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Brain functions rely on neurotransmitters that mediate communication between billions of neurons. Disruption of this communication can result in a plethora of psychiatric and neurological disorders. In this work, we combine molecular dynamics simulations, live-cell biosensor and electrophysiological assays to investigate the action of the neurotransmitter dopamine at the dopaminergic D2 receptor (D2R). The study of dopamine and closely related chemical probes reveals how neurotransmitter binding translates into the activation of distinct subsets of D2R effectors (i.e.: Gi2, GoB, Gz and β-arrestin 2). Ligand interactions with key residues in TM5 (S5.42) and TM6 (H6.55) in the D2R binding pocket yield a dopamine-like coupling signature, whereas exclusive TM5 interaction is typically linked to preferential G protein coupling (in particular GoB) over β-arrestin. Further experiments for serotonin receptors indicate that the reported molecular mechanism is shared by other monoaminergic neurotransmitter receptors. Ultimately, our study highlights how sequence variation in position 6.55 is used by nature to fine-tune β-arrestin recruitment and in turn receptor signaling and internalization of neurotransmitter receptors.

Neurotransmitter contacts within the receptor binding site differentially contribute to the overall functional response: transmembrane helix (TM) 5 contacts promote G protein coupling whereas concerted TM5–TM6 contacts enhance β-arrestin recruitment.  相似文献   
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We herein present a new concept to produce dual-color photoconvertible probes based on a mechanism called Directed Photooxidation Induced Conversion (DPIC). As a support of this mechanism, styryl-coumarins ( SCs ) bearing Aromatic Singlet Oxygen Reactive Moieties (ASORMs) like furan and pyrrole have been synthesized. SCs are bright fluorophores, which undergo a hypsochromic conversion upon visible light irradiation due to directed photooxidation of the ASORM that leads to the disruption of conjugation. SC-P , a yellow emitting probe bearing a pyrrole moiety, converts to a stable blue emitting coumarin with a 68 nm shift allowing the photoconversion and tracking of lipid droplet in live cells. This new approach might pave the way to a new generation of photoconvertible dyes for advanced bioimaging applications.  相似文献   
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We investigate the optimal filtering problem in the simplest Gaussian linear system driven by fractional Brownian motions. At first we extend to this setting the Kalman–Bucy filtering equations which are well-known in the specific case of usual Brownian motions. Closed form Volterra type integral equations are derived both for the mean of the optimal filter and the variance of the filtering error. Then the asymptotic stability of the filter is analyzed. It is shown that the variance of the filtering error converges to a finite limit as the observation time tends to infinity. This revised version was published online in August 2006 with corrections to the Cover Date.  相似文献   
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A fluorescent assay based on the chloride-sensitive probe, lucigenin, is developed for monitoring chloride transport into vesicles, and used to compare the effectiveness of three steroid-derived transporters.  相似文献   
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The important role that G-quadruplex DNA (G4 DNA) structures play in regulating biological processes is becoming widely recognised. These structures have also been proposed to be attractive drug targets. Therefore, there has been significant interest in developing small molecules that can selectively bind to G4 DNA over other topologies. In this paper we investigate the interaction between DNA and helical compounds (helicenes) based on a central carbocation trisubstituted with aromatic rings. We show that the non-planar structure of these helicenes results in a significantly reduced affinity for dsDNA when compared to their planar analogues, whilst maintaining a high affinity for G4 DNA. Additionally, the right- and left-handed enantiomers of one of these helicenes recognise the chiral DNA environments of G4 and dsDNA differently. We show that upon DNA binding the helicenes display a fluorescence switch-on effect, which we have successfully used for cellular imaging in live and fixed U2OS cells, staining mitochondria and the nucleus, respectively.

G-quadruplex DNA (G4 DNA) structures are selectively recognised by helical optical probes.  相似文献   
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Abstract— Fourier transform infrared (FTIR) difference spectroscopy of the electrochemically generated anion radical of bacteriochlorophyll a was used to follow the molecular changes upon one-electron reduction. An IR spectroelectrochemical cell was constructed, allowing in situ electrolysis in connection with spectroscopic investigations from 200 to 10 000 nm. FTIR difference spectra of the BChl a anion formation in THF d8 at U =+0.9 V (as determined by ferrocene calibration) were obtained. After complete formation of the radical, the reverse process was followed. Comparison of visible and IR spectra of the reduction and re-oxidation processes indicates that more than 90% of the BChl a anion could be formed with 90% of it being reversible. The main IR absorbance changes are observed for the conjugated and even for the non-conjugated C=O groups of BChl a . These results demonstrate the use of the combination of FTIR spectroscopy and electrochemistry for the characterization of radicals of the isolated pigments and of their in vivo bonding to the protein environment.  相似文献   
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In this work, design and fabrication of a hybrid micro-device dedicated to the selective detection of hydrogen fluoride vapours is reported. This micro-device is composed by a gas chromatographic micro-column positioned in front of a tin dioxide-based gas sensor. The efficiency of this hybrid micro-system regarding to reproducibility and reversibility for various HF concentrations was investigated. The influence of the HF concentration on the electrical responses of the sensor is also studied. The experimental results show that this hybrid micro-system is efficient since it allows the elution, separation and detection of hydrogen fluoride at a low temperature close to ambient.  相似文献   
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