Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner

Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1R) distal C-terminus-associated protein that modulates CB1R signaling via G proteins, and CB1R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB(1)Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1R and CRIP1a, and exhibits a well-characterized endocannabinoid signaling system. We developed stable CRIP1a-over-expressing and CRIP1a-siRNA-silenced knockdown clones to investigate gene dose effects of CRIP1a on CB1R plasma membrane expression. Results indicate that CP55940 or WIN55212-2 (10 nM, 5 min) reduced cell surface CB1R by a dynamin-and clathrin-dependent process, and this was attenuated by CRIP1a over-expression. CP55940-mediated cell surface CB1R loss was followed by a cycloheximide-sensitive recovery of surface receptors (30120 min), suggesting the requirement for new protein synthesis. In contrast, WIN55212-2-mediated cell surface CB(1)Rs recovered only in CRIP1a knockdown cells. Changes in CRIP1a expression levels did not affect a transient rimonabant (10 nM)mediated increase in cell surface CB(1)Rs, which is postulated to be as a result of rimonabant effects on \u27non-agonist-driven\u27 internalization. These studies demonstrate a novel role for CRIP1a in agonist-driven CB1R cell surface regulation postulated to occur by two mechanisms: 1) attenuating internalization that is agonist-mediated, but not that in the absence of exogenous agonists, and 2) biased agonist-dependent trafficking of de novo synthesized receptor to the cell surface

The structure of gravel-bed flow with intermediate submergence: a laboratory study

The paper reports an experimental study of the flow structure over an immobile gravel bed in open channel at intermediate submergence, with particular focus on the near-bed region. The experiments consisted of velocity measurements using three-component (stereoscopic) Particle Image Velocimetry (PIV) in near-bed horizontal plane and two-component PIV in three vertical planes that covered three distinctly different hydraulic scenarios where the ratio of flow depth to roughness height (i.e., relative submergence) changes from 7.5 to 10.8. Detailed velocity measurements were supplemented with fine-scale bed elevation data obtained with a laser scanner. The data revealed longitudinal low-momentum and high-momentum "strips'' in the time-averaged velocity field, likely induced by secondary currents. This depth-scale pattern was superimposed with particle-scale patches of flow heterogeneity induced by gravel particle protrusions. A similar picture emerged when considering second-order velocity moments. The interaction between the flow field and gravel-bed protrusions is assessed using cross correlations of velocity components and bed elevations in a horizontal plane just above gravel particle crests. The cross correlations suggest that upward and downward fluid motions are mainly associated with upstream-facing and lee sides of particles, respectively. Results also show that the relative submergence affects the turbulence intensity profiles for vertical velocity over the whole flow depth, while only a weak effect, limited to the near-bed region, is noticed for streamwise velocity component. The approximation of mean velocity profiles with a logarithmic formula reveals that log-profile parameters depend on relative submergence, highlighting inapplicability of a conventional "universal'' logarithmic law for gravel-bed flows with intermediate submergence

Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

Serum methylarginines and spirometry-measured lung function in older adults

Rationale: Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in animal models of lung disease but have not previously been examined for their association with spirometric measures of lung function in humans. Objectives: This study measured serum concentrations of asymmetric and symmetric dimethylarginine in a representative sample of older community-dwelling adults and determined their association with spirometric lung function measures. Methods: Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and L-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults from the Hunter Community Study. The five key lung function measures included as outcomes were Forced Expiratory Volume in 1 second, Forced Vital Capacity, Forced Expiratory Volume in 1 second to Forced Vital Capacity ratio, Percent Predicted Forced Expiratory Volume in 1 second, and Percent Predicted Forced Vital Capacity. Measurements and Main Results: In adjusted analyses there were statistically significant independent associations between a) higher asymmetric dimethylarginine, lower Forced Expiratory Volume in 1 second and lower Forced Vital Capacity; and b) lower L-arginine/asymmetric dimethylarginine ratio, lower Forced Expiratory Volume in 1 second, lower Percent Predicted Forced Expiratory Volume in 1 second and lower Percent Predicted Forced Vital Capacity. By contrast, no significant associations were observed between symmetric dimethylarginine and lung function. Conclusions: After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum asymmetric dimethylarginine was independently associated with a reduction in key measures of lung function. Further research is needed to determine if methylarginines predict the decline in lung function

Heroin versus cocaine: opposite choice as a function of context but not of drug history in the rat

Rationale Previous studies have shown that rats trained to self-administer heroin and cocaine exhibit opposite preferences, as a function of setting, when tested in a choice paradigm. Rats tested at home prefer heroin to cocaine whereas rats tested outside the home prefer cocaine to heroin. Here we investigated whether drug history would influence subsequent drug preference in distinct settings. Based on a theoretical model of drug-setting interaction, we predicted that regardless of drug history rats would prefer heroin at home and cocaine outside the home. Methods Rats with double-lumen catheters were first trained to self-administer either heroin (25 μg/kg) or cocaine (400 μg/kg) for 12 consecutive sessions. Twenty-six rats were housed in the self-administration chambers (thus, they were tested at home) whereas 30 rats lived in distinct home cages and were transferred to self-administration chambers only for the self-administration session (thus, they were tested outside the home). The rats were then allowed to choose repeatedly between heroin and cocaine within the same session for 7 sessions. Results Regardless of the training drug, the rats tested outside the home preferred cocaine to heroin whereas the rats tested at home preferred heroin to cocaine. There was no correlation between drug preference and drug intake during the training phase. Conclusion Drug preferences were powerfully influenced by the setting but, quite surprisingly, not by drug history. This suggests that, under certain conditions, associative learning processes and drug-induced neuroplastic adaptations play a minor role in shaping individual preferences for one drug or the other

Oxidative Stress and Inflammation Induced by Environmental and Psychological Stressors: A Biomarker Perspective

L.S. is supported by an Integrative Toxicology Training Partnership (ITTP) PhD studentship from the Medical Research Council (MRC). A.H. is recipient of a PhD studentship from the BHF. A.C. and G.M. are funded by SAF2013-43271-R of the Spanish Ministry of Economy and Competitiveness and European Regional Development Fund, Competitiveness Operational Program 2014–2020, grant P_37_732/2016 REDBRAIN. D.B. is supported by the H2020 MSCA project PANDORA (GA 671881) and by the Cluster project Medintech granted by the Italian MIUR. A.H. is a recipient of a BHF PhD studentship

The ongoing pursuit of neuroprotective therapies in Parkinson disease

Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD

Characterization of a fluvial aquifer at a range of depths and scales: the Triassic St Bees Sandstone Formation, Cumbria, UK

Fluvial sedimentary successions represent porous media that host groundwater and geothermal resources. Additionally, they overlie crystalline rocks hosting nuclear waste repositories in rift settings. The permeability characteristics of an arenaceous fluvial succession, the Triassic St Bees Sandstone Formation in England (UK), are described, from core-plug to well-test scale up to ~1 km depth. Within such lithified successions, dissolution associated with the circulation of meteoric water results in increased permeability (K~10−1–100 m/day) to depths of at least 150 m below ground level (BGL) in aquifer systems that are subject to rapid groundwater circulation. Thus, contaminant transport is likely to occur at relatively high rates. In a deeper investigation (> 150 m depth), where the aquifer has not been subjected to rapid groundwater circulation, well-test-scale hydraulic conductivity is lower, decreasing from K~10−2 m/day at 150–400 m BGL to 10−3 m/day down-dip at ~1 km BGL, where the pore fluid is hypersaline. Here, pore-scale permeability becomes progressively dominant with increasing lithostatic load. Notably, this work investigates a sandstone aquifer of fluvial origin at investigation depths consistent with highly enthalpy geothermal reservoirs (~0.7–1.1 km). At such depths, intergranular flow dominates in unfaulted areas with only minor contribution by bedding plane fractures. However, extensional faults represent preferential flow pathways, due to presence of high connective open fractures. Therefore, such faults may (1) drive nuclear waste contaminants towards the highly permeable shallow (< 150 m BGL) zone of the aquifer, and (2) influence fluid recovery in geothermal fields

The distribution and hydrological significance of rock glaciers in the Nepalese Himalaya

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.In the Nepalese Himalaya, there is little information on the number, spatial distribution and morphometric characteristics of rock glaciers, and this information is required if their hydrological contribution is to be understood. Based on freely available fine spatial resolution satellite data accessible through Google Earth, we produced the first comprehensive Nepalese rock glacier inventory, supported through statistical validation and field survey. The inventory includes the location of over 6000 rock glaciers, with a mean specific density of 3.4%. This corresponds to an areal coverage of 1371 km². Our approach subsampled approximately 20% of the total identified rock glacier inventory (n = 1137) and digitised their outlines so that quantitative/qualitative landform attributes could be extracted. Intact landforms (containing ice) accounted for 68% of the subsample, and the remaining were classified as relict (not containing ice). The majority (56%) were found to have a northerly aspect (NE, N, and NW), and landforms situated within north- to west-aspects reside at lower elevations than those with south- to- east aspects. In Nepal, we show that rock glaciers are situated between 3225 to 5675 m a.s.l., with the mean minimum elevation at the front estimated to be 4977±280 m a.s.l. for intact landforms and 4541±346 m a.s.l. for relict landforms. The hydrological significance of rock glaciers in Nepal was then established by statistically upscaling the results from the subsample to estimate that these cryospheric reserves store between 16.72 and 25.08 billion cubic metres of water. This study, for the first time, estimates rock glacier water volume equivalents and evaluates their relative hydrological importance in comparison to ice glaciers. Across the Nepalese Himalaya, rock glacier to ice glacier water volume equivalent is 1:9, and generally increases westwards (e.g., ratio = 1:3, West region). This inventory represents a preliminary step for understanding the spatial distribution and the geomorphic conditions necessary for rock glacier formation in the Himalaya. With continued climatically-driven ice glacier recession, the relative importance of rock glaciers in the Nepalese Himalaya will potentially increase.This work was supported by the Natural Environment Research Council (grant number: 851 NE/L002434/1 to DBJ); the Royal Geographical Society (with IBG) with a Dudley Stamp Memorial Award 852 (awarded to DBJ); the European Union Seventh Framework Programme FP7/2007-2013 (grant number: 603864 853 to SH and RAB [HELIX: High-End cLimate Impacts and eXtremes; www.helixclimate.eu]). The work of RB forms 854 part of the BEIS/Defra Met Office Hadley Centre Climate Programme GA01101.

Excess cases of prostate cancer and estimated overdiagnosis associated with PSA testing in East Anglia

This study aimed to estimate the extent of 'overdiagnosis' of prostate cancer attributable to prostate-specific antigen (PSA) testing in the Cambridge area between 1996 and 2002. Overdiagnosis was defined conceptually as detection of prostate cancer through PSA testing that otherwise would not have been diagnosed within the patient's lifetime. Records of PSA tests in Addenbrookes Hospital were linked to prostate cancer registrations by NHS number. Differences in prostate cancer registration rates between those receiving and not receiving prediagnosis PSA tests were calculated. The proportion of men aged 40 years or over with a prediagnosis PSA test increased from 1.4 to 5.2% from 1996 to 2002. The rate of diagnosis of prostate cancer was 45% higher (rate ratios (RR) = 1.45, 95% confidence intervals (CI) 1.02-2.07) in men with a history of prediagnosis PSA testing. Assuming average lead times of 5 to 10 years, 40-64% of the PSA-detected cases were estimated to be overdiagnosed. In East Anglia, from 1996 to 2000, a 1.6% excess of cases was associated with PSA testing (around a quarter of the 5.3% excess incidence cases observed in East Anglia from 1996 to 2000). Further quantification of the overdiagnosis will result from continued surveillance and from linkage of incidence to testing in other hospitals