Mouridsenrohde7347

This study investigated the dynamics of dopamine receptor desensitization and internalization, thereby proposing a new technique for non-invasive, in vivo measurements of receptor adaptations. The D2/D3 agonist quinpirole, which induces receptor internalization in vitro, was administered at graded doses in non-human primates while imaging with simultaneous positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). A pronounced temporal divergence between receptor occupancy and fMRI signal was observed occupancy remained elevated while fMRI responded transiently. Analogous experiments with an antagonist (prochlorperazine) and a lower-affinity agonist (ropinirole) exhibited reduced temporal dissociation between occupancy and function, consistent with a mechanism of desensitization and internalization that depends upon drug efficacy and affinity. We postulated a model that incorporates internalization into a neurovascular-coupling relationship. This model yielded in vivo desensitization/internalization rates (0.2/min for quinpirole) consistent with published in vitro measurements. Overall, these results suggest that simultaneous PET/fMRI enables characterization of dynamic neuroreceptor adaptations in vivo, and may offer a first non-invasive method for assessing receptor desensitization and internalization.Convergent evidence implicates regional neural responses to reward anticipation in the pathogenesis of several psychiatric disorders, such as schizophrenia, where blunted ventral striatal responses to positive reward are observed in patients and at-risk populations. In vivo oxygen amperometry measurements in the ventral striatum in awake, behaving rats reveal reward-related tissue oxygen changes that closely parallel blood oxygen level dependent (BOLD) signal changes observed in human functional magnetic resonance imaging (fMRI), suggesting that a cross-species approach targeting this mechanism might be feasible in psychopharmacology. The present study explored modulatory effects of acute, subanaesthetic doses of ketamine-a pharmacological model widely used in psychopharmacological research, both preclinically and clinically-on ventral striatum activity during performance of a reward anticipation task in both species, using fMRI in humans and in vivo oxygen amperometry in rats. In a region-of-interest analysis conducted following a cross-over placebo and ketamine study in human subjects, an attenuated ventral striatal response during reward anticipation was observed following ketamine relative to placebo during performance of a monetary incentive delay task. In rats, a comparable attenuation of ventral striatal signal was found after ketamine challenge, relative to vehicle, in response to a conditioned stimulus that predicted delivery of reward. This study provides the first data in both species demonstrating an attenuating effect of acute ketamine on reward-related ventral striatal (O2) and fMRI signals. These findings may help elucidate a deeper mechanistic understanding of the potential role of ketamine as a model for psychosis, show that cross-species pharmacological experiments targeting reward signaling are feasible, and suggest this phenotype as a promising translational biomarker for the development of novel compounds, assessment of disease status, and treatment efficacy.Cannabis is the most commonly used illicit drug worldwide, and use is typically initiated during adolescence. The endocannabinoid system has an important role in formation of the nervous system, from very early development through adolescence. Cannabis exposure during this vulnerable period might lead to neurobiological changes that affect adult brain functions and increase the risk of cannabis use disorder. The aim of this study was to investigate whether exposure to Δ(9)-tetrahydrocannabinol (THC) in adolescent rats might enhance reinforcing effects of cannabinoids in adulthood. Male adolescent rats were treated with increasing doses of THC (or its vehicle) twice/day for 11 consecutive days (PND 45-55). When the animals reached adulthood, they were tested by allowing them to intravenously self-administer the cannabinoid CB1-receptor agonist WIN55,212-2. In a separate set of animals given the same THC (or vehicle) treatment regimen, electrophysiological and neurochemical experiments were performed to assess possible modifications of the mesolimbic dopaminergic system, which is critically involved in cannabinoid-induced reward. Behavioral data showed that acquisition of WIN55,212-2 self-administration was enhanced in THC-exposed rats relative to vehicle-exposed controls. FB23-2 Neurophysiological data showed that THC-exposed rats displayed a reduced capacity for WIN55,212-2 to stimulate firing of dopamine neurons in the ventral tegmental area and to increase dopamine levels in the nucleus accumbens shell. These findings-that early, passive exposure to THC can produce lasting alterations of the reward system of the brain and subsequently increase cannabinoid self-administration in adulthood-suggest a mechanism by which adolescent cannabis exposure could increase the risk of subsequent cannabis dependence in humans.In situ amplitude modulated-atomic force microscopy (AM-AFM) has been used to probe the nanostructure of mixtures of propylammonium nitrate (PAN) with n-alkanols near a mica surface. PAN is a protic ionic liquid (IL) which has a bicontinuous sponge-like nanostructure of polar and apolar domains in the bulk, which becomes flatter near a solid surface. Mixtures of PAN with 1-butanol, 1-octanol, and 1-dodecanol at 10-70 vol% n-alkanol have been examined, along with each pure n-alkanol, to reveal the effect of composition and n-alkanol chain length. At low concentrations the butanol simply swells the PAN near-surface nanostructure, but at higher concentrations the nanostructure fragments. Octanol and dodecanol first lower the preferred curvature of the PAN near-surface nanostructure because, unlike n-butanol, their alkyl chains are too long to be accommodated alongside the PAN cations. At higher concentrations, octanol and dodecanol self-assemble into n-alkanol rich aggregates in a PAN rich matrix. The concentration at which aggregation first becomes apparent decreases with n-alkanol chain length.Microbial communities thrive in close association among themselves and with the host, establishing protein-protein interactions (PPIs) with the latter, and thus being able to benefit (positively impact) or disturb (negatively impact) biological events in the host. Despite major collaborative efforts to sequence the Human microbiome, there is still a great lack of understanding their impact. We propose a computational methodology to predict the impact of microbial proteins in human biological events, taking into account the abundance of each microbial protein and its relation to all other microbial and human proteins. This alternative methodology is centered on an improved impact estimation algorithm that integrates PPIs between human and microbial proteins with Reactome pathway data. This methodology was applied to study the impact of 24 microbial phyla over different cellular events, within 10 different human microbiomes. The results obtained confirm findings already described in the literature and explore new ones. We believe the Human microbiome can no longer be ignored as not only is there enough evidence correlating microbiome alterations and disease states, but also the return to healthy states once these alterations are reversed.Estimation of gene or isoform expression is a fundamental step in many transcriptome analysis tasks, such as differential expression analysis, eQTL (or sQTL) studies, and biological network construction. RNA-seq technology enables us to monitor the expression on genome-wide scale at single base pair resolution and offers the possibility of accurately measuring expression at the level of isoform. However, challenges remain because of non-uniform read sampling and the presence of various biases in RNA-seq data. In this paper, we present a novel hierarchical Bayesian method to estimate isoform expression. While most of the existing methods treat gene expression as a by-product, we incorporate it into our model and explicitly describe its relationship with corresponding isoform expression using a Multinomial distribution. In this way, gene and isoform expression are included in a unified framework and it helps us achieve a better performance over other state-of-the-art algorithms for isoform expression estimation. The effectiveness of the proposed method is demonstrated using both simulated data with known ground truth and two real RNA-seq datasets from MAQC project. The codes are available at http//www.math.pku.edu.cn/teachers/dengmh/GIExp/.For influenza surveillance and diagnosis typical clinical symptoms are traditionally used to discriminate influenza virus infections from infections by other pathogens. During the 2013 influenza season we performed a multiplex assay for 16 different viruses in 665 swabs from patients with acute respiratory infections (ARIs) to display the variety of different pathogens causing ARI and to test the diagnostic value of both the commonly used case definitions [ARI, and influenza like illness (ILI)] as well as the clinical judgement of physicians, respectively, to achieve a laboratory-confirmed influenza diagnosis. Fourteen different viruses were identified as causing ARI/ILI. Influenza diagnosis based on clinical signs overestimated the number of laboratory-confirmed influenza cases and misclassified cases. Furthermore, ILI case definition and physicians agreed in only 287/651 (44%) cases with laboratory confirmation. Influenza case management has to be supported by laboratory confirmation to allow evidence-based decisions. Epidemiological syndromic surveillance data should be supported by laboratory confirmation for reasonable interpretation.A zinc-catalyzed combined C-X and C-H borylation of aryl halides using B2 pin2 (pin=OCMe2 CMe2 O) to produce the corresponding 1,2-diborylarenes under mild conditions was developed. Catalytic C-H bond activation occurs ortho to the halide groups if such a site is available or meta to the halide if the ortho position is already substituted. This method thus represents a novel use of a group XII catalyst for C-H borylation. This transformation does not proceed via a free aryne intermediate, but a radical process seems to be involved.Obesity is a well-known risk factor for cancer. The associations of obesity with postmenopausal breast cancer (PBC) have been previously proven in clinical studies. The mechanisms underlying these associations remain unexplained completely, however, adipose tissue as an endocrine organ producing adipokines may interfere with cancer development. The aim of this study is to investigate the diagnostic and predictive value of serum levels of leptin, resistin and visfatin with inflammatory and tumour markers in relation to anthropometrics, clinicopathological features of PBC. This study included 298 postmenopausal Saudi females categorised into three groups. One hundred and ten BC patients with age matched, 89 healthy control (HC) and 99 females with benign breast lesion (BBL). For all subjects CA15-3, hsCRP, resistin, visfatin and leptin were measured by ELISA. Serum levels of leptin, resistin and visfatin were significantly higher in BC compared to BBL and HC groups (p less then 0.05). Their levels were also significantly higher in advanced TNM stage, tumour size, LN invasion, histological grade and negative ER or PR cases.