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Sample records for analogue calcipotriol enhances

  1. Topical vitamin D analogue calcipotriol reduces skin fibrosis in experimental scleroderma.

    PubMed

    Usategui, Alicia; Criado, Gabriel; Del Rey, Manuel J; Faré, Regina; Pablos, José L

    2014-10-01

    Vitamin D analogues can reduce TGF-β pro-fibrotic signaling in dermal fibroblasts, but they may also induce a potentially pro-fibrotic thymic stromal lymphopoietin (TSLP)-dependent Th2 cytokine local response. We have analyzed the net effect of topical vitamin D analogue calcipotriol (CPT) on the cytokine profile and the development of fibrosis in experimental model of bleomycin-induced fibrosis. Mice were simultaneously treated with topical CPT or vehicle cream and skin fibrosis was measured by collagen deposition, Masson's trichrome staining and hydroxyproline content. Cytokine and TSLP gene expression was evaluated by quantitative RT-PCR. We showed that in bleomycin injected skin, CPT administration significantly enhanced TSLP and IL-13 gene expression, but did not modify the expression of other cytokines. Skin fibrosis and hydroxyproline content were significantly reduced in CPT compared to vehicle-treated mice. In normal skin, topical administration of CPT lacked a direct pro-fibrotic effect. Our results demonstrate that topical CPT superinduces the expression of the TSLP/IL-13 Th2 axis in fibrotic skin, but it has a net anti-fibrotic effect. These data support the therapeutic use of topical vitamin D analogues for skin fibrosis.

  2. Efficacy and safety of topical calcipotriol in management of alopecia areata: A pilot study.

    PubMed

    Narang, Tarun; Daroach, Manju; Kumaran, M Sendhil

    2017-01-30

    Reports have highlighted serum vitamin D deficiency and reduced 1,25-dihydroxyvitamin D(3) receptors(VDR) expression on hair follicles of alopecia areata(AA) patients. Very few studies have demonstrated efficacy of topical calcipotriol (vitamin D analogue) in AA. We intended to study the efficacy of calcipotriol lotion 0.005% in AA and correlate its outcome with serum vitamin D levels. We conducted a prospective study, in which 22 patients with AA were treated with calcipotriol lotion 0.005% twice daily for 3 months. Clinico-epidemiological parameters including severity of AA and SALT score were calculated at baseline and at 12 weeks. Hair regrowth was assessed monthly at 4, 8, 12 weeks. Serum vitamin D levels were measured at baseline. After 12 weeks of treatment, hair regrowth was observed in 13 (59.1%) patients. Mean period for onset of disease stabilization and hair regrowth was 4 weeks and 4.21± 2.13 weeks, respectively. Among these 13 patients, SALT50 and SALT100 was observed in 6(46.2%) and 2(9%) patients, respectively. Response to treatment was better in patients with lower vitamin D levels (p < .009). Topical calcipotriol can be an alternative treatment in AA and it could prove to be more useful in patients who are vitamin D deficient.

  3. Calcium effects and systemic exposure of vitamin D3 analogues after topical treatment of active vitamin D3-containing ointments in rats.

    PubMed

    Hosomi, Atsushi; Hirabe, Maho; Tokuda, Takuya; Nakamura, Hiroaki; Amano, Toru; Okamoto, Tadao

    2016-10-05

    Topical agents containing vitamin D3 (VD3) analogues such as calcipotriol, maxacalcitol and tacalcitol and the combination of calcipotriol/betamethasone dipropionate (betamethasone) are prescribed for patients with psoriasis. However, they are known to occasionally cause hypercalcemia, and the frequency of hypercalcemia is suggested to vary according to the VD3 analogue used. In this study, to address the reason for these differences, the calcemic effects of maxacalcitol-, calcipotriol- and calcipotriol/betamethasone-containing ointments in rats were evaluated. The serum calcium levels in rats treated with ointments containing maxacalcitol, but not calcipotriol or calcipotriol/betamethasone, were significantly elevated, which is consistent with clinical observations. The serum concentration of VD3 analogue in rats treated with ointments containing calcipotriol and calcipotriol/betamethasone was lower than that in rats treated with maxacalcitol-containing ointment. Thus, the calcemic effects appear to be associated with the systemic exposure of VD3 analogues in rats. To understand the mechanism underlying the different systemic exposures of VD3 analogues, skin permeation and metabolic stability of VD3 analogues were evaluated. The cumulative amount of calcipotriol permeated through rat skin was significantly lower than that of maxacalcitol. On the other hand, the metabolic clearance of calcipotriol in rat hepatocytes was higher than that of maxacalcitol. Similar results were obtained using human skin and human hepatocytes. The current study demonstrates that the lower calcemic effects of calcipotriol- and calcipotriol/betamethasone-containing ointments are caused by the low systemic exposure of calcipotriol according to low skin permeability and rapid hepatic elimination after topical application.

  4. Calcipotriol inhibits α-synuclein aggregation in SH-SY5Y neuroblastoma cells by a Calbindin-D28k-dependent mechanism.

    PubMed

    Rcom-H'cheo-Gauthier, Alexandre N; Meedeniya, Adrian C B; Pountney, Dean L

    2017-04-01

    Many neurodegenerative diseases are characterized by the formation of microscopically visible intracellular protein aggregates. α-Synuclein is the key aggregating protein in Parkinson's disease which is characterized by neuronal cytoplasmic Lewy body inclusions. Previous studies have shown relative sparing of neurons in Parkinson's disease and dementia with Lewy bodies that are positive for the vitamin D-dependent calcium-buffering protein, calbindin-D28k, and that α-synuclein aggregates are excluded from calbindin-D28k-positive neurons. Recent cell culture studies have shown that α-synuclein aggregation can be induced by raised intracellular-free Ca(II) and demonstrated that raised intracellular calcium and oxidative stress can act synergistically to promote α-synuclein aggregation. We hypothesized that calcipotriol, a potent vitamin D analogue used pharmaceutically, may be able to suppress calcium-dependent α-synuclein aggregation by inducing calbindin-D28k expression. Immunofluorescence and western blot analysis showed that calcipotriol potently induced calbindin-D28k in a dose-dependent manner in SH-SY5Y human neuroblastoma cells. Calcipotriol significantly decreased the frequency of α-synuclein aggregate positive cells subjected to treatments that cause raised intracellular-free Ca(II) (potassium depolarization, KCl/H2 O2 combined treatment, and rotenone) in a dose-dependent manner and increased viability. Suppression of calbindin-D28k expression in calcipotriol-treated cells using calbindin-D28k-specific siRNA showed significantly higher α-synuclein aggregation levels, indicating that calcipotriol-mediated blocking of calcium-dependent α-synuclein aggregation was dependent on the induction of calbindin-D28k expression. These data indicate that targeting raised intraneuronal-free Ca(II) in the brain by promoting the expression of calbindin-D28k at the transcriptional level using calcipotriol could prevent α-synuclein aggregate formation and ameliorate

  5. Combination of calcipotriol and methotrexate in nanostructured lipid carriers for topical delivery

    PubMed Central

    Lin, Yin-Ku; Huang, Zih-Rou; Zhuo, Rou-Zi; Fang, Jia-You

    2010-01-01

    The combination of calcipotriol with methotrexate can strengthen the topical therapy for psoriasis. The aim of the present study was to evaluate the potential of nanostructured lipid carriers (NLCs) loaded with lipophilic calcipotriol and hydrophilic methotrexate as topical therapy. NLCs composed of Precirol ATO 5 with various amounts of squalene as the liquid lipid were prepared. The particle size, surface charge, molecular environment, drug permeation, and skin irritation of the carriers were assessed. Hyperproliferative skin was also used as a permeation barrier in this study. It was found that variations in the Precirol®/squalene ratio had profound effects on the physicochemical characteristics of the NLCs. The range of particle size of the NLC preparations was 270 to 320 nm, with vehicles containing a higher Precirol amount exhibiting a larger diameter. NLCs with a higher Precirol/squalene ratio also showed greater polarity in their molecular environment. Calcipotriol-loaded NLC systems provided drug fluxes of 0.62 to 1.08 μg/cm2/h, which were slightly higher or comparable to the 30% ethanol vehicle (control, 0.72 μg/cm2/h). The methotrexate amount permeating the skin was 2.4 to 4.4-times greater using NLCs compared to that with the control. Dual drug-loaded NLCs exhibited reduced skin permeation of calcipotriol but not methotrexate. The in vivo topical delivery examined by confocal laser scanning microscopy (CLSM) showed a good correlation with the in vitro results. These two drugs with extremely different polarities can successfully be combined in NLCs. Results suggest that NLCs may have the potential to serve as delivery carriers for antipsoriatic drugs because of enhanced drug permeation and limited skin irritation. PMID:20309398

  6. The hair root pattern after calcipotriol treatment for scalp psoriasis.

    PubMed

    Kuijpers, A L; van Baar, H M; van Gasselt, M W; van de Kerkhof, P C

    1995-09-01

    Scalp psoriasis is associated with hair loss and an increased telogen/anagen ratio. Topical treatment of scalp psoriasis (with corticosteroids, dithranol or tar) results in decreased scaling, induration and erythema of the plaques. Calcipotriol is effective in the treatment of psoriasis vulgaris. However, the potent growth-inhibiting potential of this compound might theoretically induce hair loss. A study was designed to find out to what extent calcipotriol treatment modulates the percentage of anagen and telogen hair during treatment of scalp psoriasis. A group of 26 patients participated in a placebo-controlled dose-finding study on the efficacy of calcipotriol in scalp psoriasis. Hair plucks before and after treatment were taken. The telogen/anagen ratio remained unaffected during 6 weeks of calcipotriol treatment. No correlation was demonstrated between efficacy of treatment and quantification of telogen/anagen ratio. It can be concluded that the growth-inhibiting potential of calcipotriol is not reflected in the in vivo hair growth pattern during calcipotriol treatment.

  7. A comparison of the effects of topical treatment of calcipotriol, camptothecin, clobetasol and tazarotene on an imiquimod-induced psoriasis-like mouse model.

    PubMed

    Sun, Jun; Dou, Wei; Zhao, Yi; Hu, Jinhong

    2014-02-01

    The interleukin-23/interleukin 17A (IL-23/IL-17A) cytokine axis plays a critical role in the pathogenesis of psoriasis. In this study, we report the effects of topical calcipotriol, camptothecin, clobetasol and tazarotene on the treatment of imiquimod (IMQ)-induced psoriasis-like inflammation, the development of which is dependent on the IL-23/IL-17A axis. IMQ-induced epidermal hyperplasia and inflammation in the BALB/c mouse ear were significantly inhibited following clobetasol treatment but not calcipotriol, camptothecin or tazarotene treatments. Real-time polymerase chain reaction showed that the mRNA levels of IL-17A, IL-17F, IL-22, IL-1β, IL-6 and TNF-α in ear skin were significantly decreased by clobetasol. In addition, we observed that calcipotriol, camptothecin and tazarotene failed to show any inhibitory effects on the IL-23/IL-17A/IL-22 axis. We also found that clobetasol treatment inhibited the proliferation of γδ T cells and C-C chemokine receptor type 6 (CCR6) expression induced by IMQ. Calcipotriol, camptothecin and tazarotene not only failed to inhibit this proliferation but also enhanced retinoic acid-related orphan receptor γ (RORγ) expression in IMQ-induced psoriasis-like inflammation. In conclusion, we suggest that clobetasol induces the relief of IMQ-induced psoriasis-like inflammation in a mouse model but that calcipotriol, camptothecin and tazarotene cannot. Therefore, we suggest that more in-depth studies on pharmacological effects of tazarotene, camptothecin and calcipotriol should be carried out.

  8. Calcipotriol/betamethasone dipropionate in the treatment of psoriasis vulgaris

    PubMed Central

    Vakirlis, Efstratios; Kastanis, Athanasios; Ioannides, Demetrios

    2008-01-01

    Psoriasis is one of the most common skin diseases. The mainstay of treatment for the vast majority of patients is topical therapy. A rising first-line treatment modality for psoriasis vulgaris is the two-compound ointment containing calcipotriol 50 μg/g plus betamethasone dipropionate 0.5 mg/g (Dovobet®, Daivobet®, Taclonex®), which combines a vitamin D analog and a corticosteroid. This innovative formulation preserves the activity and bioavailability of the two components and many clinical studies have demonstrated that it has a greater efficacy, tolerability, and a rapid onset of action compared with its individual ingredients or tacalcitol. PMID:18728704

  9. An extraordinary transmission analogue for enhancing microwave antenna performance

    SciTech Connect

    Pushpakaran, Sarin V.; Purushothaman, Jayakrishnan M.; Chandroth, Aanandan; Pezholil, Mohanan; Kesavath, Vasudevan

    2015-10-15

    The theory of diffraction limit proposed by H.A Bethe limits the total power transfer through a subwavelength hole. Researchers all over the world have gone through different techniques for boosting the transmission through subwavelength holes resulting in the Extraordinary Transmission (EOT) behavior. We examine computationally and experimentally the concept of EOT nature in the microwave range for enhancing radiation performance of a stacked dipole antenna working in the S band. It is shown that the front to back ratio of the antenna is considerably enhanced without affecting the impedance matching performance of the design. The computational analysis based on Finite Difference Time Domain (FDTD) method reveals that the excitation of Fabry-Perot resonant modes on the slots is responsible for performance enhancement.

  10. An extraordinary transmission analogue for enhancing microwave antenna performance

    NASA Astrophysics Data System (ADS)

    Pushpakaran, Sarin V.; Purushothaman, Jayakrishnan M.; Chandroth, Aanandan; Pezholil, Mohanan; Kesavath, Vasudevan

    2015-10-01

    The theory of diffraction limit proposed by H.A Bethe limits the total power transfer through a subwavelength hole. Researchers all over the world have gone through different techniques for boosting the transmission through subwavelength holes resulting in the Extraordinary Transmission (EOT) behavior. We examine computationally and experimentally the concept of EOT nature in the microwave range for enhancing radiation performance of a stacked dipole antenna working in the S band. It is shown that the front to back ratio of the antenna is considerably enhanced without affecting the impedance matching performance of the design. The computational analysis based on Finite Difference Time Domain (FDTD) method reveals that the excitation of Fabry-Perot resonant modes on the slots is responsible for performance enhancement.

  11. Chinese medicine combined with calcipotriol betamethasone and calcipotriol ointment for Psoriasis vulgaris (CMCBCOP): study protocol for a randomized controlled trial

    PubMed Central

    2014-01-01

    Background Psoriasis causes worldwide concern because of its high-prevalence, as well as its harmful, and incurable characteristics. Topical therapy is a conventional treatment for psoriasis vulgaris. Chinese medicine (CM) has been commonly used in an integrative way for psoriasis patients for many years. Some CM therapies have shown therapeutic effects for psoriasis vulgaris (PV), including relieving symptoms and improving quality of life, and may reduce the relapse rate. However, explicit evidence has not yet been obtained. The purpose of the present trial is to examine the efficacy and safety of the YXBCM01 granule, a compound Chinese herbal medicine, with a combination of topical therapy for PV patients. Methods/Design Using an add-on design, the trial is to evaluate whether the YXBCM01 granule combined topical therapy is more effective than topical therapy alone for the treatment of PV. The study design is a double-blind, parallel, randomized controlled trial comparing the YXBCM01 granule (5.5 g twice daily) to a placebo. The duration of treatment is 12 weeks. A total of 600 participants will be randomly allocated into two groups, YXBCM01 granule group and placebo group, from 11 general or dermatological hospitals in China. Topical use of calcipotriol betamethasone for the first 4 weeks and calcipotriol ointment for the remaining 8 weeks will be the same standard therapy for the two groups. Patients will be enrolled if they have a clinical diagnosis of PV, a psoriasis area severe index (PASI) of more than 10 or body surface area (BSA) of more than 10%, but PASI of less than 30 and BSA of less than 30%, are aged between 18 and 65-years-old, and provide signed informed consent. The primary outcome, relapse rate, is based on PASI assessed blindly during the treatment. Secondary outcomes include: (i) relapse time interval, (ii) time to onset, (iii) rebound rate, (iv) PASI score, (v) cumulative consumption of medicine, (vi) the dermatology quality life index

  12. Rationally designed cyclic analogues of luteinizing hormone-releasing hormone: enhanced enzymatic stability and biological properties.

    PubMed

    Laimou, Despina; Katsila, Theodora; Matsoukas, John; Schally, Andrew; Gkountelias, Kostas; Liapakis, George; Tamvakopoulos, Constantin; Tselios, Theodore

    2012-12-01

    This article describes the rational design, synthesis and pharmacological properties of amide-linked cyclic analogues of Luteinizing Hormone-Releasing Hormone (LHRH) with substitutions at positions 1 (Pro), 6 (D-Leu/D-Trp), 9 (Aze) and 10 (BABA/Acp). These LHRH analogues fulfil the conformational requirements that are known in the literature (bend in the 5-8 segment) to be essential for receptor recognition and activation. Although, they are characterised by an overall low binding affinity to the LHRH-I receptor, the cyclic analogues that were studied and especially the cyclo(1-10)[Pro(1), D-Leu(6), BABA(10)] LHRH, exhibit a profoundly enhanced in vitro and in vivo stability and improved pharmacokinetics in comparison with their linear counterpart and leuprolide. Upon receptor binding, cyclo(1-10)[Pro(1), D-Leu(6), BABA(10)] LHRH causes testosterone release in C57/B16 mice (in vivo efficacy) that is comparable to that of leuprolide. Testosterone release is an acutely dose dependent effect that is blocked by the LHRH-I receptor antagonist, cetrorelix. The pharmacokinetic advantages and efficacy of cyclo(1-10)[Pro(1), D-Leu(6), BABA(10)] LHRH render this analogue a promising platform for future rational drug design studies towards the development of non-peptide LHRH mimetics.

  13. SAMHD1 enhances nucleoside-analogue efficacy against HIV-1 in myeloid cells

    PubMed Central

    Ordonez, Paula; Kunzelmann, Simone; Groom, Harriet C. T.; Yap, Melvyn W.; Weising, Simon; Meier, Chris; Bishop, Kate N.; Taylor, Ian A.; Stoye, Jonathan P.

    2017-01-01

    SAMHD1 is an intracellular enzyme that specifically degrades deoxynucleoside triphosphates into component nucleoside and inorganic triphosphate. In myeloid-derived dendritic cells and macrophages as well as resting T-cells, SAMHD1 blocks HIV-1 infection through this dNTP triphosphohydrolase activity by reducing the cellular dNTP pool to a level that cannot support productive reverse transcription. We now show that, in addition to this direct effect on virus replication, manipulating cellular SAMHD1 activity can significantly enhance or decrease the anti-HIV-1 efficacy of nucleotide analogue reverse transcription inhibitors presumably as a result of modulating dNTP pools that compete for recruitment by viral polymerases. Further, a variety of other nucleotide-based analogues, not normally considered antiretrovirals, such as the anti-herpes drugs Aciclovir and Ganciclovir and the anti-cancer drug Clofarabine are now revealed as potent anti-HIV-1 agents, under conditions of low dNTPs. This in turn suggests novel uses for nucleotide analogues to inhibit HIV-1 in differentiated cells low in dNTPs. PMID:28220857

  14. Efficacy of adding topical simvastatin to topical calcipotriol on improvement of cutaneous plaque psoriasis

    PubMed Central

    Iraji, Fariba; Tajmirriahi, Nabet; Siadat, Amir Hossein; Momeni, Iman; Nilforoushzadeh, Mohammad Ali

    2014-01-01

    Background: Psoriasis is a common dermatologic disorder, with fluctuating response to treatment. Considering the proven immunomodulatory effects of oral simvastatin in psoriasis, this trial study was enrolled to determine whether the topical form has also antipsoriatic effects. Vitamin D analogs known to be effective and are considered the first line of therapy in mild to moderate cases. In this study, the efficacy of topical calcipotriol 0.005% ointment (as a standard method of treatment for psoriasis) versus combination of calcipotriol plus topical simvastatin is compared in the treatment of psoriasis. Materials and Methods: A total of 80 subjects with symmetric psoriasis who had body surface involvement up to 20% were divided randomly into 2 groups. Group A were treated with calcipotriol 0.005% ointment twice daily and Group B with calcipotriol 0.005% ointment twice daily and simvastatin 3% ointment twice daily for 12 weeks. The results were evaluated by a Blind Dermatologist using psoriasis area severity index (PASI) score at baseline, 4th, 8th and 12th week of treatment. In a similar way, a subjective assessment performed by patients based on photo-evaluation at the end of the study. Results: Despite a continuous reduction in PASI score in both groups, according to both physician (P = 0.603) and patient (P = 0.243) assessment topical simvastatin was not statistically more effective than conventional treatment of psoriasis at the end of the study. Conclusion: This study indicates that topical simvastatin is not associated with significant impacts in the treatment of psoriasis as compared to oral form. This study indicates that psoriasis is a systemic disorder with variable skin manifestations. PMID:24592364

  15. Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer

    PubMed Central

    Arensman, Michael D.; Nguyen, Phillip; Kershaw, Kathleen M.; Lay, Anna R.; Ostertag-Hill, Claire A.; Sherman, Mara H.; Downes, Michael; Liddle, Christopher; Evans, Ronald M.; Dawson, David W.

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy in need of more effective treatment approaches. One potential therapeutic target is Wnt/β-catenin signaling, which plays important roles in PDAC tumor initiation and progression. Among Wnt inhibitors with suitable in vivo biological activity is vitamin D, which is known to antagonize Wnt/β-catenin signaling in colorectal cancer and have anti-tumor activity in PDAC. For this study the relationship between vitamin D signaling, Wnt/β-catenin activity and tumor cell growth in PDAC was investigated through the use of calcipotriol, a potent non-hypercalcemic vitamin D analog. PDAC tumor cell growth inhibition by calcipotriol was positively correlated with vitamin D receptor (VDR) expression and Wnt/β-catenin activity. Furthermore, vitamin D and Wnt signaling activity were found to be reciprocally linked through feedback regulation. Calcipotriol inhibited autocrine Wnt/β-catenin signaling in PDAC cell lines in parallel with decreased protein levels of the low density lipoprotein receptor-related protein 6 (LRP6), a requisite co-receptor for ligand-dependent canonical Wnt signaling. Decrease in LRP6 protein seen with calcipotriol was mediated through a novel mechanism involving transcriptional upregulation of low-density lipoprotein receptor adaptor protein 1 (LDLRAP1). Finally, changes in LRP6 or LDLRAP1 expression directly altered Wnt reporter activity, supporting their roles as regulators of ligand-dependent Wnt/β-catenin signaling. Implications This study provides a novel biochemical target through which vitamin D signaling exerts inhibitory effects on Wnt/β-catenin signaling, as well as potential biomarkers for predicting and following tumor response to vitamin D-based therapy. PMID:26224368

  16. The Effect of Calcipotriol on the Expression of Human β Defensin-2 and LL-37 in Cultured Human Keratinocytes

    PubMed Central

    Kim, Beom Joon; Rho, Yong Kwan; Lee, Hye In; Jeong, Mi Sook; Li, Kapsok; Seo, Seong Jun; Kim, Myeung Nam; Hong, Chang Kwun

    2009-01-01

    Background. Vitamin D has been reported to regulate innate immunity by controlling the expression of antimicrobial peptides (AMPs). Objective. We investigated the effect of calcipotriol on the expression of AMPs in human cultured keratinocytes. Methods. Keratinocytes were treated with lipopolysaccharide (LPS), TNF-α, Calcipotriol and irradiated with UVB, cultured, and harvested. To assess the expression of human beta defensin-2 and LL-37 in the control group, not exposed to any stimulants, the experimental group was treated with LPS, TNF-α, or UVB, and another group was treated again with calcipotriol; reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical staining were performed. Results. In the experimental group treated with LPS, UVB irradiation, and TNF-α, the expression of β-defensin and LL-37 was increased more than in the control group and then decreased in the experimental group treated with calcipotriol. Conclusions. Calcipotriol suppressed HBD-2 and LL-37, which were stimulated by UVB, LPS, and TNF-α. PMID:20182640

  17. Ameliorative potential of linagliptin and/or calcipotriol on bleomycin-induced lung fibrosis: In vivo and in vitro study.

    PubMed

    Kabel, Ahmed M; Abd Elmaaboud, Maaly A; Atef, Aliaa; Baali, Mohammed H

    2017-03-01

    Pulmonary fibrosis is a serious medical problem that may significantly compromise respiratory functions. The aim of this work was to study the effect of linagliptin and/or calcipotriol on bleomycin-induced pulmonary fibrosis and to explore the possible mechanisms underlying this effect. One hundred and twenty male C57BL/6 mice were divided into 6 equal groups as follows: control group; bleomycin group; bleomycin+carboxymethylcellulose group; bleomycin+linagliptin group; bleomycin+calcipotriol group and bleomycin+linagliptin+calcipotriol group. Lung weight/body weight index, lung tissue hydroxyproline, collagen, toll-like receptor 4 (TLR4), nuclear factor-like 2 (Nrf2), heme oxygenase-1 (HO-1), malondialdehyde (MDA), glutathione peroxidase (GPx) and catalase (CAT) were measured. Also, bronchoalveolar lavage fluid (BALF) was analyzed for total and differential leucocytic count, lactate dehydrogenase, tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10) and transforming growth factor-beta 1 (TGF-β1). Vascular response to potassium chloride, phenylephrine and carbachol as well as tracheal response to carbachol were measured. Also, lung tissue was subjected to histopathological and immunohistochemical examination. Administration of linagliptin and/or calcipotriol induced significant decrease in the lung weight/body weight index, total leucocytic count, BALF lactate dehydrogenase activity, IL-10, TNF-α and TGF-β1 associated with significant decrease in lung tissue MDA, Nrf2, HO-1, TLR4, hydroxyproline and collagen content with significant increase in tissue GPx and CAT and improvement of the pulmonary architecture, vascular and tracheal response compared to bleomycin group. These effects were significant in linagliptin/calcipotriol combination group compared to the use of each of these drugs alone. In conclusion, linagliptin/calcipotriol combination may represent an effective therapeutic modality for amelioration of bleomycin-induced pulmonary fibrosis.

  18. Calcitriol and its analogues enhance the antiproliferative activity of gefitinib in breast cancer cells.

    PubMed

    Segovia-Mendoza, Mariana; Díaz, Lorenza; González-González, María Elena; Martínez-Reza, Isela; García-Quiroz, Janice; Prado-Garcia, Heriberto; Ibarra-Sánchez, María J; Esparza-López, José; Larrea, Fernando; García-Becerra, Rocío

    2015-04-01

    Coexpression of EGFR and HER2 has been associated with poor disease outcome, high rates of metastasis and resistance to conventional treatments in breast cancer. Gefitinib, a tyrosine kinase inhibitor, reduces both cell proliferation and tumor growth of breast cancer cells expressing EGFR and/or HER2. On the other hand, calcitriol and some of its synthetic analogs are important antineoplastic agents in different breast cancer subtypes. Herein, we evaluated the effects of the combined treatment of gefitinib with calcitriol or its analogs on cell proliferation in breast cancer cells. The presence of EGFR, HER2 and vitamin D receptor were evaluated by Western blot in two established breast cancer cell lines: SUM-229PE, SKBR3 and a primary breast cancer-derived cell line. The antiproliferative effects of gefitinib alone or in combination with calcitriol and its analogs, calcipotriol and EB1089, were assessed by growth assay using a DNA content-based method. Inhibitory concentrations on cell proliferation were calculated by non-linear regression analysis using sigmoidal fitting of dose-response curves. Pharmacological effects of the drug combinations were calculated by the Chou-Talalay method. Phosphorylation of ERK1/2 MAPK was evaluated by Western blot. Gene expression of EGFR, HER2 and BIM was assessed by real time PCR. BIM protein levels were analyzed in cells by flow cytometry. The effects of the drugs alone or combinated on cell cycle phases were determined using propidium iodide. Apoptosis was evaluated by detection of subG1 peak and determination of active caspase 3 by flow cytometry. Gefitinib, calcitriol, calcipotriol and EB1089 inhibited cell proliferation in a dose dependent manner. The combinations of gefitinib with calcitriol or its analogs were more effective to inhibit cell growth than each compound alone in all breast cancer cells studied. The gene expression of EGFR and HER2 was downregulated and not affected, respectively, by the combined treatment

  19. Enhancement of wound healing by shikonin analogue 93/637 in normal and impaired healing.

    PubMed

    Mani, H; Sidhu, G S; Singh, A K; Gaddipati, J; Banaudha, K K; Raj, K; Maheshwari, R K

    2004-01-01

    Wound healing is a complicated biological process, which involves interactions of multiple cell types, various growth factors, their mediators and the extracellular matrix proteins. In this study, we evaluated the effects of shikonin analogue 93/637 (SA), derived from the plant Arnebia nobilis, on normal and hydrocortisone-induced impaired healing in full thickness cutaneous punch wounds in rats. SA (0.1%) was applied topically daily as an ointment in polyethylene glycol base on wounds. SA treatment significantly accelerated healing of wounds, as measured by wound contraction compared to controls in hydrocortisone-impaired animals. SA treatment promoted formation of granulation tissue including cell migration and neovascularization, collagenization and reepithelialization. The expression of basic fibroblast growth factor (bFGF) was higher as revealed by immunohistochemistry in treated wounds compared to controls. However, the expression of transforming growth factor-beta(1) was not affected by SA treatment. Since bFGF is known to accelerate wound healing, the increased expression of bFGF by SA may be partly responsible for the enhancement of wound healing. These studies suggest that SA could be further studied for clinical use to enhance wound healing.

  20. Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter.

    PubMed

    Froimowitz, Mark; Gu, Yonghong; Dakin, Les A; Nagafuji, Pamela M; Kelley, Charles J; Parrish, Damon; Deschamps, Jeffrey R; Janowsky, Aaron

    2007-01-25

    Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays. As predicted from a pharmacophore model, most of the RR/SS diastereomers showed high potency as dopamine reuptake inhibitors. Analogues with a 4-chlorophenyl group and an unbranched initial alkyl atom had consistently enhanced selectivity for the dopamine transporter. The most potent compounds were those with a three- or four-carbon chain. The "inactive" RS/SR diastereomers showed substantial activity when the phenyl substituent was 3,4-dichloro. On a locomotor assay, one compound was found to have a slow onset and a long duration of action. The activity of these compounds provides additional evidence for a conformational/superposition model of methylphenidate with cocaine-like structures. A ketone analogue, obtained by hydrogenating a previously described vinylogous amide, had activity similar to that of methylphenidate.

  1. Quality factor enhancement for resonant MEMS applying an analogue feedback circuit driven by a lock-in amplifier

    NASA Astrophysics Data System (ADS)

    Kucera, Martin; Hofbauer, Franz; Manzaneque, Tomás.; Ruiz, Victor; Sánchez-Rojas, José Luis; Bittner, Achim; Schmid, Ulrich

    2013-05-01

    In this study, an analogue Q-control circuit is presented, based on a digital feedback loop. In this approach, a self-actuated and self-sensing piezoelectric microstructure is used in combination with a lock-in amplifier to extract the Q-control feedback signal amplitude which is proportional to the piezoelectric current. In the next step, the DC-value supported by the lock-in amplifier is multiplied with a sine signal on a custom-designed analogue circuit board containing an analogue amplifier IC. This generated analogue feedback signal allows to drive a complete analogue feedback loop enabling faster response of the Q-control and further faster measurements can be performed. Using this Q-factor enhancement technique, the Q-factor was increased from 397 to about 5357 in air without driving the used Q-control approach to its limits. These promising results will push further activities in measuring the viscosity of liquids in the future.

  2. Mutation of a conserved residue enhances the sensitivity of analogue-sensitised kinases to generate a novel approach to the study of mitosis in fission yeast.

    PubMed

    Tay, Ye-Dee; Patel, Avinash; Kaemena, Daniel F; Hagan, Iain M

    2013-11-01

    The chemical genetic strategy in which mutational enlargement of the ATP-binding site sensitises of a protein kinase to bulky ATP analogues has proved to be an elegant tool for the generation of conditional analogue-sensitive kinase alleles in a variety of model organisms. Here, we describe a novel substitution mutation in the kinase domain that can enhance the sensitivity of analogue-sensitive kinases. Substitution of a methionine residue to phenylalanine in the +2 position after HRDLKxxN motif of the subdomain VIb within the kinase domain markedly increased the sensitivities of the analogue-sensitive kinases to ATP analogues in three out of five S. pombe kinases (i.e. Plo1, Orb5 and Wee1) that harbor this conserved methionine residue. Kinome alignment established that a methionine residue is found at this site in 5-9% of kinases in key model organisms, suggesting that a broader application of this structural modification may enhance ATP analogue sensitivity of analogue-sensitive kinases in future studies. We also show that the enhanced sensitivity of the wee1.as8 allele in a cdc25.22 background can be exploited to generate highly synchronised mitotic and S phase progression at 36°C. Proof-of-principle experiments show how this novel synchronisation technique will prove of great use in the interrogation of the mitotic or S-phase functions through temperature sensitivity mutation of molecules of interest in fission yeast.

  3. [Dmt(1)]DALDA analogues with enhanced μ opioid agonist potency and with a mixed μ/κ opioid activity profile.

    PubMed

    Bai, Longxiang; Li, Ziyuan; Chen, Jiajia; Chung, Nga N; Wilkes, Brian C; Li, Tingyou; Schiller, Peter W

    2014-04-01

    Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity, were prepared by replacing Phe(3) with various 2',6'-dialkylated Phe analogues, including 2',6'-dimethylphenylalanine (Dmp), 2',4',6'-trimethylphenylalanine (Tmp), 2'-isopropyl-6'-methylphenylalanine (Imp) and 2'-ethyl-6'-methylphenylalanine (Emp), or with the bulky amino acids 3'-(1-naphthyl)alanine (1-Nal), 3'-(2-naphthyl)alanine (2-Nal) or Trp. Several compounds showed significantly increased μ agonist potency, retained μ receptor selectivity and are of interest as drug candidates for neuropathic pain treatment. Surprisingly, the Dmp(3)-, Imp(3)-, Emp(3)- and 1-Nal(3)-containing analogues showed much increased κ receptor binding affinity and had mixed μ/κ properties. In these cases, molecular dynamics studies indicated conformational preorganization of the unbound peptide ligands due to rotational restriction around the C(β)C(γ) bond of the Xxx(3) residue, in correlation with the observed κ receptor binding enhancement. Compounds with a mixed μ/κ opioid activity profile are known to have therapeutic potential for treatment of cocaine abuse.

  4. [TIC4]endomorphins, analogues of endomorphins, have significantly enhanced vasorelaxant effects in rat aorta rings.

    PubMed

    Zhao, Qian-Yu; Chen, Qiang; Feng, Yun; Lin, Xin; Wang, Rui

    2005-05-01

    [Tic(4)]EM1 and [Tic(4)]EM2, new endomorphins (EMs) analogues, caused relaxation of rat aorta rings precontracted with phenylphrine in a concentration-dependent manner and were 240- to 370-fold more potent than EMs. This effect was inhibited by endothelium removal or by incubation with NO synthase inhibitor L-NNA or opioid receptor antagonist naloxone. The results demonstrate that [Tic(4)]EMs have NO- and endothelium-dependent vasorelaxant effects which are mediated by the opioid receptor.

  5. A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents

    PubMed Central

    Tatarkiewicz, K; Hargrove, D M; Jodka, C M; Gedulin, B R; Smith, P A; Hoyt, J A; Lwin, A; Collins, L; Mamedova, L; Levy, O E; D’Souza, L; Janssen, S; Srivastava, V; Ghosh, S S; Parkes, D G

    2014-01-01

    Aim Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794. Methods AC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala2]GIP(1–42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F β-cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu14] exenatide. Human GIP or [d-Ala2]GIP(1–42) were used for comparison. Results AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala2]GIP(1–42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala2]GIP(1–42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174. Conclusions These studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes. PMID:23859463

  6. Surface-enhanced Raman difference between bombesin and its modified analogues on the colloidal and electrochemically roughen silver surfaces.

    PubMed

    Podstawka, Edyta; Ozaki, Yukihiro

    2008-10-01

    In this article, surface-enhanced Raman scattering (SERS) spectra of bombesin (BN) and its six modified analogues ([D-Phe(12)]BN, [Tyr(4)]BN, [Tyr(4),D-Phe(12)]BN, [D-Phe(12),Leu(14)]BN, [Leu(13)-(R)-Leu(14)]BN, and [Lys(3)]BN) on a colloidal silver surface are reported and compared with SERS spectra of these species immobilized onto an ellectrochemically roughen silver electrode. Changes in enhancement and wavenumber of proper bands upon adsorption on different silver surfaces are consistent with BN and its analogues adsorption primarily through Trp(8). Slightly different adsorption states of these molecules are observed depending upon natural amino acids substitution. For example, the indole ring in all the peptides interacts with silver nanoparticles in a edge-on orientation. It is additionally coordinated to the silver through the N(1)--H bond for all the peptides, except [Phe(12)]BN. This is in contrary to the results obtained for the silver roughen electrode that show direct but not strong N(1)--H/Ag interaction for all peptides except [D-Phe(12),Leu(14)]BN and [Leu(13)-(R)-Leu(14)]BN. For BN only C==O is not involved in the chemical coordination with the colloidal surface. [Lys(3)]BN and BN also adsorb with the C--N bond of NH(2) group normal and horizontal, respectively, to the colloidal surface, whereas C--NH(2) in other peptides is tilted to this surface. Also, the Trp(8) --CH(2)-- moiety of only [Tyr(4)]BN, [Lys(3)]BN, and [Tyr(4),D-Phe(12)]BN coordinates to Ag, whereas the Phe(12) ring of [Phe(12)]BN, [Tyr(4),D-Phe(12)]BN, and [D-Phe(12),Leu(14)]BN assists in the peptides binding only on the colloidal silver.

  7. Portulaca oleracea L. aids calcipotriol in reversing keratinocyte differentiation and skin barrier dysfunction in psoriasis through inhibition of the nuclear factor κB signaling pathway.

    PubMed

    Zhao, Hengguang; Li, Shuang; Luo, Fuling; Tan, Qian; Li, Hui; Zhou, Weikang

    2015-02-01

    Psoriasis affects 2-4% of the population worldwide and its treatment is currently far from satisfactory. Calcipotriol and Portulaca oleracea have been reported to exhibit the capacity to inhibit inflammation in psoriatic patients and improve their clinical condition. However, the efficacy of a combination regimen of these two components remains unknown. The aim of the present study was to explore the therapeutic efficacy of P. oleracea extract combined with calcipotriol on plaque psoriasis and its potential mechanism. Eleven patients with plaque psoriasis were treated with humectant containing the active ingredients of P. oleracea extract, with or without 0.005% calcipotriol ointment in a right-left bilateral lesion self-control study. Differences were evaluated by investigation of the clinical efficacy, adverse effects, skin barrier function, histological structure, expression and proliferation of keratinocytes, differentiation markers (cytokeratin 10, filaggrin and loricrin), inflammatory factors [tumor necrosis factor (TNF)-α and interleukin (IL)-8], as well as the status of the nuclear factor κB (NF-κB) pathway. The combination of P. oleracea and calcipotriol was revealed to decrease adverse effects, reduce transepidermal water loss, potently reverse keratinocyte differentiation dysfunction, and inhibit the expression of TNF-α and IL-8 and the phosphorylation of the NF-κB inhibitor IκBα. This treatment is therefore anticipated to be suitable for use as a novel adjuvant therapy for psoriatic patients.

  8. Portulaca oleracea L. aids calcipotriol in reversing keratinocyte differentiation and skin barrier dysfunction in psoriasis through inhibition of the nuclear factor κB signaling pathway

    PubMed Central

    ZHAO, HENGGUANG; LI, SHUANG; LUO, FULING; TAN, QIAN; LI, HUI; ZHOU, WEIKANG

    2015-01-01

    Psoriasis affects 2–4% of the population worldwide and its treatment is currently far from satisfactory. Calcipotriol and Portulaca oleracea have been reported to exhibit the capacity to inhibit inflammation in psoriatic patients and improve their clinical condition. However, the efficacy of a combination regimen of these two components remains unknown. The aim of the present study was to explore the therapeutic efficacy of P. oleracea extract combined with calcipotriol on plaque psoriasis and its potential mechanism. Eleven patients with plaque psoriasis were treated with humectant containing the active ingredients of P. oleracea extract, with or without 0.005% calcipotriol ointment in a right-left bilateral lesion self-control study. Differences were evaluated by investigation of the clinical efficacy, adverse effects, skin barrier function, histological structure, expression and proliferation of keratinocytes, differentiation markers (cytokeratin 10, filaggrin and loricrin), inflammatory factors [tumor necrosis factor (TNF)-α and interleukin (IL)-8], as well as the status of the nuclear factor κB (NF-κB) pathway. The combination of P. oleracea and calcipotriol was revealed to decrease adverse effects, reduce transepidermal water loss, potently reverse keratinocyte differentiation dysfunction, and inhibit the expression of TNF-α and IL-8 and the phosphorylation of the NF-κB inhibitor IκBα. This treatment is therefore anticipated to be suitable for use as a novel adjuvant therapy for psoriatic patients. PMID:25574190

  9. Oxaliplatin Analogues with Carboxy Derivatives of Boldine with Enhanced Antioxidant Activity

    PubMed Central

    Mellado, Marco; Jara, Carlos; Astudillo, David; Villena, Joan; Reveco, Patricio G.; Thomet, Franz A.

    2015-01-01

    A new oxaliplatin analog [Pt(dach)(L5)] (1) was synthesized and characterized as a continuation of a study of the previously reported [Pt(dach)(L6)] (2), where dach = (1R,2R)-diaminocyclohexane, L5 = 3-carboxyboldine, and L6 = 3-carboxypredicentrine. Compounds 1 and 2 exhibited a substantially enhanced antioxidant activity compared to oxaliplatin (130 and 30 times for 1 and 13 and 4 times for 2 using the DPPH and FRAP assays, resp.). In addition, 1 and 2 exhibited cytotoxic activity in the same range as oxaliplatin toward the two human tumor cell lines (MCF-7 and HT-29) studied and two to four times lower activity in the human colon nontumor cell line (CCD-841). Preadministration of L5 or L6 to the colon tumor (HT-29) and the colon nontumor (CCD-841) cell lines prior to oxaliplatin addition increased the viability of the nontumor cell line to a greater extent than that of the tumor cell line. PMID:25814916

  10. A non-calcemic sulfone version of the vitamin D(3) analogue seocalcitol (EB 1089): chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin.

    PubMed

    Posner, G H; Crawford, K R; Peleg, S; Welsh, J E; Romu, S; Gewirtz, D A; Gupta, M S; Dolan, P; Kensler, T W

    2001-09-01

    Novel side-chain diene sulfones 5, analogues of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol, 1), were designed to incorporate some of the therapeutically most favorable structural features of the Leo Pharmaceutical Company's drug candidate diene EB 1089 (seocalcitol, 4) and of the Hopkins' non-calcemic side-chain sulfone analogues 2 and 3. Synthesis of diene sulfones 5 features selective Swern oxidation of a primary silyl ether in the presence of a secondary silyl ether (9-->10) and Horner-Wadsworth-Emmons aldehyde addition by a 1-phosphonyl-3-sulfonyl stabilized carbanion regiospecifically at the 1-position to form E,E-diene sulfone 11. Sulfone diene analogue 5a with natural 1alpha,3beta-diol functionality, but not its diastereomer 5b with unnatural A-ring stereochemistry, is antiproliferative in vitro toward murine keratinocytes and malignant melanoma cells, as well as toward MCF-7 human breast cancer cells. Combining diene sulfone 5a with the currently used anticancer drug adriamycin (ADR) caused a noteworthy 3-fold enhancement of ADR antiproliferative potency in MCF-7 cells. Sulfone diene analogue 5a is weakly active transcriptionally in MCF-7 and ROS 17/2.8 cells, binds poorly but measurably to the vitamin D receptor (VDR), and desirably is non-calcemic in vivo at a daily dose (7 days) of 10 microg/kg of rat body weight.

  11. An Open Label Prospective Randomized Trial to Compare the Efficacy of Coal Tar-Salicylic Acid Ointment Versus Calcipotriol/Betamethasone Dipropionate Ointment in the Treatment of Limited Chronic Plaque Psoriasis

    PubMed Central

    Khandpur, Sujay; Sahni, Kanika

    2014-01-01

    Background: Chronic plaque psoriasis is a common papulosquamous skin disorder, for which a number of topical agents are being used including coal tar, topical steroids and more recently topical calcipotriol/betamethasone dipropionate. There is no study comparing purified coal tar preparation with calcipotriol/betamethasone dipropionate ointment in limited chronic plaque psoriasis. Aims and Objectives: A prospective randomized open label controlled trial to compare the efficacy and safety of topical application of coal tar-salicylic acid ointment with calcipotriol/betamethasone dipropionate ointment applied once at night for 12 weeks for the treatment of limited chronic plaque psoriasis. Materials and Methods: A total of 62 patients of limited chronic plaque psoriasis (body surface area <10%) were randomized into two treatment groups: Group A received topical application of 6% coal tar with 3% salicylic acid ointment and Group B received calcipotriol/betamethasone dipropionate, once at night for 12 weeks. Results were assessed based on psoriasis area severity index (PASI) scores and patient global assessment (PGA) at each visit. Results: Mean PASI was significantly lower at week 2 (P = 0.01) and week 4 follow-up (P = 0.05) and the mean reduction in PASI was significantly higher at week 2 (P = 0.02) with calcipotriol/betamethasone than coal tar-salicylic acid, but this difference was not sustained at subsequent follow-up visits. Similarly, PGA scores at weeks 2 and 4 were significantly lower with calcipotriol/betamethasone dipropionate ointment (P = 0.003 and P = 0.007 respectively). There was no significant difference in any parameter during subsequent follow-up visits or at the end of the treatment phase (12 weeks). Conclusion: Topical nightly application of calcipotriol/betamethasone dipropionate ointment leads to an initial, more rapid reduction in disease severity, but the overall outcome parameters are comparable in the two treatment groups. PMID:25484388

  12. Analogue Gravity.

    PubMed

    Barceló, Carlos; Liberati, Stefano; Visser, Matt

    2011-01-01

    Analogue gravity is a research programme which investigates analogues of general relativistic gravitational fields within other physical systems, typically but not exclusively condensed matter systems, with the aim of gaining new insights into their corresponding problems. Analogue models of (and for) gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing) and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity).

  13. Wheat germ poly(A) binding protein enhances the binding affinity of eukaryotic initiation factor 4F and (iso)4F for cap analogues.

    PubMed

    Wei, C C; Balasta, M L; Ren, J; Goss, D J

    1998-02-17

    Most eukaryotic mRNAs contain a 5' cap (m7GppX) and a 3' poly(A) tail to increase synergistically the translational efficiency. Recently, the poly(A) binding protein (PABP) and cap-binding protein, eIF-4F, were found to interact [Le et al. (1997) J. Biol. Chem. 272, 16247-16255; Tarun and Sachs (1996) EMBO J. 15, 7168-7177]. These data suggest that PABP may exert its effect on translational efficiency either by increasing the formation of initiation factor-mRNA complex or by enhancing ribosome recycling. To investigate the functional consequences of these interactions, the fluorescent cap analogue, ant-m7GTP, which is an environmentally sensitive fluorescent probe [Ren and Goss (1996) Nucleic Acids Res. 24, 3629-3634] was used to investigate the cap-binding affinity. Our data show that the binding of eIF-(iso)4F or eIF-4F to cap analogue enhanced their binding affinity toward PABP approximately 40-fold. Similarly, the eIF-4F/PABP or eIF-(iso)4F/PABP complexes show a 40-fold enhancement of cap analogue binding as compared to eIF-4F or eIF-(iso)4F alone. At least part of the enhancement of the translational initiation by PABP can be accounted for by direct changes in cap-binding affinity. The interactions of these components also suggest a mechanism whereby the poly(A) tail is brought into close proximity with m7G cap. This effect was examined by fluorescence energy transfer, and it was determined that the PABP/eIF-4F complex could bind both poly(A) and 5' cap simultaneously.

  14. Nitroglycerin enhances the propagation of cortical spreading depression: comparative studies with sumatriptan and novel kynurenic acid analogues

    PubMed Central

    Knapp, Levente; Szita, Bence; Kocsis, Kitti; Vécsei, László; Toldi, József

    2017-01-01

    Background The complex pathophysiology of migraine is not yet clearly understood; therefore, experimental models are essential for the investigation of the processes related to migraine headache, which include cortical spreading depression (CSD) and NO donor-induced neurovascular changes. Data on the assessment of drug efficacy in these models are often limited, which prompted us to investigate a novel combined migraine model in which an effective pharmacon could be more easily identified. Materials and methods In vivo electrophysiological experiments were performed to investigate the effect of nitroglycerin (NTG) on CSD induced by KCl application. In addition, sumatriptan and newly synthesized neuroactive substances (analogues of the neuromodulator kynurenic acid [KYNA]) were also tested. Results The basic parameters of CSDs were unchanged following NTG administration; however, propagation failure was decreased compared to the controls. Sumatriptan decreased the number of CSDs, whereas propagation failure was as minimal as in the NTG group. On the other hand, both of the KYNA analogues restored the ratio of propagation to the control level. Discussion The ratio of propagation appeared to be the indicator of the effect of NTG. This is the first study providing direct evidence that NTG influences CSD; furthermore, we observed different effects of sumatriptan and KYNA analogues. Sumatriptan changed the generation of CSDs, whereas the analogues acted on the propagation of the waves. Our experimental design overlaps with a large spectrum of processes present in migraine pathophysiology, and it can be a useful experimental model for drug screening. PMID:28053504

  15. Synthesis, Properties and Applications of Diazotrifluropropanoyl-Containing Photoactive Analogues of Farnesyl Diphosphate Containing Modified Linkages for Enhanced Stability

    PubMed Central

    Hovlid, Marisa L.; Edelstein, Rebecca L.; Henry, Olivier; Ochocki, Joshua; DeGraw, Amanda; Lenevich, Stepan; Talbot, Trista; Young, Victor G.; Hruza, Alan W.; Lopez-Gallego, Fernando; Labello, Nicholas P.; Strickland, Corey L.; Schmidt-Dannert, Claudia; Distefano, Mark D.

    2009-01-01

    Photoactive analogues of farnesyl diphosphate (FPP) are useful probes in studies of enzymes that employ this molecule as a substrate. Here, we describe the preparation and properties of two new FPP analogues that contain diazotrifluoropropionyl photophores linked to geranyl diphosphate via amide or ester linkages. The amide-linked analogue (3) was synthesized in 32P-labeled form from geraniol in 7 steps. Experiments with Saccharomyces cerevisiae protein farnesyltransferase (ScPFTase) showed that 3 is an alternative substrate for the enzyme. Photolysis experiments with [32P]3 demonstrate that this compound labels the β-subunits of both farnesyl- and geranylgeranyltransferase (types 1 and 2). However, the amide-linked probe 3 undergoes a rearrangement to a photochemically unreactive isomeric triazolone upon long term storage making it inconvenient to use. To address this stability issue, the ester-linked analogue 4 was prepared in 6 steps from geraniol. Computational analysis and X-ray crystallographic studies suggest that 4 binds to PFTase in a similar fashion as FPP. Compound 4 is also an alternative substrate for PFTase and a 32P-labeled form selectively photocrosslinks the β-subunit of ScPFTase as well as E. coli farnesyldiphosphate synthase and a germacrene-producing sesquiterpene synthase from Nostoc sp. strain PCC7120 (a cyanobacterial source). Finally, nearly exclusive labeling of ScPFTase in crude E. coli extract was observed, suggesting that [32P]4 manifests significant selectivity and should hence be useful for identifying novel FPP utilizing enzymes in crude protein preparations. PMID:19954434

  16. Enhancing excited state intramolecular proton transfer in 2-(2'-hydroxyphenyl)benzimidazole and its nitrogen-substituted analogues by β-cyclodextrin: the effect of nitrogen substitution.

    PubMed

    Chipem, Francis A S; Behera, Santosh Kumar; Krishnamoorthy, G

    2013-05-23

    Excited state intramolecular proton transfer (ESIPT) in nitrogen-substituted analogues of 2-(2'-hydroxyphenyl)benzimidazole (HPBI), 2-(2'-hydroxyphenyl)-3H-imidazo[4,5-b]pyridine (HPIP-b), and 2-(2'-hydroxyphenyl)-3H-imidazo[4,5-c]pyridine (HPIP-c) have been investigated in a β-cyclodextrin (β-CD) nanocavity and compared with that of HPBI. The stoichiometry and the binding constants of the complexes were determined by tautomer emissions. Both pKa and NMR experiments were employed to determine the orientation of the molecules inside of the β-CD cavity. Huge enhancement in the tautomer emission of HPIP-b and HPIP-c compared to that of HPBI in β-CD suggests that not only is the ESIPT favored inside of the cavity, but also, the environment reduces the nonradiative decay through the formation of an intramolecular charge-transfer (ICT) state. Unlike HPBI, the tautomer emission to normal emission ratio of HPIP-b increases from 0.9 to 2.6, and that of HPIP-c increases from 4.9 to 7.4 in 15 mM β-CD. The effect of dimethylsulfoxide (DMSO) on complexation was also investigated for all three guest molecules. In DMSO, HPBI is present in neutral form, but the nitrogen-substituted analogues are present in both neutral and monoanionic forms. However, in DMSO upon encapsulation by β-CD, all three molecules are present in both neutral and monoanionic forms in the nanocavity. The monoanion is stabilized more inside of the β-CD cavity. The studies revealed that the ESIPT of nitrogen-substituted analogues is more susceptible to the environment than HPBI, and therefore, they are more promising probes.

  17. Pro Free Will Priming Enhances “Risk-Taking” Behavior in the Iowa Gambling Task, but Not in the Balloon Analogue Risk Task: Two Independent Priming Studies

    PubMed Central

    Schrag, Yann; Tremea, Alessandro; Lagger, Cyril; Ohana, Noé; Mohr, Christine

    2016-01-01

    Studies indicated that people behave less responsibly after exposure to information containing deterministic statements as compared to free will statements or neutral statements. Thus, deterministic primes should lead to enhanced risk-taking behavior. We tested this prediction in two studies with healthy participants. In experiment 1, we tested 144 students (24 men) in the laboratory using the Iowa Gambling Task. In experiment 2, we tested 274 participants (104 men) online using the Balloon Analogue Risk Task. In the Iowa Gambling Task, the free will priming condition resulted in more risky decisions than both the deterministic and neutral priming conditions. We observed no priming effects on risk-taking behavior in the Balloon Analogue Risk Task. To explain these unpredicted findings, we consider the somatic marker hypothesis, a gain frequency approach as well as attention to gains and / or inattention to losses. In addition, we highlight the necessity to consider both pro free will and deterministic priming conditions in future studies. Importantly, our and previous results indicate that the effects of pro free will and deterministic priming do not oppose each other on a frequently assumed continuum. PMID:27018854

  18. A Remarkable Series of Vinblastine Analogues Displaying Enhanced Activity and an Unprecedented Tubulin Binding Steric Tolerance: C20' Urea Derivatives

    PubMed Central

    Leggans, Erick K.; Duncan, Katharine K.; Barker, Timothy J.; Schleicher, Kristin D.; Boger, Dale L.

    2012-01-01

    A systematic series of previously inaccessible key C20' urea and thiourea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH4-mediated alkene functionalization reaction of anhydrovinblastine. Their examination defined key structural features of the urea-based analogues that contribute to their properties and provided derivatives that match or exceed the potency of vinblastine by as much as 10-fold in cell-based functional assays, which is directly related to their relative tubulin binding affinity. In contrast to expectations based on apparent steric constraints of the tubulin binding site surrounding the vinblastine C20' center depicted in an x-ray co-crystal structure, remarkably large C20' urea derivatives are accommodated. PMID:23244701

  19. Topical hydrocortisone, clobetasol propionate, and calcipotriol do not increase photocarcinogenesis induced by simulated solar irradiation in hairless mice.

    PubMed

    Lerche, Catharina M; Philipsen, Peter A; Poulsen, Thomas; Wulf, Hans Christian

    2010-11-01

    Topical corticosteroids such as hydrocortisone-17-butyrate (HCB) and clobetasol-17-propionate (CP) and vitamin D(3) derivatives such as calcipotriol (CAL) are widely used to treat psoriasis. The immunosuppressive effects of corticosteroids make their topical use a concern for skin carcinogenicity. Few studies have assessed the effect of topical corticosteroids and topical vitamin D(3) derivatives on photocarcinogenesis induced by ultraviolet radiation. We investigated whether HCB, CP, or CAL can accelerate photocarcinogenesis using simulated solar radiation (SSR). HCB, CP, or CAL was applied topically to the backs of hairless, female, C3.Cg/TifBomTac-immunocompetent mice in 16 groups of 25 mice each. The drugs were applied three times weekly followed by 0, 2, 4, or 6 standard erythema doses (SED) of SSR for 365 days or until death. No change was observed in the time required for tumor development in mice treated with HCB and 2 SED (HCB-2SED) and HCB-6SED. However, the time required for tumor development increased with HCB-4SED treatment. Treatment with CP-2SED did not change the time to onset of the first and second tumor, but all other CP treatments in combination with SSR increased the time. CAL-2SED decreased the time to onset of the first tumor but not of the second and third tumor. CAL-4SED and CAL-6 SED did not change or increased the time to tumor development. Our data indicated that topical administration of HCB and CAL did not alter the photocarcinogenesis of SSR and that topical CP administration had a photoprotective effect. Thus, HCB, CP, and CAL do not increase photocarcinogenesis induced by SSR.

  20. Synthesis and Biological Activity of Diastereomeric and Geometric Analogs of Calcipotriol, PRI-2202 and PRI-2205, Against Human HL-60 Leukemia and MCF-7 Breast Cancer Cells

    PubMed Central

    Milczarek, Magdalena; Chodyński, Michał; Filip-Psurska, Beata; Martowicz, Agnieszka; Krupa, Małgorzata; Krajewski, Krzysztof; Kutner, Andrzej; Wietrzyk, Joanna

    2013-01-01

    Diastereomeric and geometric analogs of calcipotriol, PRI-2202 and PRI-2205, were synthesized as advanced intermediates from vitamin D C-22 benzothiazoyl sulfones and side-chain aldehydes using our convergent strategy. Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191) were used as the reference compounds. Among a series of tested analogs the diastereomeric analog PRI-2202 showed the strongest antiproliferative activity on the human breast cancer cell line MCF-7, whereas the geometric analog PRI-2205 was the weakest. Both analogs were less potent in antiproliferative activity against HL-60 cells compared to the reference compounds. The ability to potentiate antiproliferative effect of cisplatin or doxorubicin against HL-60 cells or that of tamoxifen against the MCF-7 cell line was observed at higher doses of PRI-2202 or PRI-2205 than those of the reference compounds. The proapoptotic activity of tamoxifen, expressed as the diminished mitochondrial membrane potential, as well as the increased phosphatidylserine expression, was partially attenuated by calcitriol, PRI-2191, PRI-2201 and PRI-2205. The treatment of the MCF-7 cells with tamoxifen alone resulted in an increase in VDR expression. Moreover, a further increase in VDR expression was observed when the analogs PRI-2201 or PRI-2205, but not PRI-2191, were used in combination with tamoxifen. This observation could partially explain the potentiation of the antiproliferative effect of tamoxifen by vitamin D analogs. PMID:24202449

  1. Mathematically-Engineered Stromal Cell-Derived Factor 1alpha Stem Cell Cytokine Analogue Enhances Mechanical Properties of Infarcted Myocardium

    PubMed Central

    Jr, John W. MacArthur; Trubelja, Alen; Shudo, Yasuhiro; Hsiao, Philip; Fairman, Alex; Yang, Elaine; Hiesinger, William; Atluri, Pavan; Woo, Y Joseph

    2014-01-01

    Background The biomechanical response to a myocardial infarction consists of ventricular remodeling that leads to dilation, loss of contractile function, abnormal stress patterns and ultimately heart failure. We hypothesized that intramyocardial injection of our previously designed pro-angiogenic chemokine, an engineered stromal cell derived factor 1alpha analogue(ESA), improves mechanical properties of the heart post-infarction. Methods Male rats (n=54) underwent either sham surgery (n=17) with no coronary artery ligation or ligation of the LAD (n=37). Rats in the MI group were then randomized to receive either saline (0.1cc, n=18) or ESA (6μg/kg, n=19) injected into the myocardium at 4 predetermined spots around the borderzone. Echocardiograms were performed preoperatively and before the terminal surgery. After 4 weeks the hearts were explanted and longitudinally sectioned. Uniaxial tensile testing was completed using an Instron 5543 Microtester. Optical strain was evaluated utilizing custom image acquisition software, Digi-Velpo, and analyzed in MATLAB. Results Compared to the saline control group at 4 weeks, the ESA injected hearts had higher ejection fractions (71.8% ± 9.0 vs. 55.3% ± 12.6, p= 0.0004) smaller end-diastolic left ventricular internal dimensions (0.686cm ± 0.110 vs. 0.763cm ± 0.160, p= 0.04), higher cardiac output (36ml/min ± 11.6 vs. 26.9ml/min ± 7.3, p= 0.05) and the tensile modulus was lower(251kPa ± 56 vs. 301kPa ± 81, p= 0.04). The tensile modulus for the sham group was 195kPa ± 56, indicating ESA injection results in a less stiff ventricle. Conclusions Direct injection of ESA alters the biomechanical response to MI, improving the mechanical properties in the post-infarct heart. PMID:23244259

  2. The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice.

    PubMed

    Lue, YanHe; Swerdloff, Ronald; Wan, Junxiang; Xiao, Jialin; French, Samuel; Atienza, Vince; Canela, Victor; Bruhn, Kevin W; Stone, Brian; Jia, Yue; Cohen, Pinchas; Wang, Christina

    2015-12-01

    Humanin is a peptide that is cytoprotective against stresses in many cell types. We investigated whether a potent humanin analogue S14G-humanin (HNG) would protect against chemotherapy-induced damage to normal cells without interfering with the chemotherapy-induced suppression of cancer cells. Young adult male mice were inoculated iv with murine melanoma cells. After 1 week, cancer-bearing mice were randomized to receive either: no treatment, daily ip injection of HNG, a single ip injection of cyclophosphamide (CP), or CP+HNG and killed at the end of 3 weeks. HNG rescued the CP-induced suppression of leucocytes and protected germ cell from CP-induced apoptosis. Lung metastases were suppressed by HNG or CP alone, and further suppressed by CP+HNG treatment. Plasma IGF-1 levels were suppressed by HNG with or without CP treatment. To investigate whether HNG maintains its protective effects on spermatogonial stem cells, sperm output, and peripheral leucocytes after repeated doses of CP, normal adult male mice received: no treatment, daily sc injection of HNG, 6 ip injections of CP at 5-day intervals, and the same regimens of CP+HNG and killed at the end of 4 weeks of treatment. Cauda epididymal sperm counts were elevated by HNG and suppressed by CP. HNG rescued the CP-induced suppression of spermatogonial stem cells, sperm count and peripheral leucocytes. We conclude that HNG 1) protects CP-induced loss of male germ cells and leucocytes, 2) enhances CP-induced suppression of cancer metastases, and 3) acts as a caloric-restriction mimetic by suppressing IGF-1 levels. Our findings suggest that humanin analogues may be promising adjuvants to chemotherapy.

  3. Efficient syntheses of a series of trehalose dimycolate (TDM)/trehalose dicorynomycolate (TDCM) analogues and their interleukin-6 level enhancement activity in mice sera.

    PubMed

    Nishizawa, Mugio; Yamamoto, Hirofumi; Imagawa, Hiroshi; Barbier-Chassefière, Véronique; Petit, Emmanuel; Azuma, Ichiro; Papy-Garcia, Dulce

    2007-03-02

    We found an IL-6 level-enhancing compound during our synthetic study of trehalose-6,6'-dimycolate (1, TDM, formerly called cord factor) analogues. TDM is a glycolipid distributed in the cell wall of Mycobacterium tuberculosis and shows significant antitumor activity based on an immunoadjuvant activity. However, due to its significant toxicity, TDM is not yet applicable for practical use. In 1993, Datta and Takayama reported the purification of trehalose-6,6'-dicorynomycolate (2c, TDCM) from Corynebacterium spp. We have previously reported the synthesis of four diastereomeric TDCMs and showed that the synthetic (2R,3R,2'R,3'R)-TDCM (2c, hereafter abbreviated RRRR-TDCM-C14) is identical to natural TDCM; we also demonstrated that 2c and SSSS-TDCM-C14 (3c) showed significant antitumor activity as well as inhibitory activity in experimental lung metastasis based on the immunoadjuvant activity. Furthermore, we found that the significant lethal toxicity in mice by TDM (1) was no longer observed with the shorter-chain analogues of TDCMs. Therefore, we have elucidated that the 2,3-antistereochemistry (RR or SS) of the fatty acid residue is promising for biological activities. The chain length of the fatty acid residue should also be important for the biological activity, and thus, we designed a general synthetic procedure for trehalose diesters with 2,3-antistereochemistry and a series of chain lengths by using Noyori's asymmetric reduction of beta,beta-ketoesters followed by antiselective alkylation according to Frater to give beta,beta-hydroxy alcohols as the key steps. Thus, we prepared trehalose diesters (TDCM) 2a-d, 3a-d, and 4a-d as well as monoesters (TMCM) 5a-d and 6a-d. Immunological activities of TDCMs and TMCMs were evaluated by determining IL-6 level enhancement in mouse serum, and we found that RRRR-TDCM-C14 (2c) and RRSS-TDCM-C14 (4c) showed significant IL-6 level enhancement activities.

  4. Fluorescence enhancement of fluorescent unnatural streptavidin by binding of a biotin analogue with spacer tail and its application to biotin sensing.

    PubMed

    Zhu, Xianwei; Shinohara, Hiroaki

    2014-01-01

    We designed a novel molecular biosensing system for the detection of biotin, an important vitamin by the combination of fluorescent unnatural streptavidin with a commercialized biotin-(AC5)2-hydrazide. A fluorescent unnatural amino acid, BODIPY-FL-aminophenylalanine (BFLAF), was position-specifically incorporated into Trp120 of streptavidin by four-base codon method. Fluorescence of the Trp120BFLAF mutant streptavidin was enhanced by the addition of biotin-(AC5)2-hydrazide with the concentration dependent, whereas fluorescence enhancement was not observed at all by the addition of natural biotin. It was considered that the spacer tail of biotin-(AC5)2-hydrazide may disturb the fluorescence quenching of the Trp120BFLAF by Trp79 and Trp108 of the neighbor subunit. Therefore, biotin sensing was carried out by the competitive binding reaction of biotin-(AC5)2-hydrazide and natural biotin to the fluorescent mutant streptavidin. The fluorescence intensity decreased by increasing free biotin concentration. The result suggested that molecular biosensor for small ligand could be successfully designed by the pair of fluorescent mutant binding protein and ligand analogue.

  5. Design, synthesis and nootropic activity of new analogues of sunifiram and sapunifiram, two potent cognition-enhancers.

    PubMed

    Martini, Elisabetta; Salvicchi, Alberto; Ghelardini, Carla; Manetti, Dina; Dei, Silvia; Guandalini, Luca; Martelli, Cecilia; Melchiorre, Michele; Cellai, Cristina; Scapecchi, Serena; Teodori, Elisabetta; Romanelli, Maria Novella

    2009-11-01

    A series of amides and sulfonamides, structurally related to DM235 (sunifiram) and MN19 (sapunifiram), derived by ring expansion or contraction, or by inversion of the exocyclic amide function, have been synthesized and tested for cognition-enhancing activity in the mouse passive-avoidance test. Some of the compounds display good antiamnesic and procognitive activity, with higher potency than piracetam, and with a potency similar to the parent compounds.

  6. A humic substance analogue AQDS stimulates Geobacter sp. abundance and enhances pentachlorophenol transformation in a paddy soil.

    PubMed

    Chen, Manjia; Tong, Hui; Liu, Chengshuai; Chen, Dandan; Li, Fangbai; Qiao, Jiangtao

    2016-10-01

    Soil humic substances can be used as redox mediators in accelerating the biotransformation of organic pollutants, and humus-respiring bacteria are widely distributed in soils. However, the impact of humic substances on the soil microbial community during the biotransformation of organic pollutants is expected to be crucial while remains to be unclear. In this study, the biostimulation of indigenous microbial communities and the consequent effects on anaerobic transformation of pentachlorophenol (PCP) by a model humic substance, anthraquinone-2,6-disulfonate (AQDS), were systematically investigated in a paddy soil. The addition of AQDS was observed to increase the production of HCl-extractable Fe(II) and enhance the PCP transformation rates consequently. The pseudo-first-order rate constants of the PCP transformation showed a positive exponential relationship with the AQDS dosage. The terminal restriction fragment length polymorphism (T-RFLP) results indicated the substantial effect of added AQDS on soil microbial community. The enhanced abundance of Geobacter sp. was disclosed to be most critical for accelerated PCP transformation when with AQDS, in which Geobacter sp. functioned for promoting the generation of active Fe(II) and consequently enhancing the PCP transformation rates. The transformation rates of PCP were exponentially correlated with the abundance of Geobacter sp. positively. The findings are expected to improve the understanding of diversity and ubiquity of microorganisms in humic substances-rich soils for accelerating the transformations of soil chlorinated pollutants.

  7. Glu-Trp-ONa or its acylated analogue (R-Glu-Trp-ONa) administration enhances the wound healing in the model of chronic skin wounds in rabbits

    PubMed Central

    Shevtsov, Maxim A; Smagina, Larisa V; Kudriavtceva, Tatiana A; Petlenko, Sergey V; Voronkina, Irina V

    2015-01-01

    The management of chronic skin wounds represents a major therapeutic challenge. The synthesized dipeptide (Glu-Trp-ONa) and its acylated analogue (R-Glu-Trp-ONa) were assessed in the model of nonhealing dermal wounds in rabbits in relation to their healing properties in wound closure. Following wound modeling, the rabbits received a course of intraperitoneal injections of Glu-Trp-ONa or R-Glu-Trp-ONa. Phosphate-buffered saline and Solcoseryl® were applied as negative and positive control agents, respectively. An injection of Glu-Trp-ONa and R-Glu-Trp-ONa decreased the period of wound healing in animals in comparison to the control and Solcoseryl-treated groups. Acylation of Glu-Trp-ONa proved to be beneficial as related to the healing properties of the dipeptide. Subsequent zymography analyses showed that the applied peptides decreased the proteolytic activity of matrix metalloproteinases MMP-9, MMP-8, and MMP-2 in the early inflammatory phase and reversely increased the activity of MMP-9, MMP-8, and MMP-1 in the remodeling phase. Histological analyses of the wound sections (hematoxylin–eosin, Mallory’s staining) confirmed the enhanced formation of granulation tissue and re-epithelialization in the experimental groups. By administering the peptides, wound closures increased significantly through the modulation of the MMPs’ activity, indicating their role in wound healing. PMID:25848208

  8. Glu-Trp-ONa or its acylated analogue (R-Glu-Trp-ONa) administration enhances the wound healing in the model of chronic skin wounds in rabbits.

    PubMed

    Shevtsov, Maxim A; Smagina, Larisa V; Kudriavtceva, Tatiana A; Petlenko, Sergey V; Voronkina, Irina V

    2015-01-01

    The management of chronic skin wounds represents a major therapeutic challenge. The synthesized dipeptide (Glu-Trp-ONa) and its acylated analogue (R-Glu-Trp-ONa) were assessed in the model of nonhealing dermal wounds in rabbits in relation to their healing properties in wound closure. Following wound modeling, the rabbits received a course of intraperitoneal injections of Glu-Trp-ONa or R-Glu-Trp-ONa. Phosphate-buffered saline and Solcoseryl® were applied as negative and positive control agents, respectively. An injection of Glu-Trp-ONa and R-Glu-Trp-ONa decreased the period of wound healing in animals in comparison to the control and Solcoseryl-treated groups. Acylation of Glu-Trp-ONa proved to be beneficial as related to the healing properties of the dipeptide. Subsequent zymography analyses showed that the applied peptides decreased the proteolytic activity of matrix metalloproteinases MMP-9, MMP-8, and MMP-2 in the early inflammatory phase and reversely increased the activity of MMP-9, MMP-8, and MMP-1 in the remodeling phase. Histological analyses of the wound sections (hematoxylin-eosin, Mallory's staining) confirmed the enhanced formation of granulation tissue and re-epithelialization in the experimental groups. By administering the peptides, wound closures increased significantly through the modulation of the MMPs' activity, indicating their role in wound healing.

  9. Enhanced energy expenditure and fat oxidation in humans with high BMI scores by the ingestion of novel and non-pungent capsaicin analogues (capsinoids).

    PubMed

    Inoue, Naohiko; Matsunaga, Yoshiko; Satoh, Hitoshi; Takahashi, Michio

    2007-02-01

    The biochemical and physiological indices were monitored in 44 subjects after 4-week capsinoids (capsaicin analogues with low pungency) intake. The subjects were randomly assigned to 3 groups: CSNs3 (3 mg/kg of capsinoids), CSNs10 (10 mg/kg of capsinoids) and the control (placebo). Measurements were performed in the morning on overnight-fasted subjects. The oxygen consumption (VO(2)), resting energy expenditure (REE) and fat oxidation increased slightly compared to pre-administration values without any adverse effects, although the increase was not significant. The increase in fat oxidation was positively and significantly correlated with the body mass index (BMI). A meta-analysis was therefore conducted on a subgroup consisting of subjects with BMI >or= 25 (n=28). As a result, not only VO(2) increased significantly (p<0.05) in the CSNs10 group, but also REE in the CSNs10 group and fat oxidation in the CSNs3 and CSNs10 groups tended to increase (p<0.1). Consequently, a capsinoids intake would be able to enhance the energy expenditure and fat burning in humans, particularly those with high BMI.

  10. Bisdemethylcurcumin and Structurally Related Hispolon Analogues of Curcumin Exhibit Enhanced Prooxidant, Anti-Proliferative and Anti-inflammatory Activities in vitro

    PubMed Central

    Ravindran, Jayaraj; Subbaraju, Gottumukkala V.; Ramani, Modukuri V.; Sung, Bokyung; Aggarwal, Bharat B.

    2010-01-01

    Curcumin, a component of turmeric (Curcuma longa), exhibits anti-inflammatory and anti-proliferative activities through the generation of reactive oxygen species (ROS). Curcumin (diferuloylemethane) contains two hydroxyl, two methoxy and two phenyl groups but how these groups contribute to its activity is poorly understood. We synthesized analogues that varied in inclusion of these groups and compared their activity. We found that bisdemethylcurcumin (BDC) was more potent than curcumin as an anti-inflammatory agent as indicated by suppression of TNF-induced NF-κB activation, more potent as an anti-proliferative agent, and more potent in inducing ROS. Hispolon, which lacks one aromatic unit in relation to curcumin, also exhibited enhanced anti-inflammatory and anti-proliferative activities. When synthetic curcumin (Cur-S) was compared with bisdemethylcurcumin (BDC), hispolon, hispolon methyl ether (HME), dehydroxy hispolon (DH), hydroxy hispolon (HH), methoxy hispolon methyl ether (MHME), and methoxy hispolon (MH), we found that following order of anti-inflammatory activity: BDC=Hispolon>HME> HH>Cur-S>MHME>MH>DH; for anti-proliferative Hispolon> BDC>MHME> Cur-S>MH>HME=HH>DH; and for prooxidant BDC>Cur-S=MHME>HH>MH+HME>DH (254-1414 mean fluorescence intensity). Thus dehydroxyhispolon was least potent for all three activities. Overall the results indicates that the substitution of a hydroxyl group for a methoxy group at the meta positions of the phenyl rings in curcumin significantly enhanced the anti-inflammatory activity, and the removal of phenyl ring at the 7th position of the heptadiene back bone and addition of hydroxyl group significantly increased the anti-proliferative activity of curcumin. PMID:20138025

  11. Sustained-Release Delivery of Prostacyclin Analogue Enhances Bone Marrow-Cell Recruitment and Yields Functional Benefits for Acute Myocardial Infarction in Mice

    PubMed Central

    Imanishi, Yukiko; Miyagawa, Shigeru; Fukushima, Satsuki; Ishimaru, Kazuhiko; Sougawa, Nagako; Saito, Atsuhiro; Sakai, Yoshiki; Sawa, Yoshiki

    2013-01-01

    Background A prostacyclin analogue, ONO-1301, is reported to upregulate beneficial proteins, including stromal cell derived factor-1 (SDF-1). We hypothesized that the sustained-release delivery of ONO-1301 would enhance SDF-1 expression in the acute myocardial infarction (MI) heart and induce bone marrow cells (BMCs) to home to the myocardium, leading to improved cardiac function in mice. Methods and Results ONO-1301 significantly upregulated SDF-1 secretion by fibroblasts. BMC migration was greater to ONO-1301-stimulated than unstimulated conditioned medium. This increase was diminished by treating the BMCs with a CXCR4-neutralizing antibody or CXCR4 antagonist (AMD3100). Atelocollagen sheets containing a sustained-release form of ONO-1301 (n = 33) or ONO-1301-free vehicle (n = 48) were implanted on the left ventricular (LV) anterior wall immediately after permanent left-anterior descending artery occlusion in C57BL6/N mice (male, 8-weeks-old). The SDF-1 expression in the infarct border zone was significantly elevated for 1 month in the ONO-1301-treated group. BMC accumulation in the infarcted hearts, detected by in vivo imaging after intravenous injection of labeled BMCs, was enhanced in the ONO-1301-treated hearts. This increase was inhibited by AMD3100. The accumulated BMCs differentiated into capillary structures. The survival rates and cardiac function were significantly improved in the ONO-1301-treated group (fractional area change 23±1%; n = 22) compared to the vehicle group (19±1%; n = 20; P = 0.004). LV anterior wall thinning, expansion of infarction, and fibrosis were lower in the ONO-1301-treated group. Conclusions Sustained-release delivery of ONO-1301 promoted BMC recruitment to the acute MI heart via SDF-1/CXCR4 signaling and restored cardiac performance, suggesting a novel mechanism for ONO-1301-mediated acute-MI heart repair. PMID:23894446

  12. B-Ring-Aryl Substituted Luotonin A Analogues with a New Binding Mode to the Topoisomerase 1-DNA Complex Show Enhanced Cytotoxic Activity

    PubMed Central

    González-Ruiz, Víctor; Pascua, Irene; Fernández-Marcelo, Tamara; Ribelles, Pascual; Bianchini, Giulia; Sridharan, Vellaisamy; Iniesta, Pilar; Ramos, M. Teresa; Olives, Ana I.; Martín, M. Antonia; Menéndez, J. Carlos

    2014-01-01

    Topoisomerase 1 inhibition is an important strategy in targeted cancer chemotherapy. The drugs currently in use acting on this enzyme belong to the family of the camptothecins, and suffer severe limitations because of their low stability, which is associated with the hydrolysis of the δ-lactone moiety in their E ring. Luotonin A is a natural camptothecin analogue that lacks this functional group and therefore shows a much-improved stability, but at the cost of a lower activity. Therefore, the development of luotonin A analogues with an increased potency is important for progress in this area. In the present paper, a small library of luotonin A analogues modified at their A and B rings was generated by cerium(IV) ammonium nitrate-catalyzed Friedländer reactions. All analogues showed an activity similar or higher than the natural luotonin A in terms of topoisomerase 1 inhibition and some compounds had an activity comparable to that of camptothecin. Furthermore, most compounds showed a better activity than luotonin A in cell cytotoxicity assays. In order to rationalize these results, the first docking studies of luotonin-topoisomerase 1-DNA ternary complexes were undertaken. Most compounds bound in a manner similar to luotonin A and to standard topoisomerase poisons such as topotecan but, interestingly, the two most promising analogues, bearing a 3,5-dimethylphenyl substituent at ring B, docked in a different orientation. This binding mode allows the hydrophobic moiety to be shielded from the aqueous environment by being buried between the deoxyribose belonging to the G(+1) guanine and Arg364 in the scissile strand and the surface of the protein and a hydrogen bond between the D-ring carbonyl and the basic amino acid. The discovery of this new binding mode and its associated higher inhibitory potency is a significant advance in the design of new topoisomerase 1 inhibitors. PMID:24830682

  13. Survey of Analogue Spacetimes

    NASA Astrophysics Data System (ADS)

    Visser, Matt

    Analogue spacetimes (and more boldly, analogue models both of and for gravity), have attracted significant and increasing attention over the last decade and a half. Perhaps the most straightforward physical example, which serves as a template for most of the others, is Bill Unruh's model for a dumb hole,(mute black hole, acoustic black hole), wherein sound is dragged along by a moving fluid—and can even be trapped behind an acoustic horizon. This and related analogue models for curved spacetimes are useful in many ways: analogue spacetimes provide general relativists with extremely concrete physical models to help focus their thinking, and conversely the techniques of curved spacetime can sometimes help improve our understanding of condensed matter and/or optical systems by providing an unexpected and countervailing viewpoint. In this chapter, I shall provide a few simple examples of analogue spacetimes as general background for the rest of the contributions.

  14. Curcumin and its analogues (PGV-0 and PGV-1) enhance sensitivity of resistant MCF-7 cells to doxorubicin through inhibition of HER2 and NF-kB activation.

    PubMed

    Meiyanto, Edy; Putri, Dyaningtyas Dewi Pamungkas; Susidarti, Ratna Asmah; Murwanti, Retno; Sardjiman; Fitriasari, Aditya; Husnaa, Ulfatul; Purnomo, Hari; Kawaichi, Masashi

    2014-01-01

    Chemoresistance of breast cancer to doxorubicin is mediated mainly through activation of NF-kB and over expression of HER2. Curcumin and its analogues (PGV-0 and PGV-1) exert cytotoxic effects on T47D breast cancer cells. Suppression of NF-kB activation is suggested to contribute to this activity. The present study aimed to explore the effects of curcumin, PGV-0, and PGV-1 singly and in combination with doxorubicin on MCF-7/Dox cells featuring over-expression of HER2. In MTT assays, curcumin, PGV-0, and PGV-1 showed cytotoxicity effects against MCF-7/Dox with IC50 values of 80 μM, 21 μM, and 82 μM respectively. These compounds increased MCF-7/Dox sensitivity to doxorubicin. Cell cycle distribution analysis exhibited that the combination of curcumin and its analogues with Dox increased sub G-1 cell populations. Curcumin and PGV-1 but not PGV-0 decreased localization of p65 into the nucleus induced by Dox, indicating that activation of NF- kB was inhibited. Molecular docking of curcumin, PGV-0, and PGV-1 demonstrated high affinity to HER2 at ATP binding site. This interaction were directly comparable with those of ATP and lapatinib. These findings suggested that curcumin, PGV-0 and PGV-1 enhance the Dox cytotoxicity to MCF-7 cells through inhibition of HER2 activity and NF-kB activation.

  15. QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells.

    PubMed

    Sundaram, Sujatha; Beckman, Matthew J; Bajwa, Amandeep; Wei, Jeffrey; Smith, Kathleen M; Posner, Gary H; Gewirtz, David A

    2006-11-01

    The enzyme 24-hydroxylase, also known as CYP24, metabolizes 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and is an established marker of vitamin D activity. Our studies evaluated the influence of a low-calcemic 1,25(OH)(2)D(3) analogue, QW-1624F2-2 (QW), on the regulation of CYP24 expression in MKL-4 cells, a metastatic mammary tumor cell model. 1,25(OH)(2)D(3) and its analogue, EB 1089, stimulated CYP24 induction at both protein and transcript levels. In contrast, QW failed to produce a sustained stimulation of CYP24, due, in large part, to a reduction in the stability of the CYP24 message. QW enhanced the capacity of 1,25(OH)(2)D(3) and EB 1089 to inhibit tumor cell proliferation by approximately 2-fold. QW also blocked the sustained induction of CYP24 expression by 1,25(OH)(2)D(3) and EB 1089, increased the potency of 1,25(OH)(2)D(3) and EB 1089, and inhibited breast tumor cell proliferation and invasion.

  16. Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo.

    PubMed

    Burch, Jason D; Barrett, Kathy; Chen, Yuan; DeVoss, Jason; Eigenbrot, Charles; Goldsmith, Richard; Ismaili, M Hicham A; Lau, Kevin; Lin, Zhonghua; Ortwine, Daniel F; Zarrin, Ali A; McEwan, Paul A; Barker, John J; Ellebrandt, Claire; Kordt, Daniel; Stein, Daniel B; Wang, Xiaolu; Chen, Yong; Hu, Baihua; Xu, Xiaofeng; Yuen, Po-Wai; Zhang, Yamin; Pei, Zhonghua

    2015-05-14

    The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure- and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiproliferative effects, which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.

  17. Sorafenib analogue SC-60 induces apoptosis through the SHP-1/STAT3 pathway and enhances docetaxel cytotoxicity in triple-negative breast cancer cells.

    PubMed

    Liu, Chun-Yu; Su, Jung-Chen; Huang, Tzu-Ting; Chu, Pei-Yi; Huang, Chun-Teng; Wang, Wan-Lun; Lee, Chia-Han; Lau, Ka-Yi; Tsai, Wen-Chun; Yang, Hsiu-Ping; Shiau, Chung-Wai; Tseng, Ling-Ming; Chen, Kuen-Feng

    2017-03-01

    Recurrent triple-negative breast cancer (TNBC) needs new therapeutic targets. Src homology region 2 domain-containing phosphatase-1 (SHP-1) can act as a tumor suppressor by dephosphorylating oncogenic kinases. One major target of SHP-1 is STAT3, which is highly activated in TNBC. In this study, we tested a sorafenib analogue SC-60, which lacks angiokinase inhibition activity, but acts as a SHP-1 agonist, in TNBC cells. SC-60 inhibited proliferation and induced apoptosis by dephosphorylating STAT3 in both a dose- and time-dependent manner in TNBC cells (MDA-MB-231, MDA-MB-468, and HCC1937). By contrast, ectopic expression of STAT3 rescued the anticancer effect induced by SC-60. SC-60 also increased the SHP-1 activity, but this effect was inhibited when the N-SH2 domain (DN1) was deleted or with SHP-1 point mutation (D61A), implying that SHP-1 is the major target of SC-60 in TNBC. The use of SC-60 in combination with docetaxel synergized the anticancer effect induced by SC-60 through the SHP-1/STAT3 pathway in TNBC cells. Importantly, SC-60 also displayed a significant antitumor effect in an MDA-MB-468 xenograft model by modulating the SHP-1/STAT3 axis, indicating the anticancer potential of SC-60 in TNBC treatment. Targeting SHP-1/p-STAT3 and the potential combination of SHP-1 agonist with chemotherapeutic docetaxel is a feasible therapeutic strategy for TNBC.

  18. GABAA Receptor Modulation by Etomidate Analogues

    PubMed Central

    Pejo, Ervin; Santer, Peter; Wang, Lei; Dershwitz, Philip; Husain, S. Shaukat; Raines, Douglas E.

    2015-01-01

    Background Etomidate is a highly potent anesthetic agent that is believed to produce hypnosis by enhancing γ-aminobutyric acid type A (GABAA) receptor function. We characterized the GABAA receptor and hypnotic potencies of etomidate analogues. We then used computational techniques to build statistical and graphical models that relate the potencies of these etomidate analogues to their structures in order to identify the specific molecular determinants of potency. Methods GABAA receptor potencies were defined with voltage-clamp electrophysiology using α1β3γ2 receptors harboring a channel mutation (α1(L264T)) that enhances anesthetic sensitivity (n = 36 – 60 measurements per concentration-response curve). The hypnotic potencies of etomidate analogues were defined using a loss of righting reflexes assay in Sprague Dawley rats (n = 9 – 21 measurements per dose-response curve). Three-dimensional quantitative structure-activity relationships were determined in silico using comparative molecular field analysis. Results The GABAA receptor and hypnotic potencies of etomidate and the etomidate analogues ranged by 91-fold and 53-fold, respectively. These potency measurements were significantly correlated (r2 = 0.72), but neither measurement correlated with drug hydrophobicity (r2 = 0.019 and 0.005, respectively). Statistically significant and predictive comparative molecular field analysis models were generated and a pharmacophore model was built that revealed both the structural elements in etomidate analogues associated with high potency and the interactions that these elements make with the etomidate binding site. Conclusion There are multiple specific structural elements in etomidate and etomidate analogues that mediate GABAA receptor modulation. Modifying any one element can alter receptor potency by an order of magnitude or more. PMID:26691905

  19. Addition of vasopressin synthetic analogue [V(4)Q(5)]dDAVP to standard chemotherapy enhances tumour growth inhibition and impairs metastatic spread in aggressive breast tumour models.

    PubMed

    Garona, Juan; Pifano, Marina; Pastrian, Maria B; Gomez, Daniel E; Ripoll, Giselle V; Alonso, Daniel F

    2016-08-01

    [V(4)Q(5)]dDAVP is a novel 2nd generation vasopressin analogue with robust antitumour activity against metastatic breast cancer. We recently reported that, by acting on vasopressin V2r membrane receptor present in tumour cells and microvascular endothelium, [V(4)Q(5)]dDAVP inhibits angiogenesis and metastatic progression of the disease without overt toxicity. Despite chemotherapy remaining as a primary therapeutic option for aggressive breast cancer, its use is limited by low selectivity and associated adverse effects. In this regard, we evaluated potential combinational benefits by adding [V(4)Q(5)]dDAVP to standard-of-care chemotherapy. In vitro, combination of [V(4)Q(5)]dDAVP with sub-IC50 concentrations of paclitaxel or carmustine resulted in a cooperative inhibition of breast cancer cell growth in comparison to single-agent therapy. In vivo antitumour efficacy of [V(4)Q(5)]dDAVP addition to chemotherapy was first evaluated using the triple-negative MDA-MB-231 breast cancer xenograft model. Tumour-bearing mice were treated with i.v. injections of [V(4)Q(5)]dDAVP (0.3 μg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.). After 6 weeks of treatment, combination regimen resulted in greater tumour growth inhibition compared to monotherapy. [V(4)Q(5)]dDAVP addition was also associated with reduction of local aggressiveness, and impairment of tumour invasion and infiltration of the skin. Benefits of combined therapy were confirmed in the hormone-independent and metastatic F3II breast cancer model by combining [V(4)Q(5)]dDAVP with carmustine (25 mg/kg i.p.). Interestingly, [V(4)Q(5)]dDAVP plus cytotoxic agents severely impaired colony forming ability of tumour cells and inhibited breast cancer metastasis to lung. The present study shows that [V(4)Q(5)]dDAVP may complement conventional chemotherapy by modulating metastatic progression and early stages of microtumour establishment, and thus supports further preclinical testing of

  20. Tren-based analogues of bacillibactin: structure and stability.

    PubMed

    Dertz, Emily A; Xu, Jide; Raymond, Kenneth N

    2006-07-10

    Synthetic analogues were designed to highlight the effect of the glycine moiety of bacillibactin on the overall stability of the ferric complex as compared to synthetic analogues of enterobactin. Insertion of a variety of amino acids to catecholamide analogues based on a Tren (tris(2-aminoethyl)amine) backbone increased the overall acidity of the ligands, causing an enhancement of the stability of the resulting ferric complex as compared to TRENCAM. Solution thermodynamic behavior of these siderophores and their synthetic analogues was investigated through potentiometric and spectrophotometric titrations. X-ray crystallography, circular dichroism, and molecular modeling were used to determine the chirality and geometry of the ferric complexes of bacillibactin and its analogues. In contrast to the Tren scaffold, addition of a glycine to the catechol chelating arms causes an inversion of the trilactone backbone, resulting in opposite chiralities of the two siderophores and a destabilization of the ferric complex of bacillibactin compared to ferric enterobactin.

  1. Aspartame and Its Analogues

    NASA Astrophysics Data System (ADS)

    Pavlova, L. A.; Komarova, T. V.; Davidovich, Yurii A.; Rogozhin, S. V.

    1981-04-01

    The results of studies on the biochemistry of the sweet taste are briefly reviewed. The methods of synthesis of "aspartame" — a sweet dipeptide — are considered, its structural analogues are described, and quantitative estimates are made of the degree of sweetness relative to sucrose. Attention is concentrated mainly on problems of the relation between the structure of the substance and its taste in the series of aspartyl derivatives. The bibliography includes 118 references.

  2. Quantum analogue computing.

    PubMed

    Kendon, Vivien M; Nemoto, Kae; Munro, William J

    2010-08-13

    We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

  3. Monochromatic excimer light versus combination of topical steroid with vitamin D3 analogue in the treatment of nonsegmental vitiligo: a randomized blinded comparative study.

    PubMed

    Abdel Latif, Azmy Ahmed; Ibrahim, Shady Mahmoud Attia

    2015-01-01

    Vitiligo is a difficult disease to treat, socially stigmatizing its patients. Monochromatic excimer light (MEL) was developed for use in dermatology and adapted for the treatment of vitiligo. Comparing the efficacy of MEL versus topical combination therapy of vitamin D3 analogue and steroid in the treatment of nonsegmental vitiligo. Forty-four patients with localized and stable nonsegmental vitiligo participated in the present study. In each patient, two lesions were selected and divided randomly into two groups, group A was treated with daily topical combination of calcipotriol and betamethasone and group B was treated with biweekly sessions of MEL for 3 months. Efficacy based on repigmentation percentages were blindly evaluated by two independent physicians and patient's satisfaction. There was significant improvement in both treatment modalities at the end of the study, but without significant differences in both groups. There was a significant difference between both groups regarding the onset of repigmentation (p-value < 0.05), whereas group B showed early sign of repigmentation in first 4 weeks of treatment in 16 patients versus 7 patients in group A. Both treatment modalities offered encouraging results and both are promising lines for the treatment of vitiligo.

  4. Adjuvant properties of a simplified C32 monomycolyl glycerol analogue.

    PubMed

    Bhowruth, Veemal; Minnikin, David E; Agger, Else Marie; Andersen, Peter; Bramwell, Vincent W; Perrie, Yvonne; Besra, Gurdyal S

    2009-04-01

    A simplified C(32) monomycolyl glycerol (MMG) analogue demonstrated enhanced immunostimulatory activity in a dioctadecyl ammonium bromide (DDA)/Ag85B-ESAT-6 formulation. Elevated levels of IFN-gamma and IL-6 were produced in spleen cells from mice immunised with a C(32) MMG analogue comparable activity to the potent Th1 adjuvant, trehalose 6,6'-di-behenate (TDB).

  5. Nanoconjugation of PSMA-Targeting Ligands Enhances Perinuclear Localization and Improves Efficacy of Delivered Alpha-Particle Emitters against Tumor Endothelial Analogues.

    PubMed

    Zhu, Charles; Bandekar, Amey; Sempkowski, Michelle; Banerjee, Sangeeta Ray; Pomper, Martin G; Bruchertseifer, Frank; Morgenstern, Alfred; Sofou, Stavroula

    2016-01-01

    This study aims to evaluate the effect on killing efficacy of the intracellular trafficking patterns of α-particle emitters by using different radionuclide carriers in the setting of targeted antivascular α-radiotherapy. Nanocarriers (lipid vesicles) targeted to the prostate-specific membrane antigen (PSMA), which is unique to human neovasculature for a variety of solid tumors, were loaded with the α-particle generator actinium-225 and were compared with a PSMA-targeted radiolabeled antibody. Actinium-225 emits a total of four α-particles per decay, providing highly lethal and localized irradiation of targeted cells with minimal exposure to surrounding healthy tissues. Lipid vesicles were derivatized with two types of PSMA-targeting ligands: a fully human PSMA antibody (mAb) and a urea-based, low-molecular-weight agent. Target selectivity and extent of internalization were evaluated on monolayers of human endothelial cells (HUVEC) induced to express PSMA in static incubation conditions and in a flow field. Both types of radiolabeled PSMA-targeted vesicles exhibit similar killing efficacy, which is greater than the efficacy of the radiolabeled control mAb when compared on the basis of delivered radioactivity per cell. Fluorescence confocal microscopy demonstrates that targeted vesicles localize closer to the nucleus, unlike antibodies which localize near the plasma membrane. In addition, targeted vesicles cause larger numbers of dsDNAs per nucleus of treated cells compared with the radiolabeled mAb. These findings demonstrate that radionuclide carriers, such as PSMA-targeted lipid-nanocarriers, which localize close to the nucleus, increase the probability of α-particle trajectories crossing the nuclei, and, therefore, enhance the killing efficacy of α-particle emitters.

  6. Nanoconjugation of PSMA-targeting ligands enhances perinuclear localization and improves efficacy of delivered alpha-particle emitters against tumor endothelial analogues

    PubMed Central

    Sempkowski, Michelle; Banerjee, Sangeeta Ray; Pomper, Martin G.; Bruchertseifer, Frank; Morgenstern, Alfred; Sofou, Stavroula

    2015-01-01

    This study aims to evaluate the effect on killing efficacy of the intracellular trafficking patterns of alpha-particle emitters by using different radionuclide carriers in the setting of targeted antivascular alpha-radiotherapy. Nanocarriers (lipid vesicles) targeted to the prostate-specific-membrane-antigen (PSMA), which is unique to human neovasculature for a variety of solid tumors, were loaded with the alpha-particle generator actinium-225 and were compared to a PSMA-targeted radiolabeled antibody. Actinium-225 emits a total of four alpha-particles per decay, providing highly lethal and localized irradiation of targeted cells with minimal exposure to surrounding healthy tissues. Lipid vesicles were derivatized with two types of PSMA-targeting ligands: a fully human PSMA antibody (mAb), and a urea-based, low-molecular-weight agent. Target selectivity and extent of internalization were evaluated on monolayers of human endothelial cells (HUVEC) induced to express PSMA in static incubation conditions and in a flow field. Both types of radiolabeled PSMA-targeted vesicles exhibit similar killing efficacy, which is greater than the efficacy of the radiolabeled control mAb when compared on the basis of delivered radioactivity per cell. Fluorescence confocal microscopy demonstrates that targeted vesicles localize closer to the nucleus, unlike antibodies which localize near the plasma membrane. In addition, targeted vesicles cause larger numbers of DNA double strand breaks per nucleus of treated cells compared to the radiolabeled mAb. These findings demonstrate that radionuclide carriers, such as PSMA-targeted lipid-nanocarriers, which localize close to the nucleus increase the probability of alpha-particle trajectories crossing the nuclei, and, therefore, enhance the killing efficacy of alpha-particle emitters. PMID:26586724

  7. Analogue-to-Digital and Digital-to-Analogue Conversion.

    ERIC Educational Resources Information Center

    Gregory, Martin

    1997-01-01

    Discusses circuits for three-bit and four-bit analogue digital converters and digital analogue converters. These circuits feature slow operating speeds that enable the circuitry to be used to demonstrate the mode of operation using oscilloscopes and signal generators. (DDR)

  8. Design of multi-epitope, analogue-based cancer vaccines.

    PubMed

    Fikes, John D; Sette, Alessandro

    2003-09-01

    The current objective of our cancer programme is to develop an effective vaccine based on rationally designed T cell epitope analogues, for use in the adjuvant setting for non-small cell lung cancer (NSCLC) and colon cancer. Analogue epitopes, enhanced for either human leukocyte antigen (HLA) binding or T cell receptor (TCR) signalling, have been shown to be more effective at breaking immunological tolerance than cognate wild-type epitopes. Although encouraging early-phase clinical data has been obtained by others using a limited number of HLA-A2-restricted epitope analogues, the clinical benefits and immune correlates for vaccines comprised of multiple epitope analogues restricted by multiple HLA supertypes remains to be investigated. Clinical studies are currently being conducted on EP-2101, a prototype vaccine that delivers multiple HLA-A2-restricted analogue epitopes. In parallel, fixed anchor and heteroclitic analogues restricted by three other commonly expressed HLA supertypes are being identified. These analogues will be incorporated into future vaccines including optimised minigenes (epigenes) and tested in preclinical and clinical studies addressing various different cancer indications.

  9. A novel synthetic C-1 analogue of 7-deoxypancratistatin induces apoptosis in p53 positive and negative human colorectal cancer cells by targeting the mitochondria: enhancement of activity by tamoxifen.

    PubMed

    Ma, Dennis; Tremblay, Phillip; Mahngar, Kevinjeet; Akbari-Asl, Pardis; Collins, Jonathan; Hudlicky, Tomas; McNulty, James; Pandey, Siyaram

    2012-06-01

    The natural compound pancratistatin (PST), isolated from the Hymenocallis littoralis plant, specifically induces apoptosis in many cancer cell lines. Unlike many other chemotherapeutics, PST is not genotoxic and has minimal adverse effects on non-cancerous cells. However, its availability for preclinical and clinical work is limited due to its low availability in its natural source and difficulties in its chemical synthesis. Several synthetic analogues of 7-deoxypancratistatin with different modifications at C-1 were synthesized and screened for apoptosis inducing activity in human colorectal cancer (CRC) cells. We found that a C-1 acetoxymethyl derivative of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), was effective in inducing apoptosis in both p53 positive (HCT 116) and p53 negative (HT-29) human CRC cell lines, demonstrating similar efficacy to that of natural PST. JCTH-4 was able to decrease mitochondrial membrane potential (MMP), increase levels of reactive oxygen species in isolated mitochondria, cause release of the apoptogenic factor cytochrome c (Cyto c) from isolated mitochondria, and induce autophagy in HCT 116 and HT-29 cells. Interestingly, when JCTH-4 was administered with tamoxifen (TAM), there was an enhanced effect in apoptosis induction, reactive oxygen species (ROS) production and Cyto c release by isolated mitochondria, and autophagic induction by CRC cells. Minimal toxicity was exhibited by a normal human fetal fibroblast (NFF) and a normal colon fibroblast (CCD-18Co) cell line. Hence, JCTH-4 is a novel compound capable of selectively inducing apoptosis and autophagy in CRC cells alone and in combination with TAM and may serve as a safer and more effective alternative to current cancer therapies.

  10. Mammary Analogue Secretory Carcinoma.

    PubMed

    Stevens, Todd M; Parekh, Vishwas

    2016-09-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor that shares the same histologic appearance and ETV6 gene (12p13) rearrangement as secretory carcinoma of the breast. Prior to its recognition, MASC cases were commonly labeled acinic cell carcinoma and adenocarcinoma, not otherwise specified. Despite distinctive histologic features, MASC may be difficult to distinguish from other salivary gland tumors, in particular zymogen-poor acinic cell carcinoma and low-grade salivary duct carcinoma. Although characteristic morphologic and immunohistochemical features form the basis of a diagnosis of MASC, the presence of an ETV6-NTRK3 gene fusion is confirmatory. Given its recent recognition the true prognostic import of MASC is not yet clearly defined.

  11. New nucleotide analogues with enhanced signal properties.

    PubMed

    Cherkasov, Dmitry; Biet, Thorsten; Bäuml, Englbert; Traut, Walther; Lohoff, Michael

    2010-01-01

    We describe synthesis and testing of a novel type of dye-modified nucleotides which we call macromolecular nucleotides (m-Nucs). Macromolecular nucleotides comprise a nucleotide moiety, a macromolecular linear linker, and a large macromolecular ligand carrying multiple fluorescent dyes. With incorporation of the nucleotide moiety into the growing nucleic acid strand during enzymatic synthesis, the macromolecular ligand together with the coupled dyes is bound to the nucleic acid. By the use of this new class of modified nucleotides, signals from multiple dye molecules can be obtained after a single enzymatic incorporation event. The modified nucleotides are considered especially useful in the fields of nanobiotechnology, where signal stability and intensity is a limiting factor.

  12. NASA/ESMD Analogue Mission Plans

    NASA Technical Reports Server (NTRS)

    Hoffman, Stephen J.

    2007-01-01

    A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

  13. Analogue peptides for the immunotherapy of human acute myeloid leukemia.

    PubMed

    Hofmann, Susanne; Mead, Andrew; Malinovskis, Aleksandrs; Hardwick, Nicola R; Guinn, Barbara-Ann

    2015-11-01

    The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies.

  14. Fluorescent analogues of methotrexate: characterization and interaction with dihydrofolate reductase.

    PubMed

    Kumar, A A; Kempton, R J; Anstead, G M; Freisheim, J H

    1983-01-18

    The dansylated derivatives of lysine and ornithine analogues of methotrexate exhibit fluorescence properties characteristic of the dansyl moiety with an excitation at 328 nm and an emission maximum at 580 nm in aqueous media. As in the case of dansyl amino acids, the fluorescence emission is dependent upon the polarity of the medium. In solvents of low dielectric constant there is an enhancement of the dansyl fluorescence intensity as well as a shift to shorter wavelengths. The dansylated analogues show a reduction in the quantum yields as compared to N epsilon-dansyl-L-lysine and 5-(N,N-dimethylamino)-1-naphthalenesulfonic acid. The absorption spectra of the two dansyl analogues are similar to the spectra of the parent basic amino acid precursors but with reduced molar extinction values. The two fluorescent analogues of methotrexate were found to be potent inhibitors of purified dihydrofolate reductases from Lactobacillus casei and from chicken liver. The binding of these fluorescent analogues to either dihydrofolate reductase resulted in 10-15-nm blue shift of the ligand emission maxima and a 2-5-fold enhancement of the emission. These fluorescent properties of the bound ligands indicate a possible interaction of the dansyl moiety with a region on the enzyme molecule which is more hydrophobic relative to the surrounding solvent.

  15. Retro-1 Analogues Differentially Affect Oligonucleotide Delivery and Toxin Trafficking.

    PubMed

    Yang, Bing; Ming, Xin; Abdelkafi, Hajer; Pons, Valerie; Michau, Aurelien; Gillet, Daniel; Cintrat, Jean-Christophe; Barbier, Julien; Juliano, Rudy

    2016-11-21

    Retro-1 is a small molecule that displays two important biological activities: First, it blocks the actions of certain toxins by altering their intracellular trafficking. Second, it enhances the activity of oligonucleotides by releasing them from entrapment in endosomes. This raises the question of whether the two actions involve the same cellular target. Herein we report the effects of several Retro-1 analogues on both toxins and oligonucleotides. We found analogues that affect toxins but not oligonucleotides and vice-versa, while Retro-1 is the only compound that affects both. This indicates that the molecular target(s) involved in the two processes are distinct.

  16. 2-Substitution of adenine nucleotide analogues containing a bicyclo[3.1.0]hexane ring system locked in a northern conformation: enhanced potency as P2Y1 receptor antagonists.

    PubMed

    Kim, Hak Sung; Ohno, Michihiro; Xu, Bin; Kim, Hea Ok; Choi, Yongseok; Ji, Xiao D; Maddileti, Savitri; Marquez, Victor E; Harden, T Kendall; Jacobson, Kenneth A

    2003-11-06

    Preference for the northern (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of P2Y(1) receptors was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute (Nandanan et al. J. Med. Chem. 2000, 43, 829-842). We have now combined the ring-constrained (N)-methanocarba modification with other functionalities at the 2-position of the adenine moiety. A new synthetic route to this series of bisphosphate derivatives was introduced, consisting of phosphorylation of the pseudoribose moiety prior to coupling with the adenine base. The activity of the newly synthesized analogues was determined by measuring antagonism of 2-methylthio-ADP-stimulated phospholipase C (PLC) activity in 1321N1 human astrocytoma cells expressing the recombinant human P2Y(1) receptor and by using the radiolabeled antagonist [(3)H]2-chloro-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine 3',5'-bisphosphate 5 in a newly developed binding assay in Sf9 cell membranes. Within the series of 2-halo analogues, the most potent molecule at the hP2Y(1) receptor was an (N)-methanocarba N(6)-methyl-2-iodo analogue 12, which displayed a K(i) value in competition for binding of [(3)H]5 of 0.79 nM and a K(B) value of 1.74 nM for inhibition of PLC. Thus, 12 is the most potent antagonist selective for the P2Y(1) receptor yet reported. The 2-iodo group was substituted with trimethyltin, thus providing a parallel synthetic route for the introduction of an iodo group in this high-affinity antagonist. The (N)-methanocarba-2-methylthio, 2-methylseleno, 2-hexyl, 2-(1-hexenyl), and 2-(1-hexynyl) analogues bound less well, exhibiting micromolar affinity at P2Y(1) receptors. An enzymatic method of synthesis of the 3',5'-bisphosphate from the corresponding 3'-monophosphate, suitable for the preparation of a radiophosphorylated analogue, was explored.

  17. Fetal bovine serum influences the stability and bioactivity of resveratrol analogues: A polyphenol-protein interaction approach.

    PubMed

    Tang, Fen; Xie, Yixi; Cao, Hui; Yang, Hua; Chen, Xiaoqing; Xiao, Jianbo

    2017-03-15

    Fetal bovine serum (FBS) is a universal growth supplement of cell and tissue culture media. Herein, the influences of FBS on the stability and antioxidant activity of 21 resveratrol analogues were investigated using a polyphenol-protein interaction approach. The structure-stability relationships of resveratrol analogues in FBS showed a clear decrease in the stability of hydroxylated resveratrol analogues in the order: resorcinol-type>pyrogallol-type>catechol-type. The glycosylation and methoxylation of resveratrol analogues enhanced their stability. A linear relationship between the stability of resveratrol analogues in FBS and the affinity of resveratrol analogues-FBS interaction was found. The oxidation process is not the only factor governing the stability of resveratrol analogues in FBS. These results facilitated the insightful investigation of the role of polyphenol-protein interactions in serum, thereby providing some fundamental clues for future clinical research and pharmacological studies on natural small molecules.

  18. Self-Powered Analogue Smart Skin.

    PubMed

    Shi, Mayue; Zhang, Jinxin; Chen, Haotian; Han, Mengdi; Shankaregowda, Smitha A; Su, Zongming; Meng, Bo; Cheng, Xiaoliang; Zhang, Haixia

    2016-04-26

    The progress of smart skin technology presents unprecedented opportunities for artificial intelligence. Resolution enhancement and energy conservation are critical to improve the perception and standby time of robots. Here, we present a self-powered analogue smart skin for detecting contact location and velocity of the object, based on a single-electrode contact electrification effect and planar electrostatic induction. Using an analogue localizing method, the resolution of this two-dimensional smart skin can be achieved at 1.9 mm with only four terminals, which notably decreases the terminal number of smart skins. The sensitivity of this smart skin is remarkable, which can even perceive the perturbation of a honey bee. Meanwhile, benefiting from the triboelectric mechanism, extra power supply is unnecessary for this smart skin. Therefore, it solves the problems of batteries and connecting wires for smart skins. With microstructured poly(dimethylsiloxane) films and silver nanowire electrodes, it can be covered on the skin with transparency, flexibility, and high sensitivity.

  19. Neuronal Analogues of Conditioning Paradigms

    DTIC Science & Technology

    1984-04-24

    Although the mechanisms of interneuronal communication have been well established, the changes underlying most forms of learning have thus far eluded...stimulating electrodes on one of the connectives was adjusted so as to produce a small excitatory postsynaptic potential ( EPSP ) in the impaled cell...two stimuli would constitute a neuronal analogue of conditioning by producing an increased EPSP in response to the test stimulus alone. If so, then

  20. Substrate analogues for isoprenoid enzymes

    SciTech Connect

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  1. Synthesis and evaluation of heterocyclic analogues of bromoxynil.

    PubMed

    Cutulle, Matthew A; Armel, Gregory R; Brosnan, James T; Best, Michael D; Kopsell, Dean A; Bruce, Barry D; Bostic, Heidi E; Layton, Donovan S

    2014-01-15

    to have a different weed control spectrum compared to bromoxynil. A pyridine analogue of bromoxynil synthesized in this research controlled several weed species greater than bromoxynil itself, potentially due to enhanced binding within the PSII binding pocket. Future research should compare this analogue to bromoxynil using optimized formulations at higher application rates.

  2. Vitamin D analogues: Potential use in cancer treatment.

    PubMed

    Duffy, Michael J; Murray, Alyson; Synnott, Naoise C; O'Donovan, Norma; Crown, John

    2017-04-01

    The vitamin D receptor (VDR) is a member of the thyroid-steroid family of nuclear transcription factors. Following binding of the active form of vitamin D, i.e., 1,25(OH)2D3 (also known as calcitriol) and interaction with co-activators and co-repressors, VDR regulates the expression of several different genes. Although relatively little work has been carried out on VDR in human cancers, several epidemiological studies suggest that low circulating levels of vitamin D are associated with both an increased risk of developing specific cancer types and poor outcome in patients with specific diagnosed cancers. These associations apply especially in colorectal and breast cancer. Consistent with these findings, calcitriol as well as several of its synthetic analogues have been shown to inhibit tumor cell growth in vitro and in diverse animal model systems. Indeed, some of these vitamin D analogues with low calcemic inducing activity (e.g., EB1089, inecalcitol, paricalcitol) have progressed to clinical trials in patients with cancer. Preliminary results from these trials suggest that these vitamin D analogues have minimal toxicity, but clear evidence of efficacy remains to be shown. Although evidence of efficacy for mono-treatment with vitamin D analogues is currently lacking, several studies have reported that supplementation with calcitriol or the presence of high endogenous circulating levels of vitamin D enhances response to standard therapies.

  3. Systematic investigation of ion suppression and enhancement effects of fourteen stable-isotope-labeled internal standards by their native analogues using atmospheric-pressure chemical ionization and electrospray ionization and the relevance for multi-analyte liquid chromatographic/mass spectrometric procedures.

    PubMed

    Remane, Daniela; Wissenbach, Dirk K; Meyer, Markus R; Maurer, Hans H

    2010-04-15

    In clinical and forensic toxicology, multi-analyte procedures are very useful to quantify drugs and poisons of different classes in one run. For liquid chromatographic/tandem mass spectrometric (LC/MS/MS) multi-analyte procedures, often only a limited number of stable-isotope-labeled internal standards (SIL-ISs) are available. If an SIL-IS is used for quantification of other analytes, it must be excluded that the co-eluting native analyte influences its ionization. Therefore, the effect of ion suppression and enhancement of fourteen SIL-ISs caused by their native analogues has been studied. It could be shown that the native analyte concentration influenced the extent of ion suppression and enhancement effects leading to more suppression with increasing analyte concentration especially when electrospray ionization (ESI) was used. Using atmospheric-pressure chemical ionization (APCI), methanolic solution showed mainly enhancement effects, whereas no ion suppression and enhancement effect, with one exception, occurred when plasma extracts were used under these conditions. Such differences were not observed using ESI. With ESI, eleven SIL-ISs showed relevant suppression effects, but only one analyte showed suppression effects when APCI was used. The presented study showed that ion suppression and enhancement tests using matrix-based samples of different sources are essential for the selection of ISs, particularly if used for several analytes to avoid incorrect quantification. In conclusion, only SIL-ISs should be selected for which no suppression and enhancement effects can be observed. If not enough ISs are free of ionization interferences, a different ionization technique should be considered.

  4. Ecstasy analogues found in cacti.

    PubMed

    Bruhn, Jan G; El-Seedi, Hesham R; Stephanson, Nikolai; Beck, Olof; Shulgin, Alexander T

    2008-06-01

    Human interest in psychoactive phenethylamines is known from the use of mescaline-containing cacti and designer drugs such as Ecstasy. From the alkaloid composition of cacti we hypothesized that substances resembling Ecstasy might occur naturally. In this article we show that lophophine, homopiperonylamine and lobivine are new minor constituents of two cactus species, Lophophora williamsii (peyote) and Trichocereus pachanoi (San Pedro). This is the first report of putatively psychoactive phenethylamines besides mescaline in these cacti. A search for further biosynthetic analogues may provide new insights into the structure-activity relationships of mescaline. An intriguing question is whether the new natural compounds can be called "designer drugs."

  5. FUNCTION GENERATOR FOR ANALOGUE COMPUTERS

    DOEpatents

    Skramstad, H.K.; Wright, J.H.; Taback, L.

    1961-12-12

    An improved analogue computer is designed which can be used to determine the final ground position of radioactive fallout particles in an atomic cloud. The computer determines the fallout pattern on the basis of known wind velocity and direction at various altitudes, and intensity of radioactivity in the mushroom cloud as a function of particle size and initial height in the cloud. The output is then displayed on a cathode-ray tube so that the average or total luminance of the tube screen at any point represents the intensity of radioactive fallout at the geographical location represented by that point. (AEC)

  6. Template polymerization of nucleotide analogues

    NASA Technical Reports Server (NTRS)

    Orgel, L. E.

    1991-01-01

    Recent work on the template-directed reactions of the natural D-nucleotides has made it clear that l-nucleotides and nucleotide-like derivatives of other sugars would strongly inhibit the formation of long oligonucleotides. Consequently, attention is focusing on molecules simpler than nucleotides that might have acted as monomers of an information transfer system. We have begun a general exploration of the template directed reactions of diverse peptide analogues. I will present work by Dr. Taifeng Wu on oxidative oligomerization of phosphorothioates and of Dr. Mary Tohidi on the cyclic polymerization of nucleoside and related cyclic pyrophosphates.

  7. Choline Analogues in Malaria Chemotherapy

    PubMed Central

    Peyrottes, Suzanne; Caldarelli, Sergio; Wein, Sharon; Périgaud, Christian; Pellet, Alain; Vial, Henri

    2012-01-01

    Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches. PMID:22607139

  8. Cysteine analogues potentiate glucose-induced insulin release in vitro

    SciTech Connect

    Ammon, H.P.; Hehl, K.H.; Enz, G.; Setiadi-Ranti, A.; Verspohl, E.J.

    1986-12-01

    In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhance insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.

  9. Integration of inherent and induced chirality into subphthalocyanine analogue

    NASA Astrophysics Data System (ADS)

    Zhao, Luyang; Qi, Dongdong; Wang, Kang; Wang, Tianyu; Han, Bing; Tang, Zhiyong; Jiang, Jianzhuang

    2016-06-01

    Conventional conjugated systems are characteristic of only either inherent or induced chirality because of synthetic challenge in combination of chiral segment into the main chromophore. In this work, chiral binaphthyl segment is directly fused into the central chromophore of a subphthalocyanine skeleton, resulting in a novel type of chiral subphthalocyanine analogue (R/S)-1 of integrated inherent and induced chirality. Impressively, an obviously enhanced optical activity is discerned for (R/S)-1 molecules, and corresponding enhancement mechanism is elucidated in detail. The synthesis strategy based on rational molecular design will open the door towards fabrication of chiral materials with giant optical activity, which will have great potential in chiroptical devices.

  10. Electrostatic evaluation of isosteric analogues

    NASA Astrophysics Data System (ADS)

    Sayle, Roger; Nicholls, Anthony

    2006-04-01

    A method is presented for enumerating a large number of isosteric analogues of a ligand from a known protein-ligand complex structure and then rapidly calculating an estimate of their binding energies. This approach takes full advantage of the observed crystal structure, by reusing the atomic co-ordinates determined experimentally for one ligand, to approximate those of similar compounds that have approximately the same shape. By assuming that compounds with similar shapes adopt similar binding poses, and that entropic and protein flexibility effects are approximately constant across such an isosteric series ("the frozen ligand approximation"), it is possible to order their binding affinities relatively accurately. Additionally, the constraint that the atomic coordinates are invariant allows for a dramatic simplification in the Poisson-Boltzmann method used to calculation the electrostatic component of the binding energy. This algorithmic improvement allows for the calculation of tens of thousands of binding energies per second for drug-like molecules, enabling this technique to be used in screening large virtual libraries of isosteric analogues. Most significantly, this procedure is shown to be able to reproduce SAR effects of subtle medicinal chemistry substitutions. Finally, this paper reports the results of the proposed methodology on␣seven model systems; dihydrofolate reductase, Lck␣kinase, ribosome inactivating protein, l-arabinose binding protein, neuraminidase, HIV-1 reverse transcriptase and COX-2.

  11. The Valles natural analogue project

    SciTech Connect

    Stockman, H.; Krumhansl, J.; Ho, C.; McConnell, V.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  12. Heteroatom-Containing Porphyrin Analogues.

    PubMed

    Chatterjee, Tamal; Shetti, Vijayendra S; Sharma, Ritambhara; Ravikanth, Mangalampalli

    2017-02-22

    The heteroatom-containing porphyrin analogues or core-modified porphyrins that resulted from the replacement of one or two pyrrole rings with other five-membered heterocycles such as furan, thiophene, selenophene, tellurophene, indene, phosphole, and silole are highly promising macrocycles and exhibit quite different physicochemical properties compared to regular azaporphyrins. The properties of heteroporphyrins depend on the nature and number of different heterocycle(s) present in place of pyrrole ring(s). The heteroporphyrins provide unique and unprecedented coordination environments for metals. Unlike regular porphyrins, the monoheteroporphyrins are known to stabilize metals in unusual oxidation states such as Cu and Ni in +1 oxidation states. The diheteroporphyrins, which are neutral macrocycles without ionizable protons, also showed interesting coordination chemistry. Thus, significant progress has been made in last few decades on core-modified porphyrins in terms of their synthesis, their use in building multiporphyrin arrays for light-harvesting applications, their use as ligands to form interesting metal complexes, and also their use for several other studies. The synthetic methods available in the literature allow one to prepare mono- and diheteroporphyrins and their functionalized derivatives, which were used extensively to prepare several covalent and noncovalent heteroporphyrin-based multiporphyrin arrays. The methods are also developed to synthesize different hetero analogues of porphyrin derivatives such as heterocorroles, heterochlorins, heterocarbaporphyrinoids, heteroatom-substituted confused porphyrins, and so on. This Review summarizes the key developments that have occurred in heteroporphyrin chemistry over the last four decades.

  13. AaeAP1 and AaeAP2: novel antimicrobial peptides from the venom of the scorpion, Androctonus aeneas: structural characterisation, molecular cloning of biosynthetic precursor-encoding cDNAs and engineering of analogues with enhanced antimicrobial and anticancer activities.

    PubMed

    Du, Qiang; Hou, Xiaojuan; Wang, Lei; Zhang, Yingqi; Xi, Xinping; Wang, Hui; Zhou, Mei; Duan, Jinao; Wei, Minjie; Chen, Tianbao; Shaw, Chris

    2015-01-23

    The main functions of the abundant polypeptide toxins present in scorpion venoms are the debilitation of arthropod prey or defence against predators. These effects are achieved mainly through the blocking of an array of ion channel types within the membranes of excitable cells. However, while these ion channel-blocking toxins are tightly-folded by multiple disulphide bridges between cysteine residues, there are additional groups of peptides in the venoms that are devoid of cysteine residues. These non-disulphide bridged peptides are the subject of much research interest, and among these are peptides that exhibit antimicrobial activity. Here, we describe two novel non-disulphide-bridged antimicrobial peptides that are present in the venom of the North African scorpion, Androctonus aeneas. The cDNAs encoding the biosynthetic precursors of both peptides were cloned from a venom-derived cDNA library using 3'- and 5'-RACE strategies. Both translated precursors contained open-reading frames of 74 amino acid residues, each encoding one copy of a putative novel nonadecapeptide, whose primary structures were FLFSLIPSVIAGLVSAIRN and FLFSLIPSAIAGLVSAIRN, respectively. Both peptides were C-terminally amidated. Synthetic versions of each natural peptide displayed broad-spectrum antimicrobial activities, but were devoid of antiproliferative activity against human cancer cell lines. However, synthetic analogues of each peptide, engineered for enhanced cationicity and amphipathicity, exhibited increases in antimicrobial potency and acquired antiproliferative activity against a range of human cancer cell lines. These data clearly illustrate the potential that natural peptide templates provide towards the design of synthetic analogues for therapeutic exploitation.

  14. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-11-08

    Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

  15. Macrolactam analogues of macrolide natural products.

    PubMed

    Hügel, Helmut M; Smith, Andrew T; Rizzacasa, Mark A

    2016-12-07

    The chemical modification of macrolide natural products into aza- or lactam analogues is a strategy employed to improve their metabolic stability and biological activity. The methods for the synthesis of several lactam analogues of macrolide natural products are highlighted and aspects of their biological properties presented.

  16. Identification of a new tadalafil analogue in commercial dietary supplements: isopropylnortadalafil.

    PubMed

    Park, Han Na; Lee, Ji Hyun; Park, Sung-Kwan; Lee, Jongkook; Baek, Sun Young

    2017-02-01

    A new tadalafil analogue was found in a commercial dietary supplement for enhancing sexual performance. The compound was detected by a high-performance liquid chromatography-diode array detector (HPLC-DAD). The analogue was isolated using semi-preparative HPLC, and its accurate mass was established by two LC-high-resolution-mass spectrometers (LC-HRMS). The structure was determined by nuclear magnetic resonance (NMR) spectroscopy. The accurate mass of the compound corresponded to a molecular formula of C24H23N3O4. The compound was identified as a structural analogue of tadalafil in which the N-methyl group of tadalafil was replaced with an N-isopropyl group. We have named the new analogue isopropylnortadalafil and it is first reported herein.

  17. The future of somatostatin analogue therapy.

    PubMed

    Stewart, P M; James, R A

    1999-10-01

    Since its discovery almost 30 years ago, the mode of action and therapeutic applications of somatostatin have been defined. In particular the cloning and characterization of somatostatin receptor subtypes has facilitated the development of high affinity analogues. In the context of pituitary disease, long-acting somatostatin analogues (octreotide, lanreotide) have been used to treat a variety of pituitary tumours but are most efficacious for the treatment of GH and TSH-secreting adenomas. In patients with acromegaly, depot preparations of these analogues are administered intramuscularly every 10-28 days and provide consistent suppression of GH levels to < 5 mU/l in approximately 50-65% of all cases. Even more specific somatostatin receptor analogues are under development. Finally, radiolabelled somatostatin analogue scintigraphy and, in larger doses, therapy, are now established tools in the evaluation and treatment of neuroendocrine tumours.

  18. Continuous analogues of matrix factorizations

    PubMed Central

    Townsend, Alex; Trefethen, Lloyd N.

    2015-01-01

    Analogues of singular value decomposition (SVD), QR, LU and Cholesky factorizations are presented for problems in which the usual discrete matrix is replaced by a ‘quasimatrix’, continuous in one dimension, or a ‘cmatrix’, continuous in both dimensions. Two challenges arise: the generalization of the notions of triangular structure and row and column pivoting to continuous variables (required in all cases except the SVD, and far from obvious), and the convergence of the infinite series that define the cmatrix factorizations. Our generalizations of triangularity and pivoting are based on a new notion of a ‘triangular quasimatrix’. Concerning convergence of the series, we prove theorems asserting convergence provided the functions involved are sufficiently smooth. PMID:25568618

  19. Fully analogue photonic reservoir computer.

    PubMed

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-03-03

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers.

  20. Fully analogue photonic reservoir computer

    PubMed Central

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-01-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers. PMID:26935166

  1. Synthesis and antioxidant activity of peptide-based ebselen analogues.

    PubMed

    Satheeshkumar, Kandhan; Mugesh, Govindasamy

    2011-04-18

    A series of di- and tripeptide-based ebselen analogues has been synthesized. The compounds were characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2) , tert-butyl hydroperoxide (tBuOOH), and cumene hydroperoxide (Cum-OOH) as substrates, and glutathione (GSH) as a cosubstrate. Although all the peptide-based compounds have a selenazole ring similar to that of ebselen, the GPx activity of these compounds highly depends on the nature of the peptide moiety attached to the nitrogen atom of the selenazole ring. It was observed that the introduction of a phenylalanine (Phe) amino acid residue in the N-terminal reduces the activity in all three peroxide systems. On the other hand, the introduction of aliphatic amino acid residues such as valine (Val) significantly enhances the GPx activity of the ebselen analogues. The difference in the catalytic activity of dipeptide-based ebselen derivatives can be ascribed mainly to the change in the reactivity of these compounds toward GSH and peroxide. Although the presence of the Val-Ala-CO(2) Me moiety facilitates the formation of a catalytically active selenol species, the reaction of ebselen analogues that has a Phe-Ile-CO(2) Me residue with GSH does not generate the corresponding selenol. To understand the antioxidant activity of the peptide-based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN-scavenging activity of the Phe-based peptide analogues was found to be comparable to that of the Val-based compounds. However, the introduction of an additional Phe residue to the ebselen analogue that had a Val-Ala dipeptide significantly reduced the potency of the parent compound in PN-mediated nitration.

  2. Stereochemical Assignment of Strigolactone Analogues Confirms Their Selective Biological Activity.

    PubMed

    Artuso, Emma; Ghibaudi, Elena; Lace, Beatrice; Marabello, Domenica; Vinciguerra, Daniele; Lombardi, Chiara; Koltai, Hinanit; Kapulnik, Yoram; Novero, Mara; Occhiato, Ernesto G; Scarpi, Dina; Parisotto, Stefano; Deagostino, Annamaria; Venturello, Paolo; Mayzlish-Gati, Einav; Bier, Ariel; Prandi, Cristina

    2015-11-25

    Strigolactones (SLs) are new plant hormones with various developmental functions. They are also soil signaling chemicals that are required for establishing beneficial mycorrhizal plant/fungus symbiosis. In addition, SLs play an essential role in inducing seed germination in root-parasitic weeds, which are one of the seven most serious biological threats to food security. There are around 20 natural SLs that are produced by plants in very low quantities. Therefore, most of the knowledge on SL signal transduction and associated molecular events is based on the application of synthetic analogues. Stereochemistry plays a crucial role in the structure-activity relationship of SLs, as compounds with an unnatural D-ring configuration may induce biological effects that are unrelated to SLs. We have synthesized a series of strigolactone analogues, whose absolute configuration has been elucidated and related with their biological activity, thus confirming the high specificity of the response. Analogues bearing the R-configured butenolide moiety showed enhanced biological activity, which highlights the importance of this stereochemical motif.

  3. Noble gas encapsulation: clathrate hydrates and their HF doped analogues.

    PubMed

    Mondal, Sukanta; Chattaraj, Pratim Kumar

    2014-09-07

    The significance of clathrate hydrates lies in their ability to encapsulate a vast range of inert gases. Although the natural abundance of a few noble gases (Kr and Xe) is poor their hydrates are generally abundant. It has already been reported that HF doping enhances the stability of hydrogen hydrates and methane hydrates, which prompted us to perform a model study on helium, neon and argon hydrates with their HF doped analogues. For this purpose 5(12), 5(12)6(8) and their HF doped analogues are taken as the model clathrate hydrates, which are among the building blocks of sI, sII and sH types of clathrate hydrate crystals. We use the dispersion corrected and gradient corrected hybrid density functional theory for the calculation of thermodynamic parameters as well as conceptual density functional theory based reactivity descriptors. The method of the ab initio molecular dynamics (AIMD) simulation is used through atom centered density matrix propagation (ADMP) techniques to envisage the structural behaviour of different noble gas hydrates on a 500 fs timescale. Electron density analysis is carried out to understand the nature of Ng-OH2, Ng-FH and Ng-Ng interactions. The current results noticeably demonstrate that the noble gas (He, Ne, and Ar) encapsulation ability of 5(12), 5(12)6(8) and their HF doped analogues is thermodynamically favourable.

  4. Plant Volatile Analogues Strengthen Attractiveness to Insect

    PubMed Central

    Sun, Yufeng; Yu, Hao; Zhou, Jing-Jiang; Pickett, John A.; Wu, Kongming

    2014-01-01

    Green leaf bug Apolygus lucorum (Meyer-Dür) is one of the major pests in agriculture. Management of A. lucorum was largely achieved by using pesticides. However, the increasing population of A. lucorum since growing Bt cotton widely and the increased awareness of ecoenvironment and agricultural product safety makes their population-control very challenging. Therefore this study was conducted to explore a novel ecological approach, synthetic plant volatile analogues, to manage the pest. Here, plant volatile analogues were first designed and synthesized by combining the bioactive components of β-ionone and benzaldehyde. The stabilities of β-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than β-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than β-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety. PMID:24911460

  5. OptZyme: Computational Enzyme Redesign Using Transition State Analogues

    PubMed Central

    Grisewood, Matthew J.; Gifford, Nathanael P.; Pantazes, Robert J.; Li, Ye; Cirino, Patrick C.; Janik, Michael J.; Maranas, Costas D.

    2013-01-01

    OptZyme is a new computational procedure for designing improved enzymatic activity (i.e., kcat or kcat/KM) with a novel substrate. The key concept is to use transition state analogue compounds, which are known for many reactions, as proxies for the typically unknown transition state structures. Mutations that minimize the interaction energy of the enzyme with its transition state analogue, rather than with its substrate, are identified that lower the transition state formation energy barrier. Using Escherichia coli β-glucuronidase as a benchmark system, we confirm that KM correlates (R2 = 0.960) with the computed interaction energy between the enzyme and the para-nitrophenyl- β, D-glucuronide substrate, kcat/KM correlates (R2 = 0.864) with the interaction energy of the transition state analogue, 1,5-glucarolactone, and kcat correlates (R2 = 0.854) with a weighted combination of interaction energies with the substrate and transition state analogue. OptZyme is subsequently used to identify mutants with improved KM, kcat, and kcat/KM for a new substrate, para-nitrophenyl- β, D-galactoside. Differences between the three libraries reveal structural differences that underpin improving KM, kcat, or kcat/KM. Mutants predicted to enhance the activity for para-nitrophenyl- β, D-galactoside directly or indirectly create hydrogen bonds with the altered sugar ring conformation or its substituents, namely H162S, L361G, W549R, and N550S. PMID:24116038

  6. Space analogue studies in Antarctica

    NASA Astrophysics Data System (ADS)

    Lugg, D.; Shepanek, M.

    1999-09-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mltogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  7. Condensed matter analogues of cosmology

    NASA Astrophysics Data System (ADS)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the

  8. Space analogue studies in Antarctica.

    PubMed

    Lugg, D; Shepanek, M

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  9. Space analogue studies in Antarctica

    NASA Technical Reports Server (NTRS)

    Lugg, D.; Shepanek, M.

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  10. Design, multicomponent synthesis, and bioactivities of novel neonicotinoid analogues with 1,4-dihydropyridine scaffold.

    PubMed

    Zhang, Wenwen; Yang, Xiaobao; Chen, Weidong; Xu, Xiaoyong; Li, Lu; Zhai, Hongbin; Li, Zhong

    2010-03-10

    Novel neonicotinoid analogues bearing a 1,4-dihydropridine scaffold were designed and synthesized by multicomponent reactions (MCRs) to enhance pi-pi stacking. The synthesized compounds were identified by (1)H NMR, (13)C NMR, high-resolution mass spectroscopy, and elemental analysis. Bioassay tests showed that some of them exhibited high insecticidal activities against pea aphid ( Aphis craccivora ).

  11. Glucagonlike Peptide 2 Analogue Teduglutide

    PubMed Central

    Chaturvedi, Lakshmi S.; Basson, Marc D.

    2015-01-01

    IMPORTANCE Short bowel syndrome occurs when a shortened intestine cannot absorb sufficient nutrients or fluids. Teduglutide is a recombinant analogue of human glucagonlike peptide 2 that reduces dependence on parenteral nutrition in patients with short bowel syndrome by promoting enterocytic proliferation, increasing the absorptive surface area. However, enterocyte function depends not only on the number of cells that are present but also on differentiated features that facilitate nutrient absorption and digestion. OBJECTIVE To test the hypothesis that teduglutide impairs human intestinal epithelial differentiation. DESIGN AND SETTING We investigated the effects of teduglutide in the modulation of proliferation and differentiation in human Caco-2 intestinal epithelial cells at a basic science laboratory. This was an in vitro study using Caco-2 cells, a human-derived intestinal epithelial cell line commonly used to model enterocytic biology. EXPOSURE Cells were exposed to teduglutide or vehicle control. MAINOUTCOMESAND MEASURES We analyzed the cell cycle by bromodeoxyuridine incorporation or propidium iodide staining and flow cytometry and measured cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. We used quantitative reverse transcription–polymerase chain reaction to assay the expression of the enterocytic differentiation markers villin, sucrase-isomaltase, glucose transporter 2 (GLUT2), and dipeptidyl peptidase 4 (DPP-4), as well as that of the putative differentiation signals schlafen 12 (SLFN12) and caudal-related homeobox intestine-specific transcription factor (Cdx2). Villin promoter activity was measured by a luciferase-based assay. RESULTS The MTS assay demonstrated that teduglutide increased cell numbers by a mean (SD) of 10% (2%) over untreated controls at a maximal 500nM (n = 6, P < .05). Teduglutide increased bromodeoxyuridine-positive cells vs untreated controls by a mean (SD

  12. On the mechanical analogue of DNA.

    PubMed

    Yakushevich, Ludmila

    2017-03-01

    The creation of mechanical analogues of biological systems is known as a useful instrument that helps to understand better the dynamical mechanisms of the functioning of living organisms. Mechanical analogues of biomolecules are usually constructed for imitation of their internal mobility, which is one of the most important properties of the molecules. Among the different types of internal motions, angular oscillations of nitrous bases are of special interest because they make a substantial contribution to the base pairs opening that in turn is an important element of the process of the DNA-protein recognition. In this paper, we investigate the possibility to construct a mechanical analogue for imitation of angular oscillations of nitrous bases in inhomogeneous DNA. It is shown that the analogue has the form of a mechanical chain of non-identical pendulums that oscillate in the gravitational field of the Earth and coupled by identical springs. The masses and lengths of pendulums, as well as the distances between neighboring pendulums and the rigidity of springs are calculated. To illustrate the approach, we present the result of construction of the mechanical analogue of the fragment of the sequence of bacteriophage T7D.

  13. Analogue Downscaling of Seasonal Rainfall Forecasts

    NASA Astrophysics Data System (ADS)

    Charles, A. N.; Timbal, B.; Hendon, H.

    2010-12-01

    We have taken an existing statistical downscaling model (SDM), based on meteorological analogues that was developed for downscaling climate change projections (Timbal et al 2009), and applied it in the seasonal forecasting context to produce downscaled rainfall hindcasts from a coupled model seasonal forecast system (POAMA). Downscaling of POAMA forecasts is required to provide seasonal climate information at local scales of interest. Analogue downscaling is a simple technique to generate rainfall forecasts appropriate to the local scale by conditioning on the large scale predicted GCM circulation and the local topography and climate. Analogue methods are flexible and have been shown to produce good results when downscaling 20th century South Eastern Australian rainfall output from climate models. A set of re-forecasts for three month rainfall at 170 observing stations in the South Murray Darling region of Australia were generated using predictors from the POAMA re-forecasts as input for the analogue SDM. The predictors were optimised over a number of different GCMS in previous climate change downscaling studies. Downscaling with the analogue SDM results in predicted rainfall with realistic variance while maintaining the modest predictive skill of the dynamical model. Evaluation of the consistency between the large scale mean of downscaled and direct GCM output precipitation is encouraging.

  14. Design, synthesis and biological evaluation of bambuterol analogues as novel inhibitors of butyrylcholinesterase.

    PubMed

    Wu, Jie; Tian, Yiguang; Wang, Shanping; Pistolozzi, Marco; Jin, Ya; Zhou, Ting; Roy, Gaurab; Xu, Ling; Tan, Wen

    2017-01-27

    An increase activity of butyrylcholinesterase is believed to contribute to Alzheimer's disease. Bambuterol is a known potent inhibitor of butyrylcholinesterase, but it has undesired cardiac effects and less lipophilicity. Thirteen bambuterol analogues were synthesized using 1-(3, 5-dihydroxyphenyl) ethanone as a starting material. In-vitro cholinesterase assay established that the majority of the compounds are specific butyrylcholinesterase inhibitors. Out of the 13 compounds, two bambuterol derivatives, BD-6 and BD-11 exhibited similar efficacies in inhibiting butyrylcholinesterase with fewer effects on heart and enhanced possibilities of permeating through the blood-brain barrier as compared to bambuterol. These bambuterol analogues may provide better alternatives for treatments of Alzheimer's disease.

  15. Integration of inherent and induced chirality into subphthalocyanine analogue

    PubMed Central

    Zhao, Luyang; Qi, Dongdong; Wang, Kang; Wang, Tianyu; Han, Bing; Tang, Zhiyong; Jiang, Jianzhuang

    2016-01-01

    Conventional conjugated systems are characteristic of only either inherent or induced chirality because of synthetic challenge in combination of chiral segment into the main chromophore. In this work, chiral binaphthyl segment is directly fused into the central chromophore of a subphthalocyanine skeleton, resulting in a novel type of chiral subphthalocyanine analogue (R/S)-1 of integrated inherent and induced chirality. Impressively, an obviously enhanced optical activity is discerned for (R/S)-1 molecules, and corresponding enhancement mechanism is elucidated in detail. The synthesis strategy based on rational molecular design will open the door towards fabrication of chiral materials with giant optical activity, which will have great potential in chiroptical devices. PMID:27294871

  16. Bisphenol A and its analogues disrupt centrosome cycle and microtubule dynamics in prostate cancer.

    PubMed

    Ho, Shuk-Mei; Rao, Rahul; To, Sarah; Schoch, Emma; Tarapore, Pheruza

    2017-02-01

    Humans are increasingly exposed to structural analogues of bisphenol A (BPA), as BPA is being replaced by these compounds in BPA-free consumer products. We have previously shown that chronic and developmental exposure to BPA is associated with increased prostate cancer (PCa) risk in human and animal models. Here, we examine whether exposure of PCa cells (LNCaP, C4-2) to low-dose BPA and its structural analogues (BPS, BPF, BPAF, TBBPA, DMBPA and TMBPA) affects centrosome amplification (CA), a hallmark of cancer initiation and progression. We found that exposure to BPA, BPS, DMBPA and TBBPA, in descending order, increased the number of cells with CA, in a non-monotonic dose-response manner. Furthermore, cells treated with BPA and their analogues initiated centrosome duplication at 8 h after release from serum starvation, significantly earlier in G-1 phase than control cells. This response was attended by earlier release of nucleophosmin from unduplicated centrosomes. BPA-exposed cells exhibited increased expression of cyclin-dependent kinase CDK6 and decreased expression of CDK inhibitors (p21(Waf1/CIP1) and p27(KIP1)). Using specific antagonists for estrogen/androgen receptors, CA in the presence of BPA or its analogues was likely to be mediated via ESR1 signaling. Change in microtubule dynamics was observed on exposure to these analogues, which, for BPA, was accompanied by increased expression of centrosome-associated protein CEP350 Similar to BPA, chronic treatment of cells with DMBPA, but not other analogues, resulted in the enhancement of anchorage-independent growth. We thus conclude that selected BPA analogues, similar to BPA, disrupt centrosome function and microtubule organization, with DMBPA displaying the broadest spectrum of cancer-promoting effects.

  17. The Structure-Activity Relationship of Glycosaminoglycans and Their Analogues with β-Amyloid Peptide.

    PubMed

    Zhou, Xiang; Jin, Lan

    2016-01-01

    Alzheimer's disease (AD) is a serious neurodegenerative disorder. β-amyloid peptide (Aβ) aggregation is believed to be the major cause of the disease. The process of Aβ aggregation can be enhanced by sulfated glycosaminoglycans. However, cell experiments have shown that sulfated glycosaminoglycan oligosaccharides or analogues may have significant neuroprotective properties and could inhibit the aggregation by competitive inhibition. The length and species of oligosaccharides or analogues can inhibit the toxicity of Aβ by inducing conformational changes of proteins in different manners. This review presents the conformational changes of Aβ in the presence of glycosaminoglycan, glycosaminoglycan oligosaccharides and analogues. The review might be helpful to comprehend the mechanism of β-amyloid fibrillations and the aggregation process.

  18. Membrane-Targeting DCAP Analogues with Broad-Spectrum Antibiotic Activity against Pathogenic Bacteria.

    PubMed

    Hurley, Katherine A; Heinrich, Victoria A; Hershfield, Jeremy R; Demons, Samandra T; Weibel, Douglas B

    2015-04-09

    We performed a structure-activity relationship study of 2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3-diol (DCAP), which is an antibacterial agent that disrupts the membrane potential and permeability of bacteria. The stereochemistry of DCAP had no effect on the biological activity of DCAP. The aromaticity and electronegativity of the chlorine-substituted carbazole was required for activity, suggesting that its planar and dipolar characteristics orient DCAP in membranes. Increasing the hydrophobicity of the tail region of DCAP enhanced its antibiotic activity. Two DCAP analogues displayed promising antibacterial activity against the BSL-3 pathogens Bacillus anthracis and Francisella tularensis. Codosing DCAP analogues with ampicillin or kanamycin increased their potency. These studies demonstrate that DCAP and its analogues may be a promising scaffold for developing chemotherapeutic agents that bind to bacterial membranes and kill strains of slow-growing or dormant bacteria that cause persistent infections.

  19. Classical Simulated Annealing Using Quantum Analogues

    NASA Astrophysics Data System (ADS)

    La Cour, Brian R.; Troupe, James E.; Mark, Hans M.

    2016-08-01

    In this paper we consider the use of certain classical analogues to quantum tunneling behavior to improve the performance of simulated annealing on a discrete spin system of the general Ising form. Specifically, we consider the use of multiple simultaneous spin flips at each annealing step as an analogue to quantum spin coherence as well as modifications of the Boltzmann acceptance probability to mimic quantum tunneling. We find that the use of multiple spin flips can indeed be advantageous under certain annealing schedules, but only for long anneal times.

  20. Insulin analogues: action profiles beyond glycaemic control.

    PubMed

    Eckardt, Kristin; Eckel, Jürgen

    2008-02-01

    A variety of studies have documented significant improvements in the treatment of type 1 and 2 diabetes after the introduction of artificial insulins. This review gives an overview of insulin analogues which are currently approved for therapeutical use. Clinical data regarding the efficiency to control blood glucose level as well as improving HbA1c level in comparison to conventional insulin preparations in type 1 and 2 diabetic patients are summarized. Furthermore, special features of insulin analogues regarding their signalling properties are discussed with focus on the proliferative effects of insulin glargine as well as some recent data of insulin detemir.

  1. Reactions of trimethylphosphine analogues of auranofin with bovine serum albumin

    SciTech Connect

    Isab, A.A.; Shaw, C.F. III; Hoeschele, J.D.; Locke, J.

    1988-10-05

    The reactions of bovine serum albumin (BSA) with (trimethylphosphine)(2,3,4,6-tetra-O-acetyl-1-thio-..beta..-D-glucopyranosato-S)gold(I), Me/sub 3/PAuSAtg, and its chloro analogue, Me/sub 3/PAuCl, were studied to develop insights into the role of the phosphine ligand in the serum chemistry of the related antiarthritic drug auranofin (triethylphosphine)(2,3,4,6-tetra-O-acetyl-1-thio-..beta..-D-glucopyranosato-S)gold(I). /sup 31/P NMR spectroscopy, protein modification, and gel-exclusion chromatography methods were employed. Comparison of the reactions of the methyl derivatives to the previously reported reactions of auranofin and Et/sub 3/PAuCl with BSA demonstrated that similar chemical species are formed but revealed three major differences. Despite these differences, the results for the methyl analogues provide important confirmation for previously developed chemical models of auranofin reactions in serum. Me/sub 3/PO was not observed in reaction mixtures lacking tetraacetylthioglucose (AtgSH); this result affirms the role of AtgSH, displaced by the reaction of Me/sub 3/PAuSAtg at Cys-34, in the generation of the phosphine oxide (an important metabolite in vivo). The weak binding sites on albumin react with Me/sub 3/PAuCl, but not Me/sub 3/PAuSAtg, demonstrating the importance of the strength and reactivity of the anionic ligand-gold bond on the reactions of auranofin analogues. The gold binding capacity of albumin is enhanced after Me/sub 3/PO is formed, consistent with reductive cleavage of albumin disulfide bonds by trimethylphosphine. 24 references, 2 figures, 3 tables.

  2. Induction of apoptosis in cholangiocarcinoma by an andrographolide analogue is mediated through topoisomerase II alpha inhibition.

    PubMed

    Nateewattana, Jintapat; Dutta, Suman; Reabroi, Somrudee; Saeeng, Rungnapha; Kasemsook, Sakkasem; Chairoungdua, Arthit; Weerachayaphorn, Jittima; Wongkham, Sopit; Piyachaturawat, Pawinee

    2014-01-15

    Cholangiocarcinoma (CCA), the common primary malignant tumor of bile duct epithelial cells, is unresponsive to most chemotherapeutic drugs. Diagnosis with CCA has a poor prognosis, and therefore urgently requires effective therapeutic agents. In the present study we investigated anti-cancer effects of andrographolide analogue 3A.1 (19-tert-butyldiphenylsilyl-8, 17-epoxy andrographolide) and its mechanism in human CCA cell line KKU-M213 derived from a Thai CCA patient. By 24h after exposure, the analogue 3A.1 exhibited a potent cytotoxic effect on KKU-M213 cells with an inhibition concentration 50 (IC50) of approximately 8.0µM. Analogue 3A.1 suppressed DNA topoisomerase II α (Topo II α) protein expression, arrested the cell cycle at sub G0/G1 phase, induced cleavage of DNA repair protein poly (ADP-ribose) polymerases-1 (PARP-1), and enhanced expression of tumor suppressor protein p53 and pro-apoptotic protein Bax. In addition, analogue 3A.1 induced caspase 3 activity and inhibited cyclin D1, CDK6, and COX-2 protein expression. These results suggest that andrographolide analogue 3A.1, a novel topo II inhibitor, has significant potential to be developed as a new anticancer agent for the treatment of CCA.

  3. Dumb holes: analogues for black holes.

    PubMed

    Unruh, W G

    2008-08-28

    The use of sonic analogues to black and white holes, called dumb or deaf holes, to understand the particle production by black holes is reviewed. The results suggest that the black hole particle production is a low-frequency and low-wavenumber process.

  4. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    2010-03-01

    Project overview provides background on carbonic anhydrase transport mechanism for CO2 in the human body and proposed approach for ARPA-E project to create a synthetic enzyme analogue and utilize it in a membrane for CO2 capture from flue gas.

  5. Solanapyrone analogues from a Hawaiian fungicolous fungus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Four new solanayrone analogues (solanapyrones J-M; 1-4) have been isolated from an unidentified fungicolous fungus collected in Hawaii. The structures and relative configurations of these compounds were determined by analysis of ID NMR, 2D NMR, and MS data. Solanapyrone J(1) showed antifungal acti...

  6. [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1.

    PubMed

    Cai, Yunxin; Lu, Dandan; Chen, Zhen; Ding, Yi; Chung, Nga N; Li, Tingyou; Schiller, Peter W

    2016-08-01

    Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2',6'-dialkylated Tyr analogues, including 2',4',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2'-isopropyl-6'-methyltyrosine (Imt) and 2',6'-diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt(1)-, Emt(1) and Det(1)-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt(1)- and Emt(1)-analogues showed improved antioxidant activity compared to the Dmt(1)-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment.

  7. Tryptophan analogues. 1. Synthesis and antihypertensive activity of positional isomers.

    PubMed

    Safdy, M E; Kurchacova, E; Schut, R N; Vidrio, H; Hong, E

    1982-06-01

    A series of tryptophan analogues having the carboxyl function at the beta-position was synthesized and tested for antihypertensive activity. The 5-methoxy analogue 46 exhibited antihypertensive activity in the rat via the oral route and was much more potent than the normal tryptophan analogue. The methyl ester was found to be a critical structural feature for activity.

  8. Vitamin D(3) enhances ATRA-mediated neurosteroid biosynthesis in human glioma GI-1 cells.

    PubMed

    Yagishita, Toshiaki; Kushida, Akira; Tamura, Hiroomi

    2012-09-01

    Emerging evidence indicates that vitamin D (VD) is an important modulator of brain development and function. To investigate whether VD modulates neurosteroid biosynthesis in neural cells, we investigated the effect of VD(3) on steroidogenic gene expression in human glioma GI-1 cells. We found that VD(3) enhanced CYP11A1 and 3β-hydroxysteroid dehydrogenase gene expression. The induction of CYP11A1 gene expression by VD(3) was dose- and incubation time-dependent. Calcipotriol, a VD(3) receptor (VDR) agonist, also induced CYP11A1 gene expression in GI-1 cells, indicating that VDR is involved in this induction. The induction of progesterone (PROG) de novo synthesis was observed along with the induction of steroidogenic genes by VD(3). Furthermore, VD(3) enhanced all-trans retinoic acid (ATRA)-induced CYP11A1 gene expression and PROG production. This suggests cooperative regulation of steroidogenic gene expression by the two fat-soluble vitamins, A and D. In addition, a mixed culture of neuronal IMR-32 cells and GI-1 cells treated with ATRA and VD(3) resulted in the induction of PROG-responsive gene expression in the IMR-32 cells. This result shows a paracrine action of PROG that is induced in and released by the GI-1 cells. The relationship between neurological dysfunction associated with VD deficiency and neurosteroid induction by VD is discussed.

  9. Optimization of propafenone analogues as antimalarial leads.

    PubMed

    Lowes, David J; Guiguemde, W Armand; Connelly, Michele C; Zhu, Fangyi; Sigal, Martina S; Clark, Julie A; Lemoff, Andrew S; Derisi, Joseph L; Wilson, Emily B; Guy, R Kiplin

    2011-11-10

    Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

  10. Enzymatic synthesis of lipid II and analogues.

    PubMed

    Huang, Lin-Ya; Huang, Shih-Hsien; Chang, Ya-Chih; Cheng, Wei-Chieh; Cheng, Ting-Jen R; Wong, Chi-Huey

    2014-07-28

    The emergence of antibiotic resistance has prompted active research in the development of antibiotics with new modes of action. Among all essential bacterial proteins, transglycosylase polymerizes lipid II into peptidoglycan and is one of the most favorable targets because of its vital role in peptidoglycan synthesis. Described in this study is a practical enzymatic method for the synthesis of lipid II, coupled with cofactor regeneration, to give the product in a 50-70% yield. This development depends on two key steps: the overexpression of MraY for the synthesis of lipid I and the use of undecaprenol kinase for the preparation of polyprenol phosphates. This method was further applied to the synthesis of lipid II analogues. It was found that MraY and undecaprenol kinase can accept a wide range of lipids containing various lengths and configurations. The activity of lipid II analogues for bacterial transglycolase was also evaluated.

  11. A microenvironment-sensitive fluorescent pyrimidine ribonucleoside analogue: synthesis, enzymatic incorporation, and fluorescence detection of a DNA abasic site.

    PubMed

    Tanpure, Arun A; Srivatsan, Seergazhi G

    2011-11-04

    Base-modified fluorescent ribonucleoside-analogue probes are valuable tools in monitoring RNA structure and function because they closely resemble the structure of natural nucleobases. Especially, 2-aminopurine, a highly environment-sensitive adenosine analogue, is the most extensively utilized fluorescent nucleoside analogue. However, only a few isosteric pyrimidine ribonucleoside analogues that are suitable for probing the structure and recognition properties of RNA molecules are available. Herein, we describe the synthesis and photophysical characterization of a small series of base-modified pyrimidine ribonucleoside analogues derived from tagging indole, N-methylindole, and benzofuran onto the 5-position of uracil. One of the analogues, based on a 5-(benzofuran-2-yl)pyrimidine core, shows emission in the visible region with a reasonable quantum yield and, importantly, displays excellent solvatochromism. The corresponding triphosphate substrate is effectively incorporated into oligoribonucleotides by T7 RNA polymerase to produce fluorescent oligoribonucleotide constructs. Steady-state and time-resolved spectroscopic studies with fluorescent oligoribonucleotide constructs demonstrate that the fluorescent ribonucleoside photophysically responds to subtle changes in its environment brought about by the interaction of the chromophore with neighboring bases. In particular, the emissive ribonucleoside, if incorporated into an oligoribonucleotide, positively reports the presence of a DNA abasic site with an appreciable enhancement in fluorescence intensity. The straightforward synthesis, amicability to enzymatic incorporation, and sensitivity to changes in the microenvironment highlight the potential of the benzofuran-conjugated pyrimidine ribonucleoside as an efficient fluorescent probe to investigate nucleic acid structure, dynamics, and recognition events.

  12. Polyamine analogues targeting epigenetic gene regulation.

    PubMed

    Huang, Yi; Marton, Laurence J; Woster, Patrick M; Casero, Robert A

    2009-11-04

    Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of

  13. Benchmarking analogue models of brittle thrust wedges

    NASA Astrophysics Data System (ADS)

    Schreurs, Guido; Buiter, Susanne J. H.; Boutelier, Jennifer; Burberry, Caroline; Callot, Jean-Paul; Cavozzi, Cristian; Cerca, Mariano; Chen, Jian-Hong; Cristallini, Ernesto; Cruden, Alexander R.; Cruz, Leonardo; Daniel, Jean-Marc; Da Poian, Gabriela; Garcia, Victor H.; Gomes, Caroline J. S.; Grall, Céline; Guillot, Yannick; Guzmán, Cecilia; Hidayah, Triyani Nur; Hilley, George; Klinkmüller, Matthias; Koyi, Hemin A.; Lu, Chia-Yu; Maillot, Bertrand; Meriaux, Catherine; Nilfouroushan, Faramarz; Pan, Chang-Chih; Pillot, Daniel; Portillo, Rodrigo; Rosenau, Matthias; Schellart, Wouter P.; Schlische, Roy W.; Take, Andy; Vendeville, Bruno; Vergnaud, Marine; Vettori, Matteo; Wang, Shih-Hsien; Withjack, Martha O.; Yagupsky, Daniel; Yamada, Yasuhiro

    2016-11-01

    We performed a quantitative comparison of brittle thrust wedge experiments to evaluate the variability among analogue models and to appraise the reproducibility and limits of model interpretation. Fifteen analogue modeling laboratories participated in this benchmark initiative. Each laboratory received a shipment of the same type of quartz and corundum sand and all laboratories adhered to a stringent model building protocol and used the same type of foil to cover base and sidewalls of the sandbox. Sieve structure, sifting height, filling rate, and details on off-scraping of excess sand followed prescribed procedures. Our analogue benchmark shows that even for simple plane-strain experiments with prescribed stringent model construction techniques, quantitative model results show variability, most notably for surface slope, thrust spacing and number of forward and backthrusts. One of the sources of the variability in model results is related to slight variations in how sand is deposited in the sandbox. Small changes in sifting height, sifting rate, and scraping will result in slightly heterogeneous material bulk densities, which will affect the mechanical properties of the sand, and will result in lateral and vertical differences in peak and boundary friction angles, as well as cohesion values once the model is constructed. Initial variations in basal friction are inferred to play the most important role in causing model variability. Our comparison shows that the human factor plays a decisive role, and even when one modeler repeats the same experiment, quantitative model results still show variability. Our observations highlight the limits of up-scaling quantitative analogue model results to nature or for making comparisons with numerical models. The frictional behavior of sand is highly sensitive to small variations in material state or experimental set-up, and hence, it will remain difficult to scale quantitative results such as number of thrusts, thrust spacing

  14. Antitumoral cyclic peptide analogues of chlamydocin.

    PubMed

    Bernardi, E; Fauchere, J L; Atassi, G; Viallefont, P; Lazaro, R

    1993-01-01

    A series of cyclic tetrapeptides bearing the bioactive alkylating group on an epsilon-amino-lysyl function have been examined for their antitumoral activity on L1210 and P388 murine leukemia cell lines. One analogue belonging to the chlamydocin family and bearing a beta-chloroethylnitrosourea group was found to be potent at inhibiting L1210 cell proliferation and had a higher therapeutic index than the reference compound bis-beta-chloroethylnitrosourea (BCNU) on the in vivo P388-induced leukemia model.

  15. Synthesis of constrained analogues of tryptophan

    PubMed Central

    Negrato, Marco; Abbiati, Giorgio; Dell’Acqua, Monica

    2015-01-01

    Summary A Lewis acid-catalysed diastereoselective [4 + 2] cycloaddition of vinylindoles and methyl 2-acetamidoacrylate, leading to methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate derivatives, is described. Treatment of the obtained cycloadducts under hydrolytic conditions results in the preparation of a small library of compounds bearing the free amino acid function at C-3 and pertaining to the class of constrained tryptophan analogues. PMID:26664620

  16. The Brookhaven electron analogue, 1953--1957

    SciTech Connect

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  17. Thymidine analogues for tracking DNA synthesis.

    PubMed

    Cavanagh, Brenton L; Walker, Tom; Norazit, Anwar; Meedeniya, Adrian C B

    2011-09-15

    Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU) and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in "tagging DNA synthesis" is the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU). The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using 'Huisgen's reaction' (1,3-dipolar cycloaddition or 'click chemistry'). This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other "unnatural bases". These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored.

  18. Blood Loss Estimation Using Gauze Visual Analogue

    PubMed Central

    Ali Algadiem, Emran; Aleisa, Abdulmohsen Ali; Alsubaie, Huda Ibrahim; Buhlaiqah, Noora Radhi; Algadeeb, Jihad Bagir; Alsneini, Hussain Ali

    2016-01-01

    Background Estimating intraoperative blood loss can be a difficult task, especially when blood is mostly absorbed by gauze. In this study, we have provided an improved method for estimating blood absorbed by gauze. Objectives To develop a guide to estimate blood absorbed by surgical gauze. Materials and Methods A clinical experiment was conducted using aspirated blood and common surgical gauze to create a realistic amount of absorbed blood in the gauze. Different percentages of staining were photographed to create an analogue for the amount of blood absorbed by the gauze. Results A visual analogue scale was created to aid the estimation of blood absorbed by the gauze. The absorptive capacity of different gauze sizes was determined when the gauze was dripping with blood. The amount of reduction in absorption was also determined when the gauze was wetted with normal saline before use. Conclusions The use of a visual analogue may increase the accuracy of blood loss estimation and decrease the consequences related to over or underestimation of blood loss. PMID:27626017

  19. Analogue modulation of back-propagating action potentials enables dendritic hybrid signalling.

    PubMed

    Brunner, János; Szabadics, János

    2016-10-05

    We report that back-propagating action potentials (bAPs) are not simply digital feedback signals in dendrites but also carry analogue information about the overall state of neurons. Analogue information about the somatic membrane potential within a physiological range (from -78 to -64 mV) is retained by bAPs of dentate gyrus granule cells as different repolarization speeds in proximal dendrites and as different peak amplitudes in distal regions. These location-dependent waveform changes are reflected by local calcium influx, leading to proximal enhancement and distal attenuation during somatic hyperpolarization. The functional link between these retention and readout mechanisms of the analogue content of bAPs critically depends on high-voltage-activated, inactivating calcium channels. The hybrid bAP and calcium mechanisms report the phase of physiological somatic voltage fluctuations and modulate long-term synaptic plasticity in distal dendrites. Thus, bAPs are hybrid signals that relay somatic analogue information, which is detected by the dendrites in a location-dependent manner.

  20. Analogue modulation of back-propagating action potentials enables dendritic hybrid signalling

    PubMed Central

    Brunner, János; Szabadics, János

    2016-01-01

    We report that back-propagating action potentials (bAPs) are not simply digital feedback signals in dendrites but also carry analogue information about the overall state of neurons. Analogue information about the somatic membrane potential within a physiological range (from −78 to −64 mV) is retained by bAPs of dentate gyrus granule cells as different repolarization speeds in proximal dendrites and as different peak amplitudes in distal regions. These location-dependent waveform changes are reflected by local calcium influx, leading to proximal enhancement and distal attenuation during somatic hyperpolarization. The functional link between these retention and readout mechanisms of the analogue content of bAPs critically depends on high-voltage-activated, inactivating calcium channels. The hybrid bAP and calcium mechanisms report the phase of physiological somatic voltage fluctuations and modulate long-term synaptic plasticity in distal dendrites. Thus, bAPs are hybrid signals that relay somatic analogue information, which is detected by the dendrites in a location-dependent manner. PMID:27703164

  1. A novel nucleic acid analogue shows strong angiogenic activity

    SciTech Connect

    Tsukamoto, Ikuko; Sakakibara, Norikazu; Maruyama, Tokumi; Igarashi, Junsuke; Kosaka, Hiroaki; Kubota, Yasuo; Tokuda, Masaaki; Ashino, Hiromi; Hattori, Kenichi; Tanaka, Shinji; Kawata, Mitsuhiro; Konishi, Ryoji

    2010-09-03

    Research highlights: {yields} A novel nucleic acid analogue (2Cl-C.OXT-A, m.w. 284) showed angiogenic potency. {yields} It stimulated the tube formation, proliferation and migration of HUVEC in vitro. {yields} 2Cl-C.OXT-A induced the activation of ERK1/2 and MEK in HUVEC. {yields} Angiogenic potency in vivo was confirmed in CAM assay and rabbit cornea assay. {yields} A synthesized small angiogenic agent would have great clinical therapeutic value. -- Abstract: A novel nucleic acid analogue (2Cl-C.OXT-A) significantly stimulated tube formation of human umbilical endothelial cells (HUVEC). Its maximum potency at 100 {mu}M was stronger than that of vascular endothelial growth factor (VEGF), a positive control. At this concentration, 2Cl-C.OXT-A moderately stimulated proliferation as well as migration of HUVEC. To gain mechanistic insights how 2Cl-C.OXT-A promotes angiogenic responses in HUVEC, we performed immunoblot analyses using phospho-specific antibodies as probes. 2Cl-C.OXT-A induced robust phosphorylation/activation of MAP kinase ERK1/2 and an upstream MAP kinase kinase MEK. Conversely, a MEK inhibitor PD98059 abolished ERK1/2 activation and tube formation both enhanced by 2Cl-C.OXT-A. In contrast, MAP kinase responses elicited by 2Cl-C.OXT-A were not inhibited by SU5416, a specific inhibitor of VEGF receptor tyrosine kinase. Collectively these results suggest that 2Cl-C.OXT-A-induces angiogenic responses in HUVEC mediated by a MAP kinase cascade comprising MEK and ERK1/2, but independently of VEGF receptor tyrosine kinase. In vivo assay using chicken chorioallantoic membrane (CAM) and rabbit cornea also suggested the angiogenic potency of 2Cl-C.OXT-A.

  2. Polyamine analogues bind human serum albumin.

    PubMed

    Beauchemin, R; N'soukpoé-Kossi, C N; Thomas, T J; Thomas, T; Carpentier, R; Tajmir-Riahi, H A

    2007-10-01

    Polyamine analogues show antitumor activity in experimental models, and their ability to alter activity of cytotoxic chemotherapeutic agents in breast cancer is well documented. Association of polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several polyamine analogues, such as 1,11-diamino-4,8-diazaundecane (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333), and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333), in aqueous solution at physiological conditions using a constant protein concentration and various polyamine contents (microM to mM). FTIR, UV-visible, and CD spectroscopic methods were used to determine the polyamine binding mode and the effects of polyamine complexation on protein stability and secondary structure. Structural analysis showed that polyamines bind nonspecifically (H-bonding) via polypeptide polar groups with binding constants of K333 = 9.30 x 10(3) M(-1), KBE-333 = 5.63 x 10(2) M(-1), and KBE-3333 = 3.66 x 10(2) M(-1). The protein secondary structure showed major alterations with a reduction of alpha-helix from 55% (free protein) to 43-50% and an increase of beta-sheet from 17% (free protein) to 29-36% in the 333, BE-333, and BE-3333 complexes, indicating partial protein unfolding upon polyamine interaction. HSA structure was less perturbed by polyamine analogues compared to those of the biogenic polyamines.

  3. New synthetic approaches towards analogues of bedaquiline.

    PubMed

    Priebbenow, Daniel L; Barbaro, Lisa; Baell, Jonathan B

    2016-10-12

    Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.

  4. The Lehmer Matrix and Its Recursive Analogue

    DTIC Science & Technology

    2010-01-01

    for failing to comply with a collection of information if it does not display a currently valid OMB control number . 1. REPORT DATE 2010 2. REPORT...TYPE 3. DATES COVERED 00-00-2010 to 00-00-2010 4. TITLE AND SUBTITLE The Lehmer matrix and its recursive analogue 5a. CONTRACT NUMBER 5b...GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND

  5. U.S. Nuclear Regulatory Commission natural analogue research program

    SciTech Connect

    Kovach, L.A.; Ott, W.R.

    1995-09-01

    This article describes the natural analogue research program of the U.S. Nuclear Regulatory Commission (US NRC). It contains information on the regulatory context and organizational structure of the high-level radioactive waste research program plan. It also includes information on the conditions and processes constraining selection of natural analogues, describes initiatives of the US NRC, and describes the role of analogues in the licensing process.

  6. CO2 Removal using a Synthetic Analogue of Carbonic Anhydrase

    SciTech Connect

    Cordatos, Harry

    2010-09-14

    Project attempts to develop a synthetic analogue for carbonic anhydrase and incorporate it in a membrane for separation of CO2 from coal power plant flue gas. Conference poster presents result of first 9 months of project progress including concept, basic system architecture and membrane properties target, results of molecular modeling for analogue - CO2 interaction, and next steps of testing analogue resistance to flue gas contaminants.

  7. Synthesis of a cyanopeptide-analogue with trypsin activating properties.

    PubMed

    Radau, G; Rauh, D

    2000-04-17

    An efficient synthesis of a peptidic analogue of cyanobacterial metabolites with proposed serine protease inhibitory activity has been developed. Surprisingly, one trypsin activating compound was obtained.

  8. Four Generations of Transition State Analogues for Human Purine Nucleoside Phosphorylase

    SciTech Connect

    Ho, M.; Shi, W; Rinaldo-Mathis, A; Tyler, P; Evans, G; Almo, S; Schramm, V

    2010-01-01

    Inhibition of human purine nucleoside phosphorylase (PNP) stops growth of activated T-cells and the formation of 6-oxypurine bases, making it a target for leukemia, autoimmune disorders, and gout. Four generations of ribocation transition-state mimics bound to PNP are structurally characterized. Immucillin-H (K*{sub i} = 58 pM, first-generation) contains an iminoribitol cation with four asymmetric carbons. DADMe-Immucillin-H (K*{sub i} = 9 pM, second-generation), uses a methylene-bridged dihydroxypyrrolidine cation with two asymmetric centers. DATMe-Immucillin-H (K*{sub i} = 9 pM, third-generation) contains an open-chain amino alcohol cation with two asymmetric carbons. SerMe-ImmH (K*{sub i} = 5 pM, fourth-generation) uses achiral dihydroxyaminoalcohol seramide as the ribocation mimic. Crystal structures of PNPs establish features of tight binding to be; (1) ion-pair formation between bound phosphate (or its mimic) and inhibitor cation, (2) leaving-group interactions to N1, O6, and N7 of 9-deazahypoxanthine, (3) interaction between phosphate and inhibitor hydroxyl groups, and (4) His257 interacting with the 5{prime}-hydroxyl group. The first generation analogue is an imperfect fit to the catalytic site with a long ion pair distance between the iminoribitol and bound phosphate and weaker interactions to the leaving group. Increasing the ribocation to leaving-group distance in the second- to fourth-generation analogues provides powerful binding interactions and a facile synthetic route to powerful inhibitors. Despite chemical diversity in the four generations of transition-state analogues, the catalytic site geometry is almost the same for all analogues. Multiple solutions in transition-state analogue design are available to convert the energy of catalytic rate enhancement to binding energy in human PNP.

  9. Fracture toughness and fatigue crack propagation rate of short fiber reinforced epoxy composites for analogue cortical bone.

    PubMed

    Chong, Alexander C M; Miller, Forrest; Buxton, McKee; Friis, Elizabeth A

    2007-08-01

    Third-generation mechanical analogue bone models and synthetic analogue cortical bone materials manufactured by Pacific Research Laboratories, Inc. (PRL) are popular tools for use in mechanical testing of various orthopedic implants and biomaterials. A major issue with these models is that the current third-generation epoxy-short fiberglass based composite used as the cortical bone substitute is prone to crack formation and failure in fatigue or repeated quasistatic loading of the model. The purpose of the present study was to compare the tensile and fracture mechanics properties of the current baseline (established PRL "third-generation" E-glass-fiber-epoxy) composite analogue for cortical bone to a new composite material formulation proposed for use as an enhanced fourth-generation cortical bone analogue material. Standard tensile, plane strain fracture toughness, and fatigue crack propagation rate tests were performed on both the third- and fourth-generation composite material formulations using standard ASTM test techniques. Injection molding techniques were used to create random fiber orientation in all test specimens. Standard dog-bone style tensile specimens were tested to obtain ultimate tensile strength and stiffness. Compact tension fracture toughness specimens were utilized to determine plane strain fracture toughness values. Reduced thickness compact tension specimens were also used to determine fatigue crack propagation rate behavior for the two material groups. Literature values for the same parameters for human cortical bone were compared to results from the third- and fourth-generation cortical analogue bone materials. Tensile properties of the fourth-generation material were closer to that of average human cortical bone than the third-generation material. Fracture toughness was significantly increased by 48% in the fourth-generation composite as compared to the third-generation analogue bone. The threshold stress intensity to propagate the crack

  10. Long-term predictions using natural analogues

    SciTech Connect

    Ewing, R.C.

    1995-09-01

    One of the unique and scientifically most challenging aspects of nuclear waste isolation is the extrapolation of short-term laboratory data (hours to years) to the long time periods (10{sup 3}-10{sup 5} years) required by regulatory agencies for performance assessment. The direct validation of these extrapolations is not possible, but methods must be developed to demonstrate compliance with government regulations and to satisfy the lay public that there is a demonstrable and reasonable basis for accepting the long-term extrapolations. Natural systems (e.g., {open_quotes}natural analogues{close_quotes}) provide perhaps the only means of partial {open_quotes}validation,{close_quotes} as well as data that may be used directly in the models that are used in the extrapolation. Natural systems provide data on very large spatial (nm to km) and temporal (10{sup 3}-10{sup 8} years) scales and in highly complex terranes in which unknown synergisms may affect radionuclide migration. This paper reviews the application (and most importantly, the limitations) of data from natural analogue systems to the {open_quotes}validation{close_quotes} of performance assessments.

  11. Growth Hormone-Releasing Hormone and Its Analogues: Significance for MSCs-Mediated Angiogenesis

    PubMed Central

    Tao, Quanwei; Ma, Qunchao; Chen, Huiqiang; Wang, Jian'an

    2016-01-01

    Mesenchymal stromal cells (MSCs) are promising candidates for regenerative medicine because of their multipotency, immune-privilege, and paracrine properties including the potential to promote angiogenesis. Accumulating evidence suggests that the inherent properties of cytoprotection and tissue repair by native MSCs can be enhanced by various preconditioning stimuli implemented prior to cell transplantation. Growth hormone-releasing hormone (GHRH), a stimulator in extrahypothalamus systems including tumors, has attracted great attentions in recent years because GHRH and its agonists could promote angiogenesis in various tissues. GHRH and its agonists are proangiogenic in responsive tissues including tumors, and GHRH antagonists have been tested as antitumor agents through their ability to suppress angiogenesis and cell growth. GHRH-R is expressed by MSCs and evolving work from our laboratory indicates that treatment of MSCs with GHRH agonists prior to cell transplantation markedly enhanced the angiogenic potential and tissue reparative properties of MSCs through a STAT3 signaling pathway. In this review we summarized the possible effects of GHRH analogues on cell growth and development, as well as on the proangiogenic properties of MSCs. We also discussed the relationship between GHRH analogues and MSC-mediated angiogenesis. The analyses provide new insights into molecular pathways of MSCs-based therapies and their augmentation by GHRH analogues. PMID:27774107

  12. Design and synthesis of novel arctigenin analogues for the amelioration of metabolic disorders.

    PubMed

    Duan, Shudong; Huang, Suling; Gong, Jian; Shen, Yu; Zeng, Limin; Feng, Ying; Ren, Wenming; Leng, Ying; Hu, Youhong

    2015-04-09

    Analogues of the natural product (-)-arctigenin, an activator of adenosine monophosphate activated protein kinase, were prepared in order to evaluate their effects on 2-deoxyglucose uptake in L6 myotubes and possible use in ameliorating metabolic disorders. Racemic arctigenin 2a was found to display a similar uptake enhancement as does (-)-arctigenin. As a result, the SAR study was conducted utilizing racemic compounds. The structure-activity relationship study led to the discovery of key substitution patterns on the lactone motif that govern 2-deoxyglucose uptake activities. The results show that replacement of the para-hydroxyl group of the C-2 benzyl moiety of arctigenin by Cl has a pronounced effect on uptake activity. Specifically, analogue 2p, which contains the p-Cl substituent, stimulates glucose uptake and fatty acid oxidation in L6 myotubes.

  13. Pressurized brines in continental Antarctica as a possible analogue of Mars.

    PubMed

    Forte, Emanuele; Dalle Fratte, Michele; Azzaro, Maurizio; Guglielmin, Mauro

    2016-09-12

    Interest in brines in extreme and cold environments has recently increased after they have been found on Mars. Those brines can be potential new subsurface habitats for peculiar ecosystems. In the McMurdo Dry Valleys of the Antarctic, the best analogue for Mars conditions, only a few cases of brines have been identified in some perennially frozen lakes and in one case in an underground aquifer. Here, we present the occurrence of pressurized brines in a shallow perennially ice-covered lake south of 70°S in an ice-free area of Victoria Land, Antarctica. For the first time, we also imaged, by means of ground penetrating radar data, the existence of a pingo-like-feature (PLF) formed by the extrusion of brines, which has also been confirmed by borehole evidence. Those brines are fed by an underground talik external to the lake basin, enhancing the possibility of unexploited ecosystems that could find an analogue in Martian environments.

  14. Pressurized brines in continental Antarctica as a possible analogue of Mars

    NASA Astrophysics Data System (ADS)

    Forte, Emanuele; Dalle Fratte, Michele; Azzaro, Maurizio; Guglielmin, Mauro

    2016-09-01

    Interest in brines in extreme and cold environments has recently increased after they have been found on Mars. Those brines can be potential new subsurface habitats for peculiar ecosystems. In the McMurdo Dry Valleys of the Antarctic, the best analogue for Mars conditions, only a few cases of brines have been identified in some perennially frozen lakes and in one case in an underground aquifer. Here, we present the occurrence of pressurized brines in a shallow perennially ice-covered lake south of 70°S in an ice-free area of Victoria Land, Antarctica. For the first time, we also imaged, by means of ground penetrating radar data, the existence of a pingo-like-feature (PLF) formed by the extrusion of brines, which has also been confirmed by borehole evidence. Those brines are fed by an underground talik external to the lake basin, enhancing the possibility of unexploited ecosystems that could find an analogue in Martian environments.

  15. Isolation and characterization of a tadalafil analogue, N-cyclopentyl nortadalafil in health supplement.

    PubMed

    Xu, Yimin; Kee, Chee-Leong; Ge, Xiaowei; Low, Min-Yong; Koh, Hwee-Ling

    2016-01-25

    A tadalafil analogue was detected for the first time during the screening of a health supplement for undeclared sexual enhancement drugs. The compound had been isolated and purified by preparative high-pressure liquid chromatography (HPLC). Its chemical structure was elucidated using high-resolution mass spectrometry (HRMS), electrospray ionization tandem mass spectrometry (ESI-MS/MS) and nuclear magnetic resonance (NMR) spectroscopy. The compound had a protonated molecular ion at m/z 444 with a chemical formula of C26H25N3O4. The data obtained from the MS analysis of the compound suggested that the N-methyl group on the piperazinedione moiety of tadalafil was substituted with a -C5H9 group. Analysis using NMR was performed and the -C5H9 group was characterized as a cyclopentyl moiety. The analogue was named N-cyclopentyl nortadalafil.

  16. Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists

    PubMed Central

    Choi, Hyun-Kyung; Choi, Sun; Lee, Yoonji; Kang, Dong Wook; Ryu, HyungChul; Maeng, Han-Joo; Chung, Suk-Jae; Pavlyukovets, Vladimir A.; Pearce, Larry V.; Toth, Attila; Tran, Richard; Wang, Yun; Morgan, Matthew A.; Blumberg, Peter M.; Lee, Jeewoo

    2009-01-01

    A series of non-vanillyl resiniferatoxin analogues, having 4-methylsulfonylaminophenyl and fluorophenyl moieties as vanillyl surrogates, have been investigated as ligands for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Although lacking the metabolically problematic 4-hydroxy substituent on the A-region phenyl ring, the compounds retained substantial agonist potency. Indeed, the 3-methoxy-4-methylsulfonylaminophenyl analog (1) was modestly (2.5-fold) more potent than RTX, with an EC50 = 0.106 nM. Further, it resembled RTX in its kinetics and pattern of stimulation of the levels of intracellular calcium in individual cells, as revealed by imaging. Compound 1 displayed modestly enhanced in vitro stability in rat liver microsomes and in plasma, suggesting that it might be a pharmacokinetically more favorable surrogate of resiniferatoxin. Molecular modeling analyses with selected analogues provide evidence that the conformational differences could affect their binding affinities, especially for the ester versus amide at the B-region. PMID:19135377

  17. Space Analogue Environments: Are the Populations Comparable?

    NASA Astrophysics Data System (ADS)

    Sandal, G. M.

    Background: Much of our present understanding about psychology in space is based on studies of groups operating in so-called analogue environments where personnel are exposed to many of the same stressors as those experienced by astronauts in space. One possible problem with extrapolating results is that personnel operating in various hazardous and confined environments might differ in characteristics influencing coping, interaction, and performance. The object of this study was to compare the psychological similarity of these populations in order to get a better understanding of whether this extrapolation is justifiable. The samples investigated include polar crossings (N= 22), personnel on Antarctic research stations (N= 183), several military occupations (N= 187), and participants in space simulation studies (N=20). Methods: Personnel in each of these environments were assessed using the Personality Characteristic Inventory (PCI) and Utrecht Coping List (UCL). The PCI is a multidimensional trait assessment battery that measures various aspects of achievement orientation and social competence. The UCL is a questionnaire designed to assess habitual coping strategies when encountering stressful or demanding situations. Results: Only minor differences in use of habitual coping strategies were evident across the different samples. In relation to personality scores, the military subjects and participants in space simulation studies indicated higher competitiveness and negative instrumentality compared to both the personnel on Antarctic research stations and participants in polar expedition. Among the personnel on Antarctic research stations, significant gender differences were found with women scoring lower on competitiveness, negative instrumentality and impatience/irritability. Compared to the other samples, the participants in polar expeditions were found to be more homogeneous in personality and no significant gender differences were evident on the traits that

  18. A nonlinear dynamic analogue model of substorms

    NASA Astrophysics Data System (ADS)

    Klimas, A. J.; Baker, D. N.; Roberts, D. A.; Fairfield, D. H.; Büchner, J.

    Linear prediction filter studies have shown that the magnetospheric response to energy transfer from the solar wind contains both directly driven and unloading components. These studies have also shown that the magnetospheric response is significantly nonlinear and, thus, the linear prediction filtering technique and other correlative techniques which assume a linear magnetospheric response cannot give a complete deacription of that response. Here, the solar wind-magnetosphere interaction is discussed within the framework of deterministic nonlinear dynamics. An earlier dripping faucet mechanical analogue to the magnetosphere is first reviewed and then the plasma physical counterpart to the mechanical model is constructed. A Faraday loop in the magnetotail is considered and the relationship of electric potentials on the loop to changes in the magnetic flux threading the loop is developed. This approach leads to a model of geomagnetic activity which is similar to the earlier mechanical model but described in terms of the geometry and plasma contents of the magnetotail. This Faraday loop response model contains analogues to both the directly driven and the storage-release magnetospheric responses and it includes, in a fundamental way, the inherent nonlinearity of the solar wind-magnetosphere system. It can be chancterized as a nonlinear, damped harmonic oscillator that is driven by the loading-unloading substorm cycle. The model is able to explain many of the features of the linear prediction filter results. In particular, at low geomagnetic activity levels the model exbibits the "regular dripping" response which provides an explanation for the unloading component at 1 hour lag in the linear prediction filters. Further, the model suggests that the disappearance of the unloading component in the linear prediction filters at high geomagnetic activity levels is due to a chaotic transition beyond which the loading-unloading mechanism becomes aperiodic. The model predicts

  19. Ribosome-Mediated Incorporation of Dipeptides and Dipeptide Analogues into Proteins in Vitro.

    PubMed

    Maini, Rumit; Dedkova, Larisa M; Paul, Rakesh; Madathil, Manikandadas M; Chowdhury, Sandipan Roy; Chen, Shengxi; Hecht, Sidney M

    2015-09-09

    Plasmids containing 23S rRNA randomized at positions 2057-2063 and 2502-2507 were introduced into Escherichia coli, affording a library of clones which produced modified ribosomes in addition to the pre-existing wild-type ribosomes. These clones were screened with a derivative of puromycin, a natural product which acts as an analogue of the 3'-end of aminoacyl-tRNA and terminates protein synthesis by accepting the growing polypeptide chain, thereby killing bacterial cells. The puromycin derivative in this study contained the dipeptide p-methoxyphenylalanylglycine, implying the ability of the modified ribosomes in clones sensitive to this puromycin analogue to recognize dipeptides. Several clones inhibited by the puromycin derivative were used to make S-30 preparations, and some of these were shown to support the incorporation of dipeptides into proteins. The four incorporated species included two dipeptides (Gly-Phe (2) and Phe-Gly (3)), as well as a thiolated dipeptide analogue (4) and a fluorescent oxazole (5) having amine and carboxyl groups approximately the same distance apart as in a normal dipeptide. A protein containing both thiolated dipeptide 4 and a 7-methoxycoumarin fluorophore was found to undergo fluorescence quenching. Introduction of the oxazole fluorophore 5 into dihydrofolate reductase or green fluorescent protein resulted in quite strong enhancement of its fluorescence emission, and the basis for this enhancement was studied. The aggregate results demonstrate the feasibility of incorporating dipeptides as a single ribosomal event, and illustrate the lack of recognition of the central peptide bond in the dipeptide, potentially enabling the incorporation of a broad variety of structural analogues.

  20. Analogue Divider by Averaging a Triangular Wave

    NASA Astrophysics Data System (ADS)

    Selvam, Krishnagiri Chinnathambi

    2017-03-01

    A new analogue divider circuit by averaging a triangular wave using operational amplifiers is explained in this paper. The triangle wave averaging analog divider using operational amplifiers is explained here. The reference triangular waveform is shifted from zero voltage level up towards positive power supply voltage level. Its positive portion is obtained by a positive rectifier and its average value is obtained by a low pass filter. The same triangular waveform is shifted from zero voltage level to down towards negative power supply voltage level. Its negative portion is obtained by a negative rectifier and its average value is obtained by another low pass filter. Both the averaged voltages are combined in a summing amplifier and the summed voltage is given to an op-amp as negative input. This op-amp is configured to work in a negative closed environment. The op-amp output is the divider output.

  1. Naturalness in an emergent analogue spacetime.

    PubMed

    Liberati, Stefano; Visser, Matt; Weinfurtner, Silke

    2006-04-21

    Effective field theories (EFTs) have been widely used as a framework in order to place constraints on the Planck suppressed Lorentz violations predicted by various models of quantum gravity. There are, however, technical problems in the EFT framework when it comes to ensuring that small Lorentz violations remain small--this is the essence of the "naturalness" problem. Herein we present an "emergent" spacetime model, based on the "analogue gravity" program, by investigating a specific condensed-matter system. Specifically, we consider the class of two-component BECs subject to laser-induced transitions between the components, and we show that this model is an example for Lorentz invariance violation due to ultraviolet physics. Furthermore, our model explicitly avoids the naturalness problem, and makes specific suggestions regarding how to construct a physically reasonable quantum gravity phenomenology.

  2. Derivatisable Cyanobactin Analogues: A Semisynthetic Approach

    PubMed Central

    Oueis, Emilia; Adamson, Catherine; Mann, Greg; Ludewig, Hannes; Redpath, Philip; Migaud, Marie

    2015-01-01

    Abstract Many natural cyclic peptides have potent and potentially useful biological activities. Their use as therapeutic starting points is often limited by the quantities available, the lack of known biological targets and the practical limits on diversification to fine‐tune their properties. We report the use of enzymes from the cyanobactin family to heterocyclise and macrocyclise chemically synthesised substrates so as to allow larger‐scale syntheses and better control over derivatisation. We have made cyclic peptides containing orthogonal reactive groups, azide or dehydroalanine, that allow chemical diversification, including the use of fluorescent labels that can help in target identification. We show that the enzymes are compatible and efficient with such unnatural substrates. The combination of chemical synthesis and enzymatic transformation could help renew interest in investigating natural cyclic peptides with biological activity, as well as their unnatural analogues, as therapeutics. PMID:26507241

  3. A simple analogue of lung mechanics.

    PubMed

    Sherman, T F

    1993-12-01

    A model of the chest and lungs can be easily constructed from a bottle of water, a balloon, a syringe, a rubber stopper, glass and rubber tubing, and clamps. The model is a more exact analogue of the body than the classic apparatus of Hering in two respects: 1) the pleurae and intrapleural fluid are represented by water rather than air, and 2) the subatmospheric "intrapleural" pressure is created by the elasticity of the "lung" (balloon) rather than by a vacuum pump. With this model, students can readily see how the lung is inflated and deflated by movements of the "diaphragm and chest" (syringe plunger) and how intrapleural pressures change as this is accomplished.

  4. Terrestrial Analogues for Lunar Impact Melt Flows

    NASA Technical Reports Server (NTRS)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; Osinski, G. R.; Lim, D.; Heldmann, J. L.

    2016-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pahoehoe and ?a ?a lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pahoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pahoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  5. Natural analogues of nuclear waste glass corrosion.

    SciTech Connect

    Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

    1999-01-06

    This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.

  6. Terrestrial analogues for lunar impact melt flows

    NASA Astrophysics Data System (ADS)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; Osinski, G. R.; Lim, D.; Heldmann, J. L.

    2017-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pāhoehoe and ´a´ā lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pāhoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pāhoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  7. Current european regulatory perspectives on insulin analogues

    PubMed Central

    2011-01-01

    Insulin analogues are increasingly considered as an alternative to human insulin in the therapy of diabetes mellitus. Insulin analogues (IAs) are chemically different from human insulin and may have different pharmacokinetic or pharmacodynamic properties. The significance of the modifications of the insulin molecule for the safety profile of IAs must be considered. This review describes the regulatory procedure and the expectations for the scientific content of European marketing authorization applications for innovative IAs submitted to the European Medicines Agency. Particular consideration is given to a potential cancer hazard. Specific regulatory guidance on how to address a possible carcinogenic or tumor promoting effect of innovative IAs in non-clinical studies is available. After marketing authorization, the factual access of patients to the new product will be determined to great extent by health technology assessment bodies, reimbursement decisions and the price. Whereas the marketing authorization is a European decision, pricing and reimbursement are national or regional responsibilities. The assessment of benefit and risk by the European Medicines Agency is expected to influence future decisions on price and reimbursement on a national or regional level. Collaborations between regulatory agencies and health technology assessment bodies have been initiated on European and national level to facilitate the use of the European Medicines Agency's benefit risk assessment as basis on which to build the subsequent health technology assessment. The option for combined or joint scientific advice procedures with regulators and health technology assessment bodies on European level or on a national level in several European Member States may help applicants to optimize their development program and dossier preparation in regard of both European marketing authorization application and reimbursement decisions. PMID:21736748

  8. Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

    PubMed

    Segal, Meirav; Fischer, Bilha

    2012-02-28

    Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

  9. LAPS-FSH: a new and effective long-acting follicle-stimulating hormone analogue for the treatment of infertility.

    PubMed

    Jung, Sunyoung; Park, Youngjin; Kim, YoungHoon; Kim, Yu Yon; Choi, Hyun-Ji; Son, Woo-Chan; Kwon, SeChang

    2014-10-01

    Although several long-acting follicle-stimulating hormone (FSH) therapies have been developed to enhance the ovarian response, a disadvantage of FSH therapy is its relatively short half-life, which requires women to receive one to two injections per day for almost 2 weeks. In the present study, we developed a novel FSH analogue by conjugating recombinant human FSH (rhFSH) and the constant region of the human immunoglobulin G4 fragment via non-peptidyl linkers. The efficacy of the FSH analogue was evaluated in vitro by cAMP level assessments, pharmacokinetic studies and a determination of ovarian weight and by comparing these findings with the results from other FSH analogues. In addition, the total number of antral and Graafian follicles was determined after 7 days of treatment with control, 6µgkg(-1) follitropin β, 6, 12 or 42µgkg(-1) corifollitropin α or 3, 6 or 12µgkg(-1) long acting protein/peptide discovery-follicle-stimulating hormone (LAPS-FSH). As a result, the animals treated with 12µgkg(-1) LAPS-FSH produced additional and larger healthy follicles. These data demonstrate that LAPS-FSH promotes growth and inhibits atresia of the ovarian follicle compared with other available drugs, suggesting that our new drug enhances the efficacy and duration of treatment. It is expected that our new FSH analogue will result in a higher chance of pregnancy in patients who are unresponsive to other drugs.

  10. Functionalized Congener Approach to Muscarinic Antagonists: Analogues of Pirenzepine

    PubMed Central

    Karton, Yishai; Bradbury, Barton J.; Baumgold, Jesse; Paek, Robert; Jacobson, Kenneth A.

    2012-01-01

    The M1-selective muscarinic receptor antagonist pirenzepine (5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one) was derivatized to explore points of attachment of functionalized side chains for the synthesis of receptor probes and ligands for affinity chromatography. The analogues prepared were evaluated in competitive binding assays versus [3H]-N-methylscopolamine at four muscarinic receptor subtypes (m1AChR-m4AChR) in membranes from rat heart tissue and transfected A9L cells. 9-(Hydroxymethyl)pirenzepine, 8-(methylthio)pirenzepine, and a series of 8-aminosulfonyl derivatives were synthesized. Several 5-substituted analogues of pirenzepine also were prepared. An alternate series of analogues substituted on the 4-position of the piperazine ring was prepared by reaction of 4-desmethylpirenzepine with various electrophiles. An N-chloroethyl analogue of pirenzepine was shown to form a reactive aziridine species in aqueous buffer yet failed to affinity label muscarinic receptors. Within a series of aminoalkyl analogues, the affinity increased as the length of the alkyl chain increased. Shorter chain analogues were generally much less potent than pirenzepine, and longer analogues (7–10 carbons) were roughly as potent as pirenzepine at m1 receptors, but were nonselective. Depending on the methylene chain length, acylation or alkyl substitution of the terminal amine also influenced the affinity at muscarinic receptors. PMID:2066986

  11. Molecular dynamics of sialic acid analogues complex with cholera toxin and DFT optimization of ethylene glycol-mediated zinc nanocluster conjugation.

    PubMed

    Sharmila, D Jeya Sundara; Jino Blessy, J

    2017-01-01

    Cholera is an infectious disease caused by cholera toxin (CT) protein of bacterium Vibrio cholerae. A sequence of sialic acid (N-acetylneuraminic acid, NeuNAc or Neu5Ac) analogues modified in its C-5 position is modelled using molecular modelling techniques and docked against the CT followed by molecular dynamics simulations. Docking results suggest better binding affinity of NeuNAc analogue towards the binding site of CT. The NeuNAc analogues interact with the active site residues GLU:11, TYR:12, HIS:13, GLY:33, LYS:34, GLU:51, GLN:56, HIE:57, ILE:58, GLN:61, TRP:88, ASN:90 and LYS:91 through intermolecular hydrogen bonding. Analogues N-glycolyl-NeuNAc, N-Pentanoyl-NeuNAc and N-Propanoyl-NeuNAc show the least XPGscore (docking score) of -9.90, -9.16, and -8.91, respectively, and glide energy of -45.99, -42.14 and -41.66 kcal/mol, respectively. Stable nature of CT-N-glycolyl-NeuNAc, CT-N-Pentanoyl-NeuNAc and CT-N-Propanoyl-NeuNAc complexes was verified through molecular dynamics simulations, each for 40 ns using the software Desmond. All the nine NeuNAc analogues show better score for drug-like properties, so could be considered as suitable candidates for drug development for cholera infection. To improve the enhanced binding mode of NeuNAc analogues towards CT, the nine NeuNAc analogues are conjugated with Zn nanoclusters through ethylene glycol (EG) as carriers. The NeuNAc analogues conjugated with EG-Zn nanoclusters show better binding energy towards CT than the unconjugated nine NeuNAc analogues. The electronic structural optimization of EG-Zn nanoclusters was carried out for optimizing their performance as better delivery vehicles for NeuNAc analogues through density functional theory calculations. These sialic acid analogues may be considered as novel leads for the design of drug against cholera and the EG-Zn nanocluster may be a suitable carrier for sialic acid analogues.

  12. Membrane-Targeting DCAP Analogues with Broad-Spectrum Antibiotic Activity against Pathogenic Bacteria

    PubMed Central

    2015-01-01

    We performed a structure–activity relationship study of 2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3-diol (DCAP), which is an antibacterial agent that disrupts the membrane potential and permeability of bacteria. The stereochemistry of DCAP had no effect on the biological activity of DCAP. The aromaticity and electronegativity of the chlorine-substituted carbazole was required for activity, suggesting that its planar and dipolar characteristics orient DCAP in membranes. Increasing the hydrophobicity of the tail region of DCAP enhanced its antibiotic activity. Two DCAP analogues displayed promising antibacterial activity against the BSL-3 pathogens Bacillus anthracis and Francisella tularensis. Codosing DCAP analogues with ampicillin or kanamycin increased their potency. These studies demonstrate that DCAP and its analogues may be a promising scaffold for developing chemotherapeutic agents that bind to bacterial membranes and kill strains of slow-growing or dormant bacteria that cause persistent infections. PMID:25941556

  13. Starting a European Space Agency Sample Analogue Collection for Robotic Exploration Missions

    NASA Astrophysics Data System (ADS)

    Smith, C. L.; Mavris, C.; Michalski, J. R.; Rumsey, M. S.; Russell, S. S.; Jones, C.; Schroeven-Deceuninck, H.

    2015-12-01

    The Natural History Museum is working closely with the European Space Agency (ESA) and the UK Space Agency to develop a European collection of analogue materials with appropriate physical/mechanical and chemical (mineralogical) properties which can support the development and verification of both spacecraft and scientific systems for potential science and exploration missions to Phobos/Deimos, Mars, C-type asteroids and the Moon. As an ESA Collection it will be housed at the ESA Centre based at Harwell, UK. The "ESA Sample Analogues Collection" will be composed of both natural and artificial materials chosen to (as closely as possible) replicate the surfaces and near-surfaces of different Solar System target bodies of exploration interest. The analogue samples will be fully characterised in terms of both their physical/mechanical properties (compressive strength, bulk density, grain shape, grain size, cohesion and angle of internal friction) and their chemical/mineralogical properties (texture, modal mineralogy, bulk chemical composition - major, minor and trace elements and individual mineralogical compositions). The Collection will be fully curated to international standards including implementation of a user-friendly database and will be available for use by engineers and scientists across the UK and Europe. Enhancement of the initial Collection will be possible through collaborations with other ESA and UK Space Agency supported activities, such as the acquisition of new samples during field trials.

  14. Starting a European Space Agency Sample Analogue Collection for Robotic Exploration Missions

    NASA Astrophysics Data System (ADS)

    Sherwood Lollar, B.; Sutcliffe, C. N.; Ballentine, C. J.; Onstott, T. C.; Lau, C. Y. M.; Magnabosco, C.; Slater, G.; Moser, D. P.

    2014-12-01

    The Natural History Museum is working closely with the European Space Agency (ESA) and the UK Space Agency to develop a European collection of analogue materials with appropriate physical/mechanical and chemical (mineralogical) properties which can support the development and verification of both spacecraft and scientific systems for potential science and exploration missions to Phobos/Deimos, Mars, C-type asteroids and the Moon. As an ESA Collection it will be housed at the ESA Centre based at Harwell, UK. The "ESA Sample Analogues Collection" will be composed of both natural and artificial materials chosen to (as closely as possible) replicate the surfaces and near-surfaces of different Solar System target bodies of exploration interest. The analogue samples will be fully characterised in terms of both their physical/mechanical properties (compressive strength, bulk density, grain shape, grain size, cohesion and angle of internal friction) and their chemical/mineralogical properties (texture, modal mineralogy, bulk chemical composition - major, minor and trace elements and individual mineralogical compositions). The Collection will be fully curated to international standards including implementation of a user-friendly database and will be available for use by engineers and scientists across the UK and Europe. Enhancement of the initial Collection will be possible through collaborations with other ESA and UK Space Agency supported activities, such as the acquisition of new samples during field trials.

  15. Promising Strategy To Improve Charge Separation in Organic Photovoltaics: Installing Permanent Dipoles in PCBM Analogues.

    PubMed

    de Gier, Hilde D; Jahani, Fatemeh; Broer, Ria; Hummelen, Jan C; Havenith, Remco W A

    2016-07-14

    A multidisciplinary approach involving organic synthesis and theoretical chemistry was applied to investigate a promising strategy to improve charge separation in organic photovoltaics: installing permanent dipoles in fullerene derivatives. First, a PCBM analogue with a permanent dipole in the side chain (PCBDN) and its reference analogue without a permanent dipole (PCBBz) were successfully synthesized and characterized. Second, a multiscale modeling approach was applied to investigate if a PCBDN environment around a central donor-acceptor complex indeed facilitates charge separation. Alignment of the embedding dipoles in response to charges present on the central donor-acceptor complex enhances charge separation. The good correspondence between experimentally and theoretically determined electronic and optical properties of PCBDN, PCBBz, and PCBM indicates that the theoretical analysis of the embedding effects of these molecules gives a reliable expectation for their influence on the charge separation process at a microscopic scale in a real device. This work suggests the following strategies to improve charge separation in organic photovoltaics: installing permanent dipoles in PCBM analogues and tuning the concentration of these molecules in an organic donor/acceptor blend.

  16. A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

    PubMed Central

    Verlee, Arno; Heugebaert, Thomas; van der Meer, Tom; Kerchev, Pavel I; Van Breusegem, Frank

    2017-01-01

    For the synthesis of m-sulfamoylbenzamide analogues, small molecules which are known for their bioactivity, a chemoselective procedure has been developed starting from m-(chlorosulfonyl)benzoyl chloride. Although a chemoselective process in batch was already reported, a continuous-flow process reveals an increased selectivity at higher temperatures and without catalysts. In total, 15 analogues were synthesized, using similar conditions, with yields ranging between 65 and 99%. This is the first automated and chemoselective synthesis of m-sulfamoylbenzamide analogues. PMID:28326139

  17. Mars on Earth: soil analogues for future Mars missions

    NASA Astrophysics Data System (ADS)

    Marlow, Jeffrey J.; Martins, Zita; Sephton, Mark A.

    2008-04-01

    Preparations for missions to Mars are a major concern for scientists. Predicting how equipment and experiments will perform on the planet is difficult because tests are restricted to Earth. Mars soil analogues are being used to solve this problem. These terrestrial materials are chemically and physically similar to martian soils and, because they contain unusual minerals and trace amounts of organic matter, are scientifically interesting in their own right. However, no current analogue is appropriate for all necessary tests. Here we describe Mars soil analogues, identify limitations and suggest the need for new Mars simulants.

  18. Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues.

    PubMed

    Roselli, Mariagrazia; Carocci, Alessia; Budriesi, Roberta; Micucci, Matteo; Toma, Maddalena; Di Cesare Mannelli, Lorenzo; Lovece, Angelo; Catalano, Alessia; Cavalluzzi, Maria Maddalena; Bruno, Claudio; De Palma, Annalisa; Contino, Marialessandra; Perrone, Maria Grazia; Colabufo, Nicola Antonio; Chiarini, Alberto; Franchini, Carlo; Ghelardini, Carla; Habtemariam, Solomon; Lentini, Giovanni

    2016-10-04

    Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.

  19. Mammary analogue secretory carcinoma mimicking salivary adenoma.

    PubMed

    Williams, Lindsay; Chiosea, Simion I

    2013-12-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor characterized by ETV6 translocation. It appears that prior studies have identified MASC by reviewing salivary gland carcinomas, such as acinic cell carcinoma and adenocarcinoma, not otherwise specified. To address the possibility of MASC mimicking benign salivary neoplasms we reviewed 12 salivary gland (cyst)adenomas diagnosed prior to the discovery of MASC. One encapsulated (cyst)adenoma of the parotid gland demonstrated features of MASC. The diagnosis was confirmed by fluorescence in situ hybridization with an ETV6 break-apart probe. An unusual complex pattern of ETV6 rearrangement with duplication of the telomeric/distal ETV6 probe was identified. This case illustrates that MASC may mimic salivary (cyst)adenomas. To more accurately assess true clinical and morphologic spectrum of MASC, future studies may have to include review of salivary (cyst)adenomas. The differential diagnosis of MASC may have to be expanded to include cases resembling salivary (cyst)adenomas.

  20. Fluorescent polyene ceramide analogues as membrane probes.

    PubMed

    Nieves, Ingrid; Artetxe, Ibai; Abad, José Luis; Alonso, Alicia; Busto, Jon V; Fajarí, Lluís; Montes, L Ruth; Sot, Jesús; Delgado, Antonio; Goñi, Félix M

    2015-03-03

    Three ceramide analogues have been synthesized, with sphingosine-like chains containing five conjugated double bonds. Pentaene I has an N-palmitoyl acyl chain, while the other two pentaenes contain also a doxyl radical, respectively, at C5 (Penta5dox) and at C16 (Penta16dox) positions of the N-acyl chain. Pentaene I maximum excitation and emission wavelengths in a phospholipid bilayer are 353 and 478 nm, respectively. Pentaene I does not segregate from the other lipids in the way natural ceramide does, but rather mixes with them in a selective way according to the lipid phases involved. Fluorescence confocal microscopy studies show that when lipid domains in different physical states coexist, Pentaene I emission is higher in gel than in fluid domains, and in liquid-ordered than in liquid-disordered areas. Electron paramagnetic resonance of the pentaene doxyl probes confirms that these molecules are sensitive to the physical state of the bilayer. Calorimetric and fluorescence quenching experiments suggest that the lipids under study orient themselves in lipid bilayers with their polar moieties located at the lipid-water interface. The doxyl radical in the N-acyl chain quenches the fluorescence of the pentaene group when in close proximity. Because of this property, Penta16dox can detect gel-fluid transitions in phospholipids. The availability of probes for lipids in the gel phase is important in view of novel evidence for the existence of gel microdomains in cell membranes.

  1. Actions of Thyroid Hormone Analogues on Chemokines

    PubMed Central

    Glinsky, Gennadi V.

    2016-01-01

    The extracellular domain of plasma membrane integrin αvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3′-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to αvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID:27493972

  2. Sulphur Spring: Busy Intersection and Possible Martian Analogue

    NASA Technical Reports Server (NTRS)

    Nankivell, A.; Andre, N.; Thomas-Keprta, K.; Allen, C.; McKay, D.

    2000-01-01

    Life in extreme environments exhibiting conditions similar to early Earth and Mars, such as Sulphur Spring, may harbor microbiota serving as both relics from the past as well as present day Martian analogues.

  3. From BPA to its analogues: Is it a safe journey?

    PubMed

    Usman, Afia; Ahmad, Masood

    2016-09-01

    Bisphenol-A (BPA) is one of the most abundant synthetic chemicals in the world due to its uses in plastics. Its widespread exposure vis-a-vis low dose effects led to a reduction in its safety dose and imposition of ban on its use in infant feeding bottles. This restriction paved the way for the gradual market entry of its analogues. However, their structural similarity to BPA has put them under surveillance for endocrine disrupting potential. The application of these analogues is increasing and so are the studies reporting their toxicity. This review highlights the reasons which led to the ban of BPA and also reports the exposure and toxicological data available on its analogues. Hence, this compilation is expected to answer in a better way whether the replacement of BPA by these analogues is safer or more harmful?

  4. Cell-cycle analyses using thymidine analogues in fission yeast.

    PubMed

    Anda, Silje; Boye, Erik; Grallert, Beata

    2014-01-01

    Thymidine analogues are powerful tools when studying DNA synthesis including DNA replication, repair and recombination. However, these analogues have been reported to have severe effects on cell-cycle progression and growth, the very processes being investigated in most of these studies. Here, we have analyzed the effects of 5-ethynyl-2'-deoxyuridine (EdU) and 5-Chloro-2'-deoxyuridine (CldU) using fission yeast cells and optimized the labelling procedure. We find that both analogues affect the cell cycle, but that the effects can be mitigated by using the appropriate analogue, short pulses of labelling and low concentrations. In addition, we report sequential labelling of two consecutive S phases using EdU and 5-bromo-2'-deoxyuridine (BrdU). Furthermore, we show that detection of replicative DNA synthesis is much more sensitive than DNA-measurements by flow cytometry.

  5. Weather and event generators based on analogues of atmospheric circulation

    NASA Astrophysics Data System (ADS)

    Yiou, Pascal

    2015-04-01

    Analogues of atmospheric circulation have had numerous applications on weather prediction, climate reconstructions and detection/attribution analyses. A stochastic weather generator based on circulation analogues was recently proposed by Yiou (2014) to simulate sequences of European temperatures. One of the features of this weather generator is that it preserves the spatial and temporal structures of the climate variables to be simulated. This method is flexible enough to be combined efficiently with a storm detection algorithm in order to generate large catalogues of high impact extra-tropical storms that hit Europe. I will present the gist of the method of circulation analogues and some performances. Two promising applications for weather generators based on this method (ensemble climate prediction and extra-tropical storms) will be tested. References Yiou, P.: AnaWEGE: a weather generator based on analogues of atmospheric circulation, Geosci. Model Dev., 7, 531-543, doi:10.5194/gmd-7-531-2014, 2014.

  6. Effect of glutamate analogues on brain tumor cell lines.

    PubMed

    Campbell, G L; Bartel, R; Freidman, H S; Bigner, D D

    1985-10-01

    Glutamate analogues have been used in many different experimental approaches in neurobiology. A small number of these analogues have been classified as gliotoxic. We have examined the effect of seven glutamate analogues (five gliotoxic and two neurotoxic) on the growth and viability of four human glioma cell lines, one human medulloblastoma cell line, and one human sarcoma cell line. Aminoadipic acid and homocysteic acid predominantly affected the growth of two glioma cell lines in the presence of 4 mM glutamine. Phosphonobutyric acid predominantly affected the other two glioma cell lines and the medulloblastoma cell line in the presence of 4 mM glutamine. In medium containing no glutamine, all three analogues had marked effects on all the cell lines except the sarcoma cell line. These effects were dose dependent. We postulate that these results can in part be explained on the basis of metabolic compartmentalization.

  7. A Non-Verbal Analogue to the Verbal Transformation Effect

    ERIC Educational Resources Information Center

    Lass, Norman J.; And Others

    1973-01-01

    Investigates the effectiveness of non-speech auditory stimuli in eliciting transformations analogous to those reported for speech stimuli to determine if a non-verbal analogue to the verbal transformation effect exists. (DD)

  8. Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

    PubMed Central

    Shrestha, Sanjib K.; Fosso, Marina Y.; Green, Keith D.

    2015-01-01

    In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6″-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C12 and C14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C4, C6, and C8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC50s) for the most potent TOB analogues (C12 and C14) against A549 and Beas 2B cells were 4- to 64-fold and 32- to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C12 and C14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs. PMID:26033722

  9. Semisynthesis of salviandulin E analogues and their antitrypanosomal activity.

    PubMed

    Aoyagi, Yutaka; Fujiwara, Koji; Yamazaki, Akira; Sugawara, Naoko; Yano, Reiko; Fukaya, Haruhiko; Hitotsuyanagi, Yukio; Takeya, Koichi; Ishiyama, Aki; Iwatsuki, Masato; Otoguro, Kazuhiko; Yamada, Haruki; Ōmura, Satoshi

    2014-01-15

    A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity.

  10. Catalytic antioxidants: regenerable tellurium analogues of vitamin E.

    PubMed

    Singh, Vijay P; Poon, Jia-fei; Engman, Lars

    2013-12-20

    In an effort to improve the chain-breaking capacity of the natural antioxidants, an octyltelluro group was introduced next to the phenolic moiety in β- and δ-tocopherol. The new vitamin E analogues quenched peroxyl radicals more efficiently than α-tocopherol and were readily regenerable by aqueous N-acetylcysteine in a simple membrane model composed of a stirring chlorobenzene/water two-phase system. The novel tocopherol analogues could also mimic the action of the glutathione peroxidase enzymes.

  11. Analogue and digital linear modulation techniques for mobile satellite

    NASA Technical Reports Server (NTRS)

    Whitmarsh, W. J.; Bateman, A.; Mcgeehan, J. P.

    1990-01-01

    The choice of modulation format for a mobile satellite service is complex. The subjective performance is summarized of candidate schemes and voice coder technologies. It is shown that good performance can be achieved with both analogue and digital voice systems, although the analogue system gives superior performance in fading. The results highlight the need for flexibility in the choice of signaling format. Linear transceiver technology capable of using many forms of narrowband modulation is described.

  12. The relevance of analogue studies for understanding obsessions and compulsions.

    PubMed

    Abramowitz, Jonathan S; Fabricant, Laura E; Taylor, Steven; Deacon, Brett J; McKay, Dean; Storch, Eric A

    2014-04-01

    Analogue samples are often used to study obsessive-compulsive (OC) symptoms and related phenomena. This approach is based on the hypothesis that results derived from such samples are relevant to understanding OC symptoms in individuals with a diagnosis of obsessive-compulsive disorder (OCD). Two decades ago, Gibbs (1996) reviewed the available literature and found initial support for this hypothesis. Since then there have been many important advances addressing this issue. The purpose of the present review was to synthesize various lines of research examining the assumptions of using analogue samples to draw inferences about people with OCD. We reviewed research on the prevalence of OC symptoms in non-clinical populations, the dimensional (vs. categorical) nature of these symptoms, phenomenology, etiology, and studies on developmental and maintenance factors in clinical and analogue samples. We also considered the relevance of analogue samples in OCD treatment research. The available evidence suggests research with analogue samples is highly relevant for understanding OC symptoms. Guidelines for the appropriate use of analogue designs and samples are suggested.

  13. Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

    PubMed Central

    Satishkumar, Sakilam; Vuram, Prasanna K.; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J.; Montemayor, Michelle M. Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K.

    2016-01-01

    Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest on the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL), and chronic lymphocytic leukemia (CLL) cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribo analogue of cladribine possessed activity, but was least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, only cladribine and its ribose analogue were most active. PMID:26556315

  14. Analogue gravitational phenomena in Bose-Einstein condensates

    NASA Astrophysics Data System (ADS)

    Finazzi, Stefano

    2012-08-01

    Analogue gravity is based on the simple observation that perturbations propagating in several physical systems can be described by a quantum field theory in a curved spacetime. While phenomena like Hawking radiation are hardly detectable in astrophysical black holes, these effects may be experimentally tested in analogue systems. In this Thesis, focusing on Bose-Einstein condensates, we present our recent results about analogue models of gravity from three main perspectives: as laboratory tests of quantum field theory in curved spacetime, for the techniques that they provide to address various issues in general relativity, and as toy models of quantum gravity. The robustness of Hawking-like particle creation is investigated in flows with a single black hole horizon. Furthermore, we find that condensates with two (white and black) horizons develop a dynamical instability known in general relativity as black hole laser effect. Using techniques borrowed from analogue gravity, we also show that warp drives, which are general relativistic spacetimes allowing faster-than-light travel, are unstable. Finally, the cosmological constant issue is investigated from an analogue gravity perspective and relativistic Bose-Einstein condensates are proposed as new analogue systems with novel interesting properties.

  15. Cladribine Analogues via O⁶-(Benzotriazolyl) Derivatives of Guanine Nucleosides.

    PubMed

    Satishkumar, Sakilam; Vuram, Prasanna K; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J; Montemayor, Michelle M Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K

    2015-10-09

    Cladribine, 2-chloro-2'-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O⁶-(benzotriazol-1-yl)-2'-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL) and chronic lymphocytic leukemia (CLL), cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH₂-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.

  16. Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers.

    PubMed

    Liu, Yun; Lehn, Jean-Marie; Hirsch, Anna K H

    2017-02-21

    Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition, molecular

  17. Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers

    PubMed Central

    2017-01-01

    Conspectus Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition

  18. Design, synthesis and biological evaluation of α-substituted isonipecotic acid benzothiazole analogues as potent bacterial type II topoisomerase inhibitors.

    PubMed

    Axford, Lorraine C; Agarwal, Piyush K; Anderson, Kelly H; Andrau, Laura N; Atherall, John; Barker, Stephanie; Bennett, James M; Blair, Michael; Collins, Ian; Czaplewski, Lloyd G; Davies, David T; Gannon, Carlie T; Kumar, Dushyant; Lancett, Paul; Logan, Alastair; Lunniss, Christopher J; Mitchell, Dale R; Offermann, Daniel A; Palmer, James T; Palmer, Nicholas; Pitt, Gary R W; Pommier, Stéphanie; Price, Daniel; Narasinga Rao, B; Saxena, Rashmi; Shukla, Tarun; Singh, Amit K; Singh, Mahipal; Srivastava, Anil; Steele, Christopher; Stokes, Neil R; Thomaides-Brears, Helena B; Tyndall, Edward M; Watson, David; Haydon, David J

    2013-12-15

    The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.

  19. Synthesis and biological evaluation of NAS-21 and NAS-91 analogues as potential inhibitors of the mycobacterial FAS-II dehydratase enzyme Rv0636.

    PubMed

    Bhowruth, Veemal; Brown, Alistair K; Besra, Gurdyal S

    2008-07-01

    The identification of potential new anti-tubercular chemotherapeutics is paramount due to the recent emergence of extensively drug-resistant strains of Mycobacterium tuberculosis (XDR-TB). Libraries of NAS-21 and NAS-91 analogues were synthesized and evaluated for their whole-cell activity against Mycobacterium bovis BCG. NAS-21 analogues 1 and 2 demonstrated enhanced whole-cell activity in comparison to the parental compound, and an M. bovis BCG strain overexpressing the dehydratase enzyme Rv0636 was resistant to these analogues. NAS-91 analogues with ortho-modifications gave enhanced whole-cell activity. However, extension with biphenyl modifications compromised the whole-cell activities of both NAS-21 and NAS-91 analogues. Interestingly, both libraries demonstrated in vitro activity against fatty acid synthase II (FAS-II) but not FAS-I in cell-free extracts. In in vitro assays of FAS-II inhibition, NAS-21 analogues 4 and 5 had IC(50) values of 28 and 19 mug ml(-1), respectively, for the control M. bovis strain, and the M. bovis BCG strain overexpressing Rv0636 showed a marked increase in resistance. In contrast, NAS-91 analogues demonstrated moderate in vitro activity, although increased resistance was again observed in FAS-II activity assays with the Rv0636-overexpressing strain. Fatty acid methyl ester (FAME) and mycolic acid methyl ester (MAME) analysis of M. bovis BCG and the Rv0636-overexpressing strain revealed that the effect of the drug was relieved in the overexpressing strain, further implicating and potentially identifying Rv0636 as the target for these known FabZ dehydratase inhibitors. This study has identified candidates for further development as drug therapeutics against the mycobacterial FAS-II dehydratase enzyme.

  20. Graphene-analogue carbon nitride: novel exfoliation synthesis and its application in photocatalysis and photoelectrochemical selective detection of trace amount of Cu2+

    NASA Astrophysics Data System (ADS)

    Xu, Hui; Yan, Jia; She, Xiaojie; Xu, Li; Xia, Jiexiang; Xu, Yuanguo; Song, Yanhua; Huang, Liying; Li, Huaming

    2014-01-01

    Graphene-analogue nanostructures defined as a new kind of promising materials with unique electronic, surface and optical properties have received much attention in the fields of catalysis, energy storage, sensing and electronic devices. Due to the distinctive structure characteristics of the graphene-analogue materials, they brought novel and amazing properties. Herein, graphene-analogue carbon nitride (GA-C3N4) was synthesized by high-yield, large-scale thermal exfoliation from the graphitic C3N4-based intercalation compound. Graphene-analogue carbon nitride exhibited 2D thin-layer structure with 6-9 atomic thickness, a high specific surface area of 30.1 m2 g-1, increased photocurrent responses and improved electron transport ability, which could give rise to enhancing the photocatalytic activity and stability. The graphene-analogue carbon nitride had a new features that could make it suitable as a sensor for Cu2+ determination. So GA-C3N4 is a new but promising candidate for heavy metal ions (Cu2+) determination in water environment. The photocatalytic mechanism and photoelectrochemical selective sensing of Cu2+ were also discussed.Graphene-analogue nanostructures defined as a new kind of promising materials with unique electronic, surface and optical properties have received much attention in the fields of catalysis, energy storage, sensing and electronic devices. Due to the distinctive structure characteristics of the graphene-analogue materials, they brought novel and amazing properties. Herein, graphene-analogue carbon nitride (GA-C3N4) was synthesized by high-yield, large-scale thermal exfoliation from the graphitic C3N4-based intercalation compound. Graphene-analogue carbon nitride exhibited 2D thin-layer structure with 6-9 atomic thickness, a high specific surface area of 30.1 m2 g-1, increased photocurrent responses and improved electron transport ability, which could give rise to enhancing the photocatalytic activity and stability. The graphene-analogue

  1. Habitability & Astrobiology Research in Mars Terrestrial Analogues

    NASA Astrophysics Data System (ADS)

    Foing, Bernard

    2014-05-01

    We performed a series of field research campaigns (ILEWG EuroMoonMars) in the extreme Utah desert relevant to Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL), or Moon geochemistry (SMART-1, LRO). We shall give an update on the sample analysis in the context of habitability and astrobiology. Methods & Results: In the frame of ILEWG EuroMoonMars campaigns (2009 to 2013) we deployed at Mars Desert Research station, near Hanksville Utah, a suite of instruments and techniques [A, 1, 2, 9-11] including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. Among the important findings are the diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed [3,4,9]. A dominant factor seems to be soil porosity and lower clay-sized particle content [6-8]. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples [10, 11]. We compare the 2009 campaign results [1-9] to new measurements from 2010-2013 campaigns [10-12] relevant to: comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life. Keywords: field analogue research, astrobiology, habitability, life detection, Earth-Moon-Mars, organics References [A] Foing, Stoker & Ehrenfreund (Editors, 2011) "Astrobiology field Research in Moon/Mars Analogue Environments", Special Issue of International

  2. Reversal of methylcholanthrene-induced changes in mouse prostates in vitro by retinoic acid and its analogues.

    PubMed Central

    Lasnitzki, I.

    1976-01-01

    The influence of vitamin A-related compounds on hyperplasia and metaplasia induced by methylcholanthrene was studied in mouse prostate glands in organ culture. Methylcholanthrene was found to cause extensive hyperplasia and squamous metaplasia of the prostatic epithelium which persisted after withdrawal of the carcinogen. The retinoids included retinoic acid and 6 of its structural analogues synthesized in an attempt to enhance the anticarcinogenic action and reduce the toxicity of the parent compound. These where the cyclopentenyl analogus 7699, A2-retinoic acid, 13-cis-alpha-retinoic acid and 3 aromatic analogues. Administration of the compounds following the carcinogen reduced the extent and incidence of hyperplasia significantly and with the exception of one compound reversed the squamous metaplasia. Two of the aromatic analogues, one with a terminal ethylamide group (1430), and the other with a terminal ethylester group (9369), proved to be the most potent inhibitors, followed by compound 7699 and (9369), proved to be the most potent inhibitors, followed by compound 7699 and retinoic acid. A2-retinoic acid and 13-cis-alpha-retinoic acid showed the lowest activity. The inhibition of hyperplasia appeared to be mediated via a reduction of DNA synthesis. It seemed unrelated to either the biological growth-promoting activity of the compounds or their surface-active properties. It is tentatively suggested that vitamin A and its analogues may act as hormones. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:987794

  3. Biological and structural characterization of new linear gomesin analogues with improved therapeutic indices.

    PubMed

    Fázio, Marcos A; Jouvensal, Laurence; Vovelle, Françoise; Bulet, Philippe; Miranda, M Terêsa M; Daffre, Sirlei; Miranda, Antonio

    2007-01-01

    Gomesin (Gm) is a potent antimicrobial peptide isolated from the spider Acanthoscurria gomesiana. The two disulfide bridges Cys(2,15) and Cys(6,11) facilitate the folding of the molecule in a beta-hairpin structure, conferring on the peptide a high stability in human plasma. We report herein biological and structural features of new linear Gm analogues, obtained by combining the removal of both disulfide bridges and the incorporation of a D- or L-proline. Regarding their biological properties, two analogues, namely, [D-Thr(2,6,11,15), Pro(9)]-D-Gm and [Thr(2,6,11,15), D-Pro(9)]-Gm, are as potent as Gm against Candida albicans and only fourfold less against Staphylococcus aureus and Escherichia coli. In addition, at 100 microM they are approximately threefold less hemolytic than Gm. The best therapeutic indices were found for [D-Thr(2,6,11,15), Pro(9)]-D-Gm and for [(Des-pGlu(1), -Thr(2), -Arg(3)), Thr(6,11,15), D-Pro(9)]-Gm with a 32-fold increase of their activity against bacteria, and from 128- to 512-fold against yeast when compared with Gm. Regarding the stability, [D-Thr(2,6,11,15), Pro(9)]-D-Gm appeared to be the most resistant in human serum, along with [D-Thr(2,6,11,15), Pro(8)]-D-Gm and [Thr(2,6,11,15), D-Arg(4,16), D-Pro(9)]-Gm. When evaluating their conformation by CD spectroscopy in sodium dodecyl sulfate (SDS), most linear analogues display beta-conformation characteristics. Moreover, considering its high therapeutic index and stability in serum, [D-Thr(2,6,11,15), Pro(9)]-D-Gm was further analyzed by NMR spectroscopy. (1)H NMR experiments in SDS micelles demonstrated that [D-Thr(2,6,11,15), Pro(9)]-D-Gm presents a conformation very similar to that of Gm. In our search for Gm analogues with enhanced potential for drug development, we demonstrated that designing cysteine-free analogues can improve the therapeutic index of Gm derivatives.

  4. Terrestrial research in Mars analogue environments

    NASA Astrophysics Data System (ADS)

    Osipov, G.

    Fatty acids (FA) content was measured by GC-MS SIM technique in Sulfide ores of present day (Mid-Atlantic Ridge and others) and ancient (Ural Paleocene, Russia) black smokers; Early Proterozoic kerites of Volyn; Siberian, Canadian and Antarctic permafrosts and also in rocks of East-European platform Achaean crystalline basement. Analysis was shown presence those and only those fatty acids which are specific to microorganisms. FA with 12 up 19 of carbon atoms are thought to be a bacterial biomass sign. 3-Hydroxy fatty acids also found in samples and are strong specific markers of gram-negative bacteria. Cultivation yield living bacteria in some cases. The East-European platform Achaean crystalline basement rocks opened by Vorotilov Deep Well (VDW) drilled through Puchezh-Katunski impact structure were studied within depths 2575 - 2805 m. 34 microbial lipid markers were detected by GC-MS and 22 species were identified. Bacteria of g. Bacillus reached 6,8 % in subsurface communities. However, members of gg. Clostridium (37,1 - 33,2 %) and Rhodococcus (27,6 - 33,7 %) were absolute dominants within studied depth interval. Some lipid patterns of kerite samples could be assessed to definite genera or, in special cases, to species of contemporary microorganisms. For instance, 2-hydroxylauric acid is specific to Pseudomonas putida group or Acinetobacter spp., and hydroxymyristic together with hydroxypalmitic are specific to P.cepacea and cyanobacteria. 3-hydroxystearic acid was known as component of Acetobacter diazothrophycus and Gloebacter violaceous cyanobacterium. 10-hydroxystearic acid associated with Nocardia spp., which oxidizes oleic acid in organic substrates. 10-methylhexadecanoic (10Me16) acid together with 10Me14, 10Me15 and 10Me17 analogues are markers of actinomycetes. Significant part of Black Smokers organic matter is probably biogenic. Fatty acid features strongly assigns it to bacterial, microeucariotic and planta cells. Par example 3-hydroxy acids are

  5. Review of Insulin and its Analogues in Diabetes Mellitus

    PubMed Central

    Mane, Krishnappa; Chaluvaraju, KC; Niranjan, MS; Zaranappa, TR; Manjuthej, TR

    2012-01-01

    Diabetes is a metabolic disorder where in human body does not produce or properly uses insulin, a hormone that is required to convert sugar, starches and other food into energy. Diabetes finally leads to more complications and to prevent these complications insulin and its analogues are used. After more than half a century of treating diabetics with animal insulin’s, recombinant DNA technologies and advanced protein chemistry made human insulin preparations available in the early 1980s. As the next step, over the last decade, insulin analogues were constructed by changing the structure of the native protein with the goal of improving the therapeutic properties of it, because the pharmacokinetic characteristics of rapid, intermediate and long-acting preparations of human insulin make it almost impossible to achieve sustained normoglycemia. The first clinically available insulin analogue, lispro, confirmed the hopes by showing that improved glycaemic control can be achieved without an increase in hypoglycaemic events. Two new insulin analogues, insulin glargine and insulin aspart, have recently been approved for clinical use in the United States and several other analogues are being intensively tested. PMID:24826038

  6. Theoretical study on absorption and emission spectra of adenine analogues.

    PubMed

    Liu, Hongxia; Song, Qixia; Yang, Yan; Li, Yan; Wang, Haijun

    2014-04-01

    Fluorescent nucleoside analogues have attracted much attention in studying the structure and dynamics of nucleic acids in recent years. In the present work, we use theoretical calculations to investigate the structural and optical properties of four adenine analogues (termed as A1, A2, A3, and A4), and also consider the effects of aqueous solution and base pairing. The results show that the fluorescent adenine analogues can pair with thymine to form stable H-bonded WC base pairs. The excited geometries of both adenine analogues and WC base pairs are similar to the ground geometries. The absorption and emission maxima of adenine analogues are greatly red shifted compared with nature adenine, the oscillator strengths of A1 and A2 are stronger than A3 and A4 in both absorption and emission spectra. The calculated low-energy peaks in the absorption spectra are in good agreement with the experimental data. In general, the aqueous solution and base pairing can slightly red-shift both the absorption and emission maxima, and can increase the oscillator strengths of absorption spectra, but significantly decrease the oscillator strengths of A3 in emission spectra.

  7. Bioluminescent properties of obelin and aequorin with novel coelenterazine analogues.

    PubMed

    Gealageas, Ronan; Malikova, Natalia P; Picaud, Sandrine; Borgdorff, Aren J; Burakova, Ludmila P; Brûlet, Philippe; Vysotski, Eugene S; Dodd, Robert H

    2014-04-01

    The main analytical use of Ca(2+)-regulated photoproteins from luminous coelenterates is for real-time non-invasive visualization of intracellular calcium concentration ([Ca(2+)]i) dynamics in cells and whole organisms. A limitation of this approach for in vivo deep tissue imaging is the fact that blue light emitted by the photoprotein is highly absorbed by tissue. Seven novel coelenterazine analogues were synthesized and their effects on the bioluminescent properties of recombinant obelin from Obelia longissima and aequorin from Aequorea victoria were evaluated. Only analogues having electron-donating groups (m-OCH3 and m-OH) on the C6 phenol moiety or an extended resonance system at the C8 position (1-naphthyl and α-styryl analogues) showed a significant red shift of light emission. Of these, only the α-styryl analogue displayed a sufficiently high light intensity to allow eventual tissue penetration. The possible suitability of this compound for in vivo assays was corroborated by studies with aequorin which allowed the monitoring of [Ca(2+)]i dynamics in cultured CHO cells and in hippocampal brain slices. Thus, the α-styryl coelenterazine analogue might be potentially useful for non-invasive, in vivo bioluminescence imaging in deep tissues of small animals.

  8. Effect of extrusion temperature and moisture content of corn flour on crystallinity and hardness of rice analogues

    NASA Astrophysics Data System (ADS)

    Budi, Faleh Setia; Hariyadi, Purwiyatno; Budijanto, Slamet; Syah, Dahrul

    2015-12-01

    Rice analogues are food products made of broken rice and/or any other carbohydrate sources to have similar texture and shape as rice. They are usually made by hot extrusion processing. The hot extrusion process may change the crystallinity of starch and influence the characteristic of rice analogues. Therefore, this research aimed to study the effect of moisture content of incoming dough and temperature of extrusion process on the crystallinity and hardness of resulting rice analogues. The dough's were prepared by mixing of corn starch-flour with ratio 10/90 (w/w) and moisture content of 35%, 40% and 45% (w/w) and extrusion process were done at temperature of 70, 80, 90°C by using of twin screw extruder BEX-DS-2256 Berto. The analyses were done to determine the type of crystal, degree of crystallinity, and hardness of the resulting rice analogues. Our result showed that the enhancement of extrusion temperature from 70 - 90°C increased degree of crystallinity from 5.86 - 15.00% to 10.70 - 18.87% and hardness from 1.71 - 4.36 kg to 2.05 - 5.70 kg. The raising of dough moisture content from 35 - 45% decreased degree of crystallinity from 15.00 - 18.87% to 5.86 - 10.70% and hardness from 4.36 - 5.70 kg to 1.71 - 2.05 kg. The increase of degree of crystallinity correlated positively with the increase of hardness of rice analogues (r = 0.746, p = 0.05).

  9. Stream food web response to a salmon carcass analogue addition in two central Idaho, U.S.A. streams

    PubMed Central

    KOHLER, ANDRE E; RUGENSKI, AMANDA; TAKI, DOUG

    2008-01-01

    suggest that SCA addition successfully increased periphyton and macroinvertebrate biomass with no detectable response in streamwater nutrient concentrations. Correspondingly, no change in nutrient limitation status was detected based on dissolved inorganic nitrogen to soluble reactive phosphorus ratios (DIN/SRP) and nutrient-diffusing substrata experiments. Salmon carcass analogues appear to increase freshwater productivity. Salmon carcass analogues represent a pathogen-free nutrient enhancement tool that mimics natural trophic transfer pathways, can be manufactured using recycled fish products, and is easily transported; however, salmon carcass analogues should not be viewed as a replacement for naturally spawning salmon and the important ecological processes they provide.

  10. New rubrolide analogues as inhibitors of photosynthesis light reactions.

    PubMed

    Varejão, Jodieh O S; Barbosa, Luiz C A; Ramos, Gabriela Álvarez; Varejão, Eduardo V V; King-Díaz, Beatriz; Lotina-Hennsen, Blas

    2015-04-01

    Natural products called rubrolides have been investigated as a model for the development of new herbicides that act on the photosynthesis apparatus. This study comprises a comprehensive analysis of the photosynthesis inhibitory ability of 27 new structurally diverse rubrolide analogues. In general, the results revealed that the compounds exhibited efficient inhibition of the photosynthetic process, but in some cases low water solubility may be a limiting factor. To elucidate their mode of action, the effects of the compounds on PSII and PSI, as well as their partial reaction on chloroplasts and the chlorophyll a fluorescence transients were measured. Our results showed that some of the most active rubrolide analogues act as a Hill reaction inhibitors at the QB level by interacting with the D1 protein at the reducing side of PSII. All of the active analogues follow Tice's rule of 5, which indicates that these compounds present physicochemical properties suitable for herbicides.

  11. Synthesis and antioxidant activity of a procyanidin B3 analogue.

    PubMed

    Mizuno, Mirei; Nakanishi, Ikuo; Matsubayashi, Satoko; Imai, Kohei; Arai, Takuya; Matsumoto, Ken-Ichiro; Fukuhara, Kiyoshi

    2017-02-15

    Proanthocyanidin, an oligomer of catechin, is a natural antioxidant and a potent inhibitor of lectin-like oxidized LDL receptor-1, which is involved in the pathogenesis of arteriosclerosis. We synthesized proanthocyanidin analogue 1, in which the geometry of one catechin molecule in procyanidin B3, a dimer of (+)-catechin, is constrained to be planar. The antioxidant activities of the compounds were evaluated in terms of their capacities to scavenge galvinoxyl radicals, and results demonstrate that while procyanidin was 3.8 times more potent than (+)-catechin, the radical scavenging activity of proanthocyanidin analogue 1 was further increased to 1.9 times that of procyanidin B3. This newly designed proanthocyanidin analogue 1 may be a promising lead compound for the treatment of arteriosclerosis and related cerebrovascular diseases.

  12. Analogue modelling of syntectonic leucosomes in migmatitic schists

    NASA Astrophysics Data System (ADS)

    Druguet, Elena; Carreras, Jordi

    2006-10-01

    Migmatites from the Cap de Creus tectonometamorphic belt display a wide variety of structures, from those formed when the leucosomes were melt-bearing, to those developed during solid-state deformation. The observed field structures have been modelled by means of analogue experiments. The materials used in the models are layered plasticine as a schist analogue, and chocolate as analogue of the crystallizing leucosome. A model for the development of syntectonic migmatites is proposed in which initial melt-bearing patches, preferentially formed within fertile pelitic layers, progressively evolve towards lens-shaped veins. Furthermore, heterogeneous deformation of anisotropic metasediments facilitates formation of extensional sites for further melt accumulation and transport. Melt crystallization implies a rapid increase in effective viscosity of leucosomes producing a reversal in competence contrast with respect to the enclosing schists. During the whole process, deformation localizes around crystallizing veins, giving rise to different and contrasting structures for melt-bearing and for solid-state stages.

  13. Design of novel CSA analogues as potential safeners and fungicides.

    PubMed

    Zheng, Yang; Liu, Bin; Gou, Zhaopin; Li, Yao; Zhang, Xiao; Wang, Yanqing; Yu, Shujing; Li, Yonghong; Sun, Dequn

    2015-02-15

    Study of safeners has been seldom reported in literature. In this work, a series of novel acylsulfamoylbenzamide analogues was designed and synthesized with newly developed safener cyprosulfamide (CSA) as the leading compound. The activity assay against the herbicide thiencarbazone-methyl (TCM) on maize revealed that fifteen compounds showed better protective effect than CSA on the fresh weight of aerial parts, twelve compounds exhibited better activity on the dry weight of aerial parts. Remarkably, two compounds (6Ih, 7II) had protective effect on the four aspects of TCM treated maize. Further antifungal assay showed their excellent activity against Physollospora piricola. The structure-activity relationships of CSA analogues as safeners and fungicides were discussed and it might be valuable for further molecular modification of new CSA analogues.

  14. Conception, synthesis, and biological evaluation of original discodermolide analogues.

    PubMed

    de Lemos, Elsa; Agouridas, Evangelos; Sorin, Geoffroy; Guerreiro, Antonio; Commerçon, Alain; Pancrazi, Ange; Betzer, Jean-François; Lannou, Marie-Isabelle; Ardisson, Janick

    2011-08-29

    Due to its intriguing biological activity profile and potential chemotherapeutic application discodermolide (DDM) proved to be an attractive target. Therefore, notable efforts have been carried out directed toward its total synthesis and toward the production and evaluation of synthetic analogues. Recently, we achieved the total synthesis of DDM. At the present, guided by the knowledge gained during our DDM total synthesis and by the requirement of keeping the bioactive "U" shape conformation, we report the convergent preparation of five original analogues. Three types of changes were realized through modification of the terminal (Z)-diene moiety, of the methyl group at the C14-position, and the lactone region. All analogues were active in the nanomolar range and two of them turned out to be equipotent to DDM.

  15. Migrastatin analogues target fascin to block tumour metastasis.

    PubMed

    Chen, Lin; Yang, Shengyu; Jakoncic, Jean; Zhang, J Jillian; Huang, Xin-Yun

    2010-04-15

    Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

  16. Rapid on-site detection of ephedrine and its analogues used as adulterants in slimming dietary supplements by TLC-SERS.

    PubMed

    Lv, Diya; Cao, Yan; Lou, Ziyang; Li, Shujin; Chen, Xiaofei; Chai, Yifeng; Lu, Feng

    2015-02-01

    Ephedrine and its analogues are in the list of prohibited substance in adulteration to botanical dietary supplements (BDS) for their uncontrollable stimulating side effects. However, they were always adulterated illegally in BDS to promote losing weight. In order to avoid detection, various kinds of ephedrine analogues were added rather than ephedrine itself. This has brought about great difficulties in authentication of BDS. In this study, we put forward for the first time a method which combined thin-layer chromatography (TLC) and surface-enhanced Raman scattering (SERS) to directly identify trace adulterant. Ephedrine, pseudoephedrine, methylephedrine, and norephedrine were mixed and used in this method to develop an analytical model. As a result, the four analogues were separated efficiently in TLC analysis, and trace-components and low-background SERS detection was realized. The limit of detection (LOD) of the four analogues was 0.01 mg/mL. Eight common Raman peaks (△υ = 620, 1003, 1030, 1159, 1181, 1205, 1454, 1603 cm(-1)) were extracted experimentally and statistically to characterize the common feature of ephedrine analogues. A TLC-SERS method coupled with common-peak model was adopted to examine nine practical samples, two of which were found to be adulterated with ephedrine analogues. Identification results were then confirmed by UPLC-QTOF/MS analysis. The proposed method was simple, rapid, and accurate and can also be employed to trace adulterant identification even when there are no available reference derivatives on-site or unknown types of ephedrine analogues are adulterated.

  17. Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue.

    PubMed

    Almaliti, Jehad; Al-Hamashi, Ayad A; Negmeldin, Ahmed T; Hanigan, Christin L; Perera, Lalith; Pflum, Mary Kay H; Casero, Robert A; Tillekeratne, L M Viranga

    2016-12-08

    A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp(3) to sp(2) at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-α-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.

  18. Synthesis of daidzin analogues as potential agents for alcohol abuse.

    PubMed

    Gao, Guang-Yao; Li, Dian-Jun; Keung, Wing Ming

    2003-09-01

    Daidzin, the active principle of an herbal remedy for 'alcohol addiction', has been shown to reduce alcohol consumption in all laboratory animals tested to date. Correlation studies using structural analogues of daidzin suggests that it acts by raising the monoamine oxidase (MAO)/mitochondrial aldehyde dehydrogenase (ALDH-2) activity ratio (J. Med. Chem. 2000, 43, 4169). Structure-activity relationship (SAR) studies on the 7-O-substituted analogues of daidzin have revealed structural features important for ALDH-2 and MAO inhibition (J. Med. Chem. 2001, 44, 3320). We here evaluated effects of substitutions at 2, 5, 6, 8, 3' and 4' positions of daidzin on its potencies for ALDH-2 and MAO inhibition. Results show that analogues with 4'-substituents that are small, polar and with hydrogen bonding capacities are most potent ALDH-2 inhibitors, whereas those that are non-polar and with electron withdrawing capacities are potent MAO inhibitors. Analogues with a 5-OH group are less potent ALDH-2 inhibitors but are more potent MAO inhibitors. All the 2-, 6-, 8- and 3'-substituted analogues tested so far do not inhibit ALDH-2 and/or have decreased potencies for MAO inhibition. This, together with the results obtained from previous studies, suggests that a potent antidipsotropic analogue would be a 4',7-disubstituted isoflavone. The 4'-substituent should be small, polar, and with hydrogen bonding capacities such as, -OH and -NH(2); whereas the 7-substituent should be a straight-chain alkyl with a terminal polar function such as -(CH(2))(n)-OH with 2< or =n < or =6, -(CH(2))(n)-COOH with 5< or =n < or =10, or -(CH(2))(n)-NH(2) with n > or =4.

  19. The Object-analogue approach for probabilistic forecasting

    NASA Astrophysics Data System (ADS)

    Frediani, M. E.; Hopson, T. M.; Anagnostou, E. N.; Hacker, J.

    2015-12-01

    The object-analogue is a new method to estimate forecast uncertainty and to derive probabilistic predictions of gridded forecast fields over larger regions rather than point locations. The method has been developed for improving the forecast of 10-meter wind speed over the northeast US, and it can be extended to other forecast variables, vertical levels, and other regions. The object-analogue approach combines the analog post-processing technique (Hopson 2005; Hamill 2006; Delle Monache 2011) with the Method for Object-based Diagnostic Evaluation (MODE) for forecast verification (Davis et al 2006a, b). Originally, MODE is used to verify mainly precipitation forecasts using features of a forecast region represented by an object. The analog technique is used to reduce the NWP systematic and random errors of a gridded forecast field. In this study we use MODE-derived objects to characterize the wind fields forecasts into attributes such as object area, centroid location, and intensity percentiles, and apply the analogue concept to these objects. The object-analogue method uses a database of objects derived from reforecasts and their respective reanalysis. Given a real-time forecast field, it searches the database and selects the top-ranked objects with the most similar set of attributes using the MODE fuzzy logic algorithm for object matching. The attribute probabilities obtained with the set of selected object-analogues are used to derive a multi-layer probabilistic prediction. The attribute probabilities are combined into three uncertainty layers that address the main concerns of most applications: location, area, and magnitude. The multi-layer uncertainty can be weighted and combined or used independently in such that it provides a more accurate prediction, adjusted according to the application interest. In this study we present preliminary results of the object-analogue method. Using a database with one hundred storms we perform a leave-one-out cross-validation to

  20. On slow light as a black hole analogue

    NASA Astrophysics Data System (ADS)

    Unruh, W. G.; Schützhold, R.

    2003-07-01

    Although slow light (electromagnetically induced transparency) would seem an ideal medium in which to institute a “dumb hole” (black hole analogue), it suffers from a number of problems. We show that the high phase velocity in the slow light regime ensures that the system cannot be used as an analogue displaying Hawking radiation. Even though an appropriately designed slow-light setup may simulate classical features of black holes—such as horizon, mode mixing, “Bogoliubov” coefficients, etc.—it does not reproduce the related quantum effects.

  1. Naturally occurring crystalline phases: analogues for radioactive waste forms

    SciTech Connect

    Haaker, R.F.; Ewing, R.C.

    1981-01-01

    Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

  2. Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors

    PubMed Central

    Florence, Gordon J.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Menzies, Stefanie K.; Morris, Joanne C.; Tulloch, Lindsay B.; Smith, Terry K.

    2015-01-01

    A series of novel bis-tetrahydropyran 1,4-triazole analogues based on the acetogenin framework display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness. A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure activity relationship studies. PMID:25145275

  3. Relationship between antimold activity and molecular structure of cinnamaldehyde analogues.

    PubMed

    Zhang, Yuanyuan; Li, Shujun; Kong, Xianchao

    2013-03-01

    A quantitative structure-activity relationship (QSAR) modeling of the antimold activity of cinnamaldehyde analogues against of Aspergillus niger and Paecilomyces variotii was presented. The molecular descriptors of cinnamaldehyde analogues were calculated by the CODESSA program, and these descriptors were selected by best multi-linear regression method (BMLR). Satisfactory multilinear regression models of Aspergillus niger and Paecilomyces variotii were obtained with R(2)=0.9099 and 0.9444, respectively. The models were also satisfactorily validated using internal validation and leave one out validation. The QSAR models provide the guidance for further synthetic work.

  4. Synthesis and antihistamine evaluations of novel loratadine analogues.

    PubMed

    Wang, Yue; Wang, Juan; Lin, Yan; Si-Ma, Li-Feng; Wang, Dong-hua; Chen, Li-Gong; Liu, Deng-Ke

    2011-08-01

    A series of loratadine analogues containing hydroxyl group and chiral center were synthesized. The effect of the synthesized compounds on the histamine-induced contractions of guinea-pig ileum muscles was studied. In addition, the in vivo asthma-relieving effect of the analogues in the histamine induced asthmatic reaction in guinea-pigs was determined. Most of the compounds exhibited definite H(1) antihistamine activity. The S-enantiomers, compounds 2, 4 and 8, are more potent than the R-enantiomers, compounds 1, 3 and 7. Compound 6 was the most active one among the eight synthesized compounds.

  5. Fluorescent diethylcarbamazine analogues: sites of accumulation in Brugia malayi.

    PubMed

    Junnila, Amy; Bohle, D Scott; Prichard, Roger; Perepichka, Inna; Spina, Carla

    2007-01-01

    New fluorescein and rhodamine B-labeled antifilarial drug DEC analogues for use in drug localization studies with confocal microscopy have been prepared by a high-yield three-step synthesis. The resulting beta-amine-substituted DEC analogue has a single ethyl substituent which is beta-aminated to accommodate the fluorophore of either fluorescein isothiocyananate or rhodamine B. Confocal microscopy is used to show that the drug accumulates in the adult filarial worms in the pharynx, esophagus, and near the nerve ring of all adults, as well as in the uteri and vulva and the testes of the females and males.

  6. Photochemistry of nucleic acid bases and their thio- and aza-analogues in solution.

    PubMed

    Pollum, Marvin; Martínez-Fernández, Lara; Crespo-Hernández, Carlos E

    2015-01-01

    The steady-state and time-resolved photochemistry of the natural nucleic acid bases and their sulfur- and nitrogen-substituted analogues in solution is reviewed. Emphasis is given to the experimental studies performed over the last 3-5 years that showcase topical areas of scientific inquiry and those that require further scrutiny. Significant progress has been made toward mapping the radiative and nonradiative decay pathways of nucleic acid bases. There is a consensus that ultrafast internal conversion to the ground state is the primary relaxation pathway in the nucleic acid bases, whereas the mechanism of this relaxation and the level of participation of the (1)πσ*, (1) nπ*, and (3)ππ* states are still matters of debate. Although impressive research has been performed in recent years, the microscopic mechanism(s) by which the nucleic acid bases dissipate excess vibrational energy to their environment, and the role of the N-glycosidic group in this and in other nonradiative decay pathways, are still poorly understood. The simple replacement of a single atom in a nucleobase with a sulfur or nitrogen atom severely restricts access to the conical intersections responsible for the intrinsic internal conversion pathways to the ground state in the nucleic acid bases. It also enhances access to ultrafast and efficient inter-system crossing pathways that populate the triplet manifold in yields close to unity. Determining the coupled nuclear and electronic pathways responsible for the significantly different photochemistry in these nucleic acid base analogues serves as a convenient platform to examine the current state of knowledge regarding the photodynamic properties of the DNA and RNA bases from both experimental and computational perspectives. Further investigations should also aid in forecasting the prospective use of sulfur- and nitrogen-substituted base analogues in photochemotherapeutic applications.

  7. Graphene-analogue carbon nitride: novel exfoliation synthesis and its application in photocatalysis and photoelectrochemical selective detection of trace amount of Cu²⁺.

    PubMed

    Xu, Hui; Yan, Jia; She, Xiaojie; Xu, Li; Xia, Jiexiang; Xu, Yuanguo; Song, Yanhua; Huang, Liying; Li, Huaming

    2014-01-01

    Graphene-analogue nanostructures defined as a new kind of promising materials with unique electronic, surface and optical properties have received much attention in the fields of catalysis, energy storage, sensing and electronic devices. Due to the distinctive structure characteristics of the graphene-analogue materials, they brought novel and amazing properties. Herein, graphene-analogue carbon nitride (GA-C₃N₄) was synthesized by high-yield, large-scale thermal exfoliation from the graphitic C₃N₄-based intercalation compound. Graphene-analogue carbon nitride exhibited 2D thin-layer structure with 6-9 atomic thickness, a high specific surface area of 30.1 m(2) g(-1), increased photocurrent responses and improved electron transport ability, which could give rise to enhancing the photocatalytic activity and stability. The graphene-analogue carbon nitride had a new features that could make it suitable as a sensor for Cu(2+) determination. So GA-C₃N₄ is a new but promising candidate for heavy metal ions (Cu(2+)) determination in water environment. The photocatalytic mechanism and photoelectrochemical selective sensing of Cu(2+) were also discussed.

  8. Intracellular uptake and intraspheroidal distribution of hypericin and hydrophilic analogues using E-cadherin transfected T-24 human bladder cancer cells

    NASA Astrophysics Data System (ADS)

    Crnolatac, Ivo; Huygens, Ann; de Witte, Peter A. M.

    2008-02-01

    Hypericin (HYP) is used after instillation as a diagnostic tool for the fluorescence detection of CIS in the human bladder. In this study the in vitro cellular accumulation and intraspheroidal distribution of HYP and three analogues (OH1, OH2, OH3) with gradually increasing hydrophilicity were studied. E-cadherin negative (T24-C1 -) and E-cadherin positive (T24-H3 ++) human bladder cancer cells were used. We report that in the presence of FBS all compounds were taken up by the monolayer cells to the same limited extent, whereas the overall intracellular accumulation was substantially higher when the incubation of the different dyes took place using cell medium not supplemented with FBS. The results of this study therefore confirm the competition between cellular uptake of HYP and analogues and binding to FBS constituents. Investigating the permeation of the compounds in spheroids, it was found that all HYP analogues diffused dramatically better through the three-dimensional cell layers than HYP itself. This enhanced ability of hydrophilic HYP analogues to permeate through the cell layers in the presence of FBS can be explained in terms of a preferred binding to HDL as compared to LDL. The results further show that all compounds, including LDL-binding HYP, substantially permeated better in T24-C1 - spheroids than in T24-H3 ++ spheroids. The data therefore support the hypothesis that a lowered cellular cohesion is the key to understand the selective uptake of hypericin and its analogues in malignant urothelial cells.

  9. Spectral characterization of Martian soil analogues

    NASA Technical Reports Server (NTRS)

    Agresti, David G.

    1987-01-01

    As previously reported, reflectance spectra of iron oxide precipitated as ultrafine particles, unlike ordinary fine grained hematite, have significant similarities to reflectance spectra from the bright regions of Mars. These particles were characterized according to composition, magnetic properties, and particle size distribution. Mossbauer, magnetic susceptibility, and optical data were obtained for samples with a range of concentrations of iron oxide in silica gel of varying pore diameters. To analyze the Mossbauer spectra, a versatile fitting program was enhanced to provide user friendly screen input and theoretical models appropriate for the superparamagnetic spectra obtained.

  10. Demonstration of flow localization in analogue partially molten system

    NASA Astrophysics Data System (ADS)

    Takashima, S.; Kumagai, I.; Kurita, K.

    2003-04-01

    Melt migration in partially molten medium is conceptually classified into two contrasting models; homogeneous permeable flow and localized channeled flow. The transition from permeable flow to localized one is promoted with advance of melting and deformation of the medium. Kelemen et al(1995) and Spiegelmanet al(2001) modeled this process taking into accounts of compaction and dissolution. But the physics behind this transition is not yet clarified well. Here we explore rheological aspect of this problem based analogue experiments using deformable soft gel as a solid phase and would like to argue the role of self-organization in the flow development. In this presentation we show two kinds of experimental results which are mutually related. One is a demonstration of development of the channeled flow in a so-called Rayleigh-Taylor Instability experiments. Dense viscous fluid(glycerol solution) is poured at the top of the matrix fluid;homogeneous mixture of soft transparent gel and visocous fluid( the viscosity is controlled by adding methyl-cellulose) having equal density. Liquid fraction is varied for this matrix fluid to see how the fraction controls the development. At the intermediate gel fraction(between70% to about 40%) the dense fluid at first migrates through the grain boundary as permeable flow. But local heterogeneity in the gel fraction induces relative movement of solid phase, which in turns enhances the localization of the flow and deformation. We measured the motion of fluid phase and solid phase separately by adoting PIV/PTV methods. Calculated relative motion describes how flow localization has developed. The deformation-induced compaction plays an important role. The second experimental result is rheology of the dense suspension of soft gel and viscous fluid. At the intermediate gel fraction, the rheology is sensitive to the mixture state. Deformation of bulk sample depends on the internal melt distribution and the melt distribution depends on the

  11. Missions to Mars: Characterisation of Mars analogue rocks for the International Space Analogue Rockstore (ISAR)

    NASA Astrophysics Data System (ADS)

    Bost, Nicolas; Westall, Frances; Ramboz, Claire; Foucher, Frédéric; Pullan, Derek; Meunier, Alain; Petit, Sabine; Fleischer, Iris; Klingelhöfer, Göstar; Vago, Jorge L.

    2013-07-01

    Instruments for surface missions to extraterrestrial bodies should be cross-calibrated using a common suite of relevant materials. Such work is necessary to improve instrument performance and aids in the interpretation of in-situ measurements. At the CNRS campus in Orléans, the Observatoire des Sciences de l'Univers en région Centre (OSUC) has created a collection of well-characterised rocks and minerals for testing and calibrating instruments to be flown in space missions. The characteristics of the analogue materials are documented in an accompanying online database. In view of the recent and upcoming rover missions to Mars (NASA's 2011 Mars Science Laboratory (MSL) and ESA/Roscosmos' 2018 ExoMars), we are concentrating initially on materials of direct relevance to the red planet. The initial collection consists of 15 well-studied rock and mineral samples, including a variety of basalts (ultramafic, weathered, silicified, primitive), sediments (volcanic sands, chert, and a banded iron formation -BIF-), and the phyllosilicate nontronite (a clay). All the samples were characterised petrographically, petrologically, and geochemically using the types of analyses likely to be performed during in-situ missions, in particular ExoMars: hand specimen description; optical microscopy; mineralogical analysis by XRD, Raman and IR spectrometry; iron phase analysis by Mössbauer spectroscopy (MBS), elemental analysis by Energy-Dispersive X-ray spectroscopy (EDX), microprobe, Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES) and Mass Spectrometry (ICP-MS); and reduced carbon analysis by Raman spectrometry.

  12. [Oxazaphosphorinane drugs. New analogues, metabolic studies, and therapeutic approaches].

    PubMed

    Misiura, Konrad

    2004-01-01

    Recent studies on oxazaphosphorinane drugs, with the main focus on those carried out in Poland, are briefly reviewed. Research leading to the introduction of the new antitumor drug (S)-(-)-bromofosfamide are presented. The utility of phosphorus nuclear magnetic resonance in studies of ifosfamide metabolism and an application of analogues of the final, active metabolite of this drug in gene therapy are shown.

  13. An Analysis of an Autoclitic Analogue in Pigeons

    ERIC Educational Resources Information Center

    Kuroda, Toshikazu; Lattal, Kennon A.; García-Penagos, Andrés

    2014-01-01

    Using a conditional discrimination procedure, pigeons were exposed to a nonverbal analogue of qualifying autoclitics such as "definitely" and "maybe." It has been suggested that these autoclitics are similar to tacts except that they are under the control of private discriminative stimuli. Instead of the conventional assumption…

  14. A Macroscopic Analogue of the Nuclear Pairing Potential

    ERIC Educational Resources Information Center

    Dunlap, Richard A.

    2013-01-01

    A macroscopic system involving permanent magnets is used as an analogue to nucleons in a nucleus to illustrate the significance of the pairing interaction. This illustrates that the view of the total nuclear energy based only on the nucleon occupancy of the energy levels can yield erroneous results and it is only when the pairing interaction is…

  15. Facile Synthesis of Natural Alkoxynaphthalene Analogues from Plant Alkoxybenzenes.

    PubMed

    Tsyganov, Dmitry V; Krayushkin, Mikhail M; Konyushkin, Leonid D; Strelenko, Yuri A; Semenova, Marina N; Semenov, Victor V

    2016-04-22

    Analogues of the bioactive natural alkoxynaphthalene pycnanthulignene D were synthesized by an efficient method. The starting plant allylalkoxybenzenes (1) are easily available from the plant essential oils of sassafras, dill, and parsley. The target 1-arylalkoxynaphthalenes (5) exhibited antiproliferative activity in a phenotypic sea urchin embryo assay.

  16. A Laboratory Analogue for the Study of Peer Sexual Harassment

    ERIC Educational Resources Information Center

    Mitchell, Damon; Hirschman, Richard; Angelone, D. J.; Lilly, Roy S.

    2004-01-01

    The purpose of this study was to develop a laboratory analogue for the study of peer sexual harassment, and to examine person and situational factors associated with male on female peer sexual harassment. One hundred twenty-two male participants were given the opportunity to tell jokes to a female confederate from a joke list that included…

  17. Interaction of tRNA with antitumor polyamine analogues.

    PubMed

    N'soukpoé-Kossi, C N; Ahmed Ouameur, A; Thomas, T; Thomas, T J; Tajmir-Riahi, H A

    2009-08-01

    We studied the interaction between tRNA and three polyamine analogues (1,11-diamino-4,8-diazaundecane.4HCl (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333), and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333)) using FTIR, UV-visible, and CD spectroscopic methods. Spectroscopic evidence showed that polyamine analogues bound tRNA via guanine N7, adenine, uracil O2, and the backbone phosphate (PO2-) groups, while the most reactive sites for biogenic polyamines were guanine N7/O6, adenine N7, uracil O2, and sugar 2'-OH groups as well as the backbone phosphate group. The binding constants of polyamine analogue-tRNA recognition were lower than those of the biogenic polyamine-tRNA complexes, with K333 = 2.8 (+/-0.5) x 10(4), K(BE-333) = 3.7 (+/-0.7) x 10(4), K(BE-3333) = 4.0 (+/-0.9) x 10(4), K(spm) = 8.7 (+/-0.9) x 10(5), K(spd) = 6.1 (+/-0.7) x 10(5), and K(put) = 1.0 (+/-0.3) x 10(5) mol/L. tRNA remained in the A-family conformation; however, it aggregated at high polyamine analogue concentrations.

  18. Cellular Cations Control Conformational Switching of Inositol Pyrophosphate Analogues.

    PubMed

    Hager, Anastasia; Wu, Mingxuan; Wang, Huanchen; Brown, Nathaniel W; Shears, Stephen B; Veiga, Nicolás; Fiedler, Dorothea

    2016-08-22

    The inositol pyrophosphate messengers (PP-InsPs) are emerging as an important class of cellular regulators. These molecules have been linked to numerous biological processes, including insulin secretion and cancer cell migration, but how they trigger such a wide range of cellular responses has remained unanswered in many cases. Here, we show that the PP-InsPs exhibit complex speciation behaviour and propose that a unique conformational switching mechanism could contribute to their multifunctional effects. We synthesised non-hydrolysable bisphosphonate analogues and crystallised the analogues in complex with mammalian PPIP5K2 kinase. Subsequently, the bisphosphonate analogues were used to investigate the protonation sequence, metal-coordination properties, and conformation in solution. Remarkably, the presence of potassium and magnesium ions enabled the analogues to adopt two different conformations near physiological pH. Understanding how the intrinsic chemical properties of the PP-InsPs can contribute to their complex signalling outputs will be essential to elucidate their regulatory functions.

  19. Fluorescence Studies Of A Cholesterol-Analogue Probe

    NASA Astrophysics Data System (ADS)

    Drew, Jacinta; Szabo, Arthur G.; Morand, Peter

    1988-06-01

    A novel cholesterol-analogue probe1,2 with a diene-(2-naphthyl) fluorophore in the sidechain (Figure 1), hereafter referred to as DN-Chol, has had its steady-state and time-resolved fluorescence properties characterized in solvents and in various viscosity mineral oils.

  20. A new analogue of fatty alcohol from Tamarix hampeana L.

    PubMed

    Aykac, Ahmet; Akgül, Yurdanur

    2010-01-01

    New analogues of a long-chain secondary alcohol (1) and laserine (2) were isolated from the flowers of Tamarix hampeana L. The isolated compounds were identified using 1D and 2D NMR, LCMS/APCI, and chemical methods. Laserine was isolated for the first time from T. hampeana L.

  1. Cyclization of nucleotide analogues as an obstacle to polymerization

    NASA Technical Reports Server (NTRS)

    Hill, A. R. Jr; Nord, L. D.; Orgel, L. E.; Robins, R. K.

    1988-01-01

    Cyclization of activated nucleotide analogues by intramolecular phosphodiester-bond formation is likely to compete very effectively with template-directed condensation except in the cases of ribo- and arabinonucleotides. This could have excluded derivatives of most sugars from growing polyribonucleotide chains and thus reduced chain-termination in prebiotic polynucleotide synthesis.

  2. Synthesis of (+)-crocacin D and simplified bioactive analogues.

    PubMed

    Pasqua, Adele E; Ferrari, Frank D; Crawford, James J; Whittingham, William G; Marquez, Rodolfo

    2015-03-01

    The total synthesis of (+)-crocacin D has been achieved in 15 steps (9 isolated intermediates) and 14% overall yield from commercially available starting materials and using (+)-crocacin C as a key intermediate. A number of simplified analogues and their biological activities are also reported.

  3. Trehalose Analogues: Latest Insights in Properties and Biocatalytic Production

    PubMed Central

    Walmagh, Maarten; Zhao, Renfei; Desmet, Tom

    2015-01-01

    Trehalose (α-d-glucopyranosyl α-d-glucopyranoside) is a non-reducing sugar with unique stabilizing properties due to its symmetrical, low energy structure consisting of two 1,1-anomerically bound glucose moieties. Many applications of this beneficial sugar have been reported in the novel food (nutricals), medical, pharmaceutical and cosmetic industries. Trehalose analogues, like lactotrehalose (α-d-glucopyranosyl α-d-galactopyranoside) or galactotrehalose (α-d-galactopyranosyl α-d-galactopyranoside), offer similar benefits as trehalose, but show additional features such as prebiotic or low-calorie sweetener due to their resistance against hydrolysis during digestion. Unfortunately, large-scale chemical production processes for trehalose analogues are not readily available at the moment due to the lack of efficient synthesis methods. Most of the procedures reported in literature suffer from low yields, elevated costs and are far from environmentally friendly. “Greener” alternatives found in the biocatalysis field, including galactosidases, trehalose phosphorylases and TreT-type trehalose synthases are suggested as primary candidates for trehalose analogue production instead. Significant progress has been made in the last decade to turn these into highly efficient biocatalysts and to broaden the variety of useful donor and acceptor sugars. In this review, we aim to provide an overview of the latest insights and future perspectives in trehalose analogue chemistry, applications and production pathways with emphasis on biocatalysis. PMID:26084050

  4. q-bosons and the q-analogue quantized field

    NASA Technical Reports Server (NTRS)

    Nelson, Charles A.

    1995-01-01

    The q-analogue coherent states are used to identify physical signatures for the presence of a 1-analogue quantized radiation field in the q-CS classical limits where the absolute value of z is large. In this quantum-optics-like limit, the fractional uncertainties of most physical quantities (momentum, position, amplitude, phase) which characterize the quantum field are O(1). They only vanish as O(1/absolute value of z) when q = 1. However, for the number operator, N, and the N-Hamiltonian for a free q-boson gas, H(sub N) = h(omega)(N + 1/2), the fractional uncertainties do still approach zero. A signature for q-boson counting statistics is that (Delta N)(exp 2)/ (N) approaches 0 as the absolute value of z approaches infinity. Except for its O(1) fractional uncertainty, the q-generalization of the Hermitian phase operator of Pegg and Barnett, phi(sub q), still exhibits normal classical behavior. The standard number-phase uncertainty-relation, Delta(N) Delta phi(sub q) = 1/2, and the approximate commutation relation, (N, phi(sub q)) = i, still hold for the single-mode q-analogue quantized field. So, N and phi(sub q) are almost canonically conjugate operators in the q-CS classical limit. The q-analogue CS's minimize this uncertainty relation for moderate (absolute value of z)(exp 2).

  5. Thymidine analogues to assess microperfusion in human tumors

    SciTech Connect

    Janssen, Hilde L.; Ljungkvist, Anna S.; Rijken, Paul F.; Sprong, Debbie; Bussink, Jan; Kogel, Albert J. van der; Haustermans, Karin M.; Begg, Adrian C. . E-mail: a.begg@nki.nl

    2005-07-15

    Purpose: To validate the use of the thymidine analogues as local perfusion markers in human tumors (no labeling indicates no perfusion) by comparison with the well-characterized perfusion marker Hoechst 33342. Methods and Materials: Human tumor xenografts from gliomas and head-and-neck cancers were injected with iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) and the fluorescent dye Hoechst 33342. In frozen sections, each blood vessel was scored for the presence of IdUrd/BrdUrd labeling and Hoechst in surrounding cells. The percentage of analogue-negative vessels was compared with the fraction of Hoechst-negative vessels. Collocalization of the two markers was also scored. Results: We found considerable intertumor variation in the fraction of perfused vessels, measured by analogue labeling, both in the human tumor xenografts and in a series of tumor biopsies from head-and-neck cancer patients. There was a significant correlation between the Hoechst-negative and IdUrd/BrdUrd-negative vessels in the xenografts (r 85, p = 0.0004), despite some mismatches on a per-vessel basis. Conclusions: Thymidine analogues can be successfully used to rank tumors according to their fraction of perfused vessels. Whether this fraction correlates with the extent of acute hypoxia needs further confirmation.

  6. Synthesis of chlorins, bacteriochlorins and their tetraaza analogues

    NASA Astrophysics Data System (ADS)

    Dudkin, S. V.; Makarova, E. A.; Lukyanets, E. A.

    2016-07-01

    The currently known methods for the synthesis of hydrogenated derivatives of synthetic porphyrins — chlorins, bacteriochlorins, isobacteriochlorins and their tetraaza analogues — are considered. Reactions involving quasi-isolated double bonds including reduction, oxidative addition and cycloaddition are presented. Examples of direct synthesis of these macroheterocycles are given. The bibliography includes 168 references.

  7. Extracellular vesicles and their synthetic analogues in aging and age-associated brain diseases

    PubMed Central

    Smith, J. A.; Leonardi, T.; Huang, B.; Iraci, N.; Vega, B.; Pluchino, S.

    2015-01-01

    Multicellular organisms rely upon diverse and complex intercellular communications networks for a myriad of physiological processes. Disruption of these processes is implicated in the onset and propagation of disease and disorder, including the mechanisms of senescence at both cellular and organismal levels. In recent years, secreted extracellular vesicles (EVs) have been identified as a particularly novel vector by which cell-to-cell communications are enacted. EVs actively and specifically traffic bioactive proteins, nucleic acids, and metabolites between cells at local and systemic levels, modulating cellular responses in a bidirectional manner under both homeostatic and pathological conditions. EVs are being implicated not only in the generic aging process, but also as vehicles of pathology in a number of age-related diseases, including cancer and neurodegenerative and disease. Thus, circulating EVs—or specific EV cargoes—are being utilised as putative biomarkers of disease. On the other hand, EVs, as targeted intercellular shuttles of multipotent bioactive payloads, have demonstrated promising therapeutic properties, which can potentially be modulated and enhanced through cellular engineering. Furthermore, there is considerable interest in employing nanomedicinal approaches to mimic the putative therapeutic properties of EVs by employing synthetic analogues for targeted drug delivery. Herein we describe what is known about the origin and nature of EVs and subsequently review their putative roles in biology and medicine (including the use of synthetic EV analogues), with a particular focus on their role in aging and age-related brain diseases. PMID:24973266

  8. Interaction of a novel fluorescent GTP analogue with the small G-protein K-Ras.

    PubMed

    Iwata, Seigo; Masuhara, Kaori; Umeki, Nobuhisa; Sako, Yasushi; Maruta, Shinsaku

    2016-01-01

    A novel fluorescent guanosine 5'-triphosphate (GTP) analogue, 2'(3')-O-{6-(N-(7-nitrobenz-2-oxa-l,3-diazol-4-yl)amino) hexanoic}-GTP (NBD-GTP), was synthesized and utilized to monitor the effect of mutations in the functional region of mouse K-Ras. The effects of the G12S, A59T and G12S/A59T mutations on GTPase activity, nucleotide exchange rates were compared with normal Ras. Mutation at A59T resulted in reduction of the GTPase activity by 0.6-fold and enhancement of the nucleotide exchange rate by 2-fold compared with normal Ras. On the other hand, mutation at G12S only slightly affected the nucleotide exchange rate and did not affect the GTPase activity. We also used NBD-GTP to study the effect of these mutations on the interaction between Ras and SOS1, a guanine nucleotide exchange factor. The mutation at A59T abolished the interaction with SOS1. The results suggest that the fluorescent GTP analogue, NBD-GTP, is applicable to the kinetic studies for small G-proteins.

  9. Structural Basis for Recognition of Guanosine by a Synthetic Tricyclic Cytosine Analogue: Guanidinium G-Clamp

    SciTech Connect

    Wilds, C.J.; Maier, M.A.; Manoharan, M.; Egli, M.

    2010-03-08

    An oligonucleotide analogue containing a novel heterocyclic analogue, the guanidinium G-clamp, was designed to allow formation of five H-bonds to guanosine. The guanidinium group was introduced postsynthetically by treatment of the deprotected oligonucleotide containing a free amino group with a solution of 1H-pyrazole-1-carboxamidine and purified by a combination of size-exclusion chromatography and reversed-phase HPLC. A single incorporation of this modification into an oligodeoxynucleotide sequence was found to increase duplex stability by 13{sup o} and 16{sup o} per modification to RNA and DNA, respectively. Crystals of a self-complementary decamer sequence containing this modification were grown and diffracted to 1-{angstrom} resolution. The structure was solved by molecular replacement and revealed that the modification forms additional H-bonds to O(6) and N(7) of guanosine through the amino and imino N-atoms, respectively. The origins of enhanced duplex stability are also attributed to increased stacking interactions mediated by the phenoxazine moiety of the G-clamp and formation of H-bond networks between the positively charged guanidinium group, H{sub 2}O molecules, and negatively charged O-atoms from phosphates on the adjacent strand.

  10. Parallel synthesis and biological evaluation of 837 analogues of procaspase-activating compound 1 (PAC-1).

    PubMed

    Hsu, Danny C; Roth, Howard S; West, Diana C; Botham, Rachel C; Novotny, Chris J; Schmid, Steven C; Hergenrother, Paul J

    2012-01-09

    Procaspase-Activating Compound 1 (PAC-1) is an ortho-hydroxy N-acyl hydrazone that enhances the enzymatic activity of procaspase-3 in vitro and induces apoptosis in cancer cells. An analogue of PAC-1, called S-PAC-1, was evaluated in a veterinary clinical trial in pet dogs with lymphoma and found to have considerable potential as an anticancer agent. With the goal of identifying more potent compounds in this promising class of experimental therapeutics, a combinatorial library based on PAC-1 was created, and the compounds were evaluated for their ability to induce death of cancer cells in culture. For library construction, 31 hydrazides were condensed in parallel with 27 aldehydes to create 837 PAC-1 analogues, with an average purity of 91%. The compounds were evaluated for their ability to induce apoptosis in cancer cells, and through this work, six compounds were discovered to be substantially more potent than PAC-1 and S-PAC-1. These six hits were further evaluated for their ability to relieve zinc-mediated inhibition of procaspase-3 in vitro. In general, the newly identified hit compounds are two- to four-fold more potent than PAC-1 and S-PAC-1 in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3.

  11. Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins

    SciTech Connect

    Ho, Meng-Chiao; Sturm, Matthew B.; Almo, Steven C.; Schramm, Vern L.

    2010-01-12

    Ricin A-chain (RTA) and saporin-L1 (SAP) catalyze adenosine depurination of 28S rRNA to inhibit protein synthesis and cause cell death. We present the crystal structures of RTA and SAP in complex with transition state analogue inhibitors. These tight-binding inhibitors mimic the sarcin-ricin recognition loop of 28S rRNA and the dissociative ribocation transition state established for RTA catalysis. RTA and SAP share unique purine-binding geometry with quadruple {pi}-stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the {pi}-stack provides cationic polarization and enhanced leaving group ability to the susceptible adenine. Common features of these ribosome-inactivating proteins include adenine leaving group activation, a remarkable lack of ribocation stabilization, and conserved glutamates as general bases for activation of the H{sub 2}O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues.

  12. Highly Fluorescent Green Fluorescent Protein Chromophore Analogues Made by Decorating the Imidazolone Ring.

    PubMed

    Gutiérrez, Sara; Martínez-López, David; Morón, María; Sucunza, David; Sampedro, Diego; Domingo, Alberto; Salgado, Antonio; Vaquero, Juan J

    2015-12-14

    The synthesis and photophysical behavior of an unexplored family of green fluorescent protein (GFP)-like chromophore analogues is reported. The compound (Z)-4-(4-hydroxybenzylidene)-1-propyl-2-(propylamino)-1H-imidazol-5(4 H)-one (p-HBDNI, 2 a) exhibits significantly enhanced fluorescence properties relative to the parent compound (Z)-5-(4-hydroxybenzylidene)-2,3-dimethyl-3,5-dihydro-4H-imidazol-4-one (p-HBDI, 1). p-HBDNI was considered as a model system and the photophysical properties of other novel 2-amino-3,5-dihydro-4H-imidazol-4-one derivatives were evaluated. Time-dependent DFT calculations were carried out to rationalize the results. The analogue AIDNI (2 c), in which the 4-hydroxybenzyl group of p-HBDNI was replaced by an azaindole group, showed improved photophysical properties and potential for cell staining. The uptake and intracellular distribution of 2 c in living cells was investigated by confocal microscopy imaging.

  13. Pressurized brines in continental Antarctica as a possible analogue of Mars

    PubMed Central

    Forte, Emanuele; Dalle Fratte, Michele; Azzaro, Maurizio; Guglielmin, Mauro

    2016-01-01

    Interest in brines in extreme and cold environments has recently increased after they have been found on Mars. Those brines can be potential new subsurface habitats for peculiar ecosystems. In the McMurdo Dry Valleys of the Antarctic, the best analogue for Mars conditions, only a few cases of brines have been identified in some perennially frozen lakes and in one case in an underground aquifer. Here, we present the occurrence of pressurized brines in a shallow perennially ice-covered lake south of 70°S in an ice-free area of Victoria Land, Antarctica. For the first time, we also imaged, by means of ground penetrating radar data, the existence of a pingo-like-feature (PLF) formed by the extrusion of brines, which has also been confirmed by borehole evidence. Those brines are fed by an underground talik external to the lake basin, enhancing the possibility of unexploited ecosystems that could find an analogue in Martian environments. PMID:27616183

  14. Targeting glucose consumption and autophagy in myeloma with the novel nucleoside analogue 8-aminoadenosine.

    PubMed

    Shanmugam, Mala; McBrayer, Samuel K; Qian, Jun; Raikoff, Kiril; Avram, Michael J; Singhal, Seema; Gandhi, Varsha; Schumacker, Paul T; Krett, Nancy L; Rosen, Steven T

    2009-09-25

    Multiple myeloma, an incurable plasma cell malignancy, is characterized by altered cellular metabolism and resistance to apoptosis. Recent connections between glucose metabolism and resistance to apoptosis provide a compelling rationale for targeting metabolic changes in cancer. In this study, we have examined the ability of the purine analogue 8-aminoadenosine to acutely reduce glucose consumption by regulating localization and expression of key glucose transporters. Myeloma cells counteracted the metabolic stress by activating autophagy. Co-treatment with inhibitors of autophagy results in marked enhancement of cell death. Glucose consumption by drug-resistant myeloma cells was unaffected by 8-aminoadenosine, and accordingly, no activation of autophagy was observed. However, these cells can be sensitized to 8-aminoadenosine under glucose-limiting conditions. The prosurvival autophagic response of myeloma to nutrient deprivation or to nucleoside analogue treatment has not been described previously. This study establishes the potential of metabolic targeting as a broader means to kill and sensitize myeloma and identifies a compound that can achieve this goal.

  15. Therapeutics of Diabetes Mellitus: Focus on Insulin Analogues and Insulin Pumps

    PubMed Central

    Valla, Vasiliki

    2010-01-01

    Aim. Inadequately controlled diabetes accounts for chronic complications and increases mortality. Its therapeutic management aims in normal HbA1C, prandial and postprandial glucose levels. This review discusses diabetes management focusing on the latest insulin analogues, alternative insulin delivery systems and the artificial pancreas. Results. Intensive insulin therapy with multiple daily injections (MDI) allows better imitation of the physiological rhythm of insulin secretion. Longer-acting, basal insulin analogues provide concomitant improvements in safety, efficacy and variability of glycaemic control, followed by low risks of hypoglycaemia. Continuous subcutaneous insulin infusion (CSII) provides long-term glycaemic control especially in type 1 diabetic patients, while reducing hypoglycaemic episodes and glycaemic variability. Continuous subcutaneous glucose monitoring (CGM) systems provide information on postprandial glucose excursions and nocturnal hypo- and/or hyperglycemias. This information enhances treatment options, provides a useful tool for self-monitoring and allows safer achievement of treatment targets. In the absence of a cure-like pancreas or islets transplants, artificial “closed-loop” systems mimicking the pancreatic activity have been also developed. Conclusions. Individualized treatment plans for insulin initiation and administration mode are critical in achieving target glycaemic levels. Progress in these fields is expected to facilitate and improve the quality of life of diabetic patients. PMID:20589066

  16. Maltose neopentyl glycol-3 (MNG-3) analogues for membrane protein study.

    PubMed

    Cho, Kyung Ho; Husri, Mohd; Amin, Anowarul; Gotfryd, Kamil; Lee, Ho Jin; Go, Juyeon; Kim, Jin Woong; Loland, Claus J; Guan, Lan; Byrne, Bernadette; Chae, Pil Seok

    2015-05-07

    Detergents are typically used to both extract membrane proteins (MPs) from the lipid bilayers and maintain them in solution. However, MPs encapsulated in detergent micelles are often prone to denaturation and aggregation. Thus, the development of novel agents with enhanced stabilization characteristics is necessary to advance MP research. Maltose neopentyl glycol-3 (MNG-3) has contributed to >10 crystal structures including G-protein coupled receptors. Here, we prepared MNG-3 analogues and characterised their properties using selected MPs. Most MNGs were superior to a conventional detergent, n-dodecyl-β-D-maltopyranoside (DDM), in terms of membrane protein stabilization efficacy. Interestingly, optimal stabilization was achieved with different MNG-3 analogues depending on the target MP. The origin for such detergent specificity could be explained by a novel concept: compatibility between detergent hydrophobicity and MP tendency to denature and aggregate. This set of MNGs represents viable alternatives to currently available detergents for handling MPs, and can be also used as tools to estimate MP sensitivity to denaturation and aggregation.

  17. Transition States and transition state analogue interactions with enzymes.

    PubMed

    Schramm, Vern L

    2015-04-21

    Enzymatic transition states have lifetimes of a few femtoseconds (fs). Computational analysis of enzyme motions leading to transition state formation suggests that local catalytic site motions on the fs time scale provide the mechanism to locate transition states. An experimental test of protein fs motion and its relation to transition state formation can be provided by isotopically heavy proteins. Heavy enzymes have predictable mass-altered bond vibration states without altered electrostatic properties, according to the Born-Oppenheimer approximation. On-enzyme chemistry is slowed in most heavy proteins, consistent with altered protein bond frequencies slowing the search for the transition state. In other heavy enzymes, structural changes involved in reactant binding and release are also influenced. Slow protein motions associated with substrate binding and catalytic site preorganization are essential to allow the subsequent fs motions to locate the transition state and to facilitate the efficient release of products. In the catalytically competent geometry, local groups move in stochastic atomic motion on the fs time scale, within transition state-accessible conformations created by slower protein motions. The fs time scale for the transition state motions does not permit thermodynamic equilibrium between the transition state and stable enzyme states. Isotopically heavy enzymes provide a diagnostic tool for fast coupled protein motions to transition state formation and mass-dependent conformational changes. The binding of transition state analogue inhibitors is the opposite in catalytic time scale to formation of the transition state but is related by similar geometries of the enzyme-transition state and enzyme-inhibitor interactions. While enzymatic transition states have lifetimes as short as 10(-15) s, transition state analogues can bind tightly to enzymes with release rates greater than 10(3) s. Tight-binding transition state analogues stabilize the rare but

  18. Non-robust numerical simulations of analogue extension experiments

    NASA Astrophysics Data System (ADS)

    Naliboff, John; Buiter, Susanne

    2016-04-01

    Numerical and analogue models of lithospheric deformation provide significant insight into the tectonic processes that lead to specific structural and geophysical observations. As these two types of models contain distinct assumptions and tradeoffs, investigations drawing conclusions from both can reveal robust links between first-order processes and observations. Recent studies have focused on detailed comparisons between numerical and analogue experiments in both compressional and extensional tectonics, sometimes involving multiple lithospheric deformation codes and analogue setups. While such comparisons often show good agreement on first-order deformation styles, results frequently diverge on second-order structures, such as shear zone dip angles or spacing, and in certain cases even on first-order structures. Here, we present finite-element experiments that are designed to directly reproduce analogue "sandbox" extension experiments at the cm-scale. We use material properties and boundary conditions that are directly taken from analogue experiments and use a Drucker-Prager failure model to simulate shear zone formation in sand. We find that our numerical experiments are highly sensitive to numerous numerical parameters. For example, changes to the numerical resolution, velocity convergence parameters and elemental viscosity averaging commonly produce significant changes in first- and second-order structures accommodating deformation. The sensitivity of the numerical simulations to small parameter changes likely reflects a number of factors, including, but not limited to, high angles of internal friction assigned to sand, complex, unknown interactions between the brittle sand (used as an upper crust equivalent) and viscous silicone (lower crust), highly non-linear strain weakening processes and poor constraints on the cohesion of sand. Our numerical-analogue comparison is hampered by (a) an incomplete knowledge of the fine details of sand failure and sand

  19. Analogue Sites for Mars Missions - A report from two workshops

    NASA Astrophysics Data System (ADS)

    Hipkin, V.; Voytek, M. A.; Glamoclija, M.

    2014-12-01

    Fieldwork, at terrestrial sites that are analogous in some way to Mars, has a key role in defining questions addressed by Mars missions. For MSL, the question is whether its landing site was habitable, and for Mars 2020, the question is how do we search for and what are signs of life in ancient habitable environments. Implementing these investigations by means of a rover mission on a distant planetary surface has challenges due to a limited set of tools and period of operations. Using this context of planetary missions is important in shaping how analog research can be used to advance planetary science. Following a successful 2010 AGU fall meeting session entitled "Analogue Sites for Mars Missions", two community workshops were held at The Woodlands, TX March 2011 and the Carnegie Institute of Washington in July 2013. These activities represent an ongoing dialogue with the analogue and mission communities. The AGU session solicited presentations of current analogue research relevant to MSL, at which time the landing site selection process was still considering four final sites. The 2011 Woodlands workshop solicited details on representative science questions and analogue sites by means of an abstract template. The output from The Woodlands workshop was an initial metric to assess the utility of analogue sites against specific science questions, as well as recommendations for future activities. The 2013 Carnegie workshop, followed up on some of the recommendations from 2011. Both on-line interactive dialogue and in person discussions targeted broad topics, including 'the advantages and problems of using a great terrestrial analog for field testing', and 'knowing what we currently do about Mars, what would be the best place on the planet to collect the first suite of samples to be returned to Earth? What would be appropriate analog sites on Earth?'. The results and recommendations from both workshops are summarized to publicize and stimulate this ongoing discussion.

  20. Biological evaluation of a novel sorafenib analogue, t-CUPM.

    PubMed

    Wecksler, Aaron T; Hwang, Sung Hee; Liu, Jun-Yan; Wettersten, Hiromi I; Morisseau, Christophe; Wu, Jian; Weiss, Robert H; Hammock, Bruce D

    2015-01-01

    Sorafenib (Nexavar®) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib.

  1. Sulphamoylated 2-Methoxyestradiol Analogues Induce Apoptosis in Adenocarcinoma Cell Lines

    PubMed Central

    Visagie, Michelle; Theron, Anne; Mqoco, Thandi; Vieira, Warren; Prudent, Renaud; Martinez, Anne; Lafanechère, Laurence; Joubert, Annie

    2013-01-01

    2-Methoxyestradiol (2ME2) is a naturally occurring estradiol metabolite which possesses antiproliferative, antiangiogenic and antitumor properties. However, due to its limited biological accessibility, synthetic analogues have been synthesized and tested in attempt to develop drugs with improved oral bioavailability and efficacy. The aim of this study was to evaluate the antiproliferative effects of three novel in silico-designed sulphamoylated 2ME2 analogues on the HeLa cervical adenocarcinoma cell line and estrogen receptor-negative breast adenocarcinoma MDA-MB-231 cells. A dose-dependent study (0.1–25 μM) was conducted with an exposure time of 24 hours. Results obtained from crystal violet staining indicated that 0.5 μM of all 3 compounds reduced the number of cells to 50%. Lactate dehydrogenase assay was used to assess cytotoxicity, while the mitotracker mitochondrial assay and caspase-6 and -8 activity assays were used to investigate the possible occurrence of apoptosis. Tubulin polymerization assays were conducted to evaluate the influence of these sulphamoylated 2ME2 analogues on tubulin dynamics. Double immunofluorescence microscopy using labeled antibodies specific to tyrosinate and detyrosinated tubulin was conducted to assess the effect of the 2ME2 analogues on tubulin dynamics. An insignificant increase in the level of lactate dehydrogenase release was observed in the compounds-treated cells. These sulphamoylated compounds caused a reduction in mitochondrial membrane potential, cytochrome c release and caspase 3 activation indicating apoptosis induction by means of the intrinsic pathway in HeLa and MDA-MB-231 cells. Microtubule depolymerization was observed after exposure to these three sulphamoylated analogues. PMID:24039728

  2. Neurochemical binding profiles of novel indole and benzofuran MDMA analogues.

    PubMed

    Shimshoni, Jakob A; Winkler, Ilan; Golan, Ezekiel; Nutt, David

    2017-01-01

    3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT2 receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT2a,b,c and NEα2 receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT2a,b,c receptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT2c receptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC50 determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT2a,c receptors as compared to MDMA.

  3. Muraymycins, novel peptidoglycan biosynthesis inhibitors: synthesis and SAR of their analogues.

    PubMed

    Yamashita, Ayako; Norton, Emily; Petersen, Peter J; Rasmussen, Beth A; Singh, Guy; Yang, Youjin; Mansour, Tarek S; Ho, Douglas M

    2003-10-06

    A series of Muraymycin analogues was synthesized. These analogues showed excellent antimicrobial activity against gram-positive organisms. These analogues also showed excellent inhibitory activity against the target peptidoglycan biosynthesis enzyme MraY, the cell membrane associated transglycosylase responsible for the formation of Lipid II.

  4. Mars methane analogue mission: Mission simulation and rover operations at Jeffrey Mine and Norbestos Mine Quebec, Canada

    NASA Astrophysics Data System (ADS)

    Qadi, A.; Cloutis, E.; Samson, C.; Whyte, L.; Ellery, A.; Bell, J. F.; Berard, G.; Boivin, A.; Haddad, E.; Lavoie, J.; Jamroz, W.; Kruzelecky, R.; Mack, A.; Mann, P.; Olsen, K.; Perrot, M.; Popa, D.; Rhind, T.; Sharma, R.; Stromberg, J.; Strong, K.; Tremblay, A.; Wilhelm, R.; Wing, B.; Wong, B.

    2015-05-01

    The Canadian Space Agency (CSA), through its Analogue Missions program, supported a microrover-based analogue mission designed to simulate a Mars rover mission geared toward identifying and characterizing methane emissions on Mars. The analogue mission included two, progressively more complex, deployments in open-pit asbestos mines where methane can be generated from the weathering of olivine into serpentine: the Jeffrey mine deployment (June 2011) and the Norbestos mine deployment (June 2012). At the Jeffrey Mine, testing was conducted over 4 days using a modified off-the-shelf Pioneer rover and scientific instruments including Raman spectrometer, Picarro methane detector, hyperspectral point spectrometer and electromagnetic induction sounder for testing rock and gas samples. At the Norbestos Mine, we used the research Kapvik microrover which features enhanced autonomous navigation capabilities and a wider array of scientific instruments. This paper describes the rover operations in terms of planning, deployment, communication and equipment setup, rover path parameters and instrument performance. Overall, the deployments suggest that a search strategy of “follow the methane” is not practical given the mechanisms of methane dispersion. Rather, identification of features related to methane sources based on image tone/color and texture from panoramic imagery is more profitable.

  5. Design and synthesis of lupeol analogues and their glucose uptake stimulatory effect in L6 skeletal muscle cells.

    PubMed

    Khan, Mohammad Faheem; Maurya, Chandan Kumar; Dev, Kapil; Arha, Deepti; Rai, Amit Kumar; Tamrakar, Akhilesh Kumar; Maurya, Rakesh

    2014-06-15

    Structure modifications of lupeol at the isopropylene moiety have been described via allylic oxidation using selenium dioxide. The antidiabetic efficacy of lupeol analogues were evaluated in vitro as glucose uptake stimulatory effect in L6 skeletal muscle cells. From all tested compounds, 2, 3, 4b and 6b showed significant stimulation of glucose uptake with respective percent stimulation of 173.1 (p <0.001), 114.1 (p <0.001), 98.3 (p <0.001) and 107.3 (p <0.001) at 10μM concentration. Stimulation of glucose uptake by these compounds is associated with enhanced translocation of glucose transporter 4 (GLUT4) and activation of IRS-1/PI3-K/AKT-dependent signaling pathway in L6 cells. Structure-activity relationship analysis of these analogues demonstrated that the integrity of α,β-unsaturated carbonyl and acetyl moieties were important in the retention of glucose uptake stimulatory effect. It is therefore proposed that naturally occurring lupeol and their analogues might reduce blood glucose, at least in part, through stimulating glucose utilization by skeletal muscles.

  6. Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities

    PubMed Central

    Lv, Wei; Liu, Jinzhong; Skaar, Todd C.; Flockhart, David A.; Cushman, Mark

    2015-01-01

    Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer. PMID:25751283

  7. Three-Dimensional Printing of Tissue/Organ Analogues Containing Living Cells.

    PubMed

    Park, Jeong Hun; Jang, Jinah; Lee, Jung-Seob; Cho, Dong-Woo

    2017-01-01

    The technical advances of three-dimensional (3D) printing in the field of tissue engineering have enabled the creation of 3D living tissue/organ analogues. Diverse 3D tissue/organ printing techniques with computer-aided systems have been developed and used to dispose living cells together with biomaterials and supporting biochemicals as pre-designed 3D tissue/organ models. Furthermore, recent advances in bio-inks, which are printable hydrogels with living cell encapsulation, have greatly enhanced the versatility of 3D tissue/organ printing. Here, we introduce 3D tissue/organ printing techniques and biomaterials that have been developed and widely used thus far. We also review a variety of applications in an attempt to repair or replace the damaged or defective tissue/organ, and develop the in vitro tissue/organ models. The potential challenges are finally discussed from the technical perspective of 3D tissue/organ printing.

  8. Photophysical and nonlinear optical studies of tetraakynyl zincphthalocyanine and its "clicked" analogue

    NASA Astrophysics Data System (ADS)

    Bankole, Owolabi M.; Nyokong, Tebello

    2015-06-01

    We report here for the first time on the photophysical and nonlinear optical behavior of tetra-substituted alkynyl zinc phthalocyanine and its "clicked" analogue (4 and 5). The compounds exhibited high triplet quantum yields in dimethylsulphoxide (DMSO). Nonlinear optical (NLO) properties were also evaluated for the two compounds at 532 nm and 10 ns in DMSO. We observed two-photon absorption (2PA) and strong reverse saturable absorption (RSA) as the dominant mechanisms at nanosecond laser excitation. The presence of electron acceptor groups fused with triazole linkers in the peripheral positions of 4 provide excellent coexistent features, such as enhanced triplet quantum yields and lifetimes compared to 5. Large third-order susceptibility (2.09 × 10-11 and 3.53 × 10-9 esu) and hyperpolarizability (1.09 × 10-30 and 9.13 × 10-29 esu) were estimated for complexs 4 and 5, respectively.

  9. An analogue conceptual rainfall-runoff model for educational purposes

    NASA Astrophysics Data System (ADS)

    Herrnegger, Mathew; Riedl, Michael; Schulz, Karsten

    2016-04-01

    Conceptual rainfall-runoff models, in which runoff processes are modelled with a series of connected linear and non-linear reservoirs, remain widely applied tools in science and practice. Additionally, the concept is appreciated in teaching due to its somewhat simplicity in explaining and exploring hydrological processes of catchments. However, when a series of reservoirs are used, the model system becomes highly parametrized and complex and the traceability of the model results becomes more difficult to explain to an audience not accustomed to numerical modelling. Since normally the simulations are performed with a not visible digital code, the results are also not easily comprehensible. This contribution therefore presents a liquid analogue model, in which a conceptual rainfall-runoff model is reproduced by a physical model. This consists of different acrylic glass containers representing different storage components within a catchment, e.g. soil water or groundwater storage. The containers are equipped and connected with pipes, in which water movement represents different flow processes, e.g. surface runoff, percolation or base flow. Water from a storage container is pumped to the upper part of the model and represents effective rainfall input. The water then flows by gravity through the different pipes and storages. Valves are used for controlling the flows within the analogue model, comparable to the parameterization procedure in numerical models. Additionally, an inexpensive microcontroller-based board and sensors are used to measure storage water levels, with online visualization of the states as time series data, building a bridge between the analogue and digital world. The ability to physically witness the different flows and water levels in the storages makes the analogue model attractive to the audience. Hands-on experiments can be performed with students, in which different scenarios or catchment types can be simulated, not only with the analogue but

  10. Actions of antidiuretic hormone analogues on intact and nystatin-permeabilized frog skins.

    PubMed

    Jared, Silviya Rajakumari; Rao, J Prakasa; Subramani, Sathya

    2009-12-01

    The roles of two antidiuretic hormone analogues, namely arginine vasotocin (AVT) and lysine vasopressin (LVP), in solute transport across the ventral abdominal skin of frogs (Rana hexadactyla) were studied using voltage-clamp methods on intact and nystatin-permeabilized preparations. Arginine vasotocin (40 nm), the amphibian analogue of antidiuretic hormone, did not have any effect on the skin of Rana hexadactyla. However, LVP, the porcine antidiuretic hormone, increased the transepithelial potential difference (TEPD) and short-circuit current (SCC) significantly, without affecting the slope conductance. Lysine vasopressin had no action subsequent to addition of amiloride (100 microm) on the apical side or ouabain (10 microm) on the basolateral side. Lysine vasopressin increased slope conductance in the nystatin-permeablized skin while decreasing TEPD. Such a change was not seen in chloride-free solutions. To elucidate the mechanism of action of LVP on intact skin, experiments were done with forskolin and a V(2) receptor blocker. The effects of forskolin (10 microm) were different from those of LVP in that forskolin significantly increased SCC and conductance of the intact skin, while decreasing TEPD. The forskolin-induced increase in conductance was not abolished by amiloride. Use of the V(2) receptor blocker inhibited the effects of LVP. We conclude that AVT does not have an action on the skin of Rana hexadactyla. Lysine vasopressin enhances transepithelial sodium transport by increasing sodium-potassium pump activity, while not affecting the epithelial sodium channel conductance. Lysine vasopressin also enhances an inward-directed conductance on the basolateral membrane, probably a chloride conductance. The action of LVP on the intact frog skin is through the V(2) receptors; however, downstream signalling does not seem to be mediated by cAMP. Analysis of the electrophysiological model of frog skin with LVP allows us additionally to conclude that modulation of

  11. Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors.

    PubMed

    Liu, Tao; Nair, Somarajan J; Lescarbeau, André; Belani, Jitendra; Peluso, Stéphane; Conley, James; Tillotson, Bonnie; O'Hearn, Patrick; Smith, Sherri; Slocum, Kelly; West, Kip; Helble, Joseph; Douglas, Mark; Bahadoor, Adilah; Ali, Janid; McGovern, Karen; Fritz, Christian; Palombella, Vito J; Wylie, Andrew; Castro, Alfredo C; Tremblay, Martin R

    2012-10-25

    Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor druglike properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure-activity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation-initiation machinery (i.e., complex 5'-untranslated region UTR) relative to simple 5'UTR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compounds 74 and 76 were shown to have similar cytotoxic potency and better ADME characteristics relative to those of silvestrol.

  12. Noncommutative analogue Aharonov-Bohm effect and superresonance

    NASA Astrophysics Data System (ADS)

    Anacleto, M. A.; Brito, F. A.; Passos, E.

    2013-06-01

    We consider the idea of modeling a rotating acoustic black hole by an idealized draining bathtub vortex which is a planar circulating flow phenomenon with a sink at the origin. We find the acoustic metric for this phenomenon from a noncommutative Abelian Higgs model. As such the acoustic metric not only describes a rotating acoustic black hole but also inherits the noncommutative characteristic of the spacetime. We address the issues of superresonance and analogue Aharonov-Bohm (AB) effect in this background. We mainly show that the scattering of planar waves by a draining bathtub vortex leads to a modified AB effect and due to spacetime noncommutativity, the phase shift persists even in the limit where the parameters associated with the circulation and draining vanish. Finally, we also find that the analogue AB effect and superresonance are competing phenomena at a noncommutative spacetime.

  13. Neutral Diboron Analogues of Archetypal Aromatic Species by Spontaneous Cycloaddition.

    PubMed

    Arrowsmith, Merle; Böhnke, Julian; Braunschweig, Holger; Celik, Mehmet Ali; Claes, Christina; Ewing, William C; Krummenacher, Ivo; Lubitz, Katharina; Schneider, Christoph

    2016-09-05

    Among the numerous routes organic chemists have developed to synthesize benzene derivatives and heteroaromatic compounds, transition-metal-catalyzed cycloaddition reactions are the most elegant. In contrast, cycloaddition reactions of heavier alkene and alkyne analogues, though limited in scope, proceed uncatalyzed. In this work we present the first spontaneous cycloaddition reactions of lighter alkene and alkyne analogues. Selective addition of unactivated alkynes to boron-boron multiple bonds under ambient conditions yielded diborocarbon equivalents of simple aromatic hydrocarbons, including the first neutral 6 π-aromatic diborabenzene compound, a 2 π-aromatic triplet biradical 1,3-diborete, and a phosphine-stabilized 2 π-homoaromatic 1,3-dihydro-1,3-diborete. DFT calculations suggest that all three compounds are aromatic and show frontier molecular orbitals matching those of the related aromatic hydrocarbons, C6 H6 and C4 H4 (2+) , and homoaromatic C4 H5 (+) .

  14. Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone

    SciTech Connect

    Bajusz, S.; Janaky, T.; Csernus, V.J.; Bokser, L.; Fekete, M.; Srkalovic, G.; Redding, T.W.; Schally, A.V. )

    1989-08-01

    Metal complexes related to the cytotoxic complexes cisplatin (cis-diamminedichloroplatinum(II)) and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer and prostate cancer cell lines in vitro. Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.

  15. All-dielectric metasurface analogue of electromagnetically induced transparency.

    PubMed

    Yang, Yuanmu; Kravchenko, Ivan I; Briggs, Dayrl P; Valentine, Jason

    2014-12-16

    Metasurface analogues of electromagnetically induced transparency (EIT) have been a focus of the nanophotonics field in recent years, due to their ability to produce high-quality factor (Q-factor) resonances. Such resonances are expected to be useful for applications such as low-loss slow-light devices and highly sensitive optical sensors. However, ohmic losses limit the achievable Q-factors in conventional plasmonic EIT metasurfaces to values <~10, significantly hampering device performance. Here we experimentally demonstrate a classical analogue of EIT using all-dielectric silicon-based metasurfaces. Due to extremely low absorption loss and coherent interaction of neighbouring meta-atoms, a Q-factor of 483 is observed, leading to a refractive index sensor with a figure-of-merit of 103. Furthermore, we show that the dielectric metasurfaces can be engineered to confine the optical field in either the silicon resonator or the environment, allowing one to tailor light-matter interaction at the nanoscale.

  16. New homoisoflavonoid analogues protect cells by regulating autophagy.

    PubMed

    Gan, Li-She; Zeng, Lin-Wei; Li, Xiang-Rong; Zhou, Chang-Xin; Li, Jie

    2017-03-15

    As a special group of naturally occurring flavonoids, homoisoflavonoids have been discovered as active components of several traditional Chinese medicines for nourishing heart and mind. In this study, twenty homoisoflavonoid analogues, including different substitution groups on rings A and B, as well as heteroaromatic B ring, were synthesized and evaluated for their cardioprotective and neuroprotective activities. In a H2O2-induced H9c2 cardiomyocytes injury assay, nine homoisoflavonoid analogues showed promising activities in the same level as the positive control, diazoxide. Six cardioprotective compounds with representative structure diversities were then evaluated for their neuroprotective effects on MPP+ induced SH-SY5Y cell injury model. Furthermore, autophagy inducing monodansylcadaverine (MDC) fluorescence staining methods and molecular docking studies indicated the action mechanism of these compounds may involve autophagy regulating via class I PI3K signaling pathway.

  17. New selenium-75 labeled radiopharmaceuticals: selenonium analogues of dopamine

    SciTech Connect

    Sadek, S.A.; Basmadjian, G.P.; Hsu, P.M.; Rieger, J.A.

    1983-07-01

    Selenium-75 labeled selenonium analogues of dopamine, (2-(3,4-dimethoxyphenyl)ethyl)dimethylselenonium iodide and its dihydroxy analogue, were prepared by reducing (/sup 75/Se)selenious acid with sodium borohydride at pH 6.0 and reacting the NaSeH produced with 1-(3,4-dimethoxyphenyl)-2-(p-toluenesulfonyloxy)ethane. Tissue distribution studies in rats given the /sup 75/Se-labeled selenonium agents intravenously demonstrated high initial heart uptake. Prolonged adrenal retention and high adrenal to blood ratio of compound 4 were observed. The high uptake and adrenal to blood ratio suggest the potential use of compound 4 as a radiopharmaceutical for the adrenal gland.

  18. Geoscience in Support of a Mars Methane Analogue Mission

    NASA Astrophysics Data System (ADS)

    Boivin, Alexandre

    The Mars Methane Analogue Mission, funded by the Canadian Space Agency through its Analogue Missions program, simulates a Mars rover mission whose purpose is to detect, analyse, and determine the source of methane emissions on the planet's surface. As part of this project, both an electromagnetic induction sounder (EMIS) and a high-resolution triangulation-based 3D laser scanner were tested in the field to demonstrate the benefit of including these instruments on future rover missions. EMIS data was inverted in order to derive information on the conductivity and magnetic susceptibility of the near subsurface. 3D laser scanner data was processed with fracture detection as a goal in order to simplify the search for areas of potential methane seepage. Both instruments were found to be very valuable for future rover missions of this type.

  19. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Jameson, Bradford A.; McDonnell, James M.; Marini, Joseph C.; Korngold, Robert

    1994-04-01

    EXPERIMENTAL allergic encephalomyelitis (EAE) is an acute inflammatory autoimmune disease of the central nervous system that can be elicited in rodents and is the major animal model for the study of multiple sclerosis (MS)1,2. The pathogenesis of both EAE and MS directly involves the CD4+ helper T-cell subset3-5. Anti-CD4 monoclonal antibodies inhibit the development of EAE in rodents6-9, and are currently being used in human clinical trials for MS. We report here that similar therapeutic effects can be achieved in mice using a small (rationally designed) synthetic analogue of the CD4 protein surface. It greatly inhibits both clinical incidence and severity of EAE with a single injection, but does so without depletion of the CD4+ subset and without the inherent immunogenicity of an antibody. Furthermore, this analogue is capable of exerting its effects on disease even after the onset of symptoms.

  20. Optical analogue of relativistic Dirac solitons in binary waveguide arrays

    SciTech Connect

    Tran, Truong X.; Longhi, Stefano; Biancalana, Fabio

    2014-01-15

    We study analytically and numerically an optical analogue of Dirac solitons in binary waveguide arrays in the presence of Kerr nonlinearity. Pseudo-relativistic soliton solutions of the coupled-mode equations describing dynamics in the array are analytically derived. We demonstrate that with the found soliton solutions, the coupled mode equations can be converted into the nonlinear relativistic 1D Dirac equation. This paves the way for using binary waveguide arrays as a classical simulator of quantum nonlinear effects arising from the Dirac equation, something that is thought to be impossible to achieve in conventional (i.e. linear) quantum field theory. -- Highlights: •An optical analogue of Dirac solitons in nonlinear binary waveguide arrays is suggested. •Analytical solutions to pseudo-relativistic solitons are presented. •A correspondence of optical coupled-mode equations with the nonlinear relativistic Dirac equation is established.

  1. Isobaric Analogue States Studied in Mirrored Fragmentation and Knockout Reactions

    SciTech Connect

    Bentley, M.A.; Pritychenko, B.; Paterson,I.; Brown,J.R.; Taylor,M.J.; Digen,C.Aa.; Adrich,P.; Bazin,D.; Cook.J.M.; Gade,A.; Glasmacher,T.; McDaniel,S.; Ratkiewicz,A.; Siwek,K.; D.Weisshaar,D.; Pritychenko,B.; Lenzi,S.M.

    2010-05-21

    A Gamma-ray spectroscopic study of excited states of isobaric multiplets has been performed in recent years, with a view to gaining a quantitative understanding of energy differences between excited states in terms of a range of Coulomb and other isospin breaking phenomena. Recently, the experimental programme has been augmented by a study of isobaric analogue states of mirror nuclei populated in mirrored fragmentation reactions. In this presentation, recent results on the T = 3/2 analogue states in the T{sub z} = {+-} 3/2 mirror pair {sup 53}Ni/{sup 53}Mn will be summarised. In this work, further strong evidence is found for the need to include an anomalous isospin-breaking two-body matrix element for angular-momentum couplings of J = 2, in addition the expected Coulomb contribution, in order to account for the experimental data.

  2. Animal analogues for the study of dental and oral diseases.

    PubMed

    Levy, B M

    1980-01-01

    The usual laboratory animals, such as rats and hamsters, may not fit the criteria for an analogue of human periodontal disease, although they may be useful in the study of dental caries. Rats, hamsters, mice, guinea pigs and rabbits have been the animals of choice in studies relating nutritional deficiencies and excesses to the dental and oral tissues. Gerbils, dogs, cats, horses, cows and fowl are useful in the study of mineralized tissues of teeth and bones. Recently, primate analogues have been developed for the study of periodontal diseaes and dental caries, the two most important dental diseases afflicting man. The use of a wide variety of laboratory animals in basic dental research makes it timely to review some of the guidelines for the selection of specific animals for particular diseases.

  3. Analogue Transformations in Physics and their Application to Acoustics

    PubMed Central

    García-Meca, C.; Carloni, S.; Barceló, C.; Jannes, G.; Sánchez-Dehesa, J.; Martínez, A.

    2013-01-01

    Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an “analogue transformation acoustics” formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft. PMID:23774575

  4. Alligator rivers analogue project an OECD/NEA international project

    SciTech Connect

    Duerden, P.; Airey, P.; Pescatore, C.

    1994-12-31

    The Koongarra uranium deposit in the Alligator Rivers Region of the Northern Territory of Australia was studied as a natural analogue of the far field behaviour of high level waste repositories following groundwater ingress. A number of mathematical modelling approaches were developed for processes as diverse as groundwater transport, host rock weathering, radionuclide sorption, evolution of the uranium dispersion fan and the distribution of uranium series nuclides between mineral assemblages in weathered host rock. Some of these models are relevant to performance assessment at the level of individual processes and subsystem performance. Through the project, new insights into the application of the natural analogue approach to the assessment of potential waste repository sites were obtained.

  5. Neurological Effects of Bisphenol A and its Analogues

    PubMed Central

    Inadera, Hidekuni

    2015-01-01

    The endocrine disrupting chemical bisphenol A (BPA) is widely used in the production of polycarbonate plastics and epoxy resins. The use of BPA-containing products in daily life makes exposure ubiquitous, and the potential human health risks of this chemical are a major public health concern. Although numerous in vitro and in vivo studies have been published on the effects of BPA on biological systems, there is controversy as to whether ordinary levels of exposure can have adverse effects in humans. However, the increasing incidence of developmental disorders is of concern, and accumulating evidence indicates that BPA has detrimental effects on neurological development. Other bisphenol analogues, used as substitutes for BPA, are also suspected of having a broad range of biological actions. The objective of this review is to summarize our current understanding of the neurobiological effects of BPA and its analogues, and to discuss preventive strategies from a public health perspective. PMID:26664253

  6. New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps

    PubMed Central

    Mi, Jia-Ning; Han, Yuwei; Xu, Yingqiong; Kou, Junping; Wang, Jing-Rong; Jiang, Zhi-Hong

    2016-01-01

    A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps. PMID:27966660

  7. New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps.

    PubMed

    Mi, Jia-Ning; Han, Yuwei; Xu, Yingqiong; Kou, Junping; Wang, Jing-Rong; Jiang, Zhi-Hong

    2016-12-14

    A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps.

  8. Synthesis of dehydroepiandrosterone analogues modified with phosphatidic acid moiety.

    PubMed

    Smuga, Damian A; Smuga, Małgorzata; Swizdor, Alina; Panek, Anna; Wawrzeńczyk, Czesław

    2010-12-12

    Dehydroepiandrosterone (DHEA) and its metabolite 7α-OH DHEA have many diverse physiological, biological and biochemical effects encompassing various cell types, tissues and organs. In in vitro studies, DHEA analogues have myriad biological actions, but in vivo, especially in oral administration, DHEA produces far more limited clinical effects. One of the possible solutions of this problem is conversion of DHEA to active analogues and/or its transformation into prodrug form. In this article, the studies on the conversion of DHEA and 7α-OH DHEA into their phosphatides by the phosphodiester approach are described. In this esterification, N,N-dicyclohexylcarbodiimide (DCC) was the most efficient coupling agent as well as p-toluenesulphonyl chloride (TsCl).

  9. Active postoperative acromegaly: sustained remission after discontinuation of somatostatin analogues

    PubMed Central

    Cardenas-Salas, Jersy

    2016-01-01

    Summary In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH) and insulin-like growth factor (IGF1) levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status). The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission. Learning points: The probability of disease recurrence is high after discontinuation of treatment with somatostatin analogues. Current data indicate that remission after treatment discontinuation may be more likely in patients with low GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on MRI, and/or in patients receiving prolonged treatment. This case report suggests that prolonged treatment with somatostatin analogues can be curative in carefully selected patients. PMID:27933171

  10. Synthesis of a platform to access bistramides and their analogues.

    PubMed

    Commandeur, Malgorzata; Commandeur, Claude; Cossy, Janine

    2011-11-18

    The platform C14-C40, which can be used to prepare bistramide C and 39-oxobistramide K, was synthesized in 19 steps with an overall yield of 6.2%. Furthermore, the chemoselective reduction of the ketone at C-39 was performed giving an easy access to bistramides A, B, D, K, and L. Finally, the versatility of the synthesis of the C14-C40 fragment can allow the preparation of a large variety of stereoisomers to produce bistramide analogues.

  11. Effect of lipophilicity on the pharmacokinetics of radiolabeled spiperone analogues

    SciTech Connect

    Moerlein, S.M.; Laufer, P.; Stocklin, G.

    1985-05-01

    Several radiolabeled analogues of the butyrophenone neuroleptic spiperone exhibit in vivo localization in D/sub 2/ receptor-rich areas of the brain. A series of N-alkylated spiperone analogues and the corresponding p-brominated compounds were synthesized to ascertain the optimum structure for labeling with /sup 18/F or /sup 75/Br. In vivo studies indicated that all analogues had D/sub 2/ receptor-binding affinity within the same order of magnitude (IC/sub 50/=2.6 nM for SP and 3.9 nM for BPSP), whereas the lipophilicity varied greatly (log P=2.7 for SP and 5.2 for BPSP). In vivo studies in the rat using the radiobrominated analogues were done using compounds labeled with n.c.a. /sup 77/Br via in-situ oxidation by dichloramine-T or H/sub 2/O/sub 2//CH/sub 3/COOH. Alkylation of BSP was found to decrease the striatum-to-cerebellum concentration at 6 hr from 8.2 for BSP to 5.2 for BPSP. Unexpectedly, the cerebral uptake did not increase with log P, the striatal concentration dropping from 390% MBC for BSP to 85% MBC for BPSP. This contrasts with previous results for SP and MSP, where the brain uptake increases slightly with log P. Increasing lipophilicity increases blood faster than brain concentrations, and it is concluded that whereas N-alkylation may be beneficial for /sup 18/F-labeld neuroleptics, non-alkylated spiperone is the optimum labeling substrate for /sup 75/Br.

  12. Bis(vinylenedithio)tetrathiafulvalene analogues of BEDT-TTF

    PubMed Central

    Demirtas, İlknur; Ozturk, Turan

    2015-01-01

    Summary This review aims to give an overview of the current status of our research on the synthesis of π-electron donor bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF, ET) analogues prepared from 1,8-diketones via a ring forming reaction. The new synthesized π-electron donors have vinyl moieties producing extended π-electron delocalization over the substituent phenyl rings at the peripheries. PMID:25977714

  13. Dimerization and DNA recognition rules of mithramycin and its analogues

    PubMed Central

    Weidenbach, Stevi; Hou, Caixia; Chen, Jhong-Min; Tsodikov, Oleg V.; Rohr, Jürgen

    2016-01-01

    The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung cancers. MTM exerts its cytotoxic effect by binding DNA as a divalent metal ion (Me2+)-coordinated dimer and disrupting the function of transcription factors. A precise molecular mechanism of action of MTM, needed to develop MTM analogues selective against desired transcription factors, is lacking. Although it is known that MTM binds G/C-rich DNA, the exact DNA recognition rules that would allow one to map MTM binding sites remain incompletely understood. Towards this goal, we quantitatively investigated dimerization of MTM and several of its analogues, MTM SDK (for Short side chain, DiKeto), MTM SA-Trp (for Short side chain and Acid), MTM SA-Ala, and a biosynthetic precursor premithramycin B (PreMTM B), and measured the binding affinities of these molecules to DNA oligomers of different sequences and structural forms at physiological salt concentrations. We show that MTM and its analogues form stable dimers even in the absence of DNA. All molecules, except for PreMTM B, can bind DNA with the following rank order of affinities (strong to weak): MTM = MTM SDK > MTM SA-Trp > MTM SA-Ala. An X(G/C)(G/C)X motif, where X is any base, is necessary and sufficient for MTM binding to DNA, without a strong dependence on DNA conformation. These recognition rules will aid in mapping MTM sites across different promoters towards development of MTM analogues as useful anticancer agents. PMID:26760230

  14. Synthesis of phosphonate and phostone analogues of ribose-1-phosphates

    PubMed Central

    Nasomjai, Pitak; Slawin, Alexandra M Z

    2009-01-01

    Summary The synthesis of phosphonate analogues of ribose-1-phosphate and 5-fluoro-5-deoxyribose-1-phosphate is described. Preparations of both the α- and β-phosphonate anomers are reported for the ribose and 5-fluoro-5-deoxyribose series and a synthesis of the corresponding cyclic phostones of each α-ribose is also reported. These compounds have been prepared as tools to probe the details of fluorometabolism in S. cattleya. PMID:19777136

  15. Novel ynamide structural analogues and their synthetic transformations

    PubMed Central

    Lu, Ting; Hsung, Richard P.

    2015-01-01

    This Highlight accounts for a recent phenomenon in which a series of novel ynamide structural analogues have emerged and caught the attention of the synthetic community. Preparations and reactions of these de novo ynamide variants are delineated here to demonstrate their accessibility as well as their reactivity. This Highlight should help reveal that these unique N-containing alkynes can become highly versatile building blocks in organic syntheses. PMID:26280027

  16. Pre-Clinical Testing of New Hydroxybutyrate Analogues

    DTIC Science & Technology

    2011-07-01

    the effects of DHB analogues to ascertain if they are longer-acting compounds than the parent compound. Although obtaining the first and only drug ...useful in the treatment of PD. Body of Work The goal of this study is to fully assess and compare the potency of compounds that are structurally...SARA 313: Carcinogenicity Classification (components present at 0.1% or more): none, unless listed below TSCA (US Toxic Substances Control Act

  17. Differential membrane fluidization by active and inactive cannabinoid analogues.

    PubMed

    Mavromoustakos, T; Papahatjis, D; Laggner, P

    2001-06-06

    The effects of the two cannabinomimetic drugs (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H-dibenzo[b,d]pyranyl-2-(hexyl)-1,3-dithiolane (AMG-3) and its pharmacologically less active 1-methoxy analogue (AMG-18) on the thermotropic and structural properties of dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC) liposomes have been studied by X-ray diffraction and differential scanning calorimetry (DSC). DSC data revealed that the incorporation of the drugs affect differently the thermotropic properties of DPPC. The presence of the more active drug distinctly broadened and attenuated both the pretransition and main phase transition of DPPC bilayers, while the inactive analogue had only minor effects. Small and wide angle X-ray diffraction data showed that the two cannabinoids have different effects on the lipid phase structures and on the hydrocarbon chain packing. The pharmacologically active analogue, AMG-3, was found to efficiently fluidize domains of the lipids in the L(beta)' gel phase, and to perturb the regular multibilayer lattice. In the liquid crystalline L(alpha) phase, AMG-3 was also found to cause irregularities in packing, suggesting that the drug induces local curvature. At the same concentration, the inactive AMG-18 had only minor structural effects on the lipids. At about 10-fold or higher concentrations, AMG-18 was found to produce similar but still less pronounced effects in comparison to those observed by AMG-3. The dose-dependent, different thermotropic and structural effects by the two cannabinoid analogues suggest that these may be related to their biological activity.

  18. Evaluation of Anti-HIV-1 Mutagenic Nucleoside Analogues*

    PubMed Central

    Vivet-Boudou, Valérie; Isel, Catherine; El Safadi, Yazan; Smyth, Redmond P.; Laumond, Géraldine; Moog, Christiane; Paillart, Jean-Christophe; Marquet, Roland

    2015-01-01

    Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the concept of “lethal mutagenesis” that prompted us to synthesize pyrimidine nucleoside analogues with antiviral activity in cell culture consistent with an accumulation of deleterious mutations in the HIV-1 genome. However, testing all potentially mutagenic compounds in cell-based assays is tedious and costly. Here, we describe two simple in vitro biophysical/biochemical assays that allow prediction of the mutagenic potential of deoxyribonucleoside analogues. The first assay compares the thermal stabilities of matched and mismatched base pairs in DNA duplexes containing or not the nucleoside analogues as follows. A promising candidate should display a small destabilization of the matched base pair compared with the natural nucleoside and the smallest gap possible between the stabilities of the matched and mismatched base pairs. From this assay, we predicted that two of our compounds, 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine, should be mutagenic. The second in vitro reverse transcription assay assesses DNA synthesis opposite nucleoside analogues inserted into a template strand and subsequent extension of the newly synthesized base pairs. Once again, only 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine are predicted to be efficient mutagens. The predictive potential of our fast and easy first line screens was confirmed by detailed analysis of the mutation spectrum induced by the compounds in cell culture because only compounds 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine were found to increase the mutation frequency by 3.1- and 3.4-fold, respectively. PMID:25398876

  19. Ungeremine and Its hemisynthesized analogues as bactericides against Flavobacterium columnare.

    PubMed

    Schrader, Kevin K; Avolio, Fabiana; Andolfi, Anna; Cimmino, Alessio; Evidente, Antonio

    2013-02-13

    The Gram-negative bacterium Flavobacterium columnare is the cause of columnaris disease, which can occur in channel catfish ( Ictalurus punctatus ). In a previous study, the betaine-type alkaloid ungeremine, 1, obtained from Pancratium maritimum L. was found to have strong antibacterial activity against F. columnare. In this study, analogues of 1 were evaluated using a rapid bioassay for activity against F. columnare to determine if the analogues might provide greater antibacterial activity and to determine structure-activity relationships of the test compounds. Several ungeremine analogues were prepared by hydrochlorination of the alkaloid and by selenium dioxide oxidation of both lycorine, 7, and pseudolycorine, 8, which yielded the isomer of ungeremine, 3, and zefbetaine, 4, respectively. The treatment of lycorine with phosphorus oxychloride allowed the synthesis of an anhydrolycorine lactam, 5, showing, with respect to 1, the deoxygenation and oxygenation of C-2 and C-7 of the C and B rings, respectively. The results of the structure-activity relationship studies showed that the aromatization of the C ring and the oxidation to an azomethine group of C-7 of the B ring are structural features important for antibacterial activity. In addition, the position of the oxygenation of the C ring as well as the presence of the 1,3-dioxole ring joined to the A ring of the pyrrolo[de]phenanthridine skeleton also plays a significant role in imparting antibacterial activity. On the basis of 24-h 50% inhibition concentration (IC(50)) results, ungeremine hydrochloride, 2, was similar in toxicity to 1, whereas 5 had the lowest activity. Analogue 2 is soluble in water, which may provide the benefit for use as an effective feed additive or therapeutant compared to ungeremine.

  20. Natural analogue studies as supplements to biomineralization research

    SciTech Connect

    McNeil, M.B.

    1995-09-01

    Chemical reactions can alter the chemistry and crystal structure of solid objects over archeological or geological times, while preserving external physical shapes. The reactions resulting in these structures offer natural analogues to laboratory experiments in biomineralization and to biologically influenced alteration of nuclear waste packages, and thus, they offer the only available way of validating models that purport waste package behavior over archaeological or geological times. Potential uses of such analogues in the construction and validation of hypothetical mechanisms of microbiological corrosion and biomineralization are reviewed. Evidence from such analogues suggests that biofilms can control materials alteration in ways usually overlooked. The newly hypothesized mechanisms involve control by biofilms of the cation flow near the solid surface and offer plausible mechanisms for the formation of mixed-cation minerals under conditions that would lead to dealloying in abiotic experiments; they also account for the formation of unusual minerals [such as posnjakite, Cu{sub 4}SO{sub 4}(OH){sub 6{center_dot}}H{sub 2}O] and mineral morphologies unusual in corrosion [malachite, Cu{sub 2}CO{sub 3}(OH){sub 2}, rarely forms botryoidally under corrosion conditions and its occasional presence on archaeological objects that appear to have undergone microbiological corrosion may be related to biofilm phenomena].

  1. Analogue Investigations into Magma-Cryosphere Interactions on Mars

    NASA Astrophysics Data System (ADS)

    Tyson, S.; Wilson, L.; Lane, S. J.; Airey, M. W.; Gilbert, J. S.

    2011-12-01

    Many landforms and morphological features thought to have resulted from magma-cryosphere interactions have been identified on Mars. However, few experimental studies have been conducted to investigate the physical and thermal changes that should occur in the subsurface during these interactions. This project aims to begin to address this by conducting a series of laboratory analogue experiments. We introduce a heat source into a block of analogue cryosphere material (a carefully-prepared mixture of solid grains and ice) and record the thermal development within the block using thermocouples. We use these measurements to interpret the physical activity within the block, such as when and where phase changes occur, what sequence of shapes the developing melt region takes, and the extent of convection of any fluid phase H20. Blocks are also dissected after each run and documented photographically to record any physical movement of grains. Results will be used to constrain variables within a heat flow model that we are developing. This model will then be applied to the interpretation of landforms on Mars to help determine what set of processes could have realistically occurred during their formation. A second series of experiments will investigate surface morphological changes on the cryosphere analogue blocks. Resultant morphologies will be recorded and compared with existing martian landforms to again provide insight into formation processes.

  2. The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression.

    PubMed

    Ferronato, María Julia; Alonso, Eliana Noelia; Gandini, Norberto Ariel; Fermento, María Eugenia; Villegas, María Emilia; Quevedo, Mario Alfredo; Arévalo, Julián; López Romero, Alejandro; Rivadulla, Marcos Lois; Gómez, Generosa; Fall, Yagamare; Facchinetti, María Marta; Curino, Alejandro Carlos

    2016-10-01

    Vitamin D has been shown to display a wide variety of antitumour effects, but their therapeutic use is limited by its severe side effects. We have designed and synthesized a Gemini vitamin D analogue of calcitriol (UVB1) which has shown to display antineoplastic effects on different cancer cell lines without causing hypercalcemia. The aim of this work has been to investigate, by employing in silico, in vitro, and in vivo assays, whether UVB1 inhibits human colorectal carcinoma progression. We demonstrated that UVB1 induces apoptotic cell death and retards cellular migration and invasion of HCT116 colorectal carcinoma cells. Moreover, the analogue reduced the tumour volume in vivo, and modulated the expression of Bax, E-cadherin and nuclear β-catenin in tumour animal tissues without producing toxic effects. In silico analysis showed that UVB1 exhibits greater affinity for the ligand binding domain of vitamin D receptor than calcitriol, and that several characteristics in the three-dimensional conformation of VDR may influence the biological effects. These results demonstrate that the Gemini vitamin D analogue affects the growth of the colorectal cancer and suggest that UVB1 is a potential chemotherapeutic agent for treatment of this disease.

  3. Design and synthesis of biotin analogues reversibly binding with streptavidin.

    PubMed

    Yamamoto, Tomohiro; Aoki, Kiyoshi; Sugiyama, Akira; Doi, Hirofumi; Kodama, Tatsuhiko; Shimizu, Yohei; Kanai, Motomu

    2015-04-01

    Two new biotin analogues, biotin carbonate 5 and biotin carbamate 6, have been synthesized. These molecules were designed to reversibly bind with streptavidin by replacing the hydrogen-bond donor NH group(s) of biotin's cyclic urea moiety with oxygen. Biotin carbonate 5 was synthesized from L-arabinose (7), which furnishes the desired stereochemistry at the 3,4-cis-dihydroxy groups, in 11% overall yield (over 10 steps). Synthesis of biotin carbamate 6 was accomplished from L-cysteine-derived chiral aldehyde 33 in 11% overall yield (over 7 steps). Surface plasmon resonance analysis of water-soluble biotin carbonate analogue 46 and biotin carbamate analogue 47 revealed that KD values of these compounds for binding to streptavidin were 6.7×10(-6)  M and 1.7×10(-10)  M, respectively. These values were remarkably greater than that of biotin (KD =10(-15)  M), and thus indicate the importance of the nitrogen atoms for the strong binding between biotin and streptavidin.

  4. Transdermal delivery of a melanotropic peptide hormone analogue

    SciTech Connect

    Dawson, B.V.; Hadley, M.E.; Kreutzfeld, K.; Dorr, R.T.; Hruby, V.J.; Al-Obeidi, F.; Don, S.

    1988-01-01

    We previously reported that topical application of (Nl3/sup 4/,D-Phe/sup 7/)alpha-MSH, a superpotent analogue of alpha-melanocyte stimulating hormone, to mice induces a darkening of follicular melanocytes throughout the skin. We now report that the melanotropin analogue can be delivered across mouse but not rat skin in an in vitro model system. Passage of the analogue from the topically applied vehicle (polyethylene glycol) across the skin into a subcutaneous receiving vessel was demonstrated by both bioassay as well as by radioimmunoassay. The bioassay data demonstrate that percutaneous absorption of the melanotropin did not result in loss of biological activity of the peptide. The differential penetration of the peptide across rodent skin reveals that one cannot predict percutaneous absorption of a substance across the stratum corneum from studies on a single species. The present results are the first to demonstrate, by direct quantitative measurements, that a bioactive peptide can be delivered across the vertebrate integument in vitro. These studies point out the potential of a topically applied melanotropin for tanning of the skin and possibly for treatment of certain hypopigmentary disorders.

  5. Contact zones and hydrothermal systems as analogues to repository conditions

    SciTech Connect

    Wollenberg, H.A.; Flexser, S.

    1984-10-01

    Radioactive waste isolation efforts in the US are currently focused on examining basalt, tuff, salt, and crystalline rock as candidate rock types to encompass waste repositories. As analogues to near-field conditions, the distributions of radio- and trace-elements have been examined across contacts between these rocks and dikes and stocks that have intruded them. The intensive study of the Stripa quartz monzonite has also offered the opportunity to observe the distribution of uranium and its daughters in groundwater and its relationship to U associated with fracture-filling and alteration minerals. Investigations of intrusive contact zones to date have included (1) a tertiary stock into Precambrian gneiss, (2) a stock into ash flow tuff, (3) a rhyodacite dike into Columbia River basalt, and (4) a kimberlite dike into salt. With respect to temperature and pressure, these contact zones may be considered "worst-case scenario" analogues. Results indicate that there has been no appreciable migration of radioelements from the more radioactive intrusives into the less radioactive country rocks, either in response to the intrusions or in the fracture-controlled hydrological systems that developed following emplacement. In many cases, the radioelements are locked up in accessory minerals, suggesting that artificial analogues to these would make ideal waste forms. Emphasis should now shift to examination of active hydrothermal systems, studying the distribution of key elements in water, fractures, and alteration minerals under pressure and temperature conditions most similar to those expected in the near-field environment of a repository. 14 refs.

  6. THE PENA BLANCA NATURAL ANALOGUE PERFORMANCE ASSESSMENT MODEL

    SciTech Connect

    G. Saulnier and W. Statham

    2006-04-16

    The Nopal I uranium mine in the Sierra Pena Blanca, Chihuahua, Mexico serves as a natural analogue to the Yucca Mountain repository. The Pena Blanca Natural Analogue Performance Assessment Model simulates the mobilization and transport of radionuclides that are released from the mine and transported to the saturated zone. The Pena Blanca Natural Analogue Performance Assessment Model uses probabilistic simulations of hydrogeologic processes that are analogous to the processes that occur at the Yucca Mountain site. The Nopal I uranium deposit lies in fractured, welded, and altered rhyolitic ash-flow tuffs that overlie carbonate rocks, a setting analogous to the geologic formations at the Yucca Mountain site. The Nopal I mine site has the following analogous characteristics as compared to the Yucca Mountain repository site: (1) Analogous source--UO{sub 2} uranium ore deposit = spent nuclear fuel in the repository; (2) Analogous geology--(i.e. fractured, welded, and altered rhyolitic ash-flow tuffs); (3) Analogous climate--Semiarid to arid; (4) Analogous setting--Volcanic tuffs overlie carbonate rocks; and (5) Analogous geochemistry--Oxidizing conditions Analogous hydrogeology: The ore deposit lies in the unsaturated zone above the water table.

  7. An adenosine nucleoside analogue NITD008 inhibits EV71 proliferation.

    PubMed

    Shang, Luqing; Wang, Yaxin; Qing, Jie; Shu, Bo; Cao, Lin; Lou, Zhiyong; Gong, Peng; Sun, Yuna; Yin, Zheng

    2014-12-01

    Enterovirus 71 (EV71), one of the major causative agents of Hand-Foot-Mouth Disease (HFMD), causes severe pandemics and hundreds of deaths in the Asia-Pacific region annually and is an enormous public health threat. However, effective therapeutic antiviral drugs against EV71 are rare. Nucleoside analogues have been successfully used in the clinic for the treatment of various viral infections. We evaluated a total of 27 nucleoside analogues and discovered that an adenosine nucleoside analogue NITD008, which has been reported to be an antiviral reagent that specifically inhibits flaviviruses, effectively suppressed the propagation of different strains of EV71 in RD, 293T and Vero cells with a relatively high selectivity index. Triphosphorylated NITD008 (ppp-NITD008) functions as a chain terminator to directly inhibit the RNA-dependent RNA polymerase activity of EV71, and it does not affect the EV71 VPg uridylylation process. A significant synergistic anti-EV71 effect of NITD008 with rupintrivir (AG7088) (a protease inhibitor) was documented, supporting the potential combination therapy of NITD008 with other inhibitors for the treatment of EV71 infections.

  8. TREATMENT OF TYPE 2 DIABETES WITH BIPHASIC INSULIN ANALOGUES

    PubMed Central

    Rizvi, Ali A.

    2016-01-01

    The majority of patients with Type 2 diabetes require insulin therapy for treating hyperglycaemia. There are several regimens available for insulin initiation and maintenance. Insulin analogues have been developed to mimic normal physiology as closely as possible. Biphasic analogues can target both fasting and postprandial hyperglycaemia, with the added advantage of being premixed and thus convenient for the patient. A practical and feasible option is to initiate insulin with one or more biphasic preparations at mealtimes, thus providing both basal and prandial coverage. Individual titration of dose and frequency of daily injections with biphasic insulin preparations has the potential for improving glycaemic control with a high degree of patient acceptance. Drawbacks include a more rigid regimen, a relative lack of flexibility, and a somewhat higher degree of glycaemic variability and hypoglycaemia when compared to multiple daily basal-bolus injections. Awareness of the advantages and limitations of biphasic insulin analogues can assist clinicians in their appropriate use for the treatment of patients with Type 2 diabetes. PMID:27918600

  9. Do film soundtracks contain nonlinear analogues to influence emotion?

    PubMed Central

    Blumstein, Daniel T.; Davitian, Richard; Kaye, Peter D.

    2010-01-01

    A variety of vertebrates produce nonlinear vocalizations when they are under duress. By their very nature, vocalizations containing nonlinearities may sound harsh and are somewhat unpredictable; observations that are consistent with them being particularly evocative to those hearing them. We tested the hypothesis that humans capitalize on this seemingly widespread vertebrate response by creating nonlinear analogues in film soundtracks to evoke particular emotions. We used lists of highly regarded films to generate a set of highly ranked action/adventure, dramatic, horror and war films. We then scored the presence of a variety of nonlinear analogues in these film soundtracks. Dramatic films suppressed noise of all types, contained more abrupt frequency transitions and musical sidebands, and fewer noisy screams than expected. Horror films suppressed abrupt frequency transitions and musical sidebands, but had more non-musical sidebands, and noisy screams than expected. Adventure films had more male screams than expected. Together, our results suggest that film-makers manipulate sounds to create nonlinear analogues in order to manipulate our emotional responses. PMID:20504815

  10. Do film soundtracks contain nonlinear analogues to influence emotion?

    PubMed

    Blumstein, Daniel T; Davitian, Richard; Kaye, Peter D

    2010-12-23

    A variety of vertebrates produce nonlinear vocalizations when they are under duress. By their very nature, vocalizations containing nonlinearities may sound harsh and are somewhat unpredictable; observations that are consistent with them being particularly evocative to those hearing them. We tested the hypothesis that humans capitalize on this seemingly widespread vertebrate response by creating nonlinear analogues in film soundtracks to evoke particular emotions. We used lists of highly regarded films to generate a set of highly ranked action/adventure, dramatic, horror and war films. We then scored the presence of a variety of nonlinear analogues in these film soundtracks. Dramatic films suppressed noise of all types, contained more abrupt frequency transitions and musical sidebands, and fewer noisy screams than expected. Horror films suppressed abrupt frequency transitions and musical sidebands, but had more non-musical sidebands, and noisy screams than expected. Adventure films had more male screams than expected. Together, our results suggest that film-makers manipulate sounds to create nonlinear analogues in order to manipulate our emotional responses.

  11. Spin Alignment in Analogues of The Local Sheet

    NASA Astrophysics Data System (ADS)

    Conidis, George J.

    2016-10-01

    Tidal torque theory and simulations of large scale structure predict spin vectors of massive galaxies should be coplanar with sheets in the cosmic web. Recently demonstrated, the giants (K s <= -22.5 mag) in the Local Volume beyond the Local Sheet have spin vectors directed close to the plane of the Local Supercluster, supporting the predictions of Tidal Torque Theory. However, the giants in the Local Sheet encircling the Local Group display a distinctly different arrangement, suggesting that the mass asymmetry of the Local Group or its progenitor torqued them from their primordial spin directions. To investigate the origin of the spin alignment of giants locally, analogues of the Local Sheet were identified in the SDSS DR9. Similar to the Local Sheet, analogues have an interacting pair of disk galaxies isolated from the remaining sheet members. Modified sheets in which there is no interacting pair of disk galaxies were identified as a control sample. Galaxies in face-on control sheets do not display axis ratios predominantly weighted toward low values, contrary to the expectation of tidal torque theory. For face-on and edge-on sheets, the distribution of axis ratios for galaxies in analogues is distinct from that in controls with a confidence of 97.6% & 96.9%, respectively. This corroborates the hypothesis that an interacting pair can affect spin directions of neighbouring galaxies.

  12. Four-quadrant analogue multiplier using operational amplifier

    NASA Astrophysics Data System (ADS)

    Riewruja, Vanchai; Rerkratn, Apinai

    2011-04-01

    A method to realise a four-quadrant analogue multiplier using general-purpose operational amplifiers (opamps) as only the active elements is described in this article. The realisation method is based on the quarter-square technique, which utilises the inherent square-law characteristic of class AB output stage of the opamp. The multiplier can be achieved from the proposed structure with using either bipolar or complementary metal-oxide-semiconductor (CMOS) opamps. The operation principle of the proposed multiplier has been confirmed by PSPICE analogue simulation program. Simulation results reveal that the principle of proposed scheme provides an adequate performance for a four-quadrant analogue multiplier. Experimental implementations of the proposed multiplier using bipolar and CMOS opamps are performed to verify the circuit performances. Measured results of the experimental proposed schemes based on the use of bipolar and CMOS opamps with supply voltage ±2.4 V show the worst-case relative errors of 0.32% and 0.47%, and the total harmonic distortions of 0.47% and 0.98%, respectively.

  13. Mammalian folylpoly-. gamma. -glutamate synthetase. 3. Specificity for folate analogues

    SciTech Connect

    George, S.; Cichowicz, D.J.; Shane, B.

    1987-01-27

    A variety of folate analogues were synthesized to explore the specificity of the folate binding site of hog liver folypolyglutamate synthetase and the requirements for catalysis. Modifications of the internal and terminal glutamate moieties of folate cause large drops in on rates and/or affinity for the protein. The only exceptions are glutamine, homocysteate, and ornithine analogues, indicating a less stringent specificity around the delta-carbon of glutamate. It is proposed that initial folate binding to the enzyme involves low-affinity interactions at a pterin and a glutamate site and that the first glutamate bound is the internal residue adjacent to the benzoyl group. Processive movement of the polyglutamate chain through the glutamate site and a possible conformational change in the protein when the terminal residue is bound would result in tight binding and would position the ..gamma..-carboxyl of the terminal glutamate in the correct position for catalysis. The 4-amino substitution of folate increases the on rate for monoglutamate derivatives but severely impairs catalysis with diglutamate derivatives. Pteroylornithine derivatives are the first potent and specific inhibitors of folylpolyglutamate synthetase to be identified and may act as analogues of reaction intermediates. Other folate derivatives with tetrahedral chemistry replacing the peptide bond, such as pteroyl-..gamma..-glutamyl-(psi,CH/sub 2/-NH)-glutamate, retain affinity for the protein but are considerably less effective inhibitors than the ornithine derivatives. Enzyme activity was assayed using (/sup 14/C)glutamate.

  14. Bilateral Choroidal Metastases from Endobronchial Carcinoid Treated with Somatostatin Analogues

    PubMed Central

    De Bruyn, Deborah; Lamont, Jan; Vanderstraeten, Erik; Van Belle, Simon; Platteau, Elise; De Zaeytijd, Julie; Hoornaert, Kristien P.

    2016-01-01

    Objective: To describe a patient with bilateral multifocal choroidal metastases from an endobronchial carcinoid treated with a somatostatin analogue. Method: A 60-year-old woman presenting with photopsia in the left eye underwent an extensive ophthalmic examination, including fluorescein angiography, OCT and ultrasound. Results: Fundoscopy revealed a small retinal tear in the left eye, for which she received laser treatment. In addition, choroidal masses were detected in both eyes. Her medical history of a pneumectomy for a bronchial carcinoid six years earlier together with recent elevated chromogranin A blood levels prompted a diagnosis of choroidal metastases. Subsequently, a Gallium-68 DOTANOC positron emitting tomography/computer tomography scan revealed a spinal cord metastasis and mediastinal as well as mesenterial lymph node invasion. Systemic treatment with Sandostatin®, a somatostatin analogue was started. Up until two years after the initial presentation and treatment, these choroidal lesions remained stable without any signs of growth. Conclusion: Endobronchial carcinoid tumors have an indolent nature and long-term follow-up is recommended for early detection of metastases. Although treatment with somatostatin analogues rarely induces complete tumor regression, tumor stabilization and prevention of symptoms related to hormone secretion is achieved. This well-tolerated systemic treatment provides a worthy alternative treatment for choroidal metastasis compared to classic radiotherapy without any risk of radiation or laser-related visual loss. PMID:27843513

  15. Stable oxyntomodulin analogues exert positive effects on hippocampal neurogenesis and gene expression as well as improving glucose homeostasis in high fat fed mice.

    PubMed

    Pathak, N M; Pathak, V; Lynch, A M; Irwin, N; Gault, V A; Flatt, P R

    2015-09-05

    The weight-lowering and gluco-regulatory actions of oxyntomodulin (Oxm) have been well-documented however potential actions of this peptide in brain regions associated with learning and memory have not yet been evaluated. The present study examined the long-term actions of a stable acylated analogue of Oxm, (dS(2))Oxm(K-γ-glu-Pal), together with parent (dS(2))Oxm peptide, on hippocampal neurogenesis, gene expression and metabolic control in high fat (HF) mice. Groups of HF mice (n = 12) received twice-daily injections of Oxm analogues (both at 25 nmol/kg body weight) or saline vehicle (0.9% wt/vol) over 28 days. Hippocampal gene expression and histology were assessed together with evaluation of energy intake, body weight, non-fasting glucose and insulin, glucose tolerance, insulin sensitivity and lipids. Oxm analogues significantly reduced body weight, improved glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity, islet architecture and lipid profile. Analysis of brain histology revealed significant reduction in hippocampal oxidative damage (8-oxoguanine), enhanced hippocampal neurogenesis (doublecortin) and improved hippocampal and cortical synaptogenesis (synaptophysin) following treatment. Furthermore, Oxm analogues up-regulated hippocampal mRNA expression of MASH1, Synaptophysin, SIRT1, GLUT4 and IRS1, and down-regulated expression of LDL-R and GSK3β. These data demonstrate potential of stable Oxm analogues, and particularly (dS(2))Oxm(K-γ-glu-Pal) to improve metabolic function and enhance neurogenesis, synaptic plasticity, insulin signalling and exert protective effects against oxidative damage in hippocampus and cortex brain regions in HF mice.

  16. Past and present of analogue modelling, and its future trend

    NASA Astrophysics Data System (ADS)

    Koyi, Hemin

    2015-04-01

    Since Hull (1815) published his article on modelling, analogue modelling has expanded to simulate both a wider range of tectonic regimes and target more challenging set-ups, and has become an integrated part of the fields of tectonics and structural geology. Establishment of new laboratories testifies for the increased attention the technique receives. The ties between modellers and field geoscientists have become stronger with the focus being on understanding the parameters that govern the evolution of a tectonic regime and the processes that dominate it. Since the first sand castle was built with damp sand on a beach, sand has proven to be an appropriate material analogue. Even though granular materials is the most widely used analogue material, new materials are also (re)introduced as rock analogues. Emphasis has been on more precise measurements of the mechanical properties of the materials and on minimizing the preparation effects, which have a great impact on scaling, interpretations and benchmarking. The analytical technique used to quantify model results has also seen a great deal of improvement. In addition to X-ray tomography used to visualise internal structures of models, new techniques (e.g. PIV, high-resolution laser scanning, and interferometry) have enabled monitoring kinematics with a higher precision. Benchmarking exercises have given modelling an additional checking tool by outlining, in addition to the rheology of the modelling materials, the impact of different preparation approaches, the effect of boundary conditions, and the human factor on model results. However, despite the different approaches and deformation rigs, results of models of different tectonic laboratories have shown a great deal of similarities. Even with the introduction of more sophisticated numerical codes and usage of more powerful computers which enable the simulation of more challenging material properties and combinations of those, and 3D model set-up, analogue modelling

  17. THE PENA BLANCA NATURAL ANALOGUE PERFORMANCE ASSESSMENT MODEL

    SciTech Connect

    G.J. Saulnier Jr; W. Statham

    2006-03-10

    The Nopal I uranium mine in the Sierra Pena Blanca, Chihuahua, Mexico serves as a natural analogue to the Yucca Mountain repository. The Pena Blanca Natural Analogue Performance Assessment Model simulates the mobilization and transport of radionuclides that are released from the mine and transported to the saturated zone. the Pena Blanca Natural Analogue Model uses probabilistic simulations of hydrogeologic processes that are analogous to the processes that occur at the Yucca Mountain site. The Nopal I uranium deposit lies in fractured, welded, and altered rhyolitic ash flow tuffs that overlie carbonate rocks, a setting analogous to the geologic formations at the Yucca Mountain site. The Nopal I mine site has the following characteristics as compared to the Yucca Mountain repository site. (1) Analogous source: UO{sub 2} uranium ore deposit = spent nuclear fuel in the repository; (2) Analogous geologic setting: fractured, welded, and altered rhyolitic ash flow tuffs overlying carbonate rocks; (3) Analogous climate: Semiarid to arid; (4) Analogous geochemistry: Oxidizing conditions; and (5) Analogous hydrogeology: The ore deposit lies in the unsaturated zone above the water table. The Nopal I deposit is approximately 8 {+-} 0.5 million years old and has been exposed to oxidizing conditions during the last 3.2 to 3.4 million years. The Pena Blanca Natural Analogue Model considers that the uranium oxide and uranium silicates in the ore deposit were originally analogous to uranium-oxide spent nuclear fuel. The Pena Blanca site has been characterized using field and laboratory investigations of its fault and fracture distribution, mineralogy, fracture fillings, seepage into the mine adits, regional hydrology, and mineralization that shows the extent of radionuclide migration. Three boreholes were drilled at the Nopal I mine site in 2003 and these boreholes have provided samples for lithologic characterization, water-level measurements, and water samples for laboratory

  18. Interglacial analogues of the Holocene and its natural near future

    NASA Astrophysics Data System (ADS)

    Yin, Qiuzhen; Berger, André

    2015-07-01

    In an attempt to find potential interglacial analogues of our present interglacial and its natural future, five interglacials (MIS-1, 5, 9, 11 and 19) are studied in terms of their astronomical characteristics, greenhouse gases concentration and climate simulated using both snapshot and transient experiments. Transient simulations covering a full range of obliquity, precession and eccentricity allow to develop an OPE index to estimate the climate sensitivity to astronomical forcing. They also show that obliquity and precession have different weight on the annual mean temperature and precipitation of different latitudinal zones, leading to varying phasing of these climate variables between different latitudes. However, the variations in boreal summer temperature of different latitudes (except the Southern Ocean) are in phase and are dominated by precession. All the interglacials are shown to be warmer than the natural climate of the present day and of the next centuries during boreal summer and for the annual mean temperature with varying duration and intensity. Such warming is mainly caused by changes in insolation, unlike the present global warming which mainly results from anthropogenic CO2 increase. The exceptionally long duration of MIS-11 is confirmed by our simulations, and it is demonstrated to be related to the long-lasting low eccentricity and high CO2 concentration and to the anti-phase relationship between obliquity maximum and precession minimum during MIS-11. As far as the variations of annual and seasonal temperatures are concerned, both snapshot and transient simulations show that MIS-19 is the best analogue of the present interglacial. MIS-11 is also a decent analogue when the impact of insolation alone is considered, but it is warmer than MIS-1 when the impact of CO2 is additionally included. Due to the large amplitude in the variations of insolation, MIS-5 and MIS-9 can hardly be considered as an analogue of the natural present-day climate and of

  19. Downscaling of surface moisture flux and precipitation in the Ebro Valley (Spain) using analogues and analogues followed by random forests and multiple linear regression

    NASA Astrophysics Data System (ADS)

    Ibarra-Berastegi, G.; Saénz, J.; Ezcurra, A.; Elías, A.; Diaz Argandoña, J.; Errasti, I.

    2011-06-01

    In this paper, reanalysis fields from the ECMWF have been statistically downscaled to predict from large-scale atmospheric fields, surface moisture flux and daily precipitation at two observatories (Zaragoza and Tortosa, Ebro Valley, Spain) during the 1961-2001 period. Three types of downscaling models have been built: (i) analogues, (ii) analogues followed by random forests and (iii) analogues followed by multiple linear regression. The inputs consist of data (predictor fields) taken from the ERA-40 reanalysis. The predicted fields are precipitation and surface moisture flux as measured at the two observatories. With the aim to reduce the dimensionality of the problem, the ERA-40 fields have been decomposed using empirical orthogonal functions. Available daily data has been divided into two parts: a training period used to find a group of about 300 analogues to build the downscaling model (1961-1996) and a test period (1997-2001), where models' performance has been assessed using independent data. In the case of surface moisture flux, the models based on analogues followed by random forests do not clearly outperform those built on analogues plus multiple linear regression, while simple averages calculated from the nearest analogues found in the training period, yielded only slightly worse results. In the case of precipitation, the three types of model performed equally. These results suggest that most of the models' downscaling capabilities can be attributed to the analogues-calculation stage.

  20. Downscaling of surface moisture flux and precipitation in the Ebro Valley (Spain) using analogues and analogues followed by random forests and multiple linear regression

    NASA Astrophysics Data System (ADS)

    Ibarra-Berastegi, G.; Saénz, J.; Ezcurra, A.; Elías, A.; Diaz de Argandoña, J.; Errasti, I.

    2011-02-01

    In this paper, reanalysis fields from the ECMWF have been statistically downscaled to predict from large-scale atmospheric fields surface moisture flux and daily precipitation at two observatories (Zaragoza and Tortosa, Ebro Valley, Spain) during the 1961-2001 period. Three types of downscaling models have been built (i) analogues, (ii) analogues followed by random forests and (iii) analogues followed by multiple linear regression. The inputs consist of data (predictor fields) taken from the ERA-40 reanalysis. The predicted fields are precipitation and surface moisture flux as measured at the two observatories. With the aim to reduce the dimensionality of the problem, the ERA-40 fields have been decomposed using empirical orthogonal functions. Available daily data has been divided into two parts: a training period used to find a group of about 300 analogues to build the downscaling model (1961-1996) and a test period (1997-2001), where models' performance has been assessed using independent data. In the case of surface moisture flux, the models based on analogues followed by random forests do not clearly outperform those built on analogues plus multiple linear regression, while simple averages calculated from the nearest analogues found in the training period, yielded only slightly worse results. In the case of precipitation, the three types of model performed equally. These results suggest that most of the models' downscaling capabilities can be attributted to the analogues-calculation stage.

  1. Intermolecular interaction of voriconazole analogues with model membrane by DSC and NMR, and their antifungal activity using NMR based metabolic profiling.

    PubMed

    Kalamkar, Vaibhav; Joshi, Mamata; Borkar, Varsha; Srivastava, Sudha; Kanyalkar, Meena

    2013-11-01

    The development of novel antifungal agents with high susceptibility and increased potency can be achieved by increasing their overall lipophilicity. To enhance the lipophilicity of voriconazole, a second generation azole antifungal agent, we have synthesized its carboxylic acid ester analogues, namely p-methoxybenzoate (Vpmb), toluate (Vtol), benzoate (Vbz) and p-nitrobenzoate (Vpnb). The intermolecular interactions of these analogues with model membrane have been investigated using nuclear magnetic resonance (NMR) and differential scanning calorimetric (DSC) techniques. The results indicate varying degree of changes in the membrane bilayer's structural architecture and physico-chemical characteristics which possibly can be correlated with the antifungal effects via fungal membrane. Rapid metabolite profiling of chemical entities using cell preparations is one of the most important steps in drug discovery. We have evaluated the effect of synthesized analogues on Candida albicans. The method involves real time (1)H NMR measurement of intact cells monitoring NMR signals from fungal metabolites which gives Metabolic End Point (MEP). This is then compared with Minimum Inhibitory Concentration (MIC) determined using conventional methods. Results indicate that one of the synthesized analogues, Vpmb shows reasonably good activity.

  2. Clearance and early hydrolysis of atrial natriuretic factor in vivo. Structural analysis of cleavage sites and design of an analogue that inhibits hormone cleavage.

    PubMed Central

    Condra, C L; Leidy, E A; Bunting, P; Colton, C D; Nutt, R F; Rosenblatt, M; Jacobs, J W

    1988-01-01

    This study examines the clearance and early hydrolysis of atrial natriuretic factor (ANF) in vivo. Radiolabeled ANF was cleared from the circulation of the rat with biphasic kinetics; the majority (90%) of ANF cleared with a t1/2 of 15 s, the remaining peptide was cleared with a t1/2 of 5 min. Microsequence analysis of ANF peptides recovered from the circulation of rats revealed five major degradation products of the intact hormone. The first cleavage occurred between amino acids 12 and 13 of the hormone and would inactivate ANF. Over time, additional fragments of the hormone were generated, including fragments of 6, 7, 21, and 24 amino acids in length. Whole body radioautography of rats injected with [123I]-ANF revealed the kidney as a predominant organ involved in clearance of ANF. Subsequent amino acid sequence analyses of radiolabeled ANF exposed to the kidney in vivo indicated that this organ generated four of the five major hydrolysis products observed in circulation, namely, the 6, 7, 16, and 21 amino acid fragments of the hormone. In an attempt to stabilize ANF in vivo, a synthetic analogue of the hormone was prepared that contained the amino acid analogue, aminoisobutyric acid, substituted at position 13. This analogue completely abolished the in vivo cleavage of ANF at this site. These studies demonstrate the usefulness of a protein chemistry approach in characterizing hormone metabolism in vivo and designing analogues with enhanced in vivo stability to cleavage. Images PMID:2966813

  3. Conformation-sensitive nucleoside analogues as topology-specific fluorescence turn-on probes for DNA and RNA G-quadruplexes

    PubMed Central

    Tanpure, Arun A.; Srivatsan, Seergazhi G.

    2015-01-01

    Development of probes that can discriminate G-quadruplex (GQ) structures and indentify efficient GQ binders on the basis of topology and nucleic acid type is highly desired to advance GQ-directed therapeutic strategies. In this context, we describe the development of minimally perturbing and environment-sensitive pyrimidine nucleoside analogues, based on a 5-(benzofuran-2-yl)uracil core, as topology-specific fluorescence turn-on probes for human telomeric DNA and RNA GQs. The pyrimidine residues of one of the loop regions (TTA) of telomeric DNA and RNA GQ oligonucleotide (ON) sequences were replaced with 5-benzofuran-modified 2′-deoxyuridine and uridine analogues. Depending on the position of modification the fluorescent nucleoside analogues distinguish antiparallel, mixed parallel-antiparallel and parallel stranded DNA and RNA GQ topologies from corresponding duplexes with significant enhancement in fluorescence intensity and quantum yield. Further, these GQ sensors enabled the development of a simple fluorescence binding assay to quantify topology- and nucleic acid-specific binding of small molecule ligands to GQ structures. Together, our results demonstrate that these nucleoside analogues are useful GQ probes, which are anticipated to provide new opportunities to study and discover efficient G-quadruplex binders of therapeutic potential. PMID:26202965

  4. Itraconazole Side Chain Analogues: Structure–Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog Signaling

    PubMed Central

    Shi, Wei; Nacev, Benjamin A.; Aftab, Blake T.; Head, Sarah; Rudin, Charles M.; Liu, Jun O.

    2012-01-01

    Itraconazole is an antifungal drug that was recently found to possess potent antiangiogenic activity and anti-hedgehog (Hh) pathway activity. To search for analogues of itraconazole with greater potency and to understand the structure–activity relationship in both antiangiogenic and Hh targeting activity, 25 itraconazole side chain analogues were synthesized and assayed for inhibition of endothelial cell proliferation and Gli1 transcription in a medulloblastoma (MB) culture. Through this analysis, we have identified analogues with increased potency for inhibiting endothelial cell proliferation and the Hh pathway, as well as VEGFR2 glycosylation that was recently found to be inhibited by itraconazole. An SAR analysis of these activities revealed that potent activity of the analogues against VEGFR2 glycosylation was generally driven by side chains of at least four carbons in composition with branching at the α or β position. SAR trends for targeting the Hh pathway were divergent from those related to HUVEC proliferation or VEGFR2 glycosylation. These results also suggest that modification of the sec-butyl side chain can lead to enhancement of the biological activity of itraconazole. PMID:21936514

  5. Preparation and Evaluation at the Delta Opioid Receptor of a Series of Linear Leu-Enkephalin Analogues Obtained by Systematic Replacement of the Amides

    PubMed Central

    2013-01-01

    Leu-enkephalin analogues, in which the amide bonds were sequentially and systematically replaced either by ester or N-methyl amide bonds, were prepared using classical organic chemistry as well as solid phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacological profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogues were also measured. Our results revealed that the last amide bond can be successfully replaced by either an ester or an N-methyl amide bond without significantly decreasing the biological activity of the corresponding analogues when compared to Leu-enkephalin. The peptidomimetics with an N-methyl amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu-enkephalin. Findings from the present study further revealed that the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin are not important for its biological activity on DOPr. Our results show that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogues with enhanced stability. Our findings further suggest that such a strategy can also be useful to study the biological roles of amide bonds. PMID:23650868

  6. Specificity of neomycin analogues bound to the packaging region of human immunodeficiency virus type 1 RNA.

    PubMed

    McPike, Mark P; Goodisman, Jerry; Dabrowiak, James C

    2004-04-15

    The packaging region of HIV-1 RNA contains a number of structural features which are important in the life cycle of the virus, making this segment of RNA a potential target for new types of AIDS-directed drugs. We studied the binding of three neomycin analogues (neo-guanidino, neo-acridine, and neo-neo) to a 171-mer RNA molecule from the packaging region of HIV-1 using quantitative footprinting and circular dichroism. Neo-guanidino produced footprinting patterns and effects on the CD similar to those observed for neomycin and paromomycin, indicating that all three compounds bind to the same regions of the 171-mer. Neo-guanidino binds to SL 1 where it joins the large internal loop, near a bulge in the stem of SL 1, and on SL 2. Neo-acridine, which has an acridine attached to neomycin, and neo-neo, which has two neomycins linked by a flexible tether, bind bivalently, and give very different footprinting and CD results from the other compounds. The neomycin portion of neo-acridine binds to the same sites as neomycin, while the attached acridine group appears to bind to a duplex region in the main stem of the folded 171-mer. Since the footprinting data for this analogue show few enhancements, bivalent binding of neo-acridine appears to stabilize the folded structure of RNA by effectively 'stapling' parts of the structure together. Neo-neo induces significant structural changes in RNA where neomycin binds. This may be related to the inability of both neomycins of neo-neo it find optimal binding sites adjacent to one another without changing RNA structure. The intensity of a strong negative CD band in the spectrum of psi-RNA at 208 nm is sensitive to drug-induced changes in RNA structure. Neo-guanidino and neo-neo (also neomycin and paromomycin), which change RNA structure, cause an increase in intensity while neo-acridine, which induces little distortion to RNA, causes a decrease in intensity. Molecular modeling analysis shows that C-5' of ribose of neo-acridine and neo

  7. α-MSH analogue attenuates blood pressure elevation in DOCA-salt hypertensive mice.

    PubMed

    Rinne, Petteri; Penttinen, Anna-Maija; Nordlund, Wendy; Ahotupa, Markku; Savontaus, Eriika

    2013-01-01

    Melanocyte-stimulating hormones, α-, β- and γ-MSH, regulate important physiological functions including energy homeostasis, inflammation and sodium metabolism. Previous studies have shown that α-MSH increases sodium excretion and promotes vascular function in rodents, but it is unexplored whether these characteristics of α-MSH could translate into therapeutic benefits in the treatment of hypertension. Therefore, we first assessed the diuretic and natriuretic properties of the stable α-MSH analogue [Nle(4), D-Phe(7)]-α-MSH (NDP-α-MSH) and investigated whether it has protective effects in deoxycorticosterone acetate (DOCA)-salt hypertensive mice. Adult male C57Bl/6N mice were subjected to DOCA-salt treatment and randomized to receive intraperitoneal injections of either saline as vehicle or NDP-α-MSH (0.3 mg/kg/day for 14 days) starting 7 days after the DOCA-salt treatment. Systemic hemodynamics, serum and urine electrolytes, and oxidative stress markers were assessed in control sham-operated and DOCA-salt mice. NDP-α-MSH elicited marked diuretic and natriuretic responses that were reversible with the MC3/4 receptor antagonist SHU9119. Chronic NDP-α-MSH treatment attenuated blood pressure elevation in DOCA-salt mice without affecting the blood pressure of normotensive control animals. Owing to the enhanced sodium excretion, NDP-α-MSH-treated mice were protected from DOCA-salt-induced hypernatremia. DOCA-salt treatment mildly increased oxidative stress at the tissue level, but NDP-α-MSH had no significant effects on the oxidative stress markers. In conclusion, treatment with NDP-α-MSH increases urinary sodium excretion and protects against DOCA-salt-induced hypertension. These findings point to the potential future use of α-MSH analogues in the treatment of hypertension.

  8. A 4-alkyl-substituted analogue of guaiacol shows greater repellency to savannah tsetse (Glossina spp.).

    PubMed

    Saini, Rajindar K; Hassanali, Ahmed

    2007-05-01

    The responses of Glossina morsitans morsitans Westwood to guaiacol (2-methoxyphenol), a mild repellent constituent of bovid odors, and seven analogues comprising 2-methoxyfuran, 2,4-dimethylphenol, 2-methoxy-4-methylphenol (4-methylguaiacol), 4-ethyl-2-methoxyphenol (4-ethylguaiacol), 4-allyl-2-methoxyphenol (4-allylguaiacol; eugenol), 3,4-methylenedioxytoluene, and 3,4-dimethoxystyrene were compared in a two-choice wind tunnel. The 4-methyl-substituted derivative (2-methoxy-4-methylphenol) was found to elicit stronger repellent responses from the flies compared with guaiacol. None of the other analogues showed significant repellent effects on flies. 4-Methylguaiacol, guaiacol, and eugenol (which was included because of previous reports of its repellency against a number of arthropods) were further evaluated in the field with wild populations of predominantly Glossina pallidipes Austen. The presence of guaiacol or eugenol near odor-baited traps caused some nonsignificant reduction in the number of tsetse catches at relatively high release rates (approximately 50 mg/hr). In contrast, the 4-methyl derivative at three different release rates (2.2, 4.5, and 9.0 mg/hr) reduced trap catches of baited traps in a dose-response manner. At 10 mg/hr release rate, it reduced the catches of baited and unbaited traps by approximately 80 and approximately 70%, respectively. In addition, the compound not only reduced the number of tsetse attracted to natural ox odor (approximately 80%), but also had an effect on their feeding responses, reducing the proportion that fed on an ox by more than 80%. Our study shows that the presence of a methyl substituent at the 4-position of guaiacol enhances the repellency of the molecule to savannah tsetse and suggests that 4-methylguaiacol may represent a promising additional tool in the arsenal of techniques in trypanosomiasis control.

  9. Enkephalin analogues with N-phenyl-N-(piperidin-2-ylmethyl) propionamide derivatives: Synthesis and biological evaluations

    PubMed Central

    Deekonda, Srinivas; Cole, Jacob; Sunna, Sydney; Rankin, David; Largent-Milnes, Tally M.; Davis, Peg; BassiriRad, Neemah M.; Lai, Josephine; Vanderah, Todd W.; Porecca, Frank; Hruby, Victor J.

    2016-01-01

    N-Phenyl-N-(piperidin-2-ylmethyl)propionamide based bivalent ligands are unexplored for the design of opioid based ligands. Two series of hybrid molecules bearing N-phenyl-N-(piperidin-2-ylmethyl)propionamide derived small molecules conjugated with an enkephalin analogues with and without a linker (β-alanine) were designed and synthesized. Both bivalent ligand series exhibited remarkable binding affinities from nanomolar to subnanomolar range at both μ and δ opioid receptors and displayed potent agonist activities as well. The replacement of Tyr with Dmt and introduction of a linker between the small molecule and enkephalin analogue resulted in highly potent ligands. Both series of ligands showed excellent binding affinities at both μ (0.6–0.9 nM) and δ (0.2–1.2 nM) opioid receptors respectively. Similarly, these bivalent ligands exhibited potent agonist activities in both MVD and GPI assays. Ligand 17 was evaluated for in vivo antinociceptive activity in non-injured rats following spinal administration. Ligand 17 was not significantly effective in alleviating acute pain. The most likely explanations for this low intrinsic efficacy in vivo despite high in vitro binding affinity, moderate in vitro activity are (i) low potency suggesting that higher doses are needed; (ii) differences in experimental design (i.e. non-neuronal, high receptor density for in vitro preparations versus CNS site of action in vitro); (iii) pharmacodynamics (i.e. engaging signalling pathways); (iv) pharmacokinetics (i.e. metabolic stability). In summary, our data suggest that further optimisation of this compound 17 is required to enhance intrinsic antinociceptive efficacy. PMID:26611918

  10. Design, Synthesis, and Evaluation of Genistein Analogues as Anti-Cancer Agents

    PubMed Central

    Xiong, Pahoua; Wang, Rubing; Zhang, Xiaojie; Torre, Eduardo DeLa; Leon, Francisco; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong

    2016-01-01

    Genistein is a bioactive isoflavone derived from soybeans. The tie-in between the intake of genistein and the decreased incidence of some solid tumors (including prostate cancer) has been demonstrated by epidemiological studies. The potential of genistein in treating prostate cancer has also been displayed by in vitro cell-based and in vivo animal experiments. Genistein has entered clinical trials for both chemoprevention and potential treatment of prostate cancer. Even though the low oral bioavailability has presented the major challenges to genistein’s further clinical development, chemical modulation of genistein holds the promise to generate potential anti-prostate cancer agents with enhanced potency and/or better pharmacokinetic profiles than genistein. As part of our ongoing project to develop natural products-based anti-prostate cancer agents, the current study was undertaken to synthesize eight genistein analogues for cytotoxic evaluation in three prostate cancer cell lines (PC-3, DU-145, LNCaP; both androgen-sensitive and androgen-refractory cell lines), as well as one aggressive cervical cancer cell line (HeLa). Eight genistein analogues have been successfully synthesized with Suzuki-Miyaura coupling reaction as a key step. Their in vitro anti-cancer potential was evaluated by trypan blue exclusion assay and WST-1 cell proliferation assay against a panel of four human cancer cell lines. The acquired data suggest i) that the C-5 and C-7 hydroxyl groups in genistein are very important for the cytotoxicity and anti-proliferative activity; and ii) that 1-alkyl-1H-pyrazol-4-yl and pyridine-3-yl might act as good bioisosteres for the 4'-hydroxyphenyl moiety in genistein. PMID:25991428

  11. Quantitative comparisons of analogue models of brittle wedge dynamics

    NASA Astrophysics Data System (ADS)

    Schreurs, Guido

    2010-05-01

    Analogue model experiments are widely used to gain insights into the evolution of geological structures. In this study, we present a direct comparison of experimental results of 14 analogue modelling laboratories using prescribed set-ups. A quantitative analysis of the results will document the variability among models and will allow an appraisal of reproducibility and limits of interpretation. This has direct implications for comparisons between structures in analogue models and natural field examples. All laboratories used the same frictional analogue materials (quartz and corundum sand) and prescribed model-building techniques (sieving and levelling). Although each laboratory used its own experimental apparatus, the same type of self-adhesive foil was used to cover the base and all the walls of the experimental apparatus in order to guarantee identical boundary conditions (i.e. identical shear stresses at the base and walls). Three experimental set-ups using only brittle frictional materials were examined. In each of the three set-ups the model was shortened by a vertical wall, which moved with respect to the fixed base and the three remaining sidewalls. The minimum width of the model (dimension parallel to mobile wall) was also prescribed. In the first experimental set-up, a quartz sand wedge with a surface slope of ˜20° was pushed by a mobile wall. All models conformed to the critical taper theory, maintained a stable surface slope and did not show internal deformation. In the next two experimental set-ups, a horizontal sand pack consisting of alternating quartz sand and corundum sand layers was shortened from one side by the mobile wall. In one of the set-ups a thin rigid sheet covered part of the model base and was attached to the mobile wall (i.e. a basal velocity discontinuity distant from the mobile wall). In the other set-up a basal rigid sheet was absent and the basal velocity discontinuity was located at the mobile wall. In both types of experiments

  12. Quinazoline antifolates inhibiting thymidylate synthase: 4-thio-substituted analogues.

    PubMed

    Thornton, T J; Jones, T R; Jackman, A L; Flinn, A; O'Connor, B M; Warner, P; Calvert, A H

    1991-03-01

    We report the synthesis of four new 4-thio-5,8-dideazafolic acid analogues and a 4-(methylthio) analogue structurally related to the thymidylate synthase (TS) inhibitor N10-propargyl-5,8-dideazafolic acid. Three N10-propargyl-4-thio-5,8-dideazafolic acid analogues had C2 amino, hydrogen, and methyl substituents. A 4-thio and a 4-(methylthio) compound each with hydrogen at C2 and ethyl at N10 were also synthesized. In general, the synthetic route involved thionation of the appropriate 4-oxoquinazoline; the sulfur thus introduced was then protected by methylation. Further protection with a pivaloyl group was required for the quinazoline bearing a 2-amino substituent. The protected quinazolines were treated with N-bromosuccinimide and the resulting 6-(bromomethyl) compounds were then coupled to the appropriate N-monoalkylated diethyl N-(4-aminobenzoyl)-L-glutamate in N,N-dimethylacetamide with calcium carbonate as base. The 4-thio-5,8-dideazafolic acids were obtained by removal of the methylthio group with sodium hydrosulfide, followed by deprotection of the carboxyl groups with cold dilute alkali. For the compound containing a pivaloyl protecting group, hot dilute alkali was used. To obtain the 5,8-dideazafolic acid containing a 4-(methylthio) substituent, the corresponding diester was treated with lithium hydroxide which selectively deprotected the carboxyl groups. The five compounds were tested as inhibitors of L1210 TS. It was found that replacement of the 4-oxygen of the quinazoline moiety by sulfur did not alter the TS inhibition. However, the introduction of a methylthio substituent at position 4 severely impaired TS inhibition. All 4-thio compounds were less cytotoxic to L1210 cells in culture than their 4-oxo counterparts.

  13. Radio-protective effect of some new curcumin analogues.

    PubMed

    El-Gazzar, Marwa G; Zaher, Nashwa H; El-Hossary, Ebaa M; Ismail, Amel F M

    2016-09-01

    In the present study, novel symmetrical curcumin analogues (2-7) have been synthesized by substituting the phenolic OH of curcumin with different linkers providing additional keto-enol tautomerism, very essential for radioprotective activity. The structures of the synthesized compounds (2-7) were elucidated by elemental analysis, IR, (1)H-NMR, (13)C-NMR and mass spectral data and were found consistent with the assigned structures. The curative effect of these new compounds, against the oxidative stress due to exposure of rats to the whole body γ-irradiation (7Gy) was investigated. Gamma-irradiated rats exhibited elevations of ALT, AST activities, urea, creatinine, triglycerides, total cholesterol, malondialdehyde (MDA), nitric oxide (NO), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α) and Nuclear Factor-kappa B (NF-κB) levels. Contrariwise, the total protein, albumin, total calcium level, SOD, CAT, GSH-Px, GST activities and GSH content were decreased. Treatment of gamma-irradiated rats with the new curcumin analogues (2-7) showed significant amelioration in the in-vivo antioxidant status, liver and kidney functions, as well as the anti-inflammatory markers (IL-6, TNF-α and NF-κB). Inhibition of NF-κB could be responsible for the improvement of the antioxidant and anti-inflammatory status in gamma-irradiated animals, by down-regulation of IL-1β and TNF-α level. In conclusion, the new curcumin analogues (2-7) exhibited post-protective effect on gamma-irradiation, by NF-κB inhibition.

  14. Dynamics of water in prussian blue analogues: Neutron scattering study

    SciTech Connect

    Sharma, V. K.; Mitra, S.; Thakur, N.; Yusuf, S. M.; Mukhopadhyay, R.; Juranyi, Fanni

    2014-07-21

    Dynamics of crystal water in Prussian blue (PB), Fe(III){sub 4}[Fe(II)(CN){sub 6}]{sub 3}.14H{sub 2}O and its analogue Prussian green (PG), ferriferricynaide, Fe(III){sub 4}[Fe(III)(CN){sub 6}]{sub 4}.16H{sub 2}O have been investigated using Quasielastic Neutron Scattering (QENS) technique. PB and its analogue compounds are important materials for their various interesting multifunctional properties. It is known that crystal water plays a crucial role towards the multifunctional properties of Prussian blue analogue compounds. Three structurally distinguishable water molecules: (i) coordinated water molecules at empty nitrogen sites, (ii) non-coordinated water molecules in the spherical cavities, and (iii) at interstitial sites exist in PB. Here spherical cavities are created due to the vacant sites of Fe(CN){sub 6} units. However, PG does not have any such vacant N or Fe(CN){sub 6} units, and only one kind of water molecules, exists only at interstitial sites. QENS experiments have been carried out on both the compounds in the temperature range of 260–360 K to elucidate the dynamical behavior of different kinds of water molecules. Dynamics is found to be much more pronounced in case of PB, compared to PG. A detailed data analysis showed that localized translational diffusion model could describe the observed data for both PB and PG systems. The average diffusion coefficient is found to be much larger in the PB than PG. The obtained domain of dynamics is found to be consistent with the geometry of the structure of the two systems. Combining the data of the two systems, a quantitative estimate of the dynamics, corresponding to the water molecules at different locations is made.

  15. Properties of granular analogue model materials: A community wide survey

    NASA Astrophysics Data System (ADS)

    Klinkmüller, M.; Schreurs, G.; Rosenau, M.; Kemnitz, H.

    2016-08-01

    We report the material properties of 26 granular analogue materials used in 14 analogue modelling laboratories. We determined physical characteristics such as bulk density, grain size distribution, and grain shape, and performed ring shear tests to determine friction angles and cohesion, and uniaxial compression tests to evaluate the compaction behaviour. Mean grain size of the materials varied between c. 100 and 400 μm. Analysis of grain shape factors shows that the four different classes of granular materials (14 quartz sands, 5 dyed quartz sands, 4 heavy mineral sands and 3 size fractions of glass beads) can be broadly divided into two groups consisting of 12 angular and 14 rounded materials. Grain shape has an influence on friction angles, with most angular materials having higher internal friction angles (between c. 35° and 40°) than rounded materials, whereas well-rounded glass beads have the lowest internal friction angles (between c. 25° and 30°). We interpret this as an effect of intergranular sliding versus rolling. Most angular materials have also higher basal friction angles (tested for a specific foil) than more rounded materials, suggesting that angular grains scratch and wear the foil. Most materials have an internal cohesion in the order of 20-100 Pa except for well-rounded glass beads, which show a trend towards a quasi-cohesionless (C < 20 Pa) Coulomb-type material. The uniaxial confined compression tests reveal that rounded grains generally show less compaction than angular grains. We interpret this to be related to the initial packing density after sifting, which is higher for rounded grains than for angular grains. Ring-shear test data show that angular grains undergo a longer strain-hardening phase than more rounded materials. This might explain why analogue models consisting of angular grains accommodate deformation in a more distributed manner prior to strain localisation than models consisting of rounded grains.

  16. Stepwise analogue downscaling for hydrology (SANDHY): validation experiments over France

    NASA Astrophysics Data System (ADS)

    Radanovics, Sabine; Vidal, Jean-Philippe; Sauquet, Eric; Ben Daoud, Aurélien; Bontron, Guillaume

    2014-05-01

    Statistical downscaling aims at finding relationships between local precipitation (predictand) and large-scale predictor fields, in various contexts, from medium-term forecasting to climate change impact studies. One of the challenges of statistical downscaling in a climate change context is that the predictor-predictand relationship should still be valid under climate change conditions. A minimum requirement is therefore to test the performance of the downscaling method on independent data under current climate conditions. The downscaling method considered is the Stepwise ANalog Downscaling method for HYdrology (SANDHY). ERA-40 reanalysis data are used as large scale predictors and daily precipitation from the French near surface reanalysis (Safran) as predictand. Two 20-year periods have been selected from the common archive period of the two data sources: 1958-1978 ('early') and 1982-2002 ('late'). SANDHY has been optimised over the late period in terms of geopotential predictor domains individually for 608 target zones covering France. The validation setup consists of 4 experiments, that all use the parameters as optimised for the late period and that are compared in terms of continous ranked probability skill score (CRPSS) with climatology as reference: Reference simulation. A simulation of the late period is performed using the late period as an archive for searching the analogue dates, thus representing the best possible case. The CRPSS shows a spatial distribution similar to the one of the mean precipitation. Out-of-sample validation. The early period is simulated using the late period as an archive for searching the analogue dates. The idea is to simulate a period whose local data is not 'known' by the model as it would be the case in any application. The average skill loss compared to the reference simulation is reasonable with some more skill loss in the northern part of the country and no loss in the southeastern part. Alternative archive. The late

  17. Organofluorine Isoselenocyanate Analogues of Sulforaphane: Synthesis and Anticancer Activity.

    PubMed

    Cierpiał, Tomasz; Łuczak, Jerzy; Kwiatkowska, Małgorzata; Kiełbasiński, Piotr; Mielczarek, Lidia; Wiktorska, Katarzyna; Chilmonczyk, Zdzisław; Milczarek, Małgorzata; Karwowska, Katarzyna

    2016-10-07

    A series of previously unknown sulforaphane analogues with organofluorine substituents bonded to the sulfinyl sulfur atom, an isoselenocyanate moiety in place of the isothiocyanate group, the central sulfur atom in various oxidation states, and different numbers of methylene groups in the central alkyl chain were synthesized and fully characterized. All new compounds were tested for their biological properties in vitro and demonstrated much higher anticancer activity against two breast cancer cell lines than that shown by native sulforaphane; at the same time, the compounds were less toxic for normal cells. The influence of the particular structural changes in the molecules on the cytotoxicity is discussed.

  18. Antineoplastic Efficacy of Novel Polyamine Analogues in Human Breast Cancer

    DTIC Science & Technology

    2007-06-01

    Principles of Molecular Medicine (2nd ed). Runge, M., and Patterson, WC. (eds), Humana Press, 2006. 2. Huang, Y., Pledgie A.M., Casero , R.A., Davidson...Dunn, V.R., Hacker, A., Frydman, B., Kink J.A., Valasinas, A.L., Reddy, V.K., Marton, L.J., Casero , R.A., and Davidson, N.E. A Novel Polyamine...E.R., Smith, R., Frydman, B., Valasinas, A.L., Reddy, V.K., Marton, L.J., Casero , R.A., and Davidson, N.E. Regulation of polyamine analogue

  19. The Canadian space agency planetary analogue materials suite

    NASA Astrophysics Data System (ADS)

    Cloutis, Edward A.; Mann, Paul; Izawa, Matthew R. M.; Applin, Daniel M.; Samson, Claire; Kruzelecky, Roman; Glotch, Timothy D.; Mertzman, Stanley A.; Mertzman, Karen R.; Haltigin, Timothy W.; Fry, Christopher

    2015-12-01

    The Canadian Space Agency (CSA) recently commissioned the development of a suite of over fifty well-characterized planetary analogue materials. These materials are terrestrial rocks and minerals that are similar to those known or suspected to occur on the lunar or martian surfaces. These include: Mars analogue sedimentary, hydrothermal, igneous and low-temperature alteration rock suites; lunar analogue basaltic and anorthositic rock suites; and a generic impactite rock suite from a variety of terrestrial impact structures. Representative thin sections of the materials have been characterized by optical microscopy and electron probe microanalysis (EPMA). Reflectance spectra have been collected in the ultraviolet, visible, near-infrared and mid-infrared, covering 0.2-25 μm. Thermal infrared emission spectra were collected from 5 to 50 μm. Raman spectra with 532 nm excitation, and laser-induced fluorescence spectra with 405 nm excitation were also measured. Bulk chemical analysis was carried out using X-ray fluorescence, with Fe valence determined by wet chemistry. Chemical and mineralogical data were collected using a field-portable Terra XRD-XRF instrument similar to CheMin on the MSL Curiosity rover. Laser-induced breakdown spectroscopy (LIBS) data similar to those measured by ChemCam on MSL were collected for powdered samples, cut slab surfaces, and as depth profiles into weathered surfaces where present. Three-dimensional laser camera images of rock textures were collected for selected samples. The CSA intends to make available sample powders (<45 μm and 45-1000 μm grain sizes), thin sections, and bulk rock samples, and all analytical data collected in the initial characterisation study to the broader planetary science community. Aiming to complement existing planetary analogue rock and mineral libraries, the CSA suite represents a new resource for planetary scientists and engineers. We envision many potential applications for these materials in the

  20. Astrobiology Field Research in Moon/Mars Analogue Environments: Preface

    NASA Technical Reports Server (NTRS)

    Foing, B. H.; Stoker, C.; Ehrenfreund, P.

    2011-01-01

    Extreme environments on Earth often provide similar terrain conditions to landing/operation sites on Moon and Mars. Several field campaigns (EuroGeoMars2009 and DOMMEX/ILEWG EuroMoonMars from November 2009 to March 2010) were conducted at the Mars Desert Research Station (MDRS) in Utah. Some of the key astrobiology results are presented in this special issue on Astrobiology field research in Moon/Mars analogue environments relevant to investigate the link between geology, minerals, organics and biota. Preliminary results from a multidisciplinary field campaign at Rio Tinto in Spain are presented.

  1. Fluorinated oxysterol analogues: Synthesis, molecular modelling and LXRβ activity.

    PubMed

    Rodriguez, Cristian R; Alvarez, Lautaro D; Dansey, M Virginia; Paolo, Luciano S; Veleiro, Adriana S; Pecci, Adali; Burton, Gerardo

    2017-01-01

    Liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. The ability of LXRs to integrate metabolic and inflammation signalling makes them attractive targets for intervention in human metabolic diseases. Several oxidized metabolites of cholesterol (oxysterols) are endogenous LXR ligands, that modulate their transcriptional responses. While 25R-cholestenoic acid is an agonist of the LXRs, the synthetic analogue 27-norcholestenoic acid that lacks the 25-methyl is an inverse agonist. This change in the activity profile is triggered by a disruption of a key interaction between residues His435 and Trp457 that destabilizes the H11-H12 region of the receptor and favors the binding of corepressors. The introduction of fluorine atoms on the oxysterol side chain can favor both hydrophobic interactions as well as hydrogen bonds with the fluorine atoms and may thus induce changes in the receptor that may lead to changes in the activity profile. To evaluate these effects we have synthesized two fluorinated 27-nor-steroids, analogues of 27-norcholestenoic acid, the 25,25-difluoroacid and the corresponding 26-alcohol. The key step was a Reformatsky reaction on the C-24 cholenaldehyde, with ethyl bromodifluoroacetate under high intensity ultrasound (HIU) irradiation, followed by a Barton-McCombie type deoxygenation. Activity was evaluated in a luciferase reporter assay in the human HEK293T cells co-transfected with full length human LXRβ expression vector. The 25,25-difluoro-27-norcholestenoic acid was an inverse agonist and antagonist similar to its non-fluorinated analogue while its reduced derivative 25,25-difluoro-27-norcholest-5-ene-3β,26-diol was an agonist. Molecular dynamics simulation of the ligand-receptor complexes showed that the difluoroacid disrupted the His435-Trp457 interaction although the resulting conformational changes were different from those induced by the non-fluorinated analogue. In the

  2. B38: an all-boron fullerene analogue

    NASA Astrophysics Data System (ADS)

    Lv, Jian; Wang, Yanchao; Zhu, Li; Ma, Yanming

    2014-09-01

    Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (~2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue.Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (~2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue. Electronic supplementary information

  3. Isobrassinin and its analogues: novel types of antiproliferative agents.

    PubMed

    Csomós, Péter; Zupkó, István; Réthy, Borbála; Fodor, Lajos; Falkay, George; Bernáth, Gábor

    2006-12-15

    Isobrassinin (2-(S-methyldithiocarbamoylaminomethyl)indole (7a), a regioisomer of the cruciferous phytoalexin brassinin (1), exerted marked antiproliferative effects on the HeLa, A431 and MCF7 cell lines (>78.6% inhibition at 30muM). For structure-activity relationships, further analogues were synthesized. The highest cytotoxic effect was displayed by 2-phenylimino-1,3-thiazino[5,6-b]indole (10) (10 microM, 76.8%-HeLa and 46.3%-MCF7). The effect of the natural phytoalexin brassinin was also determined.

  4. Pena blanca natural analogue project: summary of activities

    SciTech Connect

    Levy, Schon S; Goldstein, Steven J; Abdel - Fattah, Amr I

    2010-12-08

    The inactive Nopal I uranium mine in silicic tuff north of Chihuahua City, Chihuahua, Mexico, was studied as a natural analogue for an underground nuclear-waste repository in the unsaturated zone. Site stratigraphy was confirmed from new drill core. Datafrom site studies include chemical and isotopic compositions of saturated- and unsaturated-zone waters. A partial geochronology of uranium enrichment and mineralization was established. Evidence pertinent to uranium-series transport in the soil zone and changing redox conditions was collected. The investigations contributed to preliminary, scoping-level performance assessment modeling.

  5. Pena Blanca Natural Analogue Project: Summary of activities

    SciTech Connect

    Levy, S.; Goldstein, S.; Dobson, P.F.; Goodell, P.; Ku, T.-L.; Abdel-Fattah, A.; Saulnier, G.; Fayek, M.; de la Garza, R.

    2011-02-01

    The inactive Nopal I uranium mine in silicic tuff north of Chihuahua City, Chihuahua, Mexico, was studied as a natural analogue for an underground nuclear-waste repository in the unsaturated zone. Site stratigraphy was confirmed from new drill cores. Data from site studies include chemical and isotopic compositions of saturated- and unsaturated-zone waters. A partial geochronology of uranium enrichment and mineralization was established. Evidence pertinent to uranium-series transport in the soil zone and changing redox conditions was collected. The investigations contributed to preliminary, scoping-level performance assessment modeling.

  6. Ultraviolet variability of the solar analogue star Alpha Centauri A

    NASA Technical Reports Server (NTRS)

    Sofia, Ulysses J.; Bruhweiler, Frederick C.; Sofia, Sabatino

    1989-01-01

    Fifty-seven observations of the solar analogue Alpha Centauri A made by the IUE over a 3-year interval have been examined for variability. It is found that the UV continuum flux of this star in the 1715- to 1915-A range varies by as much as 19 percent. However, nearly all of this range in variability can occur within one stellar rotation period. Consequently, if Alpha Cen A undergoes a stellar activity cycle similar to that of the sun, the results indicate that the amplitude of this modulation is small, contrary to recently proposed empirical (theoretical) models of solar activity.

  7. Resist outgassing contamination on EUV multilayer mirror analogues

    NASA Astrophysics Data System (ADS)

    Alvarado, Diego; Kandel, Yudhishthir; Sohn, Jaewoong; Chakraborty, Tonmoy; Ashworth, Dominic; Denbeaux, Gregory

    2014-04-01

    EUV lithography is a technology enabling next generation electronic devices, but issues with photoresist sensitivity, resolution and line edge roughness as well as tool downtime and throughput remain. As part of the industry's efforts to address these problems we have worked with resist suppliers to quantify the relative contamination rate of a variety of resists on EUV multilayer mirror analogues following ASML approved protocols. Here we present results of our ongoing program to better understand the effect of process parameters such as dose and resist thickness on the contamination rate of ruthenium coated witness plates, additionally we present results from a study on the effectiveness of hydrogen cleaning.

  8. Investigation of HVDC inverter with series compensation on analogue simulator

    SciTech Connect

    Nyati, S.; Gueth, G. ); Mathur, R.M. ); Koschik, V. )

    1990-04-01

    HVdc converters connected into weak ac systems require effective application of voltage control devices to ensure satisfactory voltage control and recovery following disturbances. Both an MOV arrangement and a series capacitor were found to be potentially very cost effective solutions in investigations using digital simulation. However, although the series capacitor performed well in controlling temporary overvoltage following HVdc load rejection, satisfactory recovery from faults was difficult to obtain. This paper presents a follow-up study which uses a state-of-the-art analogue simulator to further investigate the performance of the MOV and series capacitor arrangements, especially the fault recovery performance of the latter.

  9. Oxazole-bridged combretastatin A analogues with improved anticancer properties.

    PubMed

    Biersack, Bernhard; Effenberger, Katharina; Schobert, Rainer; Ocker, Matthias

    2010-03-01

    Three new oxazole-bridged combretastatin A analogues with additional functional groups at the B-ring [-SMe, -OH, p-quinone] were tested for antiproliferative activity and specificity on human HL-60 leukemia, 518A2 melanoma, and colon carcinomas HCT-116 (wt)/(p53(-/-)) and HT-29 cells. While all oxazoles, except quinone 8, were efficacious against HCT-116 cells at submicromolar IC(50) values (48 h incubation), only thioanisole 5 achieved this potency in combretastatin-refractory HT-29 cells by significant upregulation of p21(cip1/waf1) associated with an S/G(2) cell-cycle arrest.

  10. Biological activity of silylated amino acid containing substance P analogues.

    PubMed

    Cavelier, F; Marchand, D; Martinez, J; Sagan, S

    2004-03-01

    The need to replace natural amino acids in peptides with nonproteinogenic counterparts to obtain new medicinal agents has stimulated a great deal of innovation on synthetic methods. Here, we report the incorporation of non-natural silylated amino acids in substance P (SP), the binding affinity for the two hNK-1 binding sites and, the potency to stimulate phospholipase C (PLC) and adenylate cyclase of the resulting peptide. We also assess the improvement of their stability towards enzyme degradation. Altogether, we found that replacing glycine with silaproline (Sip) in position 9 of SP leads to a potent analogue exhibiting an increased resistance to angiotensin-converting enzyme hydrolysis.

  11. Synthesis, Preliminary Bioevaluation and Computational Analysis of Caffeic Acid Analogues

    PubMed Central

    Liu, Zhiqian; Fu, Jianjun; Shan, Lei; Sun, Qingyan; Zhang, Weidong

    2014-01-01

    A series of caffeic acid amides were designed, synthesized and evaluated for anti-inflammatory activity. Most of them exhibited promising anti-inflammatory activity against nitric oxide (NO) generation in murine macrophage RAW264.7 cells. A 3D pharmacophore model was created based on the biological results for further structural optimization. Moreover, predication of the potential targets was also carried out by the PharmMapper server. These amide analogues represent a promising class of anti-inflammatory scaffold for further exploration and target identification. PMID:24857914

  12. Stimulated emission in black holes and in analogue gravity

    NASA Astrophysics Data System (ADS)

    Belgiorno, F.; Cacciatori, S. L.

    2016-11-01

    Stimulated emission by black holes is discussed in light of the analogue gravity program. We first consider initial quantum states containing a definite number of particles, and then we take into account the case where the initial state is a coherent state. The latter case is particularly significant in the case where Hawking radiation is studied in dielectric black holes, and the emission is stimulated by a laser probe. We are particularly interested in the case of the electromagnetic field, for which examples of stimulated radiation are considered.

  13. α-Azido bisphosphonates: synthesis and nucleotide analogues

    PubMed Central

    Chamberlain, Brian T.; Upton, Thomas G.; Kashemirov, Boris A.

    2011-01-01

    The first examples of α-azido bisphosphonates [(RO)2P(O)]2CX(N3) (1, R = i-Pr, X = Me; 2, R = i-Pr, X = H; 3, R = H, X = Me; 4, R = H, X = H) and corresponding β,γ-CX(N3) dGTP (5–6) and α,β-CX(N3) dATP (7–8) analogues are described. The individual diastereomers of 7 (7a, 7b) were obtained by HPLC separation of the dADP synthetic precursor (14a/b). PMID:21462930

  14. Novel nicotine analogues with potential anti-mycobacterial activity.

    PubMed

    Gandhi, Paresh T; Athmaram, Thimmasandra Narayanappa; Arunkumar, Gundaiah Ramesh

    2016-04-15

    Tuberculosis (TB) is the second leading lethal infectious disease in the world after acquired immuno deficiency (AIDs). We have developed a series of twenty-five novel nicotine analogues with de-addiction property and tested them for their activity against Mycobacterium tuberculosis (MTB). In an effort to increase the specificity of action and directing nicotine analogues to target MTB, four promising compounds were further optimized via molecular docking studies against the Dihydrofolate reductase of MTB. After lead optimization, one nicotine analogue [3-(5-(3fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one] exhibited minimum inhibitory concentration of 1 μg/mL (2.86 nM) against M. tuberculosis (H37Rv strain), a human pathogenic strain of clinically significant importance. Pharmacokinetic analysis of [3-(5-(3fluorophenyl)nicotinoyl)-1methylpyrrolidin-2-one] with lowest MIC value via oral route in Wistar rats revealed that at a dosage of 5 mg/kg body weight gave a maximum serum drug concentration (Cmax) of 2.86 μg/mL, Tmax of one hour and a half-life (T1/2) of more than 24 h and Volume of distribution (Vd) of 27.36 L. Whereas the parenteral (intra venous) route showed a Cmax of 3.37 μg/mL, Tmax of 0.05 h, T1/2 of 24 h and Vd equivalent to 23.18 L. The acute oral toxicity and repeated oral toxicity studies in female Wistar rats had an LD50>2000 mg/kg body weight. Our data suggests that nicotine derivatives developed in the present study has good metabolic stability with tunable pharmacokinetics (PK) with therapeutic potential to combat MTB. However, further in vivo studies for anti-tuberculosis activity and elucidation of mode of action could result in more promising novel drug for treating MTB. To the best of our knowledge this is the first report revealing the anti-mycobacterial potential of nicotine analogue at potential therapeutic concentrations.

  15. Frequency converter implementing an optical analogue of the cosmological redshift.

    PubMed

    Ginis, Vincent; Tassin, Philippe; Craps, Ben; Veretennicoff, Irina

    2010-03-01

    According to general relativity, the frequency of electromagnetic radiation is altered by the expansion of the universe. This effect-commonly referred to as the cosmological redshift--is of utmost importance for observations in cosmology. Here we show that this redshift can be reproduced on a much smaller scale using an optical analogue inside a dielectric metamaterial with time-dependent material parameters. To this aim, we apply the framework of transformation optics to the Robertson-Walker metric. We demonstrate theoretically how perfect redshifting or blueshifting of an electromagnetic wave can be achieved without the creation of sidebands with a device of finite length.

  16. Analysis of Vitamins D, Their Metabolites and Analogues

    NASA Astrophysics Data System (ADS)

    Makin, Hugh L. J.; Jones, Glenville; Kaufmann, Martin; Calverley, Martin J.

    The analysis of vitamins D and their metabolites and analogues has been reviewed by us on two occasions (Makin et al., 1995; Jones and Makin, 2000) over the last 10-15 years. In this chapter, we have drawn heavily on the 2000 review, up-dating it to take account of the developments in methodology that have occurred in the intervening years, but including elements of our 1995 review so that the reader can get a picture of the historical context as well as the modern developments.

  17. Captopril analogues as metallo-β-lactamase inhibitors.

    PubMed

    Yusof, Yusralina; Tan, Daniel T C; Arjomandi, Omid Khalili; Schenk, Gerhard; McGeary, Ross P

    2016-03-15

    A number of captopril analogues were synthesised and tested as inhibitors of the metallo-β-lactamase IMP-1. Structure-activity studies showed that the methyl group was unimportant for activity, and that the potencies of these inhibitors could be best improved by shortening the length of the mercaptoalkanoyl side-chain. Replacing the thiol group with a carboxylic acid led to complete loss of activity, and extending the length of the carboxylate group led to decreased potency. Good activity could be maintained by substituting the proline ring with pipecolic acid.

  18. Large scale biosynthesis of ganglioside analogues by RERF-LC-AI cells cultured in HYPERFlask.

    PubMed

    Shimura, Yumiko; Suzuki, Junya; Muraoka, Miho; Kasuya, Maria Carmelita Zulueta; Matsuoka, Koji; Hatanaka, Kenichi

    2012-01-01

    The efficient production of ganglioside analogues was accomplished using RERF-LC-AI cells cultured in HYPERFlask (High Yield PERformance Flask). Eight kinds of ganglioside analogues (GM3, GM2, sialylparagloboside, GD3, di-sialylated lacto-N-tetraose, and another three kinds of analogues with intricate structures) were synthesized by the saccharide primer method using lung squamous-cell carcinoma line RERF-LC-AI and 12-azidododecyl β-lactoside primer. The yield for each analogue obtained using HYPERFlask was higher than yields obtained from 100-mm dishes.

  19. Neurotoxicity of acrylamide and its analogues and effects of these analogues and other agents on acrylamide neuropathy.

    PubMed Central

    Edwards, P M

    1975-01-01

    N-Hydroxymethylacrylamide, N-methylacrylamide, and N,N-diethylacrylamide produce peripheral neuropathy in rats. Seven other compounds related to acrylamide do not produce neuropathy. Rats given one of the three neurotoxic compounds are more susceptible to acrylamide. A regime for testing acrylamide analogues for neuro-toxicity is suggested. DDT, phenobarbitone, or high dietary concentrations of vitamin A or E have no effect on the development of acrylamide neuropathy in rats. Acrylamide produces neuropathy in hens but not in frogs or goldfish. PMID:164879

  20. Historical space psychology: Early terrestrial explorations as Mars analogues

    NASA Astrophysics Data System (ADS)

    Suedfeld, Peter

    2010-03-01

    The simulation and analogue environments used by psychologists to circumvent the difficulties of conducting research in space lack many of the unique characteristics of future explorations, especially the mission to Mars. This paper suggests that appropriate additional analogues would be the multi-year maritime and terrestrial explorations that mapped the surface of the Earth in previous centuries. These, like Mars, often involved a hazardous trek through unknown territory, flanked by extended, dangerous voyages to and from the exploration sites. Characteristic issues included interpersonal relationships under prolonged stress, stretches of boredom interspersed with intense work demands, the impossibility of rescue, resupply, or other help from home, chronic danger, physical discomfort and lack of privacy, and the crucial role of the leader. Illustrative examples of one important factor, leadership style, are discussed. The examination of such expeditions can help to identify the psychological stressors that are likely to be experienced by Mars explorers, and can also indicate countermeasures to reduce the damaging impact of those stressors.

  1. Metabolites of saxitoxin analogues in bivalves contaminated by Gymnodinium catenatum.

    PubMed

    Vale, Paulo

    2010-01-01

    Bivalve metabolites of saxitoxin analogues, not present in microalgae, were recently described as an important toxin fraction in mussels contaminated by Alexandrium tamarense. These possess very low fluorescence, and require mass spectrometry detection. HILIC-MS was implemented to look for these metabolites in bivalves contaminated during Gymnodinium catenatum blooms at the Portuguese coast. The presence of M1 was tentatively identified in several bivalves, ranging from estuarine (Mytilus galloprovinciallis, Cerastoderma edule and Ruditapes decussatus) to oceanic habitat (Donax trunculus and Ensis spp.). It was hypothesized that M1 could contribute to an important fraction of the profile of STX analogues. M1 was more abundant in estuarine bivalves that retain longer PSP toxins, in the following order: mussels>cockles>clams. These data highlight that the study by fluorimetry alone of the carbamoyl, N-sulfocarbamoyl, and decarbamoyl families is manifestly insufficient to fully understand toxin dynamics in bivalves feeding on G. catenatum without a proper study of hydroxybenzoate and hydroxylated M-toxins.

  2. Carbon storage at defect sites in mantle mineral analogues

    NASA Astrophysics Data System (ADS)

    Wu, Jun; Buseck, Peter R.

    2013-10-01

    A significant fraction of Earth's carbon resides in the mantle, but the mode of carbon storage presents a long-standing problem. The mantle contains fluids rich in carbon dioxide and methane, carbonate-bearing melts, carbonate minerals, graphite, diamond and carbides, as well as dissolved carbon atoms in metals. However, it is uncertain whether these can sufficiently account for the total amount of carbon thought to be stored in the mantle and the volume of carbon degassed from the mantle at volcanoes. Moreover, such carbon hosts should significantly affect the physical and chemical behaviour of the mantle, including its melting temperature, electrical conductivity and oxidation state. Here we use in situ transmission electron microscopy to measure the storage of carbon within common mantle mineral analogues--nickel-doped lanthanum chromate perovskite and titanium dioxide--in laboratory experiments at high pressure and temperature. We detect elevated carbon concentrations at defect sites in the nanocrystals, maintained at high pressures within annealed carbon nanocages. Specifically, our experiments show that small stacking faults within the mantle analogue materials are effective carbon sinks at mantle conditions, potentially providing an efficient mechanism for carbon storage in the mantle. Furthermore, this carbon can be readily released under lower pressure conditions, and may therefore help to explain carbon release in volcanic eruptions.

  3. A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1

    PubMed Central

    2015-01-01

    Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1–/– cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease. PMID:24707965

  4. A selective phenelzine analogue inhibitor of histone demethylase LSD1.

    PubMed

    Prusevich, Polina; Kalin, Jay H; Ming, Shonoi A; Basso, Manuela; Givens, Jeffrey; Li, Xin; Hu, Jianfei; Taylor, Martin S; Cieniewicz, Anne M; Hsiao, Po-Yuan; Huang, Rong; Roberson, Heather; Adejola, Nkosi; Avery, Lindsay B; Casero, Robert A; Taverna, Sean D; Qian, Jiang; Tackett, Alan J; Ratan, Rajiv R; McDonald, Oliver G; Feinberg, Andrew P; Cole, Philip A

    2014-06-20

    Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.

  5. Synthesis of 5-azacastanospermine, a conformationally restricted azafagomine analogue.

    PubMed

    Søndergaard, K; Liang, X; Bols, M

    2001-06-01

    The 5-aza-6-deoxy analogue of castanospermine (+/-)-5a and its 1-epimer (+/-)-5b was synthesized. The synthesis started from the known compound 5-benzyloxy-7-hydroxyhepta-1,3-diene, which was protected and subjected to Diels-Alder reaction with 4-phenyl-1,2,4-triazoline-3,5-dione to give two epimeric adducts. One of these was transformed through epoxidation, acetolysis, a series of side-chain transformations that converted it into a terminally protected aldehyde, deprotection, and hydrogenolysis/reductive amination into 5a. By a similar set of reactions the other adduct epimer was converted into 5b. The castanospermine analogue 5a was a weaker inhibitor of almond beta-glucosidase and rice alpha-glucosidase than castanospermine (2) or 1-azafagomine (4), but was considerably more potent than its epimer 5b. This suggests that these enzymes have a strong preference for binding substrates or azasugars with the 6-OH in an axial conformation.

  6. Thermal conductivity determination of cometary and asteroid material analogues

    NASA Astrophysics Data System (ADS)

    Banaszkiewicz, M.; Seweryn, K.; Wawrzaszek, R.

    Measurements of physical properties of surface and subsurface layers of planetary bodies often provide important information about the structure of the medium and processes that occur there Thermal properties of cometary nuclues subsurface material are crucial in determining the heat and gas transport Similarly asteroid s regolith is a buffering zone in heat transfer from to surface to from interior of a body There are space experiments planned to perform temperature and thermal conductivity measurements on a comet ROSETTA and one can easily foresee such measurements carried out by future robotic missions on Mars planetary satellites and asteroids In the paper we present the results of measurements carried out with a new type of thermal sensors The elementary cylindrical sensor is made of platinum wire resistance thermometer and isotan wire heating element that can operate independently By choosing these materials the problems of temperature measurement calibration and constant heating power are resolved We confront the results of measurements made for a number of sensors combined into a long cylinder in delrin basalt ice-dust mixture comet analogue and regolith-like material with models and show that agreement is very good Therefore we can recommend both the sensors and the method of data interpretation for the thermal conductivity determination as very useful tools in future space missions and in laboratory experiments on cometary and asteroid material analogues

  7. Process standardization for rennet casein based Mozzarella cheese analogue.

    PubMed

    Shah, Rahul; Jana, Atanu H; Aparnathi, K D; Prajapati, P S

    2010-10-01

    A process for manufacture of Mozzarella cheese analogue (MCA) using rennet casein and plastic cream as protein and fat sources respectively was standardized. The formulation comprised of 25% plastic cream (72% fat), 27% rennet casein along with 3% tri-sodium citrate as emulsifying salt, 2% maltodextrin as binder, 0.55% lactic acid as pH regulator, 1% common salt for seasoning, 1% Mozzarella cheese bud as flavouring and 40.4% water. The process involved (a) dissolving the dry mixture of casein, maltodextrin, flavouring and common salt in hot emulsifying salt solution, (b) incorporation of half the quantity of acid solution in casein-maltodextrin dough, followed by addition and emulsification of plastic cream, and (c) addition of remaining half of the acid solution and heating the mass to 80 °C until a plastic cheese mass was obtained. The analogue was shaped in ball form, cooled and packaged in polyethylene bag. The MCA conformed to the PFA requirements for pizza cheese and had all the requisite baking characteristics expected of pizza cheese topping.

  8. The antiviral activity of tetrazole phosphonic acids and their analogues.

    PubMed Central

    Hutchinson, D W; Naylor, M

    1985-01-01

    5-(Phosphonomethyl)-1H-tetrazole and a number of related tetrazoles have been prepared and their effects on the replication of Herpes Simplex Viruses-1 and -2 have been investigated as well as their abilities to inhibit the DNA polymerases induced by these viruses and the RNA transcriptase activity of influenza virus A. Contrary to an earlier report, 5-(phosphonomethyl)-1H-tetrazole was not an efficient inhibitor of the replication of HSV-1 and HSV-2 in tissue culture. Analogues of 5-(phosphonomethyl)-1H-tetrazole were also devoid of significant antiviral activity. Only 5-(phosphonomethyl)-1H-tetrazole and 5-(thiophosphonomethyl)-1H-tetrazole inhibited the influenza virus transcriptase, and both were more effective as inhibitors than phosphonoacetic acid under the same conditions. The DNA polymerases induced by HSV-1 and HSV-2 were inhibited slightly by 5-(phosphonomethyl)-1H-tetrazole and to a lesser extent by its N-ethyl analogue and 3-(phosphonomethyl)-1H-1,2,4-triazole. None of these compounds were as effective as phosphonoacetic acid. 5-(Thiophosphonomethyl)-1H-tetrazole was a better inhibitor of the DNA polymerase induced by HSV-1 than 5-(phosphonomethyl)-1H-tetrazole. PMID:2417198

  9. Synthesis and cytotoxic potential of heterocyclic cyclohexanone analogues of curcumin.

    PubMed

    Yadav, Babasaheb; Taurin, Sebastien; Rosengren, Rhonda J; Schumacher, Marc; Diederich, Marc; Somers-Edgar, Tiffany J; Larsen, Lesley

    2010-09-15

    A series of 18 heterocyclic cyclohexanone analogues of curcumin have been synthesised and screened for their activity in both adherent and non-adherent cancer cell models. Cytotoxicity towards MBA-MB-231 breast cancer cells, as well as ability to inhibit NF-kappaB transactivation in non-adherent K562 leukemia cells were investigated. Three of these analogues 3,5-bis(pyridine-4-yl)-1-methylpiperidin-4-one B1, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidin-4-one B10, and 8-methyl-2,4-bis((pyridine-4-yl)methylene)-8-aza-bicyclo[3.2.1]octan-3-one C1 showed potent cytotoxicity towards MBA-MB-231, MDA-MB-468, and SkBr3 cell lines with EC50 values below 1 microM and inhibition of NF-kappaB activation below 7.5 microM. The lead drug candidate, B10, was also able to cause 43% of MDA-MB-231 cells to undergo apoptosis after 18 h. This level of activity warrants further investigation for the treatment of ER-negative breast cancer and/or chronic myelogenous leukemia as prototypical cellular models for solid and liquid tumors.

  10. Stability and exfoliation of germanane: a germanium graphane analogue.

    PubMed

    Bianco, Elisabeth; Butler, Sheneve; Jiang, Shishi; Restrepo, Oscar D; Windl, Wolfgang; Goldberger, Joshua E

    2013-05-28

    Graphene's success has shown not only that it is possible to create stable, single-atom-thick sheets from a crystalline solid but that these materials have fundamentally different properties than the parent material. We have synthesized for the first time, millimeter-scale crystals of a hydrogen-terminated germanium multilayered graphane analogue (germanane, GeH) from the topochemical deintercalation of CaGe2. This layered van der Waals solid is analogous to multilayered graphane (CH). The surface layer of GeH only slowly oxidizes in air over the span of 5 months, while the underlying layers are resilient to oxidation based on X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy measurements. The GeH is thermally stable up to 75 °C; however, above this temperature amorphization and dehydrogenation begin to occur. These sheets can be mechanically exfoliated as single and few layers onto SiO2/Si surfaces. This material represents a new class of covalently terminated graphane analogues and has great potential for a wide range of optoelectronic and sensing applications, especially since theory predicts a direct band gap of 1.53 eV and an electron mobility ca. five times higher than that of bulk Ge.

  11. [Use of somatostatin analogue for intestinal and pancreatic fistulas].

    PubMed

    Paran, H; Neufeld, D; Epstein, T; Bendahan, J; Freund, U

    1991-02-15

    The hormone somatostatin, a tetra-deca-peptide, was discovered in 1972. It inhibits the central nervous system and the endocrine and exocrine secretions of the gastrointestinal tract. The first clinical use of the hormone was to inhibit hormone-secreting tumors of the CNS. It has also been used to treat hormone-secreting tumors of the pancreas and GI tract. Treatment of small bowel and pancreatic fistulas has also been attempted. A new synthetic analogue of the hormone, SMS 210-995, (Sandostatin) has a long half-life and is highly effective after subcutaneous injection. It was used in the treatment of 3 patients with fistulas of the small bowel and pancreas. In all impressive reduction of fistula secretion was achieved within 24 hours. In 2 there was complete, spontaneous closure of the fistula: in 1 after 10 days and in the other after 15 days of treatment. In the 3rd, there was significant reduction of fistula output. There were no side-effects except for mild pain at the injection site in 1 patient. Previous reports and our own results indicate that this somatostatin analogue may be very useful in the nonsurgical treatment of GI tract fistulas.

  12. Optical Dust Characterization in Manned Mars Analogue Research Stations

    NASA Technical Reports Server (NTRS)

    Bos, B. J.; Krebs, Carolyn (Technical Monitor)

    2003-01-01

    Martian dust has been identified as a potentially serious hazard to any manned Mars landing mission. NASA and other organizations realize this risk and continue to support Martian dust research through the Matador project led by researchers at the University of Arizona. The Mars Society can contribute to this work by beginning a regimen of monitoring and measuring dust properties at its Mars analogue research stations. These research facilities offer the unique opportunity to study the transport and distribution of dust particles within a crewed habitat supporting active geologic exploration. Information regarding the amount, location and size of dust particles that may accumulate in a Mars habitat will be required to design a real Mars habitat and habitat equipment. Beginning such an effort does not require a large outlay of equipment and can be accomplished using crewmembers experienced with station operations. Various optical techniques, such as dark-field illumination, coupled with image processing algorithms enable the collection of dust grain relative size and frequency information. Such approaches can be applied in several different zones within the research stations to evaluate the various dust reduction and isolation procedures implemented during a particular crew rotation. As the stations simulation fidelity increases, the applicability of such data to a functional Mars lander will increase. This presentation describes the optical equipment and procedures for measuring dust properties in Mars analogue research stations that can be implemented during the next field season.

  13. Electromagnetic induction in New Zealand: analogue model and field results

    NASA Astrophysics Data System (ADS)

    Chen, J.; Dosso, H. W.; Ingham, M.

    The behaviour of electric and magnetic variations over North Island (New Zealand) is studied with the aid of a laboratory analogue model. The source field frequencies used in the analogue modelling simulate naturally occurring geomagnetic variations of 5-120 min periods. In-phase and quadrature magnetic and electric fields for a selection of traverses for the modelled region of North Island are presented. Since North Island is of a relatively narrow cross-section, the field responses, even for inland locations, are expected to show strongly the effects of the surrounding ocean. The irregular coastlines, as well as the strait between North and South Islands, lead to coastal and inland field anomalies due to induced currents being deflected and channelled to produce localized current densities. The comparison of model results with field station measurements obtained earlier individually by Ingham and by Midha for sites in the northeastern, central, and southern (near Cook Strait) regions of North Island demonstrates the large role the ocean has in the observed field responses. Differences in the model and field results at some sites are expected and should reflect the effects of the local geology and the conductive substructure related to the complex tectonics of the region not simulated in the model.

  14. B38: an all-boron fullerene analogue.

    PubMed

    Lv, Jian; Wang, Yanchao; Zhu, Li; Ma, Yanming

    2014-10-21

    Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (∼2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue.

  15. A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation.

    PubMed

    Ghaly, Peter E; Abou El-Magd, Rabab M; Churchill, Cassandra D M; Tuszynski, Jack A; West, F G

    2016-06-28

    Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel-resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound. Microtubule polymerization assay was used to determine the effect of the new compound on microtubules. To compare the binding affinity of noscapine and the novel compound to tubulin, we have done a fluorescence quenching assay. Finally, in silico methods using docking calculations were used to illustrate the binding mode of the new compound to α,β-tubulin. Our cytotoxicity results show that the new compound is more cytotoxic than noscapine on both SKBR-3 cell lines. This was confirmed by the stronger binding affinity of the new compound, compared to noscapine, to tubulin. Surprisingly, our new compound was found to have strong microtubule-destabilizing properties, while noscapine is shown to slightly stabilize microtubules. Our calculation indicated that the new compound has more binding affinity to the colchicine-binding site than to the noscapine site. This novel compound has a more potent cytotoxic effect on cancer cell lines than its parent, noscapine, and hence should be of interest as a potential anti-cancer drug.

  16. A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation

    PubMed Central

    Ghaly, Peter E.; Abou El-Magd, Rabab M.; Churchill, Cassandra D. M.; Tuszynski, Jack A.; West, F. G.

    2016-01-01

    Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel-resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound. Microtubule polymerization assay was used to determine the effect of the new compound on microtubules. To compare the binding affinity of noscapine and the novel compound to tubulin, we have done a fluorescence quenching assay. Finally, in silico methods using docking calculations were used to illustrate the binding mode of the new compound to α,β-tubulin. Our cytotoxicity results show that the new compound is more cytotoxic than noscapine on both SKBR-3 cell lines. This was confirmed by the stronger binding affinity of the new compound, compared to noscapine, to tubulin. Surprisingly, our new compound was found to have strong microtubule-destabilizing properties, while noscapine is shown to slightly stabilize microtubules. Our calculation indicated that the new compound has more binding affinity to the colchicine-binding site than to the noscapine site. This novel compound has a more potent cytotoxic effect on cancer cell lines than its parent, noscapine, and hence should be of interest as a potential anti-cancer drug. PMID:27777381

  17. A new antiproliferative noscapine analogue: chemical synthesis and biological evaluation.

    PubMed

    Ghaly, Peter E; El-Magd, Rabab M Abou; Churchill, Cassandra D M; Tuszynski, Jack A; West, F G

    2016-05-26

    Noscapine, a naturally occurring opium alkaloid, is a widely used antitussive medication. Noscapine has low toxicity and recently it was also found to possess cytotoxic activity which led to the development of many noscapine analogues. In this paper we report on the synthesis and testing of a novel noscapine analogue. Cytotoxicity was assessed by MTT colorimetric assay using SKBR-3 and paclitaxel-resistant SKBR-3 breast cancer cell lines using different concentrations for both noscapine and the novel compound. Microtubule polymerization assay was used to determine the effect of the new compound on microtubules. To compare the binding affinity of noscapine and the novel compound to tubulin, we have done a fluorescence quenching assay. Finally, in silico methods using docking calculations were used to illustrate the binding mode of the new compound to α,β-tubulin. Our cytotoxicity results show that the new compound is more cytotoxic than noscapine on both SKBR-3 cell lines. This was confirmed by the stronger binding affinity of the new compound, compared to noscapine, to tubulin. Surprisingly, our new compound was found to have strong microtubule-destabilizing properties, while noscapine is shown to slightly stabilize microtubules. Our calculation indicated that the new compound has more binding affinity to the colchicine-binding site than to the noscapine site. This novel compound has a more potent cytotoxic effect on cancer cell lines than its parent, noscapine, and hence should be of interest as a potential anti-cancer drug.

  18. Drug-likeness of Phytic Acid and Its Analogues.

    PubMed

    Joy, Amitha; Balaji, S

    2015-01-01

    Inositol hexakisphosphate is known to be the phosphorous reserve in plants particularly in the seeds. Though it has been known for its antinutrient properties for many years, recent research shed light to reveal it as a novel anticancer agent. Hence the present study investigates the drug-likeness of phytic acid and its analogues through bioinformatics methods. Two potential cancer drug targets such as mitogen activated kinase and inositol 1,4,5-triphosphate receptor are included in the study. Out of 50 selected analogues of phytic acid, 42 structures interact well with the chosen drug targets. The best interacting structures are 1-diphosinositol pentakisphosphate and 2,3,4,5,6-pentaphosphonooxycyclohexyl dihydrogen phosphate. For both of these structures, the negative binding energy obtained was -49.5 KJ/mol; this affirms the stability of the complex. ADME properties are also predicted to assess the drug-like properties of the compounds. The structure activity relationship model is generated for 12 compounds with experimental IC50 values.

  19. Clinical uses of gonadotropin-releasing hormone analogues.

    PubMed Central

    Casper, R F

    1991-01-01

    Gonadotropin-releasing hormone (Gn-RH) analogues are synthetic derivatives of the native hypothalamic peptide with alterations in their chemical structure that result in changes in biologic activity. Several Gn-RH agonists are available for clinical use, and all act through the same mechanism: first to stimulate and then to inhibit gonadotropin and gonadal steroid secretion by downregulating the pituitary Gn-RN receptors. This review should provide clinicians with a working knowledge of the physiologic and pharmacokinetic features of Gn-RH agonists. Although over 2000 articles concerning Gn-RH analogues have been published I chose to review only those that were the first to report a novel clinical application. Gn-RH agonists have proved to be extremely efficacious in treating gonadal steroid-dependent problems such as endometriosis, uterine leiomyoma, precocious puberty and prostate and breast cancers, and they have resulted in very few side effects. Long-term use may, however, lead to skeletal calcium loss in women as a consequence of hypoestrogenism. Further research is needed to prevent this and maintain clinical efficacy. PMID:1986827

  20. Martian Analogues Emissivity Spectra From the Berlin Emissivity Database (BED)

    NASA Astrophysics Data System (ADS)

    Maturilli, A.; Helbert, J.; Moroz, L.

    2006-12-01

    Remote sensing infrared spectroscopy is the principal field of investigation for planetary surfaces composition. Past, present and future missions to bodies in the solar system include in their payload instruments measuring the emerging radiation in the infrared range. For the interpretation of the measured data an emissivity spectral library of planetary analog materials is needed. The Berlin Emissivity Database (BED) currently contains emissivity spectra of plagioclase and potassium feldspars, low Ca and high Ca pyroxenes, olivine, elemental sulphur, and Martian analogue minerals, measured in the wavelength range from 7 to 22 microns as a function of particle size. For each sample we measured the spectra of four particle size separates ranging from 0 to 250 microns. The device we used is built at DLR (Berlin) and is coupled to a Fourier transform infrared spectrometer (Bruker IFS 88), purged with dry air and equipped with a cooled detector (MCT). All spectra were acquired with a spectral resolution of 4 cm-1. We present here the results of our analysis on well knew and characterized Martian analogue minerals: JSC Mars-1, Salten Skov, and Palagonite from Mauna Kea, Hawaii. We are currently working to upgrade our emissivity facility. A new spectrometer (Bruker VERTEX 80v) and new detectors will allow us to measure the emissivity of samples in the wavelength range from 1 to 50 microns, even in a vacuum environment.

  1. The molecular interactions of buspirone analogues with the serotonin transporter.

    PubMed

    Jarończyk, Małgorzata; Chilmonczyk, Zdzisław; Mazurek, Aleksander P; Nowak, Gabriel; Ravna, Aina W; Kristiansen, Kurt; Sylte, Ingebrigt

    2008-10-15

    A major problem with the selective serotonin reuptake inhibitors (SSRIs) is the delayed onset of action. A reason for that may be that the initial SSRI-induced increase in serotonin levels activates somatodendritic 5-HT(1A) autoreceptors, causing a decrease in serotonin release in major forebrain areas. It has been suggested that compounds combining inhibition of the serotonin transport protein with antagonistic effects on the 5-HT(1A) receptor will shorten the onset time. The anxiolytic drug buspirone is known as 5-HT(1A) partial agonist. In the present work, we are studying the inhibition of the serotonin transporter protein by a series of buspirone analogues by molecular modelling and by experimental affinity measurements. Models of the transporter protein were constructed using the crystal structure of the Escherichia coli major facilitator family transporter-LacY and the X-ray structure of the neurotransmitter symporter family (NSS) transporter-LeuT(Aa) as templates. The buspirone analogues were docked into both SERT models and the interactions with amino acids within the protein were analyzed. Two putative binding sites were identified on the LeuT(Aa) based model, one suggested to be a high-affinity site, and the other suggested to be a low-affinity binding site. Molecular dynamic simulations of the LacY based model in complex with ligands did not induce a helical architecture of the LacY based model into an arrangement more similar to that of the LeuT(Aa) based model.

  2. The costal landslide from analogue experiments: perspectives and limitation

    NASA Astrophysics Data System (ADS)

    Del Ventisette, C.; Nolesini, T.; Moretti, S.; Fanti, R.

    2010-12-01

    Understanding the triggering mechanism of coastal landslides (triggered and/or developed at air-water interface) and their evolution is fundamental to evaluate their hazard and, predicting the energy, the associated tsunami risk. The aim of this work is to verify the suitability of analogue modelling to understand the triggering mechanism and the evolution of landslide along the costal line. As a starting case study the Sciara del Fuoco (SdF), northwest flank of the volcanic island of Stromboli (Italy), was chosen. The analogue modelling technique has been proven to represent an useful tool to understand many geological processes, as it allows studying the progressive deformation, providing also useful indications about the role of distinct factors controlling the final deformation pattern. The models simulated at a first approximation the geological geometries observed at Stromboli, a composite volcano forming the northernmost island of the Aeolian Archipelago (Tyrrhenian Sea). The activity of Stromboli volcano is characterized by a persistent mild explosive activity at the summit craters sporadically interrupted by episodes of lava effusion and violent paroxysmal explosions as in 2002-2003 and in 2007. During the 2002 effusion a large landslide occurred on the SdF. The landslide caused a tsunami, which produced severe damages along the island shores. A series of analogue models was performed to investigate the influence of two different types of triggering mechanism and the behaviour of landslides both in air and air-water interface: 1) surface bulging due to the intrusion of a dike; 2) accumulation of material due to an uppermost landslide or due to opening of a new vent. The models, constructed in a Plexiglas tank, were scaled to the natural prototype following the geometrical, rheological, kinematical and dynamical similarities (e.g. Hubbert, 1937; Ramberg, 1981). The modelling material (Fontainbleau sand and rice) was sieved on a slope, inclination of which

  3. Analogue Missions on Earth, a New Approach to Prepare Future Missions on the Moon

    NASA Astrophysics Data System (ADS)

    Lebeuf, Martin

    Human exploration of the Moon is a target by 2020 with an initial lunar outpost planned in polar regions. Current architectures maintain a capability for sorties to other latitudes for science activities. In the early stages of design of lunar outpost infrastructure and science activity planning, it has been recognized that analogue missions could play a major role in Moon mission design. Analogue missions, as high fidelity simulations of human and robotic surface operations, can help field scientists and engineers develop and test strategies as well as user requirements, as they provide opportunities to groundtruth measurements, and for the team to share understanding of key science needs and key engineering trades. These types of missions also provide direct training in planning science operations, and in team building and communication. The Canadian Space Agency's Exploration Core Program targets the development of technology infrastructure elements in key areas of science, technology and robotics in preparation for its role in the future exploration of the Moon and Mars. Within this Program, Analogue Missions specifically target the operations requirements and lessons learned that will reduce costs and lower the risk of planetary surface missions. Analogue missions are simulations of planetary surface operations that take place at analogue sites on Earth. A terrestrial analogue site resembles in some key way: eg. geomorphologically or geochemically, a surface environment of another planet. An analogue mission can, therefore, be defined as an integrated set of activities that represent (or simulate) entire mission designs or narrowly focus on specific aspects of planned or potential future planetary exploration missions. Within the CSA's Exploration Core Program, Analogue Missions facilitate the maturation of science instruments and mission concepts by integrating ongoing space instrument and technology development programs with science and analogue elements. As

  4. Unhydrolyzable analogues of adenosine 3':5'-monophosphate demonstrating growth inhibition and differentiation in human cancer cells.

    PubMed

    Yokozaki, H; Tortora, G; Pepe, S; Maronde, E; Genieser, H G; Jastorff, B; Cho-Chung, Y S

    1992-05-01

    A set of adenosine 3':5'-monophosphate (cAMP) analogues that combine exocyclic sulfur substitutions in the equatorial (Rp) or the axial (Sp) position of the cyclophosphate ring with modifications in the adenine base of cAMP were tested for their effect on the growth of HL-60 human promyelocytic leukemia cells and LS-174T human colon carcinoma cells. Both diasteromeres of the phosphorothioate derivatives were growth inhibitory, exhibiting a concentration inhibiting 50% of cell proliferation of 3-100 microM. Among the analogues tested, Rp-8-Cl-cAMPS and Sp-8-Br-cAMPS were the two most potent. Rp-8-Cl-cAMPS was 5- to 10-fold less potent than 8-Cl-cAMP while Sp-8-Br-cAMPS was approximately 6-fold more potent than 8-Br-cAMP. The growth inhibition was not due to a block in a specific phase of the cell cycle or due to cytotoxicity. Rp-8-Cl-cAMPS enhanced its growth-inhibitory effect when added together with 8-Cl-cAMP and increased differentiation in combination with N6-benzyl-cAMP. The binding kinetics data showed that these Sp and Rp modifications brought about a greater decrease in affinity for Site B than for Site A of RI (the regulatory subunit of type I cAMP-dependent protein kinase) and a substantial decrease of affinity for Site A of RII (the regulatory subunit of type II protein kinase) but only a small decrease in affinity for Site B of RII, indicating the importance of the Site B binding of RII in the growth-inhibitory effect. These results show that the phosphorothioate analogues of cAMP are useful tools to investigate the mechanism of action of cAMP in growth control and differentiation and may have practical implication in the suppression of malignancy.

  5. Semisynthesis of SY-1 for investigation of breast cancer stem cell selectivity of C-ring-modified salinomycin analogues.

    PubMed

    Huang, Xiaoli; Borgström, Björn; Månsson, Linda; Persson, Lo; Oredsson, Stina; Hegardt, Cecilia; Strand, Daniel

    2014-07-18

    Salinomycin, a naturally occurring polyether ionophore was recently found to selectively reduce the proportion of CD44(+)/CD24(-) cells, a phenotype associated with breast cancer stem cells. Subsequent studies from our group showed that chemical modification of the allylic C20 hydroxyl of salinomycin, located at the C-ring, can enhance the activity of derivatives against breast cancer cells over 5-fold compared to the native structure. Access to C-ring-modified salinomycin analogues is thus of interest from both a mechanistic and a synthetic perspective. Here, we report efficient strategies for gram scale synthesis of the natural product SY-1 (20-deoxy salinomycin), and a saturated analogue, 18,19-dihydro SY-1, for a comparative in vitro investigation of the biological profiles of these compounds with that of salinomycin. Across several assays, the deoxygenated structures required higher concentrations to elicit similar cellular responses to that of salinomycin. Similarly to salinomycin, SY-1 or 18,19-dihydro SY-1 treatment was found to reduce the proportion of CD44(+)/CD24(-) cells with essentially complete selectivity up to ∼IC25. Importantly, the proportion of CD44(+)/CD24(-) cells showed a pronounced U-shaped dose response curve for salinomycin and its derivatives, but not for paclitaxel. The concentration for maximum response in this assay followed differences in IC50 for salinomycin and its analogues, which emphasizes the importance of taking concentration dependence into account when comparing effects on the CD44(+)/CD24(-) phenotype. Small differences in the global conformation within the triad of compounds investigated together with differences in activity across assays emphasize the importance of substitution at C20 for the activity of salinomycin and its derivatives.

  6. Mechanism of Safening Action of Dymuron and Its Two Monomethyl Analogues against Bensulfuron-methyl Injury to Rice (Oryza sativa)

    PubMed

    Omokawa; Wu; Hatzios

    1996-05-01

    The comparative efficacy and mechanism of action of the herbicide dymuron and its two optically active monomethyl analogues, (R)-1-(alpha-methylbenzyl)-3-(p-tolylurea) (R-MBTU) and S-MBTU, as safeners of rice against injury from bensulfuron-methyl were investigated. Bioassays using etiolated seedlings of rice (Oryza sativa L., cv. Lemont), grown either in agar or in liquid media containing bensulfuron-methyl, showed that this sulfonylurea herbicide is a potent inhibitor of rice root growth (I50 = 120 nM). Similar studies with the herbicide dymuron and its two optically active monomethyl analogues (R-MTBU and S-MTBU) showed that at 10 μM, dymuron and R-MBTU reduced rice root length by 25 and 17%, respectively, whereas S-MBTU had no effect on root growth of Lemont rice. Combined treatments with bensulfuron-methyl and dymuron or each of its two analogues confirmed that S-MTBU is an excellent safener of rice against bensulfuron-methyl, far more effective than either dymuron or R-MTBU. The protective action of S-MTBU appeared to result mainly from a drastic reduction in the uptake of bensulfuron-methyl by safened rice seedlings. Dymuron and R-MTBU reduced also the uptake of bensulfuron-methyl by rice seedlings, but to a lesser extent than S-MTBU. Quantitative changes in the metabolism of bensulfuron-methyl by safened rice seedlings were also observed, but did not appear to support the involvement of enhanced herbicide metabolism in the safening action of S-MBTU, R-MBTU, and dymuron. The major metabolites of bensulfuron-methyl detected in both safened and unsafened rice seedlings were tentatively identified as methyl-(4-hydroxy-6-methoxypyrimidin-2-yl-carbamoylsulfamoyl)-o-toluate; methyl-(aminosulfonyl)-o-toluate; and 1H-2,3-benzothiazin-4-(3H)-one-2,2-dioxide.

  7. Monitoring of Geoengineering Effects and their Natural and Anthropogenic Analogues

    NASA Astrophysics Data System (ADS)

    Duren, R. M.; Robock, A.; Stephens, G. L.; MacMynowski, D. G.

    2011-12-01

    A number of climate intervention concepts, referred to as "geoengineering," are being considered as an alternative approach to managing climate change. However, before we go down the path of deliberate climate intervention including precursor field-experiments, it is essential that we take the necessary steps to validate our understanding that underpins any of the proposed intervention concepts in order to understand all likely consequences and put in place the necessary strategies for monitoring the expected and unintended consequences of such intervention. The Keck Institute for Space Studies (KISS) is undertaking a project to identify specific priorities for improved scientific understanding and focused efforts to address selected priorities. The KISS project does not advocate the deployment of geoengineering or monitoring systems for potential field experiments but is rather a precautionary study with the following goals: 1) enumeration of where major gaps in our understanding exist in solar radiation management (SRM) approaches, 2) identification of the research that would be required to improve understanding of such impacts including modeling and observation of natural and anthropogenic analogues to geoengineering, and 3) a preliminary assessment of where gaps exist in observations of relevance to SRMs and what is needed to fill such gaps. This study focuses primarily on SRM rather than other proposed geoengineering techniques such as carbon dioxide removal from the atmosphere because there exist a number of analogues to the SRMs that currently operate on Earth that provide a unique opportunity to assess our understanding of the response of the climate system to associated changes in solar radiation. Additionally, the processes related to these analogues are also fundamental to understanding climate change itself being of central relevance to how climate is forced by aerosol and respond through clouds, among other influences (e.g., such research has potential

  8. Isoelectronic analogues of PN: Remarkably stable multiply charged cations

    SciTech Connect

    Wong, Ming Wah; Radom, L. )

    1990-01-25

    The structures and stabilities of PN and its 27 isoelectronic analogues, CS, SiO, BCl, AlF, BeAr, MgNe, Sn{sup +}, PO{sup +}, CCl{sup +}, SiF{sup +}, BAr{sup +}, AlNe{sup +}, SO{sup 2+}, NCl{sup 2+}, PF{sup 2+}, CAr{sup 2+}, SiNe{sup 2+}, OCl{sup 3+}, SF{sup 3+}, NAr{sup 3+}, PNe{sup 3+}, FCl{sup 4+}, OAr{sup 4+}, SNe{sup 4+}, FAr{sup 5+}, ClNe{sup 5+}, and ArNe{sup 6+}, have been examined by ab initio molecular orbital theory. The CASSCF/6-311G(MC)(d) level was used to determine the ground-state potential energy curves and spectroscopic constants for the 28 diatomic systems. Equilibrium structures were also obtained with the 6-311G(MC)(d) basis set at the MP3 and ST4CCD levels, and dissociation energies were determined at the MP4/6-311 + G(MC)(2df) and MP4/6-311 + G(MC)(3d2f) levels. For the neutral and monocation analogues of PN, the calculated equilibrium geometries (at MP3/6-311G(MC)(d)) and dissociation energies (at MP4/6-311 + G(MC)(3d2f)) are in very good agreement with available experimental values. All the dication analogues of PN, namely, SO{sup 2+}, NCl{sup 2+}, PF{sup 2+}, CAr{sup 2+}, and SiNe{sup 2+}, are predicted to be experimentally observable species. Of these, the SO{sup 2+}, NCl{sup 2+}, and CAr{sup 2+} dications are calculated to be kinetically stable species, with large barriers associated with the exothermic charge-separation reactions, while the PF{sup 2+} and SiNe{sup 2+} dications are predicted not only to be kinetically stable but also to be thermodynamically stable species.

  9. Properties of granular analogue model materials: A community wide survey

    NASA Astrophysics Data System (ADS)

    Klinkmüller, Matthias; Schreurs, Guido; Rosenau, Matthias; Kemnitz, Helga

    2016-04-01

    We report the material properties of 26 granular analogue materials used in 14 analogue modelling laboratories. We determined physical characteristics such as bulk density, grain size distribution, and grain shape, and performed ring shear tests to determine friction angles and cohesion, and uniaxial compression tests to evaluate the compaction behaviour. Mean grain size of the materials varied between (c. 100 and 400 micrometer). Analysis of grain shape factors show that the four different classes of granular materials (14 quartz sands, 5 dyed quartz sands, 4 heavy mineral sands and 3 size fractions of glass beads) can be broadly divided into two groups consisting of 12 angular and 14 rounded materials. Grain shape has an influence on friction angles, with most angular materials having higher internal friction angles (between c. 35° and 40°) than rounded materials, whereas well-rounded glass beads have the lowest internal friction angles (between c. 25° and 30°). We interpret this as an effect of intergranular sliding versus rolling . Most angular materials have also higher basal friction angles (tested for a specific foil) than more rounded materials, suggesting that angular grains scratch and wear the foil., Most materials have a cohesion in the order of 10-100 Pa except for well-rounded glass beads, which show a trend towards a quasi-cohesionless (C <10 Pa) Coulomb-type material. The uniaxial confined compression tests reveal that rounded grains generally show less compaction than angular grains. We interpret this to be related to the initial packing density reached during sieving which is higher for rounded grains than for angular grains. Ring-shear test data show that angular grains undergo a longer strain-hardening phase than more rounded materials. This might explain why analogue models consisting of angular grains accommodate deformation in a more distributed manner prior to strain localisation than models consisting of rounded grains. Also, models

  10. Carbocyclic nucleoside analogues: classification, target enzymes, mechanisms of action and synthesis

    NASA Astrophysics Data System (ADS)

    Matyugina, E. S.; Khandazhinskaya, A. P.; Kochetkov, Sergei N.

    2012-08-01

    Key biological targets (S-adenosyl-L-homocysteine hydrolase, telomerase, human immunodeficiency virus reverse transcriptase, herpes virus DNA polymerase and hepatitis B virus DNA polymerase) and the mechanisms of action of carbocyclic nucleoside analogues are considered. Structural types of analogues are discussed. Methods of synthesis for the most promising compounds and the spectrum of their biological activities are described. The bibliography includes 126 references.

  11. Making Connections in Math: Activating a Prior Knowledge Analogue Matters for Learning

    ERIC Educational Resources Information Center

    Sidney, Pooja G.; Alibali, Martha W.

    2015-01-01

    This study investigated analogical transfer of conceptual structure from a prior-knowledge domain to support learning in a new domain of mathematics: division by fractions. Before a procedural lesson on division by fractions, fifth and sixth graders practiced with a surface analogue (other operations on fractions) or a structural analogue (whole…

  12. How Analogue Research Can Advance Descriptive Evaluation Theory: Understanding (and Improving) Stakeholder Dialogue

    ERIC Educational Resources Information Center

    Campbell, Bernadette; Mark, Melvin M.

    2015-01-01

    Evaluation theories can be tested in various ways. One approach, the experimental analogue study, is described and illustrated in this article. The approach is presented as a method worthy to use in the pursuit of what Alkin and others have called descriptive evaluation theory. Drawing on analogue studies conducted by the first author, we…

  13. The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

    PubMed Central

    Roth, Bryan L.; Gibbons, Simon; Arunotayanun, Warunya; Huang, Xi-Ping; Setola, Vincent; Treble, Ric; Iversen, Les

    2013-01-01

    In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as ‘designer drugs’ and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects. PMID:23527166

  14. Synthesis and GABA(A) receptor activity of 2,19-sulfamoyl analogues of allopregnanolone.

    PubMed

    Durán, Fernando J; Edelsztein, Valeria C; Ghini, Alberto A; Rey, Mariana; Coirini, Héctor; Dauban, Philippe; Dodd, Robert H; Burton, Gerardo

    2009-09-15

    The synthesis of new analogues of allopregnanolone with a bridged sulfamidate ring over the beta-face of ring A has been achieved from easily available precursors, using an intramolecular aziridination strategy. The methodology also allows the synthesis of 3alpha-substituted analogues such as the 3alpha-fluoro derivative. GABA(A) receptor activity of the synthetic analogues was evaluated by assaying their effect on the binding of [(3)H]flunitrazepam and [(3)H]muscimol. The 3alpha-hydroxy-2,19-sulfamoyl analogue and its N-benzyl derivative were more active than allopregnanolone for stimulating binding of [(3)H]flunitrazepam. For the binding of [(3)H]muscimol, both synthetic analogues and allopregnanolone stimulated binding to a similar extent, with the N-benzyl derivative exhibiting a higher EC(50). The 3alpha-fluoro derivative was inactive in both assays.

  15. Memory amplification for trauma: Investigating the role of analogue PTSD symptoms in the laboratory.

    PubMed

    Oulton, Jacinta M; Takarangi, Melanie K T; Strange, Deryn

    2016-08-01

    Victims of trauma often remember their experience as being more traumatic later, compared to immediately after, the event took place. This finding-the "memory amplification effect"-is associated with increased re-experiencing symptoms. However, the effect has been found almost exclusively in field-based studies. We examined whether the effect could be replicated in the laboratory. In two studies, we exposed participants to negative photographs and assessed their memory for the photographs and analogue PTSD symptoms on two occasions. In Study 1, analogue symptoms at follow-up were positively associated with remembering more negative photos over time. In Study 2, we focused on "memory amplifiers": people whose memory of the photos amplified over time. Consistent with field research, analogue re-experiencing symptoms were associated with memory amplification. Overall, our findings confirm that analogue PTSD symptoms are also associated with an amplified memory for a trauma analogue.

  16. Isoxazole analogues bind the System xc− Transporter: Structure-activity Relationship and Pharmacophore Model

    PubMed Central

    Patel, Sarjubhai A.; Rajale, Trideep; O’Brien, Erin; Burkhart, David J.; Nelson, Jared K.; Twamley, Brendan; Blumenfeld, Alex; Szabon-Watola, Monika I.; Gerdes, John M.; Bridges, Richard J.; Natale, Nicholas R.

    2009-01-01

    Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc−. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc−, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y′=3,5-(CF3)2, which both inhibited glutamate up-take by the System xc− transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships. PMID:19932968

  17. Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism.

    PubMed

    Redwan, Elrashdy M; Linjawi, Moustafa H; Uversky, Vladimir N

    2016-03-17

    Therapeutic insulin, in its native and biosynthetic forms as well as several currently available insulin analogues, continues to be the protein of most interest to researchers. From the time of its discovery to the development of modern insulin analogues, this important therapeutic protein has passed through several stages and product generations. Beside the well-known link between diabetes and cancer risk, the currently used therapeutic insulin analogues raised serious concerns due to their potential roles in cancer initiation and/or progression. It is possible that structural variations in some of the insulin analogues are responsible for the appearance of new oncogenic species with high binding affinity to the insulin-like growth factor 1 (IGF1) receptor. The question we are trying to answer in this work is: are there any specific features of the distribution of intrinsic disorder propensity within the amino acid sequences of insulin analogues that may provide an explanation for the carcinogenicity of the altered insulin protein?

  18. Synthetic isoprenoid analogues for the study of prenylated proteins: Fluorescent imaging and proteomic applications.

    PubMed

    Wang, Yen-Chih; Distefano, Mark D

    2016-02-01

    Protein prenylation is a posttranslational modification catalyzed by prenyltransferases involving the attachment of farnesyl or geranylgeranyl groups to residues near the C-termini of proteins. This irreversible covalent modification is important for membrane localization and proper signal transduction. Here, the use of isoprenoid analogues for studying prenylated proteins is reviewed. First, experiments with analogues containing small fluorophores that are alternative substrates for prenyltransferases are described. Those analogues have been useful for quantifying binding affinity and for the production of fluorescently labeled proteins. Next, the use of analogues that incorporate biotin, bioorthogonal groups or antigenic moieties is described. Such probes have been particularly useful for identifying proteins that are naturally prenylated within mammalian cells. Overall, the use of isoprenoid analogues has contributed significantly to the understanding of protein prenlation.

  19. New optimized piperamide analogues with potent in vivo hypotensive properties.

    PubMed

    de Mattos Duarte, Carolina; Verli, Hugo; de Araújo-Júnior, João Xavier; de Medeiros, Isac Almeida; Barreiro, Eliezer J; Fraga, Carlos Alberto Manssour

    2004-12-01

    We describe herein the structural optimization of new piperamide analogues, designed from two natural prototypes, piperine 1 and piperdardine 2, obtained from Piper tuberculatum Jacq. (Piperaceae). Molecular modeling studies using semiempirical AM1 method were made in order to establish rational modifications to optimize them by molecular simplification. The targeted compounds (10) and (11) were respectively obtained using benzaldehyde (12) and para-anisaldehyde (13) as starting materials. 1H NMR spectra showed that the target compounds were diastereoselectively obtained as the (E)-isomer, the same geometry of the natural prototypes. These new synthetic amides presented significant hypotensive effects in cardiovascular essays using in vivo methodologies. Compound 11 (N-[5-(4'-methoxyphenyl)-2(E)-pentenoyl]thiomorpholine) showed a potency 10,000 times greater than its prototype 5, evidencing an optimization of the molecular architecture for this class of hypotensive drug candidates.

  20. Measurement of stimulated Hawking emission in an analogue system.

    PubMed

    Weinfurtner, Silke; Tedford, Edmund W; Penrice, Matthew C J; Unruh, William G; Lawrence, Gregory A

    2011-01-14

    Hawking argued that black holes emit thermal radiation via a quantum spontaneous emission. To address this issue experimentally, we utilize the analogy between the propagation of fields around black holes and surface waves on moving water. By placing a streamlined obstacle into an open channel flow we create a region of high velocity over the obstacle that can include surface wave horizons. Long waves propagating upstream towards this region are blocked and converted into short (deep-water) waves. This is the analogue of the stimulated emission by a white hole (the time inverse of a black hole), and our measurements of the amplitudes of the converted waves demonstrate the thermal nature of the conversion process for this system. Given the close relationship between stimulated and spontaneous emission, our findings attest to the generality of the Hawking process.

  1. Quasinormal modes and classical wave propagation in analogue black holes

    SciTech Connect

    Berti, Emanuele; Cardoso, Vitor; Lemos, Jose P.S.

    2004-12-15

    Many properties of black holes can be studied using acoustic analogues in the laboratory through the propagation of sound waves. We investigate in detail sound wave propagation in a rotating acoustic (2+1)-dimensional black hole, which corresponds to the 'draining bathtub' fluid flow. We compute the quasinormal mode frequencies of this system and discuss late-time power-law tails. Because of the presence of an ergoregion, waves in a rotating acoustic black hole can be superradiantly amplified. We also compute superradiant reflection coefficients and instability time scales for the acoustic black hole bomb, the equivalent of the Press-Teukolsky black hole bomb. Finally we discuss quasinormal modes and late-time tails in a nonrotating canonical acoustic black hole, corresponding to an incompressible, spherically symmetric (3+1)-dimensional fluid flow.

  2. The Mojave vadose zone: a subsurface biosphere analogue for Mars.

    PubMed

    Abbey, William; Salas, Everett; Bhartia, Rohit; Beegle, Luther W

    2013-07-01

    If life ever evolved on the surface of Mars, it is unlikely that it would still survive there today, but as Mars evolved from a wet planet to an arid one, the subsurface environment may have presented a refuge from increasingly hostile surface conditions. Since the last glacial maximum, the Mojave Desert has experienced a similar shift from a wet to a dry environment, giving us the opportunity to study here on Earth how subsurface ecosystems in an arid environment adapt to increasingly barren surface conditions. In this paper, we advocate studying the vadose zone ecosystem of the Mojave Desert as an analogue for possible subsurface biospheres on Mars. We also describe several examples of Mars-like terrain found in the Mojave region and discuss ecological insights that might be gained by a thorough examination of the vadose zone in these specific terrains. Examples described include distributary fans (deltas, alluvial fans, etc.), paleosols overlain by basaltic lava flows, and evaporite deposits.

  3. Analogue of Cosmological Particle Creation in an Ion Trap

    SciTech Connect

    Schuetzhold, Ralf; Uhlmann, Michael; Petersen, Lutz; Schmitz, Hector; Friedenauer, Axel; Schaetz, Tobias

    2007-11-16

    We study phonons in a dynamical chain of ions confined by a trap with a time-dependent (axial) potential strength and demonstrate that they behave in the same way as quantum fields in an expanding or contracting Universe. Based on this analogy, we present a scheme for the detection of the analogue of cosmological particle creation which should be feasible with present day technology. In order to test the quantum nature of the particle creation mechanism and to distinguish it from classical effects such as heating, we propose to measure the two-phonon amplitude via the 2nd red sideband transition and to compare it with the one-phonon amplitude (1st red sideband)

  4. Total Synthesis and Evaluation of Phostriecin and Key Structural Analogues

    PubMed Central

    Burke, Christopher P.; Swingle, Mark R.; Honkanen, Richard E.; Boger, Dale L.

    2010-01-01

    Full details of the total synthesis of phostriecin (2), the assignment of its relative and absolute stereochemistry, and the resultant structural reassignment of the natural product previously represented as sultriecin (1), a phosphate versus sulfate monoester, are detailed. Studies with authentic material confirmed that phostriecin, but not sultriecin, is an effective and selective inhibitor of protein phosphatase 2A (PP2A) defining a mechanism of action responsible for its antitumor activity. The extension of the studies to the synthesis and evaluation of a series of key synthetic analogues is disclosed that highlights the importance of the natural product phosphate monoester (vs sulfate or free alcohol, inactive and >250-fold), the α,β-unsaturated lactone (12-fold), and the hydrophobic Z,Z,E-triene tail (C12–C22, ca. 200-fold) including the unique importance of its unsaturation (50-fold, and no longer PP2A selective). PMID:20669916

  5. A computational study of open-chain epothilone analogue

    NASA Astrophysics Data System (ADS)

    Kamel, Karol; Rusinska-Roszak, Danuta

    Molecular mechanics (MM/Ambers) calculations were applied to probe the conformational profile of open-chain epothilone analogue [Org Lett 2006, 8, 685], cytotoxic against some cell lines. Geometries of the most stable conformers were optimized at DFT level using the B3LYP functional and then compared to known both experimental and virtual conformers of epothilone. One of the most stable structures is III (1.47 kcal/mol above global minimum) which represents high similarity to the appropriate fragment of the Taylor's model of epothilone A, but two other conformers: XIV and XX, although they have almost the same conformation as the mother structure, are very unstable (6.7 and 12.4 kcal/mol above the global minimum).0

  6. Nitrooxymethyl-substituted analogues of rofecoxib: synthesis and pharmacological characterization.

    PubMed

    Boschi, Donatella; Cena, Clara; Di Stilo, Antonella; Rolando, Barbara; Manzini, Paola; Fruttero, Roberta; Gasco, Alberto

    2010-05-01

    Nitrooxymethyl-substituted derivatives of Rofecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting activity in whole human blood, vasodilator potency on rat aorta strips, and for their capacity of inhibiting platelet aggregation of human platelet-rich plasma. The results show that their potency and selectivity in inhibiting COX isoforms, as well as their anti-aggregatory properties, are closely dependent on the position at which the NO-donor nitrooxymethyl function is introduced into the Rofecoxib scaffold. All the products were capable of dilating rat aorta strips precontracted with phenylephrine in a dose-dependent manner, through a cGMP-dependent mechanism. Compound 10 emerged as a quite potent COX-2-selective inhibitor endowed with good vasodilator activity. Interestingly, compound 19 behaved as a potent selective COX-1 inhibitor, and displayed good vasodilator and anti-aggregatory properties. The hydroxymethyl derivatives, potential metabolites of the nitrooxymethyl analogues, were similarly studied for a comparison.

  7. Nitrooxymethyl-substituted analogues of celecoxib: synthesis and pharmacological characterization.

    PubMed

    Boschi, Donatella; Lazzarato, Loretta; Rolando, Barbara; Filieri, Andrea; Cena, Clara; Di Stilo, Antonella; Fruttero, Roberta; Gasco, Alberto

    2009-03-01

    Nitrooxymethyl-substituted analogues of celecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting, vasodilator, and anti-aggregatory activities, as well as for their metabolic stability in human serum and whole blood. The results showed their potency and selectivity in inhibiting the COX isoforms, evaluated in whole human blood, as well as their anti-aggregatory activity to depend closely on the position at which the NO-donor moiety is introduced. All products dilated rat aorta strips precontracted with phenylephrine in a dose-dependent manner through a cGMP-dependent mechanism. They were stable in human serum while, in blood, they were metabolically transformed, principally to the related alcohols.

  8. Modelling the warm interglacials: analogues of MIS1

    NASA Astrophysics Data System (ADS)

    Herold, N.; Yin, Q. Z.; Karami, M. P.; Berger, A.

    2012-04-01

    Determining interglacial diversity, primarily as a function of duration, intensity and unique climate responses to Earth's orbital variations has become a focal point for researchers trying to better understand our current interglacial. Numerous interglacials have been espoused as Marine Isotopic Stage (MIS) 1 analogues or windows into the future of Holocene climate based on their astronomical characteristics, seasonal insolation patterns or their similarity with predicted anthropogenic warming. However, to date there has been little quantitative study of the climate of these interglacials within a physically robust framework. Here we examine the climate response to peak interglacial forcing during MIS1, 5, 9, 11 and 19 using the Community Climate System Model 3. We determine which interglacial provides the closest analogue to peak MIS1 conditions as well as the mechanisms which dominate the surface climate responses of these interglacials. Considering the differences in astronomical parameters and greenhouse gases we discount MIS5 and 9 as analogues to peak MIS1 conditions due to their significant warmth and stronger precipitation and vegetation responses. Conversely, based on seasonal and hemispheric averages of surface temperature, precipitation and sea-ice cover, MIS11 and 19 are most similar to MIS1, with MIS11 actually exhibiting a higher affinity particularly during boreal summer. This is attributed to a greater similarity in the seasonal and latitudinal distribution of insolation over middle latitude Eurasia and North America, which are the regions most sensitive to insolation change given the absence of ice-sheet dynamics in our model. Global ocean overturning circulation during MIS11 is also closer to MIS1 than circulation during MIS19 is, due predominantly to differences in Weddell Sea bottom water formation. Thus, under the assumption of present-day ice-sheets MIS11 appears to be the better climatic analogue to peak MIS1 conditions. In addition to the

  9. Raman spectroscopy of ion-irradiated interplanetary carbon dust analogues

    NASA Astrophysics Data System (ADS)

    Baratta, G. A.; Mennella, V.; Brucato, J. R.; Colangeli, L.; Leto, G.; Palumbo, M. E.; Strazzulla, G.

    Interplanetary dust particles (IDPs) and meteorites provide an unique opportunity to study extraterrestrial materials in laboratory. Different Raman studies have shown that most of IDPs exhibit the characteristic amorphous carbon Raman feature. Different degrees of order have been recognised in the amorphous carbon phase of IDPs testifying either to different origin or to different processing under different physical conditions (temperature, pressure etc.). This paper presents a comparison between the amorphous carbon Raman features of IDPs, and those of carbon dust analogues obtained in the laboratory by ion irradiation of carbon containing frozen gases and by arc discharge. We propose a possible mechanism able to induce an "evolution" of IDPs. In particular amorphous carbon with different degrees of order could be indicative of different irradiation doses by solar wind particles and fast solar protons, suffered by IDPs in the interplanetary medium before collection in the Earth's atmosphere.

  10. Mechanism of cis-prenyltransferase reaction probed by substrate analogues.

    PubMed

    Lu, Yen-Pin; Liu, Hon-Ge; Teng, Kuo-Hsun; Liang, Po-Huang

    2010-10-01

    Undecaprenyl pyrophosphate synthase (UPPS) is a cis-type prenyltransferases which catalyzes condensation reactions of farnesyl diphosphate (FPP) with eight isopentenyl pyrophosphate (IPP) units to generate C(55) product. In this study, we used two analogues of FPP, 2-fluoro-FPP and [1,1-(2)H(2)]FPP, to probe the reaction mechanism of Escherichia coli UPPS. The reaction rate of 2-fluoro-FPP with IPP under single-turnover condition is similar to that of FPP, consistent with the mechanism without forming a farnesyl carbocation intermediate. Moreover, the deuterium secondary KIE of 0.985±0.022 measured for UPPS reaction using [1,1-(2)H(2)]FPP supports the associative transition state. Unlike the sequential mechanism used by trans-prenyltransferases, our data demonstrate E. coli UPPS utilizes the concerted mechanism.

  11. Superconducting analogue of the parafermion fractional quantum Hall states

    NASA Astrophysics Data System (ADS)

    Vaezi, Abolhassan

    2014-03-01

    Read and Rezayi Zk parafermion wavefunctions describe ν = 2 + k /(kM + 2) fractional quantum Hall (FQH) states. These states support non-Abelian excitations from which protected quantum gates can be designed. However, there is no experimental evidence for these non-Abelian anyons to date. In this talk, we discuss the ν = 2 / k FQH-superconductor heterostructure and through analytical and numerical calculations we argue that it can yield the superconducting analogue of the Zk parafermion FQH state. The resulting topological state has a gapless chiral edge state with Zk parafermion conformal field theory description. For instance, we find that a ν = 2 / 3 FQH in proximity to a superconductor produces a Z3 parafermion superconducting state. This state can host Fibonacci anyons capable of performing universal quantum computation through braiding operations. We finally discuss our experimental proposal for realizing parafermion superconductors. Reference: arXiv:1307.8069

  12. Synthesis and Biological Evaluation of 7-Deoxy-Epothilone Analogues

    PubMed Central

    Woods, Laura M.; Arico, Joseph W.; Frein, Jeffrey D.; Sackett, Dan L.; Taylor, Richard E.

    2017-01-01

    The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand–target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to maintain the conformational preferences of their biologically active parent congeners through computer modeling and nuclear magnetic resonance (NMR) studies. The significant decrease in observed potency for each compound suggests that a hydrogen bond between the C7-hydroxyl group and the tubulin binding site plays a critical role in the energetics of binding in the epothilone class of polyketides. PMID:28304361

  13. Procedures for monitoring recombinant erythropoietin and analogues in doping control.

    PubMed

    Segura, Jordi; Pascual, José A; Gutiérrez-Gallego, Ricardo

    2007-08-01

    The present report summarizes the main analytical strategies developed to identify the presence of recombinant erythropoietin (EPO) administered as a doping agent. Indirect evidence is based on the analysis of blood parameters (haemoglobin, haematocrit, reticulocytes, macrocytes, etc.) and serum markers (concentration of EPO and serum transferrin receptors, etc.). The problem of intertechnique comparison for reliable results evaluation is emphasized, especially for serum markers. Charge differences between isoforms of recombinant EPO and native urinary EPO are the grounds for the isoelectric focusing-double blotting-chemiluminescence detection method presently approved for doping control. Works addressing its advantages and limitations are presented and commented on. The chemical bases of the differential detection are highlighted and some future approaches for detection are also presented. The appearance and detectability of EPO analogues and mimetics susceptible for abuse are also addressed.

  14. Synthesis, characterization and biological studies of diosgenyl analogues.

    PubMed

    Huang, Baozhan; Du, Dan; Zhang, Rui; Wu, Xiaohua; Xing, Zhihua; He, Yang; Huang, Wen

    2012-12-15

    A series of optical amino acid diosgenyl esters and diosgenyl salicylate conjugates were designed and synthesized to develop new anticancer and anti-inflammatory agents. The analogue 9c that contains an 6-aminohexanoic acid residue at C-3 of diosgenin exhibits higher potency against all three tumor cell lines with IC(50) values ranging from 4.7 μM in C26 cells to 14.6 μM in Hep G2 cells. In addition, seven of newly synthesized compounds significantly inhibit xylene-induced ear edema and exhibit comparable or better anti-inflammatory activities than those of diosgenin and aspirin. Furthermore, preliminary structure-activity relationship studies demonstrate that diosgenyl salicylate conjugates have stronger anti-inflammatory activities than amino acid diosgenyl esters.

  15. Phosphorus-based SAHA analogues as histone deacetylase inhibitors.

    PubMed

    Kapustin, Galina V; Fejér, György; Gronlund, Jennifer L; McCafferty, Dewey G; Seto, Edward; Etzkorn, Felicia A

    2003-08-21

    [structure: see text] Three analogues of suberoyl anilide hydroxamic acid (SAHA) with phosphorus metal-chelating functionalities were synthesized as inhibitors of histone deacetylases (HDACs). The compounds showed weak activity for HeLa nuclear extracts (IC(50) = 0.57-6.1 mM), HDAC8 (IC(50) = 0.28-0.41 mM), and histone-deacetylase-like protein (HDLP, IC(50) = 0.33-1.9 mM), suggesting that the transition state of HDAC is not analogous to zinc proteases. Antiproliferative activity against A2780 cancer cells (IC(50) = 0.11-0.12 mM), comparable to SAHA (0.15 mM), was observed.

  16. Global analogue of the Aharonov-Bohm effect

    SciTech Connect

    Navin, R.L.

    1993-12-31

    This thesis deals with a global analogue of the Aharonov-Bohm effect previously pointed out by other authors. The effect was not well understood because the pure Aharonov-Bohm cross section was thought to be merely an approximate low energy limit. This thesis provides a detailed analysis and reveals that in the particular model considered, there is an exact Aharonov-Bohm cross section over the energy range that a mass splitting occurs. At energies slightly above the mass splitting, the effect has completely disappeared and there is effectively no scattering at large distances. This is a curious observation as it was previously thought that a global theory would not act exactly like a local one over an extended range of energies. It begs the heretical speculation that experimentally observed forces modelled with Lagrangians possessing local symmetries may have an underlying global theory.

  17. Simulated Milky Way analogues: implications for dark matter indirect searches

    SciTech Connect

    Calore, Francesca; Bozorgnia, Nassim; Lovell, Mark; Bertone, Gianfranco; Schaller, Matthieu; Frenk, Carlos S.; Theuns, Tom; Trayford, James W.; Crain, Robert A.; Schaye, Joop E-mail: N.Bozorgnia@uva.nl E-mail: g.bertone@uva.nl E-mail: C.S.Frenk@durham.ac.uk E-mail: schaye@strw.leidenuniv.nl E-mail: j.w.trayford@durham.ac.uk

    2015-12-01

    We study high-resolution hydrodynamic simulations of Milky Way type galaxies obtained within the 'Evolution and Assembly of GaLaxies and their Environments' (EAGLE) project, and identify those that best satisfy observational constraints on the Milky Way total stellar mass, rotation curve, and galaxy shape. Contrary to mock galaxies selected on the basis of their total virial mass, the Milky Way analogues so identified consistently exhibit very similar dark matter profiles inside the solar circle, therefore enabling more accurate predictions for indirect dark matter searches. We find in particular that high resolution simulated haloes satisfying observational constraints exhibit, within the inner few kiloparsecs, dark matter profiles shallower than those required to explain the so-called Fermi GeV excess via dark matter annihilation.

  18. Synthesis and biological evaluation of novel tamoxifen analogues.

    PubMed

    Christodoulou, Michael S; Fokialakis, Nikolas; Passarella, Daniele; García-Argáez, Aída Nelly; Gia, Ornella Maria; Pongratz, Ingemar; Dalla Via, Lisa; Haroutounian, Serkos A

    2013-07-15

    A collection of compounds, structurally related to the anticancer drug tamoxifen, used in breast cancer therapy, were designed and synthesized as potential anticancer agents. McMurry coupling reaction was used as the key synthetic step in the preparation of these analogues and the structural assignment of E, Z isomers was determined on the basis of 2D-NOESY experiments. The compounds were evaluated for their antiproliferative activity on breast cancer (MCF-7), cervix adenocarcinoma (HeLa) and biphasic mesothelioma (MSTO-211H) human tumor cell lines. The estrogen like properties of the novel compounds were compared with those of the untreated controls using an estrogen responsive element-based (ERE) luciferase reporter assay and compared to 17β-estradiol (E2). Finally, with the aim to correlate the antiproliferative activity with an intracellular target(s), the effect on relaxation activity of DNA topoisomerases I and II was assayed.

  19. Photochemical hole burning of ionic porphins and the deuterated analogues

    NASA Astrophysics Data System (ADS)

    Sakoda, Kazuaki; Maeda, Masayuki

    1994-01-01

    The quantum yields of photochemical hole burning (PHB) of three ionic porphins and their deuterated analogues doped in poly(vinylalcohol) and poly(sodium 4-styrenesulfonate) were estimated. The deuterated compounds, whose two hydrogen atoms at the nitrogen sites in the porphin ring were exchanged with deuterium atoms, were synthesized by reacting the non-deuterated compounds with heavy water. The quantum yield of the deuterated porphin was 18 to 45 times smaller than that of the non-deuterated compound. Besides, the hole area did not decrease at least up to about 60 K. These two facts definitely show that the main mechanism of PHB in this system is not a photophysical process, but the tautomerization of the porphin ring.

  20. Novel Cyclic Biphalin Analogue with Improved Antinociceptive Properties

    PubMed Central

    2014-01-01

    Two novel opioid analogues have been designed by substituting the native d-Ala residues in position 2,2′ of biphalin with two residues of d-penicillamine or l-penicillamine and by forming a disulfide bond between the thiol groups. The so-obtained compound 9 containing d-penicillamines showed excellent μ/δ mixed receptor affinities (Kiδ = 5.2 nM; Kiμ = 1.9 nM), together with an efficacious capacity to trigger the second messenger and a very good in vivo antinociceptive activity, whereas product 10 was scarcely active. An explanation of the two different pharmacological behaviors of products 9 and 10 was found by studying their conformational properties. PMID:25221662

  1. [Antioxidant properties of 3-oxypyridine analogues: mexidol, emoxipin, proxipin].

    PubMed

    Klebanov, G I; Liubitskiĭ, O B; Vasil'eva, O V; Klimov, Iu V; Penzulaeva, O B; Tepliashin, A S; Tolstykh, M P; Promorenko, V K; Vladimirov, Iu A

    2001-01-01

    Using three chemiluminescent model systems of oxidation (suspension of phospholipid liposomes, a geous solution of haemoglobin-hydrogen peroxide-luminol and a geous solution 2,2'-azo-bis-(2-methylpropionamidine)dihydrochloride-luminol) the antioxidant activity and mechanism of antioxidant action of three 3-oxypyridine analogues: (mexidol, emoxipin and proxipin) were studied. These compounds were shown: a) to interact with catalitically active two valency iron ions (Fe2+), that causes elimination of ions from the model system; b) to scavenge reactive oxygen species and/or luminol radicals produced in the model systems. Their activity reduced in the following order: mexidol > emoxipin > proxipin. The antioxidant activity of 3-oxypyridines may underline known clinical effects of these compounds.

  2. Synthesis of Dihydropyridine Analogues for Sperm Immobilizing Activity

    NASA Astrophysics Data System (ADS)

    Sadeghipour Roodsari, H. R.; Amini, M.; Naghibi Harat, Z.; Daneshgar, P.; Vosooghi, M.; Shafiee, A.

    In the present study, the activity of seven newly synthesized dihydropyridine analogues on the motility of sperm were determined and compared to nifedipine activity that was used as standard. Sperm motility reduced value for test compounds 6a-g shows a gradual increase proportional to the size elongation of alkyl ester groups. Consequently the size of alkyl is important in the activity of test compounds and finally increase in the lipophil size of hydrocarbon`s ester (R1) is inversely related to the activity of the synthetic compounds. As a result, the methyl ester of the test compounds with 50% of nifedipine activity (in two hours group) is the most active test compound.

  3. Scattering matrices and expansion coefficients of martian analogue palagonite particles

    NASA Astrophysics Data System (ADS)

    Laan, E. C.; Volten, H.; Stam, D. M.; Muñoz, O.; Hovenier, J. W.; Roush, T. L.

    2009-01-01

    We present measurements of ratios of elements of the scattering matrix of martian analogue palagonite particles for scattering angles ranging from 3° to 174° and a wavelength of 632.8 nm. To facilitate the use of these measurements in radiative transfer calculations we have devised a method that enables us to obtain, from these measurements, a normalized synthetic scattering matrix covering the complete scattering angle range from 0° to 180°. Our method is based on employing the coefficients of the expansions of scattering matrix elements into generalized spherical functions. The synthetic scattering matrix elements and/or the expansion coefficients obtained in this way, can be used to include multiple scattering by these irregularly shaped particles in (polarized) radiative transfer calculations, such as calculations of sunlight that is scattered in the dusty martian atmosphere.

  4. Using analogues to quantify geological uncertainty in stochastic reserve modelling

    SciTech Connect

    Wells, B.; Brown, I.

    1995-08-01

    The petroleum industry seeks to minimize exploration risk by employing the best possible expertise, methods and tools. Is it possible to quantify the success of this process of risk reduction? Due to inherent uncertainty in predicting geological reality and due to changing environments for hydrocarbon exploration, it is not enough simply to record the proportion of successful wells drilled; in various parts of the world it has been noted that pseudo-random drilling would apparently have been as successful as the actual drilling programme. How, then, should we judge the success of risk reduction? For many years the E&P industry has routinely used Monte Carlo modelling to generate a probability distribution for prospect reserves. One aspect of Monte Carlo modelling which has received insufficient attention, but which is essential for quantifying risk reduction, is the consistency and repeatability with which predictions can be made. Reducing the subjective element inherent in the specification of geological uncertainty allows better quantification of uncertainty in the prediction of reserves, in both exploration and appraisal. Building on work reported at the AAPG annual conventions in 1994 and 1995, the present paper incorporates analogue information with uncertainty modelling. Analogues provide a major step forward in the quantification of risk, but their significance is potentially greater still. The two principal contributors to uncertainty in field and prospect analysis are the hydrocarbon life-cycle and the geometry of the trap. These are usually treated separately. Combining them into a single model is a major contribution to the reduction risk. This work is based in part on a joint project with Oryx Energy UK Ltd., and thanks are due in particular to Richard Benmore and Mike Cooper.

  5. Analogue modeling of instabilities in crater lake hydrothermal systems

    NASA Astrophysics Data System (ADS)

    Vandemeulebrouck, Jean; Stemmelen, Didier; Hurst, Tony; Grangeon, Jacques

    2005-02-01

    We carried out analogue experiments on two-phase boiling systems, using a porous vertical cylinder, saturated with water. The base of the cylinder was heated, and the top was cooled, as in a natural hydrothermal system. Previous work had shown that once the two-phase zone reached a certain level, thermal instabilities would develop. We made measurements of the acoustic energy related to boiling, and we found that high levels of acoustic noise were associated with the part of the cycle in which there was upward water movement. We repeated our experiments with a cooling water tank at the top of the system, representing a crater lake. This showed that periodic thermal instabilities still developed in this situation. We then compared our analogue measurements to two natural systems known to exhibit periodic behavior. There is good agreement between the thermal and acoustic cycling seen in our model and the observations made at Inferno Crater Lake in the Waimangu Geothermal area, New Zealand, whose level cycles by nearly 10 m, with a typical period of 38 days. Particularly notable is how in both systems high levels of acoustic noise are associated with rising water level. The much larger Ruapehu Crater Lake, also in New Zealand, cycled with a period of several months to a year for over a decade prior to the 1995 eruption. Strong acoustic and seismic energy usually occurred just before the lake temperature started to rise. This suggests a slightly different model, in which the increasing two-phase flow zone triggers more general convection once it reaches the base of the lake.

  6. Early Earth rock analogues for Martian subsurface processes

    NASA Astrophysics Data System (ADS)

    Bishop, J. L.; Grosch, E. G.; Maturilli, A.; Helbert, J.

    2015-12-01

    Sub-surface mafic-ultramafic crustal and hydrothermal environments on early Earth and Mars may have been very similar [1]. Hydrogen production from low-temperature alteration of ultramafic and basaltic rocks has been proposed to support early microbial life in Earth's earliest subsurface environments [1]. Similarly, evidence for microbial sulphate reduction has been reported from early Archean metabasaltic pillow lavas [2]. As such, Archean terrestrial rock environments preserved in greenstone belts may play an important role in understanding early Martian subsurface environments, which in turn may have led to preservation of early traces of life. In this context, the rock sequences of the Paleoarchean Barberton greenstone belt of South Africa provide unique Martian analogues as these rocks are exceptionally well preserved and record early Earth (and perhaps Martian-type) subsurface processes. In-situ exploration by rovers, remote sensing studies, and meteorite evidence has indicated the presence of altered gabbros, olivine-/pyroxene-bearing basalts and possible felsic porphyries on Mars. In this study we present a range of relevant 3.5 billion year old Archean greenstone belt analogue samples that include altered tholeiitic basalts, basaltic komatiites, serpentinized ultramafic komatiites and a felsic tonalite. The petrography and mineralogy of the samples are presented in terms of relic igneous phases and clay mineral alteration. We are acquiring visible/near-infrared reflectance and mid-IR emission spectra on these early Archean samples with the aim of using the hyperspectral data for ground truthing remote sensing data and mineral identification/environments on Mars.[1]. Grosch et al. (2014). Microscale mapping of alteration conditions and potential biosignatures in basaltic-ultramafic rocks on early Earth and beyond, Astrobiology 14 (3), 216-228. [2]. McLoughlin et al. (2012) Sulfur isotope evidence for a Paleoarchean subseafloor biosphere, Barberton, South

  7. Mapping Densities in Analogue Laboratory Turbulent Plumes Using Dye Concentration

    NASA Astrophysics Data System (ADS)

    Fisher, M. A.; Kobs-Nawotniak, S. E.

    2014-12-01

    Changing tephra concentration in volcanic eruption columns is difficult to measure in the field due to fluid opacity. The bulk fluid erupted may be higher density than the surrounding atmosphere at the vent and then transition to positive buoyancy through the ingestion and heating of ambient air; thus, the concentration of the plume fluid as it rises is critical to determining whether the material rises in a sustained plume or collapses into a pyroclastic density current. We evaluate the changing concentration of an analogue plume via tracer dye intensity and relate it to plume radius expansion and vent distance. To calibrate our concentration metric, we calculated the density and dye concentration of pre-determined tracer-water mixtures. The density of the solution was directly measured using a micropipette and high precision balance. The calculated density falls within the standard error of the measured density for each step. Five photographs were taken of each concentration using a mounted Ex-FH100 digital camera with identical lighting. Using a MATLAB script, the RGB (Red-Green-Blue) color value was extracted from five pixels located at the same coordinates in each image, confirming that there was no inherent error caused by the camera and that the RGB value was the same across an entire image. We created a color map to convert from the RGB color value of a pixel in an image to its corresponding concentration. This method algorithm can then be applied to an analogue volcanic tank model, using the color variations in the plume eddies to determine the tracer concentration, and thereby density distribution, in the plume.

  8. Cyclic cholecystokinin analogues with high selectivity for central receptors.

    PubMed Central

    Charpentier, B; Pelaprat, D; Durieux, C; Dor, A; Reibaud, M; Blanchard, J C; Roques, B P

    1988-01-01

    Taking as a model the N-terminal folding of the cholecystokinin tyrosine-sulfated octapeptide [CCK-8; Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] deduced from conformational studies, two cyclic cholecystokinin (CCK) analogues were synthesized by conventional peptide synthesis: Boc-D-Asp-Tyr(SO3H)-Ahx-D-Lys-Trp-Ahx-Asp-Phe-NH2 [compound I (Ahx, 2-aminohexanoic acid)] and Boc-gamma-D-Glu-Tyr(SO3H)-Ahx-D-Lys-Trp-Ahx-Asp-Phe-NH2 (compound II). The binding characteristics of these peptides were investigated on brain cortex membranes and pancreatic acini of guinea pig. Compounds I and II were competitive inhibitors of [3H]Boc[Ahx28,31]CCK-(27-33) binding to central CCK receptors and showed a high degree of selectivity for these binding sites (compound I: Ki for pancreas/Ki for brain, 179; compound II: Ki for pancreas/Ki for brain, 1979). This high selectivity was associated with a high affinity for central CCK receptors (compound I: Ki, 5.1 nM; compound II: Ki, 0.49 nM). Similar affinities and selectivities were found when 125I Bolton-Hunter-labeled CCK-8 was used as a ligand. Moreover, these compounds were only weakly active in the stimulation of amylase release from guinea pig pancreatic acini (EC50 greater than 10,000 nM) and were unable to induce contractions in the guinea pig ileum (to 10(-6) M). The two cyclic CCK analogues, therefore, appear to be synthetic ligands exhibiting both high affinity and high selectivity for central CCK binding sites. These compounds could help clarify the respective role of central and peripheral receptors for various CCK-8-induced pharmacological effects. PMID:3162318

  9. The Arctic Mars Analogue Svalbard Expedition 2010. (Invited)

    NASA Astrophysics Data System (ADS)

    Steele, A.; Benning, L. G.; Fogel, M. L.; Amundsen, H.; Schmitz, N.; Amase 2010 Team

    2010-12-01

    The Arctic Mars Analogue Svalbard Expeditions (AMASE) 2010 was the latest of a series of expeditions that are NASA ASTEP and ESA funded and have as their primary goals 1) testing portable instruments for their robustness as field instruments for life detection, 2) assessing Mars analogue environments for abiosignatures and biosignatures, 3) refining protocols for contamination reduction, 4) defining a minimal instrument suite for Astrobiology science on Mars and 5) sample acquisition, collection and caching of suitable samples by rover platforms containing sample acquisition hardware: first Cliffbot, then Athena. As well as testing ESA instrumentation for the ExoMars mission and NASA instruments for Mars Science Laboratory, the goals and technologies used during this 2010 campaign are very similar to that proposed by the current MEPAG MAX-C mission concept and therefore set the stage for future sample return missions. As such the field-tested technologies, procedures and protocols can be used to address specific science objectives proposed for the 2018 Mars mission opportunity. As NASA and ESA enter a new era of collaboration, AMASE has provided and will continue to provide, a test bed for both current in-situ robotic missions and Mars Sample Return mission architectures. AMASE has proved to be a unique platform to build understanding and collaboration amongst scientists and engineers from Europe and the USA. AMASE 2010 team (other than those mentioned above): Ivar Midtkandal, Kjell Ove Storvik, Garret Huntress, Verena Starke, Pan Conrad, Francis McCubbin, Tor Viscor, Antonio Sensano, Laureline Josset, Jean-Luc Josset, Mihaela Glamoclija, Steve Squyres, Inge Loes Ten Kate, Kyong Hou, Jen Stern, Amy McAdam, Dave Blake, Dick Morris, Claire Cousins, Arnold Bauer, Carole Phillippon, Eckhard Steinmetz, Dave Potts, Dominique Tobler, Guillermo Lopez.

  10. Chicoric acid analogues as HIV-1 integrase inhibitors.

    PubMed

    Lin, Z; Neamati, N; Zhao, H; Kiryu, Y; Turpin, J A; Aberham, C; Strebel, K; Kohn, K; Witvrouw, M; Pannecouque, C; Debyser, Z; De Clercq, E; Rice, W G; Pommier, Y; Burke, T R

    1999-04-22

    The present study was undertaken to examine structural features of L-chicoric acid (3) which are important for potency against purified HIV-1 integrase and for reported cytoprotective effects in cell-based systems. Through a progressive series of analogues, it was shown that enantiomeric D-chicoric acid (4) retains inhibitory potency against purified integrase equal to its L-counterpart and further that removal of either one or both carboxylic functionalities results in essentially no loss of inhibitory potency. Additionally, while two caffeoyl moieties are required, attachment of caffeoyl groups to the central linking structure can be achieved via amide or mixed amide/ester linkages. More remarkable is the finding that blockage of the catechol functionality through conversion to tetraacetate esters results in almost no loss of potency, contingent on the presence of at least one carboxyl group on the central linker. Taken as a whole, the work has resulted in the identification of new integrase inhibitors which may be regarded as bis-caffeoyl derivatives of glycidic acid and amino acids such as serine and beta-aminoalanine. The present study also examined the reported ability of chicoric acid to exert cytoprotective effects in HIV-infected cells. It was demonstrated in target and cell-based assays that the chicoric acids do not significantly inhibit other targets associated with HIV-1 replication, including reverse transcription, protease function, NCp7 zinc finger function, or replication of virus from latently infected cells. In CEM cells, for both the parent chicoric acid and selected analogues, antiviral activity was observable under specific assay conditions and with high dependence on the multiplicity of viral infection. However, against HIV-1- and HIV-2-infected MT-4 cells, the chicoric acids and their tetraacetylated esters exhibited antiviral activity (50% effective concentration (EC50) ranging from 1.7 to 20 microM and 50% inhibitory concentration (IC50

  11. Anticancer Properties of a Novel Class of Tetrafluorinated Thalidomide Analogues.

    PubMed

    Beedie, Shaunna L; Peer, Cody J; Pisle, Steven; Gardner, Erin R; Mahony, Chris; Barnett, Shelby; Ambrozak, Agnieszka; Gütschow, Michael; Chau, Cindy H; Vargesson, Neil; Figg, William D

    2015-10-01

    Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenic pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogues (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the antiangiogenic properties of these newly synthesized compounds. We examined the specific antiangiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. In addition, further in vitro efficacy was evaluated using human umbilical vein endothelial cells (HUVEC) and PC3 cells treated with 5 and 10 μmol/L doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as to inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The antiangiogenic properties of the compounds were also examined in vivo in fli1:EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo:GFP zebrafish embryos, whereas Gu998 and Gu992 showed no difference. The compounds' antitumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogues as a promising immunomodulatory class with anticancer effects that warrant further development to characterize their mechanisms of action.

  12. Transitional lava flows as potential analogues for lunar impact melts

    NASA Astrophysics Data System (ADS)

    Neish, Catherine; Hughes, Scott; Hamilton, Christopher; Kobs Nawotniak, Shannon; Garry, William Brent; Skok, John Roma; Elphic, Richard; Carter, Lynn; Bandfield, Joshua; Osinski, Gordon; Lim, Darlene; Heldmann, Jennifer

    2015-11-01

    Lunar impact melt deposits are among the roughest surface materials on the Moon at the decimeter scale, even though they appear smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pāhoehoe and ´a´ā lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will inform us as to the circumstances under which they were formed. Although there is no perfect archetype for lunar impact melts on Earth, certain terrestrial environments lend themselves as functional analogues. Specifically, a variety of transitional lava flow types develop if the surface of a pāhoehoe-like flow is disrupted, producing ‘slabby’ or ‘rubbly’ flows that are extremely rough at the decimeter scale. We investigated the surface roughness of transitional lava flows at Craters of the Moon (COTM) National Monument, comparing radar imagery and high-resolution topographic profiles to similar data sets acquired by the Lunar Reconnaissance Orbiter for impact melt deposits on the Moon. Results suggest that the lava flows at COTM have similar radar properties to lunar impact melt deposits, but the terrestrial flows are considerably rougher at the meter scale. It may be that lunar impact melts represent a unique lava type not observed on Earth, whose surface texture is influenced by their high emplacement temperatures and/or cooling in a vacuum. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  13. Potent and selective inhibition of varicella-zoster virus (VZV) by nucleoside analogues with an unusual bicyclic base.

    PubMed

    McGuigan, C; Yarnold, C J; Jones, G; Velázquez, S; Barucki, H; Brancale, A; Andrei, G; Snoeck, R; De Clercq, E; Balzarini, J

    1999-11-04

    We herein report the discovery of an entirely new category of potent antiviral agents based on novel deoxynucleoside analogues with unusual bicyclic base moieties. Target structures, previously known as byproducts in Pd-catalyzed coupling of terminal alkynes with 5-iodo-nucleosides, are recognized herein for the first time to be potent and selective inhibitors of varicella-zoster virus (VZV) in vitro. As an unusual structure-activity relationship we noted the absolute requirement of a long alkyl side chain, with an optimum length of C(8)-C(10), for antiviral activity. We thus report the synthesis and characterization of a series of chain-modified analogues and their extensive in vitro evaluation. The lead compounds have a ca. 300-fold enhancement in anti-VZV activity over the reference compound acyclovir, with no detectable in vitro cytotoxicity. The novel structure of these compounds, coupled with their ease of synthesis, excellent antiviral profile, and promising physical properties, makes them of great interest for possible antiviral drug development.

  14. Design, Synthesis, and Immunological Evaluation of Benzyloxyalkyl-Substituted 1,2,3-Triazolyl α-GalCer Analogues

    PubMed Central

    2015-01-01

    Replacement of the amide moiety in the structure of α-GalCer with a 1,2,3-triazole linker is known to elicit a response skewed toward Th2 immunity, and glycolipids containing an aromatic ring in the terminus of their acyl or phytosphingosine structural component exhibit an enhanced Th1 immune response. In the current study, synthesis and immunological screening of a focused library of benzyloxyalkyl-substituted 1,2,3-triazolyl α-GalCer analogues are reported. The novel α-GalCer analogues activate invariant natural killer T (iNKT) cells via CD1d mediated presentation, which was confirmed by in vitro tests performed on iNKT hybridomas incubated with CD1d proteins. When tested on isolated murine splenocytes, the T1204B and T1206B compounds stimulated higher levels of both IFN-γ and IL-4 cytokine expression in vitro compared to that of α-GalCer. PMID:26985293

  15. Insulin degludec, a long-acting once-daily basal analogue for type 1 and type 2 diabetes mellitus.

    PubMed

    Berard, Lori; MacNeill, Gail

    2015-02-01

    Here, we discuss certain practical issues related to use of insulin degludec, a new long-acting basal insulin analogue. Degludec provides uniform ("peakless") action that extends over more than 24 hours and is highly consistent from dose to dose. Like the 2 previously available basal analogues (detemir and glargine), degludec is expected to simplify dose adjustment and enable patients to reach their glycemic targets with reduced risk of hypoglycemia. Phase 3 clinical trials involving type 1 and type 2 diabetes have demonstrated that degludec was noninferior to glargine in allowing patients to reach a target glycated hemoglobin (A1C) of 7%, and nocturnal hypoglycemia occurred significantly less frequently with degludec. In addition, when dosing intervals vary substantially from day to day, degludec continues to be effective and to maintain a low rate of nocturnal hypoglycemia. Degludec thus has the potential to reduce risk of nocturnal hypoglycemia, to enhance the flexibility of the dosing schedule and to improve patient and caregiver confidence in the stability of glycemic control. A dedicated injector, the FlexTouch prefilled pen, containing degludec 200 units/mL, will be recommended for most patients with type 2 diabetes. Degludec will also be available as 100 units/mL cartridges, to be used in the NovoPen 4 by patients requiring smaller basal insulin doses, including most patients with type 1 diabetes.

  16. An electromagnetic modulator based on electrically controllable metamaterial analogue to electromagnetically induced transparency

    NASA Astrophysics Data System (ADS)

    Fan, Yuancheng; Qiao, Tong; Zhang, Fuli; Fu, Quanhong; Dong, Jiajia; Kong, Botao; Li, Hongqiang

    2017-01-01

    Electromagnetically induced transparency (EIT) is a promising technology for the enhancement of light-matter interactions, and recent demonstrations of the EIT analogue realized in artificial micro-structured medium have remarkably reduced the extreme requirement for experimental observation of EIT spectrum. In this paper, we propose to electrically control the EIT-like spectrum in a metamaterial as an electromagnetic modulator. A diode acting as a tunable resistor is loaded in the gap of paired wires to inductively tune the magnetic resonance, which induces remarkable modulation on the EIT-like spectrum through the metamaterial sample. The experimental measurements confirmed that the prediction of electromagnetic modulation in three narrow bands on the EIT-like spectrum, and a modulation contrast of up to 31 dB was achieved on the transmission through the metamaterial. Our results may facilitate the study on active/dynamical technology in translational metamaterials, which connect extraordinary manipulations on the flow of light in metamaterials, e.g., the exotic EIT, and practical applications in industry.

  17. Evaluation of novel imidazotetrazine analogues designed to overcome temozolomide resistance and glioblastoma regrowth.

    PubMed

    Ramirez, Yulian P; Mladek, Ann C; Phillips, Roger M; Gynther, Mikko; Rautio, Jarkko; Ross, Alonzo H; Wheelhouse, Richard T; Sakaria, Jann N

    2015-01-01

    The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multiforme (GBM) cell lines and primary culture models are reported. Dose-response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repopulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR functions. DP68-induced interstrand DNA cross-links were demonstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell-cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced antiglioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collectively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DNA.

  18. An electromagnetic modulator based on electrically controllable metamaterial analogue to electromagnetically induced transparency

    PubMed Central

    Fan, Yuancheng; Qiao, Tong; Zhang, Fuli; Fu, Quanhong; Dong, Jiajia; Kong, Botao; Li, Hongqiang

    2017-01-01

    Electromagnetically induced transparency (EIT) is a promising technology for the enhancement of light-matter interactions, and recent demonstrations of the EIT analogue realized in artificial micro-structured medium have remarkably reduced the extreme requirement for experimental observation of EIT spectrum. In this paper, we propose to electrically control the EIT-like spectrum in a metamaterial as an electromagnetic modulator. A diode acting as a tunable resistor is loaded in the gap of paired wires to inductively tune the magnetic resonance, which induces remarkable modulation on the EIT-like spectrum through the metamaterial sample. The experimental measurements confirmed that the prediction of electromagnetic modulation in three narrow bands on the EIT-like spectrum, and a modulation contrast of up to 31 dB was achieved on the transmission through the metamaterial. Our results may facilitate the study on active/dynamical technology in translational metamaterials, which connect extraordinary manipulations on the flow of light in metamaterials, e.g., the exotic EIT, and practical applications in industry. PMID:28091539

  19. Synthesis and biological evaluation of analogues of AKT (protein kinase B) inhibitor-IV.

    PubMed

    Sun, Qi; Wu, Runzhi; Cai, Sutang; Lin, Yuan; Sellers, Llewlyn; Sakamoto, Kaori; He, Biao; Peterson, Blake R

    2011-03-10

    Inhibitors of the PI3-kinase/AKT (protein kinase B) pathway are under investigation as anticancer and antiviral agents. The benzimidazole derivative AKT inhibitor-IV (ChemBridge 5233705) affects this pathway and exhibits potent anticancer and antiviral activity. To probe its biological activity, we synthesized AKT inhibitor-IV and 21 analogues using a novel six-step route based on ZrCl(4)-catalyzed cyclization of 1,2-arylenediamines with α,β-unsaturated aldehydes. We examined effects on viability of HeLa carcinoma cells, viability of normal human cells (NHBE), replication of recombinant parainfluenza virus 5 (PIV5) in HeLa cells, and replication of the intracellular bacterium Mycobacterium fortuitum in HeLa cells. Replacement of the benzimidazole N-ethyl substitutent of AKT inhibitor-IV with N-hexyl and N-dodecyl groups enhanced antiviral activity and cytotoxicity against the cancer cell line, but these compounds showed substantially lower toxicity (from 6-fold to >20-fold) against NHBE cells and no effect on M. fortuitum, suggesting inhibition of one or more host protein(s) required for proliferation of cancer cells and PIV5. The key structural elements identified here may facilitate identification of targets of this highly biologically active scaffold.

  20. In vivo pharmacological profile of substituted (3-pyridyl)-2-phenylisoxazolidine analogues of nicotine as novel antinociceptives

    PubMed Central

    Sethi, N.; Bhatti, R.; Ishar, M.P.S.

    2014-01-01

    Nicotinic ligands have been studied as novel therapeutic interventions in pain therapeutics since a long time. Several nicotinic agonists have been withdrawn from later stages of clinical trials due to lack of efficacy or narrow therapeutic window. These have been documented to act in the central nervous system and produce a wide range of pharmacological effects, including memory enhancing and analgesic actions, antianxiety, antidepressant and muscle coordination. Taking cognizance of the wide pharmacological profile of nicotine and its ligands, it was decided to evaluate some novel isoxazolidine analogues of nicotine for their potential as analgesics, using animal models like Eddy's hot plate and Tail immersion method. The compounds showed marked decrease in hyperalgesic response as compared to pentazocine at a wide range of doses. They were well tolerated as none of the compounds was found to have any seizure potential or mortality even at the highest doses. Thus, these compounds can be developed as potent antinociceptives with better safety profile than nicotine and other currently available pain therapeutics. PMID:25598800

  1. Decorated graphyne and its boron nitride analogue as versatile nanomaterials for CO detection

    NASA Astrophysics Data System (ADS)

    Omidvar, Akbar; Mohajeri, Afshan

    2015-12-01

    The sensitivity of a new two-dimensional (2D) carbon allotrope built from sp- and sp2-hybridised carbon atoms, graphyne (GY), as well as its boron nitride analogue (BN-yne) towards CO molecule has been theoretically investigated. Indeed, a theoretical understanding of the interaction between gas molecules and extended carbon-based network structures is crucial for developing new materials that could have a wide range of applications. Here, we report our first-principles calculations to explore the impact of metal decoration on the GY and BN-yne upon the CO adsorption. We predict that Ca and Li decorations significantly enhance the CO-sensing ability of the GY and BN-yne compared to that of their pristine sheets. Owing to strong interactions between CO and the decorated GY and BN-yne, dramatic changes in the electronic properties of the sheets together with large band gap variations were observed. The present study sheds a deep insight into the sensing properties of the novel carbon-based 2D structures beyond the graphene sheet.

  2. 2beta-Substituted analogues of 4'-iodococaine: synthesis and dopamine transporter binding potencies.

    PubMed

    Avor, K S; Singh, S; Seale, T W; Pouw, B; Basmadjian, G P

    1998-06-18

    A series of 2beta-substituted analogues of 4'-iodococaine (3) was synthesized and evaluated in an in vitro dopamine transporter (DAT) binding assay. Selective hydrolysis at the 2beta-position of 3 gave the carboxylic acid 15 that served as the intermediate for the synthesis of compounds 4, 5, and 6-11. The 2beta-alkyl derivatives were obtained from ecgonine methyl ester (17) through a series of reactions leading to the aldehyde 20. Wittig reaction of 20 with methyltriphenylphosphorane followed by hydrogenation and benzoylation gave the products 12 and 13. The binding affinity of 4'-iodococaine (3) was 10-fold less than that of cocaine. The hydroxymethane, acetate, amide, benzyl ester, oxidazole, and ethane derivatives of 3 exhibited decreased binding while the vinyl, phenyl, and ethyl esters showed a moderate increase in binding affinity. Only the isopropyl derivative 8 exhibited a 2-fold increase in binding affinity compared with 4'-iodococaine (3). Hydroxylation of 8 at the 2'-position gave 14 which enhanced not only the binding potency at the DAT by another 2-fold but also the selectivity at the DAT over the norepinephrine and serotonin transporters. Compound 14 failed to stimulate locomotor activity in C57BL/6J mice over a wide dose range and blocked cocaine-induced locomotor stimulant action.

  3. Evaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowth

    PubMed Central

    Ramirez, Yulian P.; Mladek, Ann C.; Phillips, Roger M.; Gynther, Mikko; Rautio, Jarkko; Ross, Alonzo H.; Wheelhouse, Richard T.; Sakaria, Jann N.

    2014-01-01

    The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multiforme (GBM) cell lines and primary culture models are reported. Dose-response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. Based on a serial neurosphere assay, DP68 inhibits repopulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR functions. DP68-induced interstrand DNA crosslinks were demonstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biological response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced anti-glioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collectively, these data demonstrate that DP68 is a novel and potent anti-glioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to crosslink strands of DNA. PMID:25351918

  4. An electromagnetic modulator based on electrically controllable metamaterial analogue to electromagnetically induced transparency.

    PubMed

    Fan, Yuancheng; Qiao, Tong; Zhang, Fuli; Fu, Quanhong; Dong, Jiajia; Kong, Botao; Li, Hongqiang

    2017-01-16

    Electromagnetically induced transparency (EIT) is a promising technology for the enhancement of light-matter interactions, and recent demonstrations of the EIT analogue realized in artificial micro-structured medium have remarkably reduced the extreme requirement for experimental observation of EIT spectrum. In this paper, we propose to electrically control the EIT-like spectrum in a metamaterial as an electromagnetic modulator. A diode acting as a tunable resistor is loaded in the gap of paired wires to inductively tune the magnetic resonance, which induces remarkable modulation on the EIT-like spectrum through the metamaterial sample. The experimental measurements confirmed that the prediction of electromagnetic modulation in three narrow bands on the EIT-like spectrum, and a modulation contrast of up to 31 dB was achieved on the transmission through the metamaterial. Our results may facilitate the study on active/dynamical technology in translational metamaterials, which connect extraordinary manipulations on the flow of light in metamaterials, e.g., the exotic EIT, and practical applications in industry.

  5. Switching magnetic interactions in the NiFe Prussian Blue Analogue: an ab initio inspection.

    PubMed

    Krah, Tim; Amor, Nadia Ben; Robert, Vincent

    2014-05-28

    The magnetic interaction in the Ni(ii)-Fe(iii) Prussian Blue Analogue is investigated by means of Difference Dedicated Configuration Interaction (DDCI) calculations. Embedded cluster calculations are performed to extract the exchange coupling constant J with respect to an opening of the Ni-NC-Fe bridge while maintaining a rigid Fe(CN)6 unit. It is shown that such active distortion significantly modifies the magnetic interaction scheme in the material. Not only a ferromagnetic to antiferromagnetic transition is observed, but the J value is varied from +11.4 cm(-1) to -12.5 cm(-1) when the Ni-Fe cyanide bridge is opened by 20°. The enhancement of the intersite hopping electron transfer integral by a factor of 1.5 can be correlated with the observed Na(+)-ion mobility in a unified "cation-coupled electron transfer" (CCET) process. These results stress the complexity and originality of this class of compounds evidenced by the versatility of their magnetic network.

  6. Synthesis and Thermal Responses of Polygonal Poly(ethylene glycol) Analogues.

    PubMed

    Kawasaki, Shunichi; Muraoka, Takahiro; Hamada, Tsutomu; Shigyou, Kazuki; Nagatsugi, Fumi; Kinbara, Kazushi

    2016-04-05

    As a new type of topological poly(ethylene glycol) (PEG) analogue, a series of polygonal PEGs with digonal to hexagonal structures were developed. Polygonal PEGs with structures between the digonal and tetragonal types showed molecular-level dispersion in water at 20 °C, whereas the pentagonal and hexagonal PEGs aggregated, which is suggestive of enhanced hydrophobicity by ring expansion. Heating induced conformational changes in the polygonal PEGs and increased their hydrophobicity. Among the polygonal PEGs, only the trigonal and hexagonal PEGs showed a distinct thermal response to form and increase the size of the aggregates, respectively. Given that tetragonal and pentagonal PEGs only marginally responded to heat treatment, the thermal responses are likely due to a topological effect. At low temperatures, the larger polygonal PEGs are more restricted despite the expanded rings. The trigonal PEG showed the largest change in mobility, whereas the tetragonal PEG exhibited the smallest change. Hence, the topology of the polygonal PEGs influences the intramolecular packing and the local dynamics.

  7. 3D characterization of the fracture network in a deformed chalk reservoir analogue: The Lagerdorf case

    SciTech Connect

    Koestler, A.G.; Reksten, K.

    1994-12-31

    Quantitative descriptions of the 3D fracture networks in terms of connectivity, fracture types, fracture surface roughness and flow characteristics are necessary for reservoir evaluation, management, and enhanced oil recovery programs of fractured reservoirs. For a period of 2 years, a research project focused on an analogue to fractured chalk reservoirs excellently exposed near Laegerdorf, NW Germany. Upper Cretaceous chalk has been uplifted and deformed by an underlying salt diapir, and is now exploited for the cement industry. In the production wall of a quarry, the fracture network of the deformed chalk was characterized and mapped at different scales. The wall was scraped off as chalk exploitation proceeded, continuously revealing new sections through the faulted and fractured chalk body. A 230 m long part of the 35m high production wall was investigated during its recess of 25m. The large amount of fracture data were analyzed with respect to parameters such as fracture density distribution, orientation- and length distribution, and in terms of the representativity of data sets collected from restricted rock volumes. This 3D description and analysis of a fracture network revealed quantitative generic parameters of importance for modeling chalk reservoirs with less data and lower data quality.

  8. Structure of synthetic peptide analogues of an eggshell protein of Schistosoma mansoni.

    PubMed Central

    Middaugh, C. R.; Thomson, J. A.; Burke, C. J.; Mach, H.; Naylor, A. M.; Bogusky, M. J.; Ryan, J. A.; Pitzenberger, S. M.; Ji, H.; Cordingley, J. S.

    1993-01-01

    The peptide (Gly-L-Tyr-L-Asp-L-Lys-L-Tyr)6, referred to as F4-6, was synthesized as a model for a schistosome eggshell protein in which the Gly-Tyr-Asp-Lys-Tyr consensus sequence is repeated over 40 times. Analysis by CD, Fourier transform infrared spectroscopy, potentiometric and spectrophotomertric titrations, NMR, and molecular modeling suggests that F4-6 forms some type of left-handed structure. A likely possibility appears to be a left-handed alpha-helix stabilized by Lysi-Aspi +4 salt bridges and possibly Aspi-Tyri +4 hydrogen bonding and Tyr-Tyr interactions. Spectroscopic studies of a number of F4-6 analogues support this conclusion. For example, substitution of D-Ala for Gly produces a peptide with enhanced left-handed helical spectral characteristics, whereas an L-Ala substitution results in a peptide with minimal structure. These studies suggest that the F4 protein from Schistosoma mansoni may be the first example of a naturally occurring protein devoid of proline and carbohydrate that forms a left-handed helix composed of L-amino acids, although alternative forms of other left-handed structures have yet to be rigorously excluded. PMID:8318895

  9. Vata-L: Visual-Analogue Test Assessing Anosognosia for Language Impairment

    PubMed Central

    Cocchini, Gianna; Gregg, Nicola; Beschin, Nicoletta; Dean, Michael; Sala, Sergio Della

    2010-01-01

    Lack of awareness (anosognosia) for one's own language impairments has rarely been investigated, despite hampering language rehabilitation. Assessment of anosognosia by means of self-report is particularly complex, as a patient's language difficulties may seriously prevent or bias the assessment. Other methods, such as measures of self-correction and error detection, have provided valuable information, although they are an indirect form of assessment of anosognosia and are not exempt from methodological criticisms. In this study we report on a new tool, the VATA-L (Visual-Analogue Test for Anosognosia for Language impairment), geared at assessing explicit anosognosia for aphasia. The VATA-L compares the patient's self-evaluation with caregivers’ evaluations of the patient's verbal communication abilities in a series of common situations. By means of non-verbal support and a system of check questions, this test minimizes some of the methodological limitations of existing diagnostic tools (e.g., structured interviews), enhancing reliability, and enabling assessment of patients with aphasia. Finally, normative data provided in the study allow a clearer interpretation of the patient's performance and facilitate assessment of anosognosia. PMID:21108150

  10. Structure-activity study on the Phe side chain arrangement of endomorphins using conformationally constrained analogues.

    PubMed

    Tömböly, Csaba; Kövér, Katalin E; Péter, Antal; Tourwé, Dirk; Biyashev, Dauren; Benyhe, Sándor; Borsodi, Anna; Al-Khrasani, Mahmoud; Rónai, András Z; Tóth, Géza

    2004-01-29

    Endomorphins-1 and -2 were substituted with all the beta-MePhe stereoisomers in their Phe residues to generate a conformationally constrained peptide set. This series of molecules was subjected to biological assays, and for beta-MePhe(4)-endomorphins-2, a conformational analysis was performed. Incorporation of (2S,3S)-beta-MePhe(4) resulted in the most potent analogues of both endomorphins with enhanced enzymatic stability. Their micro opioid affinities were 4-times higher than the parent peptides, they stimulated [(35)S]GTPgammaS binding, and they were found to be full agonists. NMR experiments revealed that C-terminal (2S,3S)-beta-MePhe in endomorphin-2 strongly favored the gauche (-) spatial orientation which implies the presence of the chi(1) = -60 degrees rotamer of Phe(4) in the binding conformer of endomorphins. Our results emphasize that the appropriate orientation of the C-terminal aromatic side chain of endomorphins is substantial for binding to the micro opioid receptor.

  11. Uranium in selected endorheic basins as partial analogue for spent fuel behavior in salt

    SciTech Connect

    Van Luik, A.E.

    1987-01-01

    If uranium (U) behavior with respect to the components of certain endorheic (closed) basin subsurface, playa, or terminal lake brines were quantitatively understood, the ability to predict the long-term redistribution of emplaced U among analogous components of salt formations may be enhanced. Tests that determine the nature of U interactions with pure mineral and organic matter surfaces are important, but studying the natural systems available could give indications of long-term stabilities of processes, and of preferential processes. For example, some metals present in trace quantities, such as U, may be coprecipitated in the oxidized zone with an evaporite mineral that may afterward undergo diagenesis, especially if conditions become more reducing. During diagenesis, the trace metal may be remobilized, but scavenged by sulfides or organic particulates, leaving the evaporite mineral depleted of its trace metal content. A survey of the literature shows trace metal behavior in closed basins has been studied. However, information on U consists of only a few abundance determinations for some evaporite systems. Obtaining and interpreting natural analogue data for the U and Th decay series in selected endorheic basin environments is suggested. 44 refs., 3 figs.

  12. Insulin analogues may accelerate progression of diabetic retinopathy after impairment of inner blood-retinal barrier.

    PubMed

    Kaya, Abdullah; Kar, Taner; Aksoy, Yakup; Özalper, Veysel; Başbuğ, Barbaros

    2013-12-01

    Diabetic retinopathy regresses after spontaneous infarction or surgical ablation of pituitary gland. Growth hormone deficiency seems to be a protective factor for development of diabetic retinopathy in dwarfs. Despite the same glycemic control, development of diabetic retinopathy is significantly higher in pubertal subjects than pre-pubertal subjects. These evidences indicate a strong relationship between growth hormone and progression of diabetic retinopathy. Insulin like growth factor-1 (IGF-1) is the most important mediator of effects of growth hormone (GH). It stimulates IGF-1 receptor. Insulin analogues also stimulate IGF-1 receptor. Therefore insulin analogues may show similar effects like growth hormone and deteriorate diabetic retinopathy. However we suggest that impairment degree of inner blood-retinal barrier should be considered for this claim. We hypothesize that insulin analogues have dual effects (beneficial and worsening) depending on stage of impairment of inner blood-retinal barrier. Insulin analogues protect pericytes and blood-retinal barrier by decreasing blood glucose level. Analogues may pass into the retinal tissue in very low amounts when inner blood-retinal barrier is intact. Therefore, insulin analogues may not deteriorate diabetic retinopathy but also have beneficial effect by protecting blood-retinal barrier at this stage. However, they may pass into the retinal tissue in much more amounts when inner blood-retinal barrier impairs. Analogues may deteriorate cellular composition of retina through stimulation of IGF-1 receptors. A number of different cell types, including glia, retinal pigment epithelial cells and fibroblast-like cells have been identified in diabetic epiretinal tissues. Insulin analogues may cause proliferation in these cells. A type of glial cell named Non-astrocytic Inner Retinal Glia-like (NIRG) cell was identified to be stimulated and proliferate by IGF-1. IGF has been reported to generate traction force in retinal

  13. Experimentally determined attenuation and modulus in Earth analogue materials over a wide range of frequency

    NASA Astrophysics Data System (ADS)

    McCarthy, C.; Fujisawa, K.; Takei, Y.; Hiraga, T.

    2009-12-01

    Seismic observations, particularly in areas of active tectonics, show large variations and can be affected by many variables, including temperature, composition, grain size, volatile content and the presence of small quantities of melt or other fluids. The understanding and interpretation of seismic wave dispersion and attenuation data can be significantly enhanced through improved knowledge of material dynamic response at the grain scale (and smaller). The organic binary system borneol-diphenylamine is a suitable analogue of melting in the Earth’s mantle. Not only does the solid phase deform through the same deformation mechanisms (diffusion creep, dislocation creep) observed in geologic materials, but the moderate and controllable dihedral angle (40° at 316 K) exhibited by this system provides an equilibrium melt-geometry very similar to that of the olivine + basalt system [Takei, 2000]. With a eutectic melting temperature (TE = 316 K at ambient pressure) just above room temperature, borneol-diphenylamine provides an attractive chemical analogue to study the properties of solid-melt interaction, obviating the difficulties associated with high-temperature, high-pressure experimentation. We have initiated compression-compression cyclic loading experiments on single phase (borneol; TM = 477 K) and multiphase (borneol-diphenylamine) aggregates. Our newly developed apparatus is able to apply and measure very small stress and strain amplitudes with high accuracy using a piezoelectric actuator and optical displacement meters, respectively. The planned experimental conditions are P = 1 atm, T = 298 - 333 K, strain amplitude <10-5, f = 10-4 - 102 Hz, and melt fraction φ = 0 - 0.1. The combination of low (sub seismic) frequency data obtained from these forced oscillation experiments and high-frequency data (f = 102 - 106) from ultrasonic wave transmission measurements allows us to explore the dissipation and Young’s modulus over a frequency range of some ten decades

  14. Quality of shrimp analogue product as affected by addition of modified potato starch.

    PubMed

    Remya, S; Basu, S; Venkateshwarlu, G; Mohan, C O

    2015-07-01

    The present study was aimed to investigate the effects of addition of modified potato starch on the biochemical and textural properties of shrimp analogue/imitation shrimp, a popular value-added product prepared from surimi. Three batches of shrimp analogues were prepared with 0 % (NPS), 50 % (CPS) and 100 % (MPS) of modified starch incorporation and various quality attributes were monitored at regular intervals during frozen storage (-20 °C). Loss of myofibrillar protein was least for the shrimp analogue sample added with 100 % modified potato starch. The expressible moisture content of MPS (2.48 %) was less affected by long term storage compared to CPS (3.38 %) and NPS (3.99 %). During extended low temperature storage, the textural quality of sea food analogue was highly influenced by the type of starch added to it. The percentage of modified potato starch added to shrimp analogue significantly (p ≤ 0.05) affected its hardness and fracturability. MPS samples did not show significant changes in hardness during storage as compared to other two samples. Springiness of shrimp analogue increased 2.57, 1.5 and 1.77 times with the storage period for samples with NPS, CPS and MPS, respectively. Addition of modified potato starch improved the sensory quality and textural properties of shrimp analogue and reduced the quality degradation during frozen storage as compared to NPS which contained only native potato starch.

  15. Iodination and stability of somatostatin analogues: comparison of iodination techniques. A practical overview.

    PubMed

    de Blois, Erik; Chan, Ho Sze; Breeman, Wouter A P

    2012-01-01

    For iodination ((125/127)I) of tyrosine-containing peptides, chloramin-T, Pre-Coated Iodo-Gen(®) tubes and Iodo-Beads(®) (Pierce) are commonly used for in vitro radioligand investigations and there have been reliant vendors hereof for decades. However, commercial availability of these radio-iodinated peptides is decreasing. For continuation of our research in this field we investigated and optimized (radio-)iodination of somatostatin analogues. In literature, radioiodination using here described somatostatin analogues and iodination techniques are described separately. Here we present an overview, including High Performance Liquid Chromatography (HPLC) separation and characterisation by mass spectrometry, to obtain mono- and di-iodinated analogues. Reaction kinetics of (125/127)I iodinated somatostatin analogues were investigated as function of reaction time and concentration of reactants, including somatostatin analogues, iodine and oxidizing agent. To our knowledge, for the here described somatostatin analogues, no (127)I iodination and optimization are described. (Radio-)iodinated somatostatin analogues could be preserved with a >90% radiochemical purity for 1 month after reversed phase HPLC-purification.

  16. An analogue peptide from the Cancer/Testis antigen PASD1 induces CD8+ T cell responses against naturally processed peptide.

    PubMed

    Hardwick, Nicola; Buchan, Sarah; Ingram, Wendy; Khan, Ghazala; Vittes, Gisella; Rice, Jason; Pulford, Karen; Mufti, Ghulam; Stevenson, Freda; Guinn, Barbara-ann

    2013-01-01

    We have previously identified the novel Cancer/Testis antigen PASD1 by immunoscreening a testis library with pooled acute myeloid leukemia (AML) patient sera. To develop a cytotoxic T lymphocyte (CTL)-inducing vaccine, we have now investigated the carboxy-terminal region, known to contain serological determinants, for MHC class I (HLA-A⋆0201)-binding peptides. Algorithm-selected natural peptides failed to show detectable HLA-A⋆0201 binding in T2 assays. However, anchor-modified analogue peptides showed enhanced binding, with decreased off-rates. Analogue peptide-loaded antigen-presenting cells (APCs) induced IFN-γ production by T cells from normal donors and patients. In addition, peptide-specific T cells could be expanded from cancer patients by stimulation with the PASD1 analogue peptide Pa14. For clinical application, a DNA fusion gene vaccine encoding Pa14 was designed and tested in "humanized" mice. Splenocytes from vaccinated mice showed in vitro cytotoxicity against tumour cells, either exogenously loaded with the corresponding wild-type peptide (Pw8) or expressing endogenously processed PASD1 protein. We show for the first time that a DNA vaccine encoding an altered PASD1 epitope can induce CTLs to target the natural peptide expressed by human tumour cells.

  17. Selective Sensing of Phosphates by a New Bis-heteroleptic Ru(II) Complex through Halogen Bonding: A Superior Sensor over Its Hydrogen-Bonding Analogue.

    PubMed

    Chowdhury, Bijit; Sinha, Sanghamitra; Ghosh, Pradyut

    2016-12-12

    The selective phosphate-sensing property of a bis-heteroleptic Ru(II) complex, 1[PF6 ]2 , which has a halogen-bonding iodotriazole unit, is demonstrated and is shown to be superior to its hydrogen-bonding analogue, 2[PF6 ]2 . Complex 1[PF6 ]2 , exploiting halogen-bonding interactions, shows enhanced phosphate recognition in both acetonitrile and aqueous acetonitrile compared with its hydrogen-bonding analogue, owing to considerable amplification of the Ru(II) -center-based metal-to-ligand charge transfer (MLCT) emission response and luminescence lifetime. Detailed solution-state studies reveal a higher association constant, lower limit of detection, and greater change in lifetime for complex 1 in the presence of phosphates compared with its hydrogen-bonding analogue, complex 2. The (1) H NMR titration study with H2 PO4(-) ascertains that the binding of H2 PO4(-) occurs exclusively through halogen-bonding or hydrogen-bonding interactions in complexes 1[PF6 ]2 and 2[PF6 ]2 , respectively. Importantly, the single-crystal X-ray structure confirms the first ever report on metal-assisted second-sphere recognition of H2 PO4(-) and H2 P2 O7(2-) with 1 through a solitary C-I⋅⋅⋅anion halogen-bonding interaction.

  18. Antidiabetic activity of 3-hydroxyflavone analogues in high fructose fed insulin resistant rats

    PubMed Central

    Nayak, Yogendra; Venkatachalam, H.; Daroji, Vijay Kumar; Mathew, Geetha; Jayashree, B.S.; Unnikrishnan, M.K.

    2014-01-01

    Synthetic 3-hydroxyflavone analogues (JY-1, JY-2, JY-3, JY-4), were tested for antidiabetic activity in high-fructose-diet-fed (66 %, for 6 weeks) insulin-resistant Wistar rats (FD-fed rats). The fasting blood glucose, insulin, creatinine and AGEs were decreased to near normal upon treatment with test compounds. Insulin resistance markers such as HOMA-IR, K-ITT, plasma triglycerides, lipids, endogenous antioxidant defense and glycogen were restored in FD-fed rats after treatment with 3-hydroxyflavones. It is known that insulin resistance is partly because of oxidative stress and hence antioxidant activity was determined. They exhibited significant in vitro DPPH and ABTS radical scavenging activity (IC50: 10.66-66.63 µM). Test compounds inhibited ROS and NO production in RAW 264.7 cells (IC50: 10.39–42.63 µM) and they were found as potent as quercetin. Further, the test compounds inhibited lipid peroxidation at low concentrations (IC50: 99.61-217.47 µM). All test compounds at concentrations 100-200 µM protected calf thymus DNA-damage by Fenton reaction. In addition, test compounds inhibited protein glycation in different in vitro antiglycation assays. JY-2 showed maximum potency in all the stages of glycation which was comparable to the standard quercetin and aminoguanidine. Test compounds also enhanced the glucose uptake by L6 myotubes at an EC50 much lower than that of quercetin. Thus the synthetic 3-hydroxyflavones were found to have good antidiabetic activity by pleotropic and multimodal suppression of insulin resistance and enhancement of glucose uptake by skeletal muscles. These compounds are non-toxic at the doses tested. Further, the combined antioxidant and antiglycation activities of these molecules have complementary benefits in management of diabetes. PMID:26417321

  19. Analogue Models Of Volcanic Spreading At Mt. Vesuvius

    NASA Astrophysics Data System (ADS)

    De Matteo, Ada; Castaldo, Raffaele; D'Auria, Luca; James, Michael; Lane, Steve; Massa, Bruno; Pepe, Susi; Tizzani, Pietro

    2015-04-01

    Somma-Vesuvius is a quiescent strato-volcano of the Neapolitan district, southern Italy, for which various geophysical and geological evidences (e.g. geodetic measurements, geological and structural data, seismic profiles interpretations and surface deformation analysis with Differential Interferometric Synthetic Aperture Radar (DInSAR)) indicate ongoing spreading deformation. In this research we investigate the spreading deformation and associated surface deformation pattern by performing analogue experiments and comparing the results with actual ground deformation as measured using DInSAR data recorded between 1992 and 2010. Somma-Vesuvius consists of a volcanic cone (Gran Cono) lying within an asymmetric caldera (Somma). The Somma caldera is the result of at least 7 Plinian eruptions, the last of which was the 79 CE. Pompeii eruption. The current cone of Mt. Vesuvius grew within the caldera in the following centuries as the effect of continued explosive and effusive activity of the volcano. The volcano lies on a substratum consisting of a Mesozoic carbonatic basement, overlapped by Holocene clastic sediments and volcanic rocks. Our analogue models were built to simulate the shape of the Somma-Vesuvius top a scale of about 1:100000, emplaced on a sand layer (brittle behaviour) laid on a silicone layer (ductile behaviour). Models are based on the Fluid-dynamics Dimensionless Analysis (FDA), according to the Buckingham-Π theorem. In this context, we considered few dimensionless parameters that allowed the setting of a reliable scaled model. To represent the complex Somma-Vesuvius geometry, an asymmetric model was built by setting a truncated cone (mimicking the topography of Somma edifice) topped by another small cone (mimicking the Gran Cono) shifted off the axis of the main cone. Different experiments were carried out in which the thickness of the basal sand layer and of the silicone one were varied. To quantify the vertical and horizontal displacements the

  20. Chasing An Analogue For The Holocene : The Astronomical Forcing

    NASA Astrophysics Data System (ADS)

    Loutre, M.; Crucifix, M.; Berger, A.

    2008-12-01

    Astronomical theories of paleoclimate, e.g. the Milankovitch theory, explain the long-term variations of climate by the changes in the Earth orbit and position against the Sun, and consequently by the change in the distribution of the solar energy reaching the Earth. On the other hand, anthropogenic activities from early agricultural practices to more recent fossil fuel burning also impact climate change. Models, from conceptual ones to the most sophisticated general circulation models can be used to try to disentangle the contribution from human activity and the natural contribution in the record of climate change. Alternatively, a comparison of the climate records during past interglacials similar to the one we are living in can give some insight into the natural behaviour of the climate system during an interglacial. As far as the long-term climate change is mostly orbitally driven, we will search orbital and insolation time series for past analogues of the non-human perturbed Holocene. When doing so, some key questions must be answered. The first one is related to the time interval to be used as target. A previous study (Loutre and Berger, 2000) focused on the interglacial itself, assuming that the preceding deglaciation had a negligible impact on the interglacial. Rather we decided here to choose a target time interval that includes the deglaciation. Another question is related to the choice of the variable that will be used for correlation. It can be the orbital parameters themselves. It is also possible to use top-of-the-atmosphere insolation. If daily insolation is chosen, the latitude and time in the year for which it is computed are crucial; if a more time- integrated insolation is used (e.g. seasonal insolation), the time interval for the integration is an essential feature. Loutre and Berger (2000) used mid-June insolation at 65N and identified MIS11 as the most recent potential analogue for the future climate. A higher correlation of the insolation was

  1. Structure-Activity Relationships and Anti-inflammatory Activities of N-Carbamothioylformamide Analogues as MIF Tautomerase Inhibitors.

    PubMed

    Zhang, Yu; Xu, Lei; Zhang, Zhiqiang; Zhang, Zhiyu; Zheng, Longtai; Li, Dan; Li, Youyong; Liu, Feng; Yu, Kunqian; Hou, Tingjun; Zhen, Xuechu

    2015-09-28

    Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is an attractive therapeutic target for the treatment of inflammatory diseases. In our previous study, 3-[(biphenyl-4-ylcarbonyl)carbamothioyl]amino benzoic acid (compound 1) was discovered as a potent inhibitor of MIF by docking-based virtual screening and bioassays. Here, a series of analogues of compound 1 derived from similarity search and chemical synthesis were evaluated for their MIF tautomerase activities, and their structure-activity relationships were then analyzed. The most potent inhibitor (compound 5) with an IC50 of 370 nM strongly suppressed lipopolysaccharide (LPS)-induced production of TNF-α and IL-6 in a dose-dependent manner and significantly enhanced the survival rate of mice with LPS-induced endotoxic shock from 0 to 35% at 0.5 mg/kg and to 45% at 1 mg/kg, highlighting the therapeutic potential of the MIF tautomerase inhibition in inflammatory diseases.

  2. Synthesis and biological evaluation of novel fluconazole analogues bearing 1,3,4-oxadiazole moiety as potent antifungal agents.

    PubMed

    Liao, Jun; Yang, Fan; Zhang, Lei; Chai, Xiaoyun; Zhao, Qingjie; Yu, Shichong; Zou, Yan; Meng, Qingguo; Wu, Qiuye

    2015-04-01

    A novel series of fluconazole based mimics incorporating 1,3,4-oxadiazole moiety were designed and synthesized. All the title compounds were characterized by (1)H-NMR, (13)C-NMR, and Q-TOF-MS. Preliminary results revealed that most of analogues exhibited significant antifungal activity against seven pathogenic fungi. Compounds 9g and 9k (MIC80 ≤ 0.125 μg/mL, respectively) were found more potent than the positive controls itraconazole and fluconazole as broad-spectrum antifungal agents. The observed docking results showed that the 1,3,4-oxadiazole moiety enhanced the affinity binding to the cytochrome P450 14α-demethylase (CYP51).

  3. Deposition of latex colloids at rough mineral surfaces: an analogue study using nanopatterned surfaces.

    PubMed

    Krishna Darbha, Gopala; Fischer, Cornelius; Michler, Alex; Luetzenkirchen, Johannes; Schäfer, Thorsten; Heberling, Frank; Schild, Dieter

    2012-04-24

    irrespective of the impact of roughness. For polydisperse solutions, an increase in the polydispersity and flow velocity resulted in a reduction of colloid deposition efficiency due to the resulting enhanced double-layer repulsion. Quantification of surface topography variations of two endmembers of natural grain surfaces showed that half-pore depths and roughness of sedimentary quartz grains are mainly in the micrometer range. Grains with diagenetically formed quartz overgrowths, however, show surface roughness mainly in the submicrometer range. Thus, surface topography features applied in the here presented analogue study and resulting variation in particle retention can serve as quantitative analogue for particle reactions in diagenetically altered quartz sands and sandstones. The reported impact of particle polydispersity can have an important application for quantitative prediction of retention of varying types of minerals, such as different clay minerals in the environment under prevailing unfavorable conditions.

  4. Efficacy of Antimicrobials on Bacteria Cultured in a Spaceflight Analogue

    NASA Technical Reports Server (NTRS)

    Nickerson, CA; Wotring, Virginia; Barrila, Jennifer; Crabbe, Aurelie; Castro, Sarah; Davis, Richard; Rideout, April; McCarthy, Breanne; Ott, C. Mark

    2014-01-01

    As humans travel in space, they will interact with microbial flora from themselves, other crewmembers, their food, and the environment. While evaluations of microbial ecology aboard the Mir and ISS suggest a predominance of common environmental flora, the presence of (and potential for) infectious agents has been well documented. Likewise, pathogens have been detected during preflight monitoring of spaceflight food, resulting in the disqualification of that production lot from flight. These environmental and food organisms range from the obligate pathogen, Salmonella enterica serovar Typhimurium (S. Typhimurium), which has been responsible for disqualification and removal of food destined for ISS and has previously been reported from Shuttle crew refuse, to the opportunistic pathogen Staphylococcus aureus, isolated numerous times from ISS habitable compartments and the crew. Infectious disease events have affected spaceflight missions, including an upper respiratory infection that delayed the launch of STS-36 and an incapacitating Pseudomonas aeruginosa urinary tract infection of a crewmember during Apollo 13. These observations indicate that the crew has the potential to be exposed to obligate and opportunistic pathogens. This risk of exposure is expected to increase with longer mission durations and increased use of regenerative life support systems. As antibiotics are the primary countermeasure after infection, determining if their efficacy during spaceflight missions is comparable to terrestrial application is of critical importance. The NASA Rotating Wall Vessel (RWV) culture system has been successfully used as a spaceflight culture analogue to identify potential alterations in several key microbial characteristics, such as virulence and gene regulation, in response to spaceflight culture. We hypothesized that bacteria cultured in the low fluid shear RWV environment would demonstrate changes in efficacy of antibiotics compared to higher fluid shear controls

  5. Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

    PubMed Central

    Rabe, Patrick; Klapschinski, Tim A; Brock, Nelson L; Citron, Christian A; D’Alvise, Paul; Gram, Lone

    2014-01-01

    Summary Tropodithietic acid (TDA) is a structurally unique sulfur-containing antibiotic from the Roseobacter clade bacterium Phaeobacter inhibens DSM 17395 and a few other related species. We have synthesised several structural analogues of TDA and used them in bioactivity tests against Staphylococcus aureus and Vibrio anguillarum for a structure–activity relationship (SAR) study, revealing that the sulfur-free analogue of TDA, tropone-2-carboxylic acid, has an antibiotic activity that is even stronger than the bioactivity of the natural product. The synthesis of this compound and of several analogues is presented and the bioactivity of the synthetic compounds is discussed. PMID:25161739

  6. The stereospecific synthesis of P-chiral biophosphates and their analogues by the Stec reaction.

    PubMed

    Wozniak, Lucyna A; Okruszek, Andrzej

    2003-05-01

    This manuscript summarizes the results of studies on the application of the reaction of dialkyl (aryl) phosphoramidate anions with carbonyl electrophiles for stereospecific synthesis of P-chiral biophosphates (Stec reaction). Following the results obtained with organic phosphoramidates which delineated the scope of the reaction and its stereochemical course, the application of the title reaction is presented for the preparation of diastereomerically pure P-chiral cyclic nucleotide analogues (phosphorothioates, phosphoroselenoates, phosphoroselenothioates, isotopomeric 18O-phosphates), and P-chiral nucleoside monophosphate analogues, as well as dinucleoside phosphate analogues (phosphorothioates, methanephosphonates).

  7. New synthetic strategies towards psammaplin A, access to natural product analogues for biological evaluation.

    PubMed

    Baud, Matthias G J; Leiser, Thomas; Meyer-Almes, Franz-Josef; Fuchter, Matthew J

    2011-02-07

    New synthetic routes towards the natural product psammaplin A were developed with the particular view to preparing diverse analogues for biological assessment. These routes utilize cheap and commercially available starting materials, and allowed access to psammaplin A analogues not accessible via currently reported methods. Preliminary biological studies revealed these compounds to be the most potent non peptidic inhibitors of the enzyme histone deacetylase 1 (HDAC1, class I) discovered so far. Interestingly, psammaplin A and our synthetic analogues show class I selectivity in vitro, an important feature for the design and synthesis of future isoform selective inhibitors.

  8. GnRH Analogues in the Prevention of Ovarian Hyperstimulation Syndrome

    PubMed Central

    Alama, Pilar; Bellver, Jose; Vidal, Carmen; Giles, Juan

    2013-01-01

    The GnRH analogue (agonist and antagonist GnRH) changed ovarian stimulation. On the one hand, it improved chances of pregnancy to obtain more oocytes and better embryos. This leads to an ovarian hyper-response, which can be complicated by the ovarian hyperstimulation syndrome (OHSS). On the other hand, the GnRH analogue can prevent the incidence of OHSS: GnRH antagonist protocols, GnRH agonist for triggering final oocyte maturation, either together or separately, coasting, and the GnRH analogue may prove useful for avoiding OHSS in high-risk patients. We review these topics in this article. PMID:23825982

  9. 3D-QSAR-Assisted Design, Synthesis, and Evaluation of Novobiocin Analogues

    PubMed Central

    2012-01-01

    Hsp90 is an attractive therapeutic target for the treatment of cancer. Extensive structural modifications to novobiocin, the first Hsp90 C-terminal inhibitor discovered, have produced a library of novobiocin analogues and revealed some structure–activity relationships. On the basis of the most potent novobiocin analogues generated from prior studies, a three-dimensional quantitative structure–activity (3D QSAR) model was built. In addition, a new set of novobiocin analogues containing various structural features supported by the 3D QSAR model were synthesized and evaluated against two breast cancer cell lines. Several new inhibitors produced antiproliferative activity at midnanomolar concentrations, which results through Hsp90 inhibition. PMID:23606927

  10. Isolation and structural elucidation of a new tadalafil analogue in health supplements: bisprenortadalafil.

    PubMed

    Lee, Ji Hyun; Park, Han Na; Ganganna, Bogonda; Jeong, Ji Hye; Park, Sung-Kwan; Lee, Jongkook; Baek, Sun Young

    2016-06-01

    A new tadalafil analogue was found, along with nortadalafil, using HPLC-DAD during the inspection of a health product sold without official approval. The analogue was separated using a semi-preparative HPLC system and its structure was determined by a combination of mass spectrometry and NMR spectroscopy. The compound was identified as a tadalafil analogue in which the N-methyl group of tadalafil was replaced with a tadalafil precursor moiety. Nuclear Overhauser effect spectroscopy experiments suggested a cis-relationship between the substituents on a piperidine ring in the tadalafil moiety.

  11. Hierarchically Superstructured Prussian Blue Analogues: Spontaneous Assembly Synthesis and Applications as Pseudocapacitive Materials

    SciTech Connect

    Yue, Yanfeng; Zhang, Zhiyong; Binder, Andrew J.; Chen, Jihua; Jin, Xianbo; Overbury, Steven; Dai, Sheng

    2014-11-10

    Hierarchically superstructured Prussian blue analogues (hexa- conventional hybrid graphene/MnO2 nanostructured textiles. cyanoferrate, M = NiII, CoII and CuII) are synthesized through Because sodium or potassium ions are involved in energy stor- a spontaneous assembly technique. In sharp contrast to mac- age processes, more environmentally neutral electrolytes can roporous-only Prussian blue analogues, the hierarchically su- be utilized, making the superstructured porous Prussian blue perstructured porous Prussian blue materials are demonstrated analogues a great contender for applications as high-per- to possess a high capacitance, which is similar to those of the formance pseudocapacitors.

  12. The role of the "Casimir force analogue" at the microscopic processes of crystallization and melting

    NASA Astrophysics Data System (ADS)

    Chuvildeev, V. N.; Semenycheva, A. V.

    2016-10-01

    Melting (crystallization), a phase transition from a crystalline solid to a liquid state, is a common phenomenon in nature. We suggest a new factor, "the Casimir force analogue", to describe mechanisms of melting and crystallization. The Casimir force analogue is a force occurring between the surfaces of solid and liquid phases of metals caused by different energy density of phonons of these phases. It explains abrupt changes in geometry and thermodynamic parameters at a melting point. "The Casimir force analogue" helps to estimate latent melting heat and to gain an insight into a solid-liquid transition problem.

  13. Hierarchically Superstructured Prussian Blue Analogues: Spontaneous Assembly Synthesis and Applications as Pseudocapacitive Materials

    DOE PAGES

    Yue, Yanfeng; Zhang, Zhiyong; Binder, Andrew J.; ...

    2014-11-10

    Hierarchically superstructured Prussian blue analogues (hexa- conventional hybrid graphene/MnO2 nanostructured textiles. cyanoferrate, M = NiII, CoII and CuII) are synthesized through Because sodium or potassium ions are involved in energy stor- a spontaneous assembly technique. In sharp contrast to mac- age processes, more environmentally neutral electrolytes can roporous-only Prussian blue analogues, the hierarchically su- be utilized, making the superstructured porous Prussian blue perstructured porous Prussian blue materials are demonstrated analogues a great contender for applications as high-per- to possess a high capacitance, which is similar to those of the formance pseudocapacitors.

  14. Synthesis of a des-B-ring bryostatin analogue leads to an unexpected ring expansion of the bryolactone core.

    PubMed

    Kraft, Matthew B; Poudel, Yam B; Kedei, Noemi; Lewin, Nancy E; Peach, Megan L; Blumberg, Peter M; Keck, Gary E

    2014-09-24

    A convergent synthesis of a des-B-ring bryostatin analogue is described. This analogue was found to undergo an unexpected ring expansion of the bryolactone core to generate the corresponding 21-membered macrocycle. The parent analogue and the ring-expanded product both displayed nanomolar binding affinity for PKC. Despite containing A-ring substitution identical to that of bryostatin 1 and displaying bryostatin-like biological function, the des-B-ring analogues displayed a phorbol-like biological function in cells. These studies shed new light on the role of the bryostatin B-ring in conferring bryo-like biological function to bryostatin analogues.

  15. Novel dual agonist peptide analogues derived from dogfish glucagon show promising in vitro insulin releasing actions and antihyperglycaemic activity in mice.

    PubMed

    O'Harte, F P M; Ng, M T; Lynch, A M; Conlon, J M; Flatt, P R

    2016-08-15

    The antidiabetic potential of thirteen novel dogfish glucagon derived analogues were assessed in vitro and in acute in vivo studies. Stable peptide analogues enhanced insulin secretion from BRIN-BD11 β-cells (p < 0.001) and reduced acute glycaemic responses following intraperitoneal glucose (25 nmol/kg) in healthy NIH Swiss mice (p < 0.05-p<0.001). The in vitro insulinotropic actions of [S2a]dogfish glucagon, [S2a]dogfish glucagon-exendin-4(31-39) and [S2a]dogfish glucagon-Lys(30)-γ-glutamyl-PAL, were blocked (p < 0.05-p<0.001) by the specific GLP-1 and glucagon receptor antagonists, exendin-4(9-39) and (desHis(1)Pro(4)Glu(9))glucagon amide but not by (Pro(3))GIP, indicating lack of GIP receptor involvement. These analogues dose-dependently stimulated cAMP production in GLP-1 and glucagon (p < 0.05-p<0.001) but not GIP-receptor transfected cells. They improved acute glycaemic and insulinotropic responses in high-fat fed diabetic mice and in wild-type C57BL/6J and GIPR-KO mice (p < 0.05-p<0.001), but not GLP-1R-KO mice, confirming action on GLP-1 but not GIP receptors. Overall, dogfish glucagon analogues have potential for diabetes therapy, exerting beneficial metabolic effects via GLP-1 and glucagon receptors.

  16. Sarcoplasmic reticulum calcium ATPase is inhibited by organic vanadium coordination compounds: pyridine-2,6-dicarboxylatodioxovanadium(V), BMOV, and an amavadine analogue.

    PubMed

    Aureliano, Manuel; Henao, Fernando; Tiago, Teresa; Duarte, Rui O; Moura, J J G; Baruah, Bharat; Crans, Debbie C

    2008-07-07

    The general affinity of the sarcoplasmic reticulum (SR) Ca (2+)-ATPase was examined for three different classes of vanadium coordination complexes including a vanadium(V) compound, pyridine-2,6-dicarboxylatodioxovanadium(V) (PDC-V(V)), and two vanadium(IV) compounds, bis(maltolato)oxovanadium(IV) (BMOV), and an analogue of amavadine, bis( N-hydroxylamidoiminodiacetato)vanadium(IV) (HAIDA-V(IV)). The ability of vanadate to act either as a phosphate analogue or as a transition-state analogue with enzymes' catalysis phosphoryl group transfer suggests that vanadium coordination compounds may reveal mechanistic preferences in these classes of enzymes. Two of these compounds investigated, PDC-V(V) and BMOV, were hydrolytically and oxidatively reactive at neutral pH, and one, HAIDA-V(IV), does not hydrolyze, oxidize, or otherwise decompose to a measurable extent during the enzyme assay. The SR Ca (2+)-ATPase was inhibited by all three of these complexes. The relative order of inhibition was PDC-V(V) > BMOV > vanadate > HAIDA-V(IV), and the IC 50 values were 25, 40, 80, and 325 microM, respectively. Because the observed inhibition is more potent for PDC-V(V) and BMOV than that of oxovanadates, the inhibition cannot be explained by oxovanadate formation during enzyme assays. Furthermore, the hydrolytically and redox stable amavadine analogue HAIDA-V(IV) inhibited the Ca (2+)-ATPase less than oxovanadates. To gauge the importance of the lipid environment, studies of oxidized BMOV in microemulsions were performed and showed that this system remained in the aqueous pool even though PDC-V(V) is able to penetrate lipid interfaces. These findings suggest that the hydrolytic properties of these complexes may be important in the inhibition of the calcium pump. Our results show that two simple coordination complexes with known insulin enhancing effects can invoke a response in calcium homeostasis and the regulation of muscle contraction through the SR Ca (2+)-ATPase.

  17. Reversal of arsenic-induced hepatic apoptosis with combined administration of DMSA and its analogues in guinea pigs: role of glutathione and linked enzymes.

    PubMed

    Mishra, Deepshikha; Mehta, Ashish; Flora, Swaran J S

    2008-02-01

    Arsenicosis, due to contaminated drinking water in the Indo-Bangladesh region, is a serious health hazard in terms of morbidity and mortality. Reactive oxygen species (ROS) generated due to arsenic toxicity have been attributed as one of the initial signals that impart cellular toxicity, which is controlled by the internal antioxidant glutathione (GSH). In the present study, we investigated (i) the role of GSH and its linked enzymes, glutathione peroxidase and glutathione reductase, in reversing chronic arsenic toxicity using a thiol chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA), or one of its analogues individually or in combination; (ii) if alterations in the carbon side chain of DMSA increased efficacy; and (iii) whether the combination therapy enhance arsenic removal from hepatic tissue and prevent hepatic apoptosis. Results indicated that chronic arsenic exposure led to a ROS-mediated, mitochondrial-driven, caspase-dependent apoptosis in hepatic cells with a significant increase in glutathione disulfide (GSSG) levels and decreased glutathione reductase levels. Monotherapy with DMSA and its analogues did show minimal recovery postchelation. However, the combination of DMSA with long carbon chain analogues like monoisoamyl DMSA (MiADMSA) or monocyclohexyl DMSA (MchDMSA) showed a better efficacy in terms of reducing the arsenic burden as well as reversing altered biochemical variables indicative of oxidative stress and apoptosis. We also observed that GSH and its linked enzymes, especially glutathione reductase, play a vital role in scavenging ROS, maintaining GSH pools, and providing clinical recoveries. On the basis of the above observations, we recommend that combinational therapy of DMSA and its long carbon chain analogues MiADMSA or MchDMSA would be more effective in arsenic toxicity.

  18. Pyrrolines as prodrugs of gamma-aminobutyric acid analogues.

    PubMed

    Callery, P S; Geelhaar, L A; Nayar, M S; Stogniew, M; Rao, K G

    1982-04-01

    delta 1-Pyrroline, 5-methyl-delta 1-pyrroline, and 5,5-dimethyl-delta 1-pyrroline have been identified as substances metabolized to gamma-aminobutyric acid (GABA), 4-aminopentanoic acid (methylGABA), and 4-amino-4-methylpentanoic acid (dimethylGABA), respectively. An enzyme system residing in the soluble fraction of rabbit liver catalyzes the conversion of delta 1-pyrroline to GABA and its lactam, 2-pyrrolidinone. Acetaldehyde, allopurinol, and cyanide inhibited the reaction. Incubation of deuterium-labeled delta 1-pyrroline with mouse brain homogenates produced deuterated GABA. Mouse liver 10,000 g supernatant and mouse brain homogenates converted 5-methyl-delta 1-pyrroline to methylGABA, and 5,5-dimethyl-delta 1-pyrroline to dimethylGABA. Four hours after intraperitoneal injection of 5-methyl-delta 1-pyrroline (200 mg/kg), methylGABA was detected in mouse brain (0.27 mumol/g). DimethylGABA (1.21 mumol/g) was determined in mouse brain 30 min after intraperitoneal administration of 5,5-dimethyl-delta 1-pyrroline (200 mg/kg). Neither methylGABA nor dimethylGABA penetrated into the central nervous system when administered in the periphery. The present studies suggest that pyrrolines may represent a chemical class of brain-penetrating precursors of pharmacologically active analogues of GABA.

  19. Bioactive phenylpropanoid analogues from Piper betle L. var. haldia leaves.

    PubMed

    Atiya, Akhtar; Sinha, Barij Nayan; Lal, Uma Ranjan

    2017-02-15

    Phytochemical analyses of the chloroform extract of Piper betle L. var. birkoli, Piperaceae, leaves led to the isolation of two new phenylpropanoid analogues: bis-chavicol dodecanoyl ester (2) and bis-hydroxychavicol dodecanoyl ester (3), along with one known compound: allyl-3-methoxy-4-hydroxybenzene (1) on the basis of spectroscopic data 1D ((1)H and (13)C) and 2D ((1)H-(1)H COSY and HMBC) NMR, as well as ESI-MS, FT-IR, HR-ESI-MS and LC-ESI-MS. Compound 2 and 3 exhibited excellent antioxidant DPPH radical scavenging activity with IC50 values of 12.67 μg/mL and 1.08 μg/mL compared to ascorbic acid as a standard antioxidant drug with IC50 value of 6.60 μg/mL. Evaluation of cytotoxic activity against two human oral cancer cell lines (AW13516 and AW8507) showed significant effect with GI50 values of 19.61 and 23.01 μg/mL for compound 2 and 10.25 and 13.12 μg/mL for compound 3, compared to Doxorubicin(®) as a standard cytotoxic drug with GI50 value of < 10 μg/mL.

  20. An analogue of Wagner's theorem for decompositions of matrix algebras

    NASA Astrophysics Data System (ADS)

    Ivanov, D. N.

    2004-12-01

    Wagner's celebrated theorem states that a finite affine plane whose collineation group is transitive on lines is a translation plane. The notion of an orthogonal decomposition (OD) of a classically semisimple associative algebra introduced by the author allows one to draw an analogy between finite affine planes of order n and ODs of the matrix algebra M_n(\\mathbb C) into a sum of subalgebras conjugate to the diagonal subalgebra. These ODs are called WP-decompositions and are equivalent to the well-known ODs of simple Lie algebras of type A_{n-1} into a sum of Cartan subalgebras. In this paper we give a detailed and improved proof of the analogue of Wagner's theorem for WP-decompositions of the matrix algebra of odd non-square order an outline of which was earlier published in a short note in "Russian Math. Surveys" in 1994. In addition, in the framework of the theory of ODs of associative algebras, based on the method of idempotent bases, we obtain an elementary proof of the well-known Kostrikin-Tiep theorem on irreducible ODs of Lie algebras of type A_{n-1} in the case where n is a prime-power.

  1. Bioactivity of permselective PVA hydrogels with mixed ECM analogues.

    PubMed

    Nafea, Eman H; Poole-Warren, Laura A; Martens, Penny J

    2015-12-01

    The presentation of multiple biological cues, which simulate the natural in vivo cell environment within artificial implants, has recently been identified as crucial for achieving complex cellular functions. The incorporation of two or more biological cues within a largely synthetic network can provide a simplified model of multifunctional ECM presentation to encapsulated cells. Therefore, the aim of this study was to examine the effects of simultaneously and covalently incorporating two dissimilar biological molecules, heparin and gelatin, within a PVA hydrogel. PVA was functionalized with 7 and 20 methacrylate functional groups per chain (FG/c) to tailor the permselectivity of UV photopolymerized hydrogels. Both heparin and gelatin were covalently incorporated into PVA at an equal ratio resulting in a final PVA:heparin:gelatin composition of 19:0.5:0.5. The combination of both heparin and gelatin within a PVA network has proven to be stable over time without compromising the PVA base characteristics including its permselectivity to different proteins. Most importantly, this combination of ECM analogues supplemented PVA with the dual functionalities of promoting cellular adhesion and sequestering growth factors essential for cellular proliferation. Multi-functional PVA hydrogels with synthetically controlled network characteristics and permselectivity show potential in various biomedical applications including artificial cell implants.

  2. Hydrogen adsorption in thin films of Prussian blue analogue

    SciTech Connect

    Yang, Dali; Ding, Vivian; Luo, Junhua; Currier, Robert P; Obrey, Steve; Zhao, Yusheng

    2008-01-01

    Quartz crystal microbalance with dissipation (QCM-D) measurement was used to investigate the kinetics of the molecular hydrogen adsorption into thin films of prussian blue analogues - Cu{sub 3}[Co(CN){sub 6}]{sub 2} at ambient conditions. Although the equilibrium adsorption seems to be independent of the thickness, the adsorption rate substantially decreases with the thickness of the films. In addition, the reversibility of H{sub 2} adsorption into the Cu{sub 3}[Co(CN){sub 6}]{sub 2} films was investigated. The results indicate that the Cu{sub 3}[Co(CN){sub 6}]{sub 2} maily interacts with H{sub 2} molecules physically. The highest H{sub 2} uptake by the Cu{sub 3}[Co(CN){sub 6}]{sub 2} films is obtained when the gas phase is stagnant inside the testing cell. However, the unusual high H{sub 2} uptake obtained from the QCM-D measurement makes us question how reliable this analytic methodology is.

  3. Encoding complexity within supramolecular analogues of frustrated magnets

    NASA Astrophysics Data System (ADS)

    Cairns, Andrew B.; Cliffe, Matthew J.; Paddison, Joseph A. M.; Daisenberger, Dominik; Tucker, Matthew G.; Coudert, François-Xavier; Goodwin, Andrew L.

    2016-05-01

    The solid phases of gold(I) and/or silver(I) cyanides are supramolecular assemblies of inorganic polymer chains in which the key structural degrees of freedom—namely, the relative vertical shifts of neighbouring chains—are mathematically equivalent to the phase angles of rotating planar (‘XY’) spins. Here, we show how the supramolecular interactions between chains can be tuned to mimic different magnetic interactions. In this way, the structures of gold(I) and/or silver(I) cyanides reflect the phase behaviour of triangular XY magnets. Complex magnetic states predicted for this family of magnets—including collective spin-vortices of relevance to data storage applications—are realized in the structural chemistry of these cyanide polymers. Our results demonstrate how chemically simple inorganic materials can behave as structural analogues of otherwise inaccessible ‘toy’ spin models and also how the theoretical understanding of those models allows control over collective (‘emergent’) phenomena in supramolecular systems.

  4. The degree of biogenicity of micrites and terrestrial Mars analogues .

    NASA Astrophysics Data System (ADS)

    D'Elia, M.; Blanco, A.; Orofino, V.; Fonti, S.; Mastandrea, A.; Guido, A.; Tosti, F.; Russo, F.

    A number of indications, as the past presence of water, a denser atmosphere and a mild climate on early Mars, suggest that environmental conditions favorable to the emergence of life must have been present on that planet in the first hundred million years, or even more recently. If life actually existed on Mars, biomarkers could be still preserved with some degree of degradation. In previous laboratory works we have investigated the infrared spectral modifications induced by thermal processing on different carbonate samples, in the form of recent shells and fossils of different ages, whose biogenic origin is indisputable. The goal was to develop a method able to discriminate carbonate biogenic samples from their abiogenic counterparts. The method has been successfully applied to microbialites, i.e. bio-induced carbonates deposits, and particularly to stromatolites, the laminated fabric of microbialites, some of which can be ascribed among the oldest traces of biological activity known on Earth. This result is of valuable importance since such carbonates are linked to primitive living organisms which can be considered as good analogues for putative Martian life forms. In this work we show that, studying different parts of the same carbonate rock sample, we are able to distinguish, on the base of the degree of biogenicity, the various micrite types (i.e. detrital vs autochthonous).

  5. Effects of cognitive and pharmacologic strategies on analogued labor pain.

    PubMed

    Geden, E A; Beck, N C; Anderson, J S; Kennish, M E; Mueller-Heinze, M

    1986-01-01

    Using an analogued labor pain procedure, the efficacy of combinations of five cognitive and one pharmacologic approach to pain management was examined. Nulliparous undergraduates (N = 120) were randomly assigned to 1 of 12 groups. Cognitive groups included: systematic desensitization (SYS DENS); sensory description (SEN DESC); sensory transformation (ST); modeling (M); and relaxation (R); combined groups: SYS DENS, SEN DESC, and ST; SEN DESC, ST, and R; SEN DESC, R, ST, and Demerol. Pharmacologic groups included expected Demerol, did not expect Demerol, placebo, and no treatment control. Subjects assigned to a cognitive group received two 1-hour training sessions 1 week apart. Remaining subjects were given the assigned pharmacologic treatment one-half hour prior to the exposure to the painful stimulus. Assessment of the cognitive and pharmacologic approaches were made in a 1-hour session involving twenty 80-second exposures to a laboratory pain stimulus patterned to resemble labor contractions. Dependent variables included self-reported pain, blood pressure, frontalis electromyograph, heart rate, and respiratory rate. Significant treatment by trials and treatment effects were found for self-reported pain. No other effects achieved statistical significance.

  6. The Disk and Planets of Solar Analogue τCeti

    NASA Astrophysics Data System (ADS)

    Lawler, S. M.; Francesco, J. Di; Kennedy, G.; Sibthorpe, B.; Booth, M.; Vandenbussche, B.; Matthews, B.; Tuomi, M.

    2015-01-01

    τ Ceti is a nearby, mature star very similar to our Sun, with a massive Kuiper belt analogue tep{Greavesetal2004} and possible multiplanet system tep{Tuomietal2013} that has been compared to our Solar System. We present infrared and submillimeter observations of the debris disk from the Herschel Space Observatory and the James Clerk Maxwell Telescope (JCMT). We find the best model of the disk is a wide annulus ranging from 5-55 AU, inclined from face-on by 30°. tet{Tuomietal2013} report five possible super-Earths tightly nestled inside 1.4 AU, and we model this planetary system and place dynamical constraints on the inner edge of the disk. We find that due to the low masses and fairly circular orbits of the planets, the disk could reach as close to the star as 1.5 AU, with some stable orbits even possible between the two outermost planets. The photometric modelling cannot rule out a disk inner edge as close to the star as 1 AU, though 5-10 AU produces a better fit to the data. Dynamical modelling shows that the 5 planet system is stable with the addition of a Saturn-mass planet on an orbit outside 5 AU, where the Tuomi et al. analysis would not have detected a planet of this mass.

  7. High-affinity carbamate analogues of morphinan at opioid receptors.

    PubMed

    Peng, Xuemei; Knapp, Brian I; Bidlack, Jean M; Neumeyer, John L

    2007-03-15

    A series of carbamate analogues were synthesized from levorphanol (1a), cyclorphan (2a) or butorphan (3a) and evaluated in vitro for their binding affinity at mu, delta, and kappa opioid receptors. Functional activities of these compounds were measured in the [(35)S]GTPgammaS binding assay. Phenyl carbamate derivatives 2d and 3d showed the highest binding affinity for kappa receptor (K(i)=0.046 and 0.051 nM) and for mu receptor (K(i)=0.11 and 0.12 nM). Compound 1c showed the highest mu selectivity. The preliminary assay for agonist and antagonist properties of these ligands in stimulating [(35)S]GTPgammaS binding mediated by the kappa opioid receptor illustrated that all of these ligands were kappa agonists. At the mu receptor, compounds 1b, 1c, 2b, and 3b were agonists, while compounds 2c-e and 3c-e were mu agonists/antagonists.

  8. A Visual Analogue Scale in the Assessment of Dental Anxiety

    PubMed Central

    Luyk, Neil H.; Beck, Frank M.; Weaver, Joel M.

    1988-01-01

    The purpose of this study is to determine the validity of the visual analogue scale (VAS) in the assessment of changing levels of dental anxiety, through correlation with the dental anxiety scale (DAS) and the state portion (A-state) of the statetrait anxiety inventory (STAI). Forty-five adult patients attending an oral surgery clinic for a routine dental extraction participated. Before any treatment, each patient completed the DAS, the STAI, and a 100mm VAS. The order of administration was randomly determined. Following completion of the dental extraction under local anesthesia and just before discharge, the patients were once more asked to complete the DAS, the A-State, and a VAS which were again randomly ordered. All three measures demonstrate a significant reduction in mean anxiety scores from presurgery to postsurgery. There are significant correlations among the three measures both pre- and postsurgery. The VAS appears to correlate well with both the DAS and the A-State under changing levels of anxiety. PMID:3166350

  9. Digitally Programmable Analogue Circuits for Sensor Conditioning Systems

    PubMed Central

    Zatorre, Guillermo; Medrano, Nicolás; Sanz, María Teresa; Aldea, Concepción; Calvo, Belén; Celma, Santiago

    2009-01-01

    This work presents two current-mode integrated circuits designed for sensor signal preprocessing in embedded systems. The proposed circuits have been designed to provide good signal transfer and fulfill their function, while minimizing the load effects due to building complex conditioning architectures. The processing architecture based on the proposed building blocks can be reconfigured through digital programmability. Thus, sensor useful range can be expanded, changes in the sensor operation can be compensated for and furthermore, undesirable effects such as device mismatching and undesired physical magnitudes sensor sensibilities are reduced. The circuits were integrated using a 0.35 μm standard CMOS process. Experimental measurements, load effects and a study of two different tuning strategies are presented. From these results, system performance is tested in an application which entails extending the linear range of a magneto-resistive sensor. Circuit area, average power consumption and programmability features allow these circuits to be included in embedded sensing systems as a part of the analogue conditioning components. PMID:22412331

  10. Digitally programmable analogue circuits for sensor conditioning systems.

    PubMed

    Zatorre, Guillermo; Medrano, Nicolás; Sanz, María Teresa; Aldea, Concepción; Calvo, Belén; Celma, Santiago

    2009-01-01

    This work presents two current-mode integrated circuits designed for sensor signal preprocessing in embedded systems. The proposed circuits have been designed to provide good signal transfer and fulfill their function, while minimizing the load effects due to building complex conditioning architectures. The processing architecture based on the proposed building blocks can be reconfigured through digital programmability. Thus, sensor useful range can be expanded, changes in the sensor operation can be compensated for and furthermore, undesirable effects such as device mismatching and undesired physical magnitudes sensor sensibilities are reduced. The circuits were integrated using a 0.35 μm standard CMOS process. Experimental measurements, load effects and a study of two different tuning strategies are presented. From these results, system performance is tested in an application which entails extending the linear range of a magneto-resistive sensor. Circuit area, average power consumption and programmability features allow these circuits to be included in embedded sensing systems as a part of the analogue conditioning components.

  11. Role of Cosmic Dust Analogues in prebiotic chemistry

    NASA Astrophysics Data System (ADS)

    Brucato, J. R.; Strazzulla, G.; Baratta, G. A.; Saladino, R.; di Mauro, E.

    Dust grains could have played an important role in driving the formation of complex molecular compounds relevant for the prebiotic chemistry occurred in the early Earth. Dust and molecular compounds present in space experienced very different environments, with temperatures ranging from few to thousands of Kelvins, and with very harsh conditions due to particle and UV irradiations. Astronomical observations of the interstellar medium, coupled with direct in-situ investigations of solar system bodies performed by space missions and laboratory analyses of extraterrestrial material have shown the presence of large amount of organic molecules. The detection of more than one hundred molecules demonstrates that chemical reactions can proceed successfully in space. However, due to low efficiency, formation of complex molecules in gas phase is not feasible, then an active chemistry has been suggested to take place at cryogenic temperatures (~10 K) on cosmic dust grains acting as catalysts. We will present laboratory results on catalytic effects of Cosmic Dust Analogues (CDAs) with olivine composition, in the synthesis of organic molecules under different physical conditions by using formamide (NH2COH). We will show the important role of CDAs in prebiotic chemistry experiments simulating processes occurring in astronomical environments relevant for the origin of life in the Solar System.

  12. Detecting Pyrolysis Products from Bacteria in a Mars Soil Analogue

    NASA Technical Reports Server (NTRS)

    Glavin, D. P.; Cleaves, H. J.; Schubert, M.; Aubrey, A.; Buch, A.; Mahaffy, P. R.; Bada, J. L.

    2004-01-01

    One of the primary objectives of the 1976 Viking missions was to determine whether organic compounds, possibly of biological origin, were present in the Martian surface soils. The Viking gas chromatography mass spectrometry (GCMS) instruments found no evidence for any organic compounds of Martian origin above a few parts per billion in the upper 10 cm of surface soil, suggesting the absence of a widely distributed Martian biota. However, it is now known that key organic compounds important to biology, such as amino acids, carboxylic acids and nucleobases, would likely have been missed by the Viking GCMS instruments. In this study, a Mars soil analogue that was inoculated with approx. 10 billion Escherichia coli cells was heated at 500 C under Martian ambient pressure to release volatile organic compounds from the sample. The pyrolysis products were then analyzed for amino acids and nucleobases using high performance liquid chromatography (HPLC) and GCMS. Our experimental results indicate that at the part per billion level, the degradation products generated from several million bacterial cells per gram of Martian soil would not have been detected by the Viking GCMS instruments. Upcoming strategies for Mars exploration will require in-situ analyses by instruments that can assess whether any organic compounds, especially those that might be associated with life, are present in Martian surface samples.

  13. Probing riboswitch-ligand interactions using thiamine pyrophosphate analogues.

    PubMed

    Chen, Liuhong; Cressina, Elena; Dixon, Neil; Erixon, Karl; Agyei-Owusu, Kwasi; Micklefield, Jason; Smith, Alison G; Abell, Chris; Leeper, Finian J

    2012-08-14

    The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, thiamine pyrophosphate (TPP or thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch-ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.

  14. Upheaval Dome, An Analogue Site for Gale Center

    NASA Technical Reports Server (NTRS)

    Conrad, P. G.; Eignebrode, J. L.

    2011-01-01

    We propose Upheaval Dome in southeastern Utah as an impact analogue site on Earth to Mars Science Laboratory candidate landing site Gale Crater. The genesis of Upheaval Dome was a mystery for some time--originally thought to be a salt dome. The 5 km crater was discovered to possess shocked quartz and other shock metamorphic features just a few years ago, compelling evidence that the crater was formed by impact, although the structural geology caused Shoemaker and Herkenhoff to speculate an impact origin some 25 years earlier. The lithology of the crater is sedimentary. The oldest rocks are exposed in the center of the dome, upper Permian sandstones, and progressively younger units are well exposed moving outward from the center. These are Triassic sandstones, siltstones and shales, which are intruded by clastic dikes. There are also other clay-rich strata down section, as is the case with Gale Crater. There is significant deformation in the center of the crater, with folding and steeply tilted beds, unlike the surrounding Canyonlands area, which is relatively undeformed. The rock units are well exposed at Upheaval Dome, and there are shatter cones, impactite fragments, shocked quartz grains and melt rocks present. The mineral shock features suggest that the grains were subjected to dynamic pressures> 10 GPa.

  15. Preliminary results of Mn partitioning experiments on Murchison analogues

    NASA Technical Reports Server (NTRS)

    Boesenberg, Joseph S.; Delaney, Jeremy S.

    1993-01-01

    Eucrites, howardites, and diogenites have Fe/Mn ratios between 30 and 45, while carbonaceous chondrites have much higher values between 90 and 150. Stolper (1977) first showed that basaltic achondrites could evolve from a precursor chondritic material through simple partial melting. These experiments indicated that chondritic material heated to temperatures near 1180 C with a fugacity of one log unit below the iron-wustite buffer curve, produced a eucritic mineralogy that contained olivine, pigeonite, plagioclase, spinel, glass, and metal. The partial melting experiments of Jurewicz et al. (1992) on an hydrous Murchison and Allende also showed that HED compositions were produceable at temperatures between 1130 C and 1325 C with fugacities below and above the iron-wustite buffer curve. However, the MnO abundances of Jurewicz were too low to produce suitable Fe/Mn ratios for HED's. We present below our results of partial melting experiments on Murchison analogues that involved temperatures between 1180 C and 1580 C and fugacities below the iron-wustite buffer curve. Our experiments resulted in MnO abundances nearly twice that of Jurewicz and indicate that the production of basaltic achondrite-like Fe/Mn ratios from precursor chondritic material are possible.

  16. Effects of melatonin and its analogues on neural stem cells.

    PubMed

    Chu, Jiaqi; Tu, Yalin; Chen, Jingkao; Tan, Dunxian; Liu, Xingguo; Pi, Rongbiao

    2016-01-15

    Neural stem cells (NSCs) are multipotent cells which are capable of self-replication and differentiation into neurons, astrocytes or oligodendrocytes in the central nervous system (CNS). NSCs are found in two main regions in the adult brain: the subgranular zone (SGZ) in the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ). The recent discovery of NSCs in the adult mammalian brain has fostered a plethora of translational and preclinical studies to investigate novel approaches for the therapy of neurodegenerative diseases. Melatonin is the major secretory product synthesized and secreted by the pineal gland and shows both a wide distribution within phylogenetically distant organisms from bacteria to humans and a great functional versatility. Recently, accumulated experimental evidence showed that melatonin plays an important role in NSCs, including its proliferation, differentiation and survival, which are modulated by many factors including MAPK/ERK signaling pathway, histone acetylation, neurotrophic factors, transcription factors, and apoptotic genes. The purpose of this review is to summarize the beneficial effects of melatonin on NSCs and further to discuss the potential usage of melatonin and its derivatives or analogues in the treatment of CNS neurodegenerative diseases.

  17. Generalized uncertainty principle and analogue of quantum gravity in optics

    NASA Astrophysics Data System (ADS)

    Braidotti, Maria Chiara; Musslimani, Ziad H.; Conti, Claudio

    2017-01-01

    The design of optical systems capable of processing and manipulating ultra-short pulses and ultra-focused beams is highly challenging with far reaching fundamental technological applications. One key obstacle routinely encountered while implementing sub-wavelength optical schemes is how to overcome the limitations set by standard Fourier optics. A strategy to overcome these difficulties is to utilize the concept of a generalized uncertainty principle (G-UP) which has been originally developed to study quantum gravity. In this paper we propose to use the concept of G-UP within the framework of optics to show that the generalized Schrödinger equation describing short pulses and ultra-focused beams predicts the existence of a minimal spatial or temporal scale which in turn implies the existence of maximally localized states. Using a Gaussian wavepacket with complex phase, we derive the corresponding generalized uncertainty relation and its maximally localized states. Furthermore, we numerically show that the presence of nonlinearity helps the system to reach its maximal localization. Our results may trigger further theoretical and experimental tests for practical applications and analogues of fundamental physical theories.

  18. Herkinorin Analogues with Differential Beta-Arrestin-2 Interactions

    PubMed Central

    Tidgewell, Kevin; Groer, Chad E.; Harding, Wayne W.; Lozama, Anthony; Schmidt, Matthew; Marquam, Alfred; Hiemstra, Jessica; Partilla, John S.; Dersch, Christina M.; Rothman, Richard B.; Bohn, Laura M.; Prisinzano, Thomas E.

    2008-01-01

    Salvinorin A is a psychoactive natural product that has been found to be a potent and selective κ opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent κ opioid receptor signaling yet leads to less receptor downregulation than observed with other κ agonists. Our initial chemical modifications of salvinorin A have yielded one analogue, herkinorin (1c), with high affinity at the μOR. We recently reported that 1c does not promote the recruitment of βarrestin-2 to the μOR or receptor internalization. Here we describe three new derivatives of 1c (3c, 3f, and 3i) with similar properties and one, benzamide 7b, that promotes recruitment of βarrestin-2 to the μOR and receptor internalization. Considering the important role μ opioid receptor regulation plays in determining physiological responsiveness to opioid narcotics, μ opioids derived from salvinorin A may offer a unique template for the development of functionally selective μ opioid receptor ligands with the ability to produce analgesia while limiting adverse side effects. PMID:18380425

  19. Molecular mechanisms underlying a cellular analogue of operant reward learning

    PubMed Central

    Lorenzetti, Fred D.; Baxter, Douglas A.; Byrne, John H.

    2008-01-01

    SUMMARY Operant conditioning is a ubiquitous but mechanistically poorly understood form of associative learning in which an animal learns the consequences of its behavior. Using a single-cell analogue of operant conditioning in neuron B51 of Aplysia, we examined second-messenger pathways engaged by activity and reward and how they may provide a biochemical association underlying operant learning. Conditioning was blocked by Rp-cAMP, a peptide inhibitor of PKA, a PKC inhibitor and by expressing a dominant negative isoform of Ca2+-dependent PKC (apl-I). Thus, both PKA and PKC were necessary for operant conditioning. Injection of cAMP into B51 mimicked the effects of operant conditioning. Activation of PKC also mimicked conditioning, but was dependent on both cAMP and PKA, suggesting that PKC acted at some point upstream of PKA activation. Our results demonstrate how these molecules can interact to mediate operant conditioning in an individual neuron important for the expression of the conditioned behavior. PMID:18786364

  20. Laboratory simulation on EUV photolysis of inorganic interstellar ice analogues

    NASA Astrophysics Data System (ADS)

    Chen, Y. J.; Nuevo, M.; Yih, T. S.; Ip, W. H.; Wu, C. Y.; Fung, H. S.; Lee, Y. Y.; Cheng, C.; Tsai, H. R.

    In this report we focused on the formation of large organic molecules from most simple cosmic inorganic ice analogues consisting of H 2 O CO 2 and NH 3 irradiated by extreme ultraviolet EUV photons We employed an ultra-high vacuum chamber equipped with a closed- cycle helium cryostat to simulate the environment of the space beyond the atmosphere The necessary intense simulation of solar radiation is provided by a synchrotron beam in the wide 4 -- 20eV range at National Synchrotron Radiation Research Center in Hsinchu Taiwan After exposure to 10 20 photon dose the icy sample was warmed up to room temperature under dynamic vacuum then we deposited another icy sample as well as last one and EUV irradiated and warmed up to room temperature again and again for six times the KBr substrate was then removed in an environment filled with argon gas After removed into laboratory the sample was washed with distilled water and hydrolyzed in a standard procedure the residue was then analyzed by HPLC The result shows that we could clearly identify 8 amino acids such as glycine Banaline Bserine ldots etc which were left over in the residue Associated with those basic amino acids are several other large molecules that could be tentatively identified as basic organic materials evolved from photolysis process