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  • Singh, N.
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  • 1
    In: Genes, Chromosomes and Cancer, December 2014, Vol.53(12), pp.999-1007
    Description: Small cell lung cancer (SCLC) is an aggressive disease with a poor prognosis. These cancers are deficient in glucocorticoid receptor () expression, and therefore, resistant to glucocorticoids. Overexpression of the both in vivo and in vitro leads to apoptotic cell death suggesting that loss of is favorable for cancer growth. Indeed, the promoter is silenced in SCLC cells by methylation. We now show that treatment of the SCLC cell line (DMS79) cells with the demethylating agent, 5‐aza‐2′‐deoxycytidine (5‐aza), results in significant endogenous re‐expression of both α and the ligand‐independent . The gene has a complex promoter region comprising nine alternative promoters, the proximal seven of which lie within a CpG island. The endogenous re‐expression seen is attributed to the constitutive promoters 1B and 1C and 1J but predominantly 1F, which we show to be heavily methylated in SCLC cells. Flow cytometric analysis using the apoptotic marker, Annexin V, shows that this endogenous re‐expression is sufficient to drive the SCLC cells to apoptosis. Apoptotic induction is specific to re‐expression as cotreatment with 5‐aza and the antagonist, RU486 prevented apoptosis. Of the three functional GR domains (the DNA binding domain, ligand binding domain, and transactivation domain), we identified that the transactivation domain is essential for apoptosis in SCLC. The discovery that endogenous re‐expression of the GR in SCLC cells is sufficient to induce apoptotic cell death by reversing a cancer‐driven DNA methylation effect may lead to the development of novel adjunct therapies. © 2014 Wiley Periodicals, Inc.
    Keywords: Lung Cancer – Analysis ; Methylation – Analysis ; Glucocorticoids – Analysis ; Apoptosis – Analysis ; Steroids (Organic Compounds) – Analysis;
    ISSN: 1045-2257
    E-ISSN: 1098-2264
    E-ISSN: 10916490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 02 January 2018, Vol.115(1), pp.47-52
    Description: In this work, we propose a model for nonequilibrium vibrational and rotational energy distributions in nitrogen using surprisal analysis. The model is constructed by using data from direct molecular simulations (DMSs) of rapidly heated nitrogen gas using an ab initio potential energy surface (PES). The surprisal-based model is able to capture the overpopulation of high internal energy levels during the excitation phase and also the depletion of high internal energy levels during the quasi-steady-state (QSS) dissociation phase. Due to strong coupling between internal energy and dissociation chemistry, such non-Boltzmann effects can influence the overall dissociation rate in the gas. Conditions representative of the flow behind strong shockwaves, relevant to hypersonic flight, are analyzed. The surprisal-based model captures important molecular-level nonequilibrium physics, yet the simple functional form leads to a continuum-level expression that now accounts for the underlying energy distributions and their coupling to dissociation.
    Keywords: High-Temperature Thermochemistry ; Hypersonic Flows ; Nonequilibrium Distribution ; Shock Waves ; Surprisal Analysis
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Chemical Physics Letters, 18 May 2011, Vol.508(1-3), pp.29-32
    Description: ► Electronic structure and optical properties of the Zintl compound Eu In P . ► Anisotropy of the parallel and perpendicular components in the frequency dependent optical spectra. ► Important role of dipole matrix elements. We have performed full-potential calculations of the electronic structure and optical properties of the newly found Zintl compound Eu In P . Eu In P turns out to be a small gap semiconductor with an energy gap of 0.42 eV, which is in agreement with the experimental value of 0.452 eV. The peaks of the optical spectra originate mainly from transitions between occupied Eu 4 states in the valence band and unoccupied Eu 5 states in the conduction band. A considerable anisotropy is observed for the parallel and perpendicular components in the frequency dependent optical spectra. The spectral features are explained in terms of the band structure.
    Keywords: Chemistry
    ISSN: 0009-2614
    E-ISSN: 1873-4448
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  • 4
    Language: English
    In: Tetrahedron, 09 September 2015, Vol.71(36), pp.6143-6147
    Description: We synthesized a dinuclear Cu(II) paddle-wheel complex containing a benzimidazolium ligand and explored using it as a fluorescence turn-ON sensor for detecting phosphates in water. The sensor exhibited both fluorescence and electrochemical responses to phosphates with high selectivity and sensitivity over other anions, which makes it useful for the detection of harmful organophosphates.
    Keywords: Sensors ; Inorganic–Organic Hybrid Polymer ; Fluorescence Spectroscopy ; Electrochemistry ; Molecular Recognition ; Chemistry
    ISSN: 0040-4020
    E-ISSN: 1464-5416
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  • 5
    In: International Journal of Cancer, 15 November 2013, Vol.133(10), pp.2307-2314
    Description: We recently reported on the isolation and characterization of calcium sensing receptor (CaSR) null human colon cancer cells (Singh et al., Int J Cancer 2013; 1996–2005). CaSR null cells possess a myriad of molecular features that are linked to a highly malignant and drug resistant phenotype of colon cancer. The CaSR null phenotype can be maintained in defined human embryonic stem cell culture medium. We now show that the CaSR null cells can be induced to differentiate in conventional culture medium, regained the expression of CaSR with a concurrent reversal of the cellular and molecular features associated with the null phenotype. These features include cellular morphology, expression of colon cancer stem cell markers, expression of survivin and thymidylate synthase and sensitivity to fluorouracil. Other features include the expression of epithelial mesenchymal transition linked molecules and transcription factors, oncogenic miRNAs and tumor suppressive molecule and miRNA. With the exception of cancer stem cell markers, the reversal of molecular features, upon the induction of CaSR expression, is directly linked to the expression and function of CaSR because blocking CaSR induction by shRNA circumvented such reversal. We further report that methylation and demethylation of the CaSR gene promoter underlie CaSR expression. Due to the malignant nature of the CaSR null cells, inclusion of the CaSR null phenotype in disease management may improve on the mortality of this disease. Because CaSR is a robust promoter of differentiation and mediates its action through diverse mechanisms and pathways, inactivation of CaSR may serve as a new paradigm in colon carcinogenesis. What's new? Expression of the calcium sensor receptor (CaSR) coincides with colonic epithelial cell differentiation, its expression intensifying as stem cells migrate from the depths of colonic crypts. When CaSR expression is lost, a highly malignant phenotype of colon cancer ensues. This study demonstrates that the malignant CaSR null phenotype can be circumvented by induction of CaSR expression and function in CaSR null cells. CaSR expression was found to be driven by methylation and demethylation of the CaSR gene promoter. The findings could have clinical implications, with CaSR inactivation serving as a marker of colon carcinogenesis.
    Keywords: Casr ; Colon Cancer ; Molecular Phenotype
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 6
    Language: English
    In: Physical Review Letters, 09 December 2011, Vol.107(24)
    Description: Despite the widely discussed role of whistler waves in mediating magnetic reconnection (MR), the direct connection between such waves and the MR has not been demonstrated by comparing the characteristic temporal and spatial features of the waves and the MR process. Using the whistler wave dispersion relation, we theoretically predict the experimentally measured rise time ({tau}{sub rise}) of a few microseconds for the fast rising MR rate in the Versatile Toroidal Facility at MIT. The rise time is closely given by the inverse of the frequency bandwidth of the whistler waves generated in the evolving current sheet. The wave frequencies lie much above the ion cyclotron frequency, but they are limited to less than 0.1% of the electron cyclotron frequency in the argon plasma. The maximum normalized MR rate R=0.35 measured experimentally is precisely predicted by the angular dispersion of the whistler waves.
    Keywords: 70 Plasma Physics And Fusion Technology ; Classical And Quantum Mechanics, General Physics ; Argon ; Cyclotron Frequency ; Dispersion Relations ; Electrons ; Magnetic Reconnection ; Plasma ; Pulse Rise Time ; Whistler Instability ; Whistlers ; Electromagnetic Radiation ; Elementary Particles ; Elements ; Fermions ; Fluids ; Gases ; Instability ; Leptons ; Noise ; Nonmetals ; Plasma Instability ; Plasma Macroinstabilities ; Radiations ; Radio Noise ; Radiowave Radiation ; Rare Gases ; Timing Properties ; Physics
    ISSN: 0031-9007
    E-ISSN: 1079-7114
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  • 7
    Language: English
    In: Physical review letters, 05 October 2012, Vol.109(14), pp.145001
    Description: Electron current layers (ECLs) are the sites where magnetic reconnection initiates in a current sheet. Using three-dimensional particle-in-cell simulations, we study the plasma processes that occur in an ECL as it evolves rapidly over a short time scale much shorter than the ion cyclotron period. The processes include its thinning, generation of electrostatic instabilities, trapping and heating of electrons in growing waves, its rebroadening, generation of anomalous resistivity, and eventually the generation of large-amplitude magnetic fluctuations. These fluctuations could be interpreted in terms of electron tearing and/or Weibel instabilities, which are commonly invoked as mechanisms for the magnetic reconnection onset. The widths of the broadened ECL are compared with those measured in the magnetic reconnection experiment, showing excellent agreement.
    ISSN: 00319007
    E-ISSN: 1079-7114
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  • 8
    Language: English
    In: International Social Work, May 2015, Vol.58(3), pp.375-384
    Description: Water resources in India are projected to face severe climate-induced stress. In the North-Eastern Hill region, where lifestyles are closely connected to nature, this holds great implications for human development. While scientific knowledge regarding climate change and water is growing at global and regional scales, an equally diverse body of knowledge on the human dimensions of the same at local levels is weak. This article attempts to bridge this knowledge gap by presenting micro-level evidence on the gendered impact of increasing water stress and the innovative gendered local adaptive strategies in this region. It urges for the need to re-think on adaptation planning, basing it on local templates for greater sustainability.
    Keywords: Adaptation ; Climate Change ; Gender ; India ; Water ; Social Welfare & Social Work
    ISSN: 0020-8728
    E-ISSN: 1461-7234
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  • 9
    Language: English
    In: Tetrahedron Letters, 28 September 2011, Vol.52(39), pp.5094-5097
    Description: We synthesized a dinuclear Zn complex that is useful as a sensor for ATP in a DMSO/H O (1:9, v/v) solvent system via a simple indicator displacement assay (IDA). This chromogenic sensor method can be used to analyze 0.1–2.0 μM of ATP with no interference from ADP or AMP.
    Keywords: Receptor ; IDA ; Fluorescein ; Recognition ; ATP ; Adp ; Amp ; Zn(II) Complex ; Chemistry
    ISSN: 0040-4039
    E-ISSN: 1873-3581
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  • 10
    Language: English
    In: Life Sciences, 13 June 2014, Vol.106(1-2), pp.1-11
    Description: This review focuses on the development of drugs targeting phosphodiesterase 9A (PDE9A). PDE9A normally regulates cGMP (cyclic guanosine monophosphate) levels, which in turn regulate signal transduction. However, in pathological conditions, PDE9A inhibition is required to treat diseases that lower the level of cGMP. Hence, there is a need for specific PDE9A inhibitors. Aligning the 3D structure of PDE9A with other phosphodiesterases reveals residues crucial to inhibitor selectivity. GLU406 is unique to PDE9A and stabilizes the side chain of an invariant glutamine (GLN453). TYR424 is another relevant residue, unique only to PDE9A and PDE8A. Therefore, TYR424 could discriminate between PDE9A and all other PDEs except PDE8A. TYR424 should also be considered in the design of selective inhibitors because PDE8A has low expression levels in the brain. Hence, GLU406 and TYR424 are important target residues in the design of PDE9A-selective inhibitors.
    Keywords: Phosphodiesterase ; Pde9a ; Cgmp ; Bay 73-9961 ; Pf-04447943 ; Brain ; Sciences (General) ; Biology
    ISSN: 0024-3205
    E-ISSN: 1879-0631
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