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  • 1
    Publication Date: 2011-09-23
    Description: Blood-feeding insects such as mosquitoes are efficient vectors of human infectious diseases because they are strongly attracted by body heat, carbon dioxide and odours produced by their vertebrate hosts. Insect repellents containing DEET (N,N-diethyl-meta-toluamide) are highly effective, but the mechanism by which this chemical wards off biting insects remains controversial despite decades of investigation. DEET seems to act both at close range as a contact chemorepellent, by affecting insect gustatory receptors, and at long range, by affecting the olfactory system. Two opposing mechanisms for the observed behavioural effects of DEET in the gas phase have been proposed: that DEET interferes with the olfactory system to block host odour recognition and that DEET actively repels insects by activating olfactory neurons that elicit avoidance behaviour. Here we show that DEET functions as a modulator of the odour-gated ion channel formed by the insect odorant receptor complex. The functional insect odorant receptor complex consists of a common co-receptor, ORCO (ref. 15) (formerly called OR83B; ref. 16), and one or more variable odorant receptor subunits that confer odour selectivity. DEET acts on this complex to potentiate or inhibit odour-evoked activity or to inhibit odour-evoked suppression of spontaneous activity. This modulation depends on the specific odorant receptor and the concentration and identity of the odour ligand. We identify a single amino-acid polymorphism in the second transmembrane domain of receptor OR59B in a Drosophila melanogaster strain from Brazil that renders OR59B insensitive to inhibition by the odour ligand and modulation by DEET. Our data indicate that natural variation can modify the sensitivity of an odour-specific insect odorant receptor to odour ligands and DEET. Furthermore, they support the hypothesis that DEET acts as a molecular 'confusant' that scrambles the insect odour code, and provide a compelling explanation for the broad-spectrum efficacy of DEET against multiple insect species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203342/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203342/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pellegrino, Maurizio -- Steinbach, Nicole -- Stensmyr, Marcus C -- Hansson, Bill S -- Vosshall, Leslie B -- R01 DC008600/DC/NIDCD NIH HHS/ -- R01 DC008600-02/DC/NIDCD NIH HHS/ -- R01 DC008600-02S1/DC/NIDCD NIH HHS/ -- R01 DC008600-03/DC/NIDCD NIH HHS/ -- R01 DC008600-03S1/DC/NIDCD NIH HHS/ -- R01 DC008600-03S2/DC/NIDCD NIH HHS/ -- R01 DC008600-04/DC/NIDCD NIH HHS/ -- R01 DC008600-05/DC/NIDCD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Sep 21;478(7370):511-4. doi: 10.1038/nature10438.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Neurogenetics and Behaviour, The Rockefeller University, 1230 York Avenue, Box 63, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21937991" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Avoidance Learning/drug effects ; Brazil ; DEET/*pharmacology ; Drosophila Proteins ; Drosophila melanogaster/classification/genetics/metabolism ; Insect Repellents/*pharmacology ; Ligands ; *Odors ; Olfactory Receptor Neurons/drug effects ; Polymorphism, Genetic/genetics ; Protein Structure, Tertiary ; Receptors, Odorant/chemistry/*genetics/*metabolism ; Species Specificity ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-04-10
    Description: Human cancers frequently display defects in Ag processing and presentation allowing for immune evasion, and they therefore constitute a significant challenge for T cell–based immunotherapy. We have previously demonstrated that the antigenicity of tumor-associated Ags can be significantly enhanced through unconventional residue modifications as a novel tool for MHC class I (MHC-I)–based immunotherapy approaches. We have also previously identified a novel category of cancer neo-epitopes, that is, T cell epitopes associated with impaired peptide processing (TEIPP), that are selectively presented by MHC-I on cells lacking the peptide transporter TAP. In this study, we demonstrate that substitution of the nonanchoring position 3 into a proline residue of the first identified TEIPP peptide, the murine Trh4, results in significantly enhanced recognition by antitumor CTLs toward the wild-type epitope. Although higher immunogenicity has in most cases been associated with increased MHC/peptide complex stability, our results demonstrate that the overall stability of H-2D b in complex with the highly immunogenic altered peptide ligand Trh4-p3P is significantly reduced compared with wild-type H-2D b /Trh4. Comparison of the crystal structures of the H-2D b /Trh4-p3P and H-2D b /Trh4 complexes revealed that the conformation of the nonconventional methionine anchor residue p5M is altered, deleting its capacity to form adequate sulfur– interactions with H-2D b residues, thus reducing the overall longevity of the complex. Collectively, our results indicate that vaccination with Thr4-p3P significantly enhances T cell recognition of targets presenting the wild-type TEIPP epitope and that higher immunogenicity is not necessarily directly related to MHC/peptide complex stability, opening for the possibility to design novel peptide vaccines with reduced MHC/peptide complex stability.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 3
    ISSN: 1432-1017
    Keywords: Ion channels ; Markov processes ; Conditional distributions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Physics
    Notes: Abstract A method to test the Markov nature of ion channel gating is proposed. It makes use of singly and doubly conditional distributions. The application of this method to recordings from single BK channels provides evidence that at least two states of the underlying kinetic scheme are left at a constant rate. Moreover, the probabilities, when leaving a state, of reaching another given state are shown to be constant for all the states of the system.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1017
    Keywords: Key words Ion channels ; Hirudo medicinalis ; Periodic forcing ; Kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Physics
    Notes: Abstract An unconventional approach to studying ion channel kinetics is exploited. Here we describe the effects of a periodically varying membrane potential on the open-closed transitions of single K+ channels. The use of cycle histograms allows one to measure the transition probabilities as functions of the stimulus phase. The results show that such probabilities vary with the stimulation frequency and with the stimulus history, thus highlighting a dynamic aspect in the switching of this ion channel.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The ontogeny of I-Ak antigens in murine tissues of nonlymphoid origin has been evaluated by reacting acetone-fixed cryostat sections of embryonic, neonate, and adult tissues with the MoAb 10-2.16 in indirect immunofluorescence. Thymus dendritic cells appear to be the first to express I-Ak antigens which become detectable only after birth in skin Langerhans cells, gastrointestinal epithelium, septal cells in lung alveoli, and some endothelia. The full expression of I-Ak antigens as detected in adult mice is reached only at I month of age.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0649
    Keywords: 42.55 D ; 42.60 B ; 42.80 L
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract An ir CO2, dc current pumped, optical waveguide (WG) amplifier has been built, and its active medium optical parameters measured for several CO2 emission lines, and their dependence from active medium total pressure, discharge current and temperature was investigated. High gain is found which, coupled with relatively high saturation power in the WG fundamental mode and ease of fabrication with this technology in long (up to 1.5 m) lengths, indicates promising use to efficiently amplify high spectral and spatial purity output of a short, highly tunable WG laser up to power levels suited for nonlinear spectroscopy and optical pumping. The dependence of the small signal gain coefficient and of the saturation parameter for individual rotational lines on the radiation intensity was computed using experimentally known parameters of the discharge plasma. The computation was carried out using the two mode rate equation approach for CO2−N2−He gas mixtures. A satisfactory agreement between theoretical and experimental results was obtained.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The goal of this study was to characterize the stretch-activated ion channels (SACs) of adult identified neurons of the leech Hirudo medicinalis and to test the role of SACs in neurite outgrowth of isolated cells. Using cell-attached patch recording, we established that SACs are densely distributed in the growth cone membrane of cultured neurons. In excised patches, we found that these channels are permeable to Ca2+, as well as to monovalent cations. The channels are blocked by the extracellular application of gadolinium (Gd3+), amiloride and gentamicin. Amiloride and gentamicin, respectively, induce a partial and complete voltage-dependent block. Time-lapse video recordings of neurite outgrowth from single cultured neurons were used to study the effects of blocking SACs with gentamicin. Within 20 h of plating in the presence of the aminoglycoside, the total length of neuronal arborization was significantly greater than that measured in its absence. The amount of assembled axon per unitary surface area remained constant over 40 h and did not differ significantly with or without gentamicin. Our findings show that SACs of leech neurons admit Ca2+, are densely distributed in the growth cone membrane and exhibit typical pharmacological features of mechanotransducer ion channels. In addition, our data suggest that these cation channels participate in the early interaction between growing neurites and culture substrate.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary Background Mixed tumours are composed of an admixture of an epithelial/myoepithelial and usually a myxochondroid stromal component. Adipocytes are found more rarely, and account for a minor part of the tumour. To date, only three cases of mixed tumour/pleomorphic adenoma of the salivary gland have been described, showing an extensive adipocyte content of more than 90% of the tumour tissue. Owing to this peculiarity, some authors have defined it as ‘lipomatous pleomorphic adenoma’. We are not aware of previously reported similar lesions in the skin. Objectives We report a case of a tumour that occurred as a 2 × 2 × 1·5 cm nodule in the scalp of a 65-year-old man. Analogies with salivary lipomatous pleomorphic adenoma, as well as histogenesis and differential diagnoses are discussed here. Methods A histological, immunohistochemical and ultrastructural study was performed. Results The tumour was well-circumscribed and showed a substantial mature adipose tissue component intermingled with epithelial cells arranged in ducts and branching tubules, embedded in a fibromyxoid stroma, which was diagnostic of a chondroid syringoma/mixed tumour. Adipocytes strongly expressed S-100 protein and cytokeratin 14. Transitional elements from epithelial/myoepithelial cells into adipocytes were observed. They coexpressed cytokeratin 14, S-100 protein and vimentin, and showed lipid droplets, desmosome-type junctions, cytoplasmic tonofilaments and basal lamina. Conclusions The tumour differed from lipomas with myxoid stroma and from lipoadenomas, which show non-proliferating normal sweat glands admixed with adipose tissue. Because of the similarity to lipomatous pleomorphic adenoma/mixed tumour of salivary glands, we suggest that it should be called ‘lipomatous mixed tumour of the skin’.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background Cyclosporin induces a dramatic reversal to normality in psoriatic lesions, with a reduction of inflammatory infiltrate and epidermal proliferation. It is known that the cell cycle and cell proliferation are regulated by the sequential activation of cyclin-dependent kinase/cyclin complexes. Aim We evaluated epidermal cell turnover and thickness, as well as the expression of cyclins D1, B and A in psoriatic skin before and after therapy with cyclosporin. Methods Epidermal thickness, mitotic and apoptotic indices (MI, AI), as well as the percentages of epidermal cell nuclei positive for Ki-67 and cyclins D1, B and A were calculated. Cytoplasmic positivity to cyclin B was also evaluated. Results After 6 weeks of therapy, we observed a clinical improvement of the disease and normalization of the epidermis. Epidermal thickness and Ki-67-, cyclins B- and A-positive nuclei percentage were significantly higher before therapy than after (0·52 ± 0·05 mm vs. 0·21 ± 0·03 mm, P 〈 0·001; 19 vs. 2·6, 19 vs. 3, and 12 vs. 1, respectively; P 〈 0·0005); cytoplasmic positivity to cyclin B was slightly higher before therapy (score 3 vs. 2–3). Cyclin D1 was negative or expressed in a low percentage of nuclei in psoriasis before therapy (0·78), whereas it was always negative after therapy. MI was 0·15 before therapy, whereas mitoses were almost absent afterwards. Apoptoses were undetectable before therapy, whereas a few apoptoses were observed after treatment (AI = 0·4). Conclusions Overexpression of cyclins B and A, rather than D1 seems to characterize psoriasis. Their evaluation could provide further insights in understanding the development of this disorder and could be used to verify the efficacy of currently used therapies as well as future ones.
    Type of Medium: Electronic Resource
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