295 research outputs found
Distribution of serotonin receptor of type 6 in human brain post-mortem. A pharmacology, autoradiography and immunohistochemistry study.
The neurotransmitter 5-hydroxytryptamine (5-HT), known as serotonin, is acknowledged, since long time ago, to be able to influence anxiety and depression, as well as various physiological functions such as sleep feeding behavior, sexuality, mood and circadian rhythms. Hence, the most part of the research about the 5-HT are focused on these fields. However, more attention has been recently directed to the relationship between 5-HT neurotransmission and memory.
The serotonin receptors of type 6 (5-HT6R) are recently identified. They are quiet different from all the other 5-HT receptors, because they are characterized by a short third cytoplasmatic loop and a long C-terminal tail, and because they contain one intron, located in the middle of the third cytoplasmatic loop. After some initial controversies, the available findings are now apparently more congruent. Nevertheless, the discrepancies concerning, for example, the binding affinity, the effects of 5-HT6 ligands on brain catecholamines and the behavioral syndromes mediated by them, still exist. Much interest on 5-HT6 receptors was triggered by the evidence that some antipsychotics could bind to them. Subsequently, despite the lack of completed informations on metabolic patterns of the various compounds, some of 5-HT6 receptor ligands entered the clinical development as potential anti-dementia, antipsychotic and anti-obese drugs. Anyway, the available information on both the pharmacology of 5-HT6 receptors is still quite inadequate.
The purpose of this study was to investigate the distribution of 5-HT6 receptors in some human brain areas obtained postmortem, by means of binding techniques, and to characterize them pharmacologically where possible. In addition, autoradiography of brain sections were performed, as well as immunohistochemistry and immunofluorescence for a better localization of the receptors
Dispute Resolution in Voting
In voting, disputes arise when a voter claims that the voting authority is
dishonest and did not correctly process his ballot while the authority claims
to have followed the protocol. A dispute can be resolved if any third party can
unambiguously determine who is right. We systematically characterize all
relevant disputes for a generic, practically relevant, class of voting
protocols. Based on our characterization, we propose a new definition of
dispute resolution for voting that accounts for the possibility that both
voters and the voting authority can make false claims and that voters may
abstain from voting.
A central aspect of our work is timeliness: a voter should possess the
evidence required to resolve disputes no later than the election's end. We
characterize what assumptions are necessary and sufficient for timeliness in
terms of a communication topology for our voting protocol class. We formalize
the dispute resolution properties and communication topologies symbolically.
This provides the basis for verification of dispute resolution for a broad
class of protocols. To demonstrate the utility of our model, we analyze a
mixnet-based voting protocol and prove that it satisfies dispute resolution as
well as verifiability and receipt-freeness. To prove our claims, we combine
machine-checked proofs with traditional pen-and-paper proofs
Synthesis, Structures and Their Application in the Suzuki-Miyaura Cross Coupling Reaction
A series of novel palladium(ii) acetylacetonato complexes bearing mesoionic
carbenes (MICs) have been synthesized and characterized. The synthesis of the
complexes of type (MIC)Pd(acac)I (MIC =
1-mesityl-3-methyl-4-phenyl-1,2,3-triazol-5-ylidene (1),
1,4-(2,4,6-methyl)-phenyl-3-methyl-1,2,3-triazol-5-ylidene (2),
1,4-(2,6-diisopropyl)-phenyl-3-methyl-1,2,3-triazol-5-ylidene (3); acac =
acetylacetonato) via direct metalation starting from the corresponding
triazolium iodides and palladium(ii) acetylacetonate is described herein. All
complexes were characterized by 1H- and 13C-NMR spectroscopy and high
resolution mass spectrometry. Additionally, two of the complexes were
characterized by single crystal X-ray crystallography confirming a square-
planar coordination geometry of the palladium(ii) center. A delocalized
bonding situation was observed within the triazolylidene rings as well as for
the acac ligand respectively. Complex 2 was found to be an efficient pre-
catalyst for the Suzuki-Miyaura cross coupling reaction between aryl-bromides
or -chlorides with phenylboronic acid. View Full-Tex
Blockade of MIF-CD74 Signalling on Macrophages and Dendritic Cells Restores the Antitumour Immune Response Against Metastatic Melanoma
Mounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. While immunotherapies have shown a remarkable success in melanoma treatment, patients develop resistance by mechanisms that include the establishment of an immune suppressive tumor microenvironment. Thus, understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that macrophages (MOs) and dendritic cells (DCs) are suppressed in metastatic melanoma and that the Ig-CDR-based peptide C36L1 is able to restore MOs and DCs' antitumorigenic and immunogenic functions and to inhibit metastatic growth in lungs. Specifically, C36L1 treatment is able to repolarize M2-like immunosuppressive MOs into M1-like antitumorigenic MOs, and increase the number of immunogenic DCs, and activated cytotoxic T cells, while reducing the number of regulatory T cells and monocytic myeloid-derived suppressor cells in metastatic lungs. Mechanistically, we find that C36L1 directly binds to the MIF receptor CD74 which is expressed on MOs and DCs, disturbing CD74 structural dynamics and inhibiting MIF signaling on these cells. Interfering with MIF-CD74 signaling on MOs and DCs leads to a decrease in the expression of immunosuppressive factors from MOs and an increase in the capacity of DCs to activate cytotoxic T cells. Our findings suggest that interfering with MIF-CD74 immunosuppressive signaling in MOs and DCs, using peptide-based immunotherapy can restore the antitumor immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the antitumor immune response in metastatic melanoma
Interferon gamma secretion of adaptive and innate immune cells as a parameter to describe leukaemia-derived dendritic-cell-mediated immune responses in acute myeloid leukaemia in vitro
INTRODUCTION: Myeloid leukaemic blasts can be converted into leukaemia-derived dendritic cells (DCleu), characterised by the simultaneous expression of dendritic- and leukaemia-associated antigens, which have the competence to prime and enhance (leukaemia-specific) immune responses with the whole leukaemic antigen repertoire. To display and further specify dendritic cell (DC)- and DCleu-mediated immune responses, we analysed the interferon gamma (IFNy) secretion of innate and adaptive immune cells. METHODS: DC/DCleu were generated from leukaemic whole blood (WB) with (blast)modulatory Kit-I (granulocyte-macrophage colony-stimulating factor [GM-CSF] + Picibanil [OK-432]) and Kit-M (GM-CSF + prostaglandin E1) and were used to stimulate T cell-enriched immunoreactive cells. Initiated anti-leukaemic cytotoxicity was investigated with a cytotoxicity fluorolysis assay. Initiated IFNy secretion of T, NK, CIK, and iNKT cells was investigated with a cytokine secretion assay (CSA). IFNy positivity was additionally evaluated with an intracellular cytokine assay (ICA). Recent activation of leukaemia-specific cells was verified through addition of leukaemia-associated antigens (LAA; WT-1 and Prame) RESULTS: We found Kit-I and Kit-M competent to generate mature DC and DCleu from leukaemic WB without induction of blast proliferation. Stimulation of immunoreactive cells with DC/DCleu regularly resulted in an increased anti-leukaemic cytotoxicity and increased IFNy secretion of T, NK, and CIK cells, pointing to the significant role of DC/DCleu in leukaemia-specific alongside anti-leukaemic reactions. Interestingly, an addition of LAA did not further increase IFNy secretion, suggesting an efficient activation of leukaemia-specific cells. Here, both the CSA and ICA yielded comparable frequencies of IFNy-positive cells. Remarkably, the anti-leukaemic cytotoxicity positively correlated with the IFNy secretion in TCD3+, TCD4+, TCD8+, and NKCD56+ cells. CONCLUSION: Ultimately, the IFNy secretion of innate and adaptive immune cells appeared to be a suitable parameter to assess and monitor the efficacy of in vitro and potentially in vivo acute myeloid leukaemia immunotherapy. The CSA in this regard proved to be a convenient and reproducible technique to detect and phenotypically characterise IFNy-secreting cells. In respect to our studies on DC-based immunomodulation, we were able to display the potential of DC/DCleu to induce or improve leukaemia-specific and anti-leukaemic activity
Generation of Leukaemia-Derived Dendritic Cells (DCleu) to improve anti-leukaemic activity in AML: selection of the most efficient response modifier combinations
Dendritic cells (DC) and leukaemia derived DC (DC(leu)) are potent stimulators of anti-leukaemic activity in acute myeloid leukaemia (AML) and can be generated from mononuclear cells in vitro following standard DC/DC(leu)-generating protocols. With respect to future clinical applications though, DC/DC(leu)-generating protocols specifically designed for application in a whole-blood-(WB)-environment must be established. Therefore, we developed ten new DC/DC(leu)-generating protocols (kits; Kit-A/-C/-D/-E/-F/-G/-H/-I/-K/-M) for the generation of DC/DC(leu) from leukaemic WB, containing calcium-ionophore, granulocyte-macrophage-colony-stimulating-factor (GM-CSF), tumour-necrosis-factor-alpha, prostaglandin-E(1) (PGE(1)), prostaglandin-E(2) (PGE(2)) and/or picibanil (OK-432). All protocols were evaluated regarding their performance in generating DC/DC(leu) using refined classification and/or ranking systems; DC/DC(leu) were evaluated regarding their performance in stimulating anti-leukaemic activity using a cytotoxicity fluorolysis assay. Overall, we found the new kits capable to generate (mature) DC/DC(leu) from leukaemic WB. Through refined classification and ranking systems, we were able to select Kit-I (GM-CSF + OK-432), -K (GM-CSF + PGE(2)) and -M (GM-CSF + PGE(1)) as the most efficient kits in generating (mature) DC/DC(leu), which are further competent to stimulate immunoreactive cells to show an improved anti-leukaemic cytotoxicity as well. This great performance of Kit-I, -K and -M in mediating DC/DC(leu)-based anti-leukaemic immunity in a WB-environment in vitro constitutes an important and directive step for translating DC/DC(leu)-based immunotherapy of AML into clinical application
Designing organometallic compounds for catalysis and therapy
Bioorganometallic chemistry is a rapidly developing area of research. In recent years organometallic compounds have provided a rich platform for the design of effective catalysts, e.g. for olefin metathesis and transfer hydrogenation. Electronic and steric effects are used to control both the thermodynamics and kinetics of ligand substitution and redox reactions of metal ions, especially Ru II. Can similar features be incorporated into the design of targeted organometallic drugs? Such complexes offer potential for novel mechanisms of drug action through incorporation of outer-sphere recognition of targets and controlled activation features based on ligand substitution as well as metal- and ligand-based redox processes. We focus here on η 6-arene, η 5-cyclopentadienyl sandwich and half-sandwich complexes of Fe II, Ru II, Os II and Ir III with promising activity towards cancer, malaria, and other conditions. © 2012 The Royal Society of Chemistry
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