer; Morishita, Toru

    2015-05-15

    Within the leading-order, single-active-electron, and frozen-nuclei approximation of the weak-field asymptotic theory, the rate of tunneling ionization of a molecule in an external static uniform electric field is determined by the structure factor for the highest occupied molecular orbital. We present the results of systematic calculations of structure factors for 40 homonuclear and heteronuclear diatomic molecules by the Hartree–Fock method using a numerical grid-based approach implemented in the program X2DHF.

  2. Validating and understanding ring conformations using small molecule crystallographic data.

    PubMed

    Cottrell, Simon J; Olsson, Tjelvar S G; Taylor, Robin; Cole, Jason C; Liebeschuetz, John W

    2012-04-23

    Understanding the conformational preferences of ring structures is fundamental to structure-based drug design. Although the Cambridge Structural Database (CSD) provides information on the preferred conformations of small molecules, analyzing this data can be very time-consuming. In order to overcome this hurdle, tools have been developed for quickly extracting geometrical preferences from the CSD. Here we describe how the program Mogul has been extended to analyze and compare ring conformations, using a library derived from over 900 000 ring fragments in the CSD. We illustrate how these can be used to understand the conformational preferences of molecules in a crystal lattice and bound to proteins. PMID:22372622

  3. 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.

  4. Cold collisions between boson or fermion molecules

    SciTech Connect

    Kajita, Masatoshi

    2004-01-01

    We theoretically investigate collisions between electrostatically trapped cold polar molecules and compare boson and fermion isotopes. Evaporative cooling seems possible for fermion molecules as the ratio of the collision loss cross section to the elastic collision cross section (R) gets smaller as the molecular temperature T lowers. With boson molecules, R gets larger as T lowers, which makes evaporative cooling difficult. The elastic collision cross section between fermion molecules can be larger than that for boson molecules with certain conditions.

  5. 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.

  6. 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…

  7. Electrochemical detection of single molecules.

    PubMed

    Fan, F R; Bard, A J

    1995-02-10

    The electrochemical behavior of a single molecule can be observed by trapping a small volume of a dilute solution of the electroactive species between an ultramicroelectrode tip with a diameter of approximately 15 nanometers and a conductive substrate. A scanning electrochemical microscope was used to adjust the tip-substrate distance ( approximately 10 nanometers), and the oxidation of [(trimethylammonio)methyl] ferrocene (Cp(2)FeTMA(+)) to Cp(2)FeTMA(2+) was carried out. The response was stochastic, and anodic current peaks were observed as the molecule moved into and out of the electrode-substrate gap. Similar experiments were performed with a solution containing two redox species, ferrocene carboxylate (Cp(2)FeCOO(-)) and Os(bpy)(3)(2+) (bpy is 2,2'-bipyridyl). PMID:17813918

  8. X(3872): charmonium or molecule?

    SciTech Connect

    Nefediev, A. V.

    2011-05-23

    A theoretical analysis of the recent experimental data from the Belle and BABAR Collaborations on the charmonium state X(3872) is performed. The analysis takes into account the proximity of an S-wave mesonic threshold and a possible presence of molecule component in the resonance wave function, finite width of the molecule constituents, and a possible interference in the final state. In particular, a model-independent approach is formulated, based on the Flatte parametrisation of near-threshold observables as well as on the Weinberg analysis of the nature of weakly bound systems generalised to the case of unstable constituents. Conclusion is made that the X(3872) is generated dynamically by a strong coupling of the bare {chi}{sub c1} charmonium to the DD-bar* hadronic channel, with a large admixture of the DD-bar* molecular component.

  9. Bioactive molecules from sea hares.

    PubMed

    Kamiya, H; Sakai, R; Jimbo, M

    2006-01-01

    Sea hares, belonging to the order Opisthobranchia, subclass Gastropoda, are mollusks that have attracted many researchers who are interested in the chemical defense mechanisms of these soft and "shell-less" snails. Numbers of small molecules of dietary origin have been isolated from sea hares and some have ecologically relevant activities, such as fish deterrent activity or toxicity. Recently, however, greater attention has been paid to biomedically interesting sea hare isolates such as dolastatins, a series of antitumor peptide/macrolides isolated from Dolabella auricularia. Another series of bioactive peptide/macrolides, as represented by aplyronines, have been isolated from sea hares in Japanese waters. Although earlier studies indicated the potent antitumor activity of aplyronines, their clinical development has never been conducted because of the minute amount of compound available from the natural source. Recent synthetic studies, however, have made it possible to prepare these compounds and analogs for a structure-activity relationship study, and started to uncover their unique action mechanism towards their putative targets, microfilaments. Here, recent findings of small antitumor molecules isolated from Japanese sea hares are reviewed. Sea hares are also known to produce cytotoxic and antimicrobial proteins. In contrast to the small molecules of dietary origin, proteins are the genetic products of sea hares and they are likely to have some primary physiological functions in addition to ecological roles in the sea hare. Based on the biochemical properties and phylogenetic analysis of these proteins, we propose that they belong to one family of molecule, the "Aplysianin A family," although their molecular weights are apparently divided into two groups. Interestingly, the active principles in Aplysia species and Dolabella auricularia were shown to be L-amino acid oxidase (LAAO), a flavin enzyme that oxidizes an alpha-amino group of the substrate with

  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