Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.

Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5-10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction

Proteomics Reveal a Concerted Upregulation of Methionine Metabolic Pathway Enzymes, and Downregulation of Carbonic Anhydrase-III, in Betaine Supplemented Ethanol-Fed Rats

We employed a proteomic profiling strategy to examine the effects of ethanol and betaine diet supplementation on major liver protein level changes. Male Wistar rats were fed control, ethanol or betaine supplemented diets for 4 weeks. Livers were removed and liver cytosolic proteins resolved by onedimensional and two-dimensional separation techniques. Significant upregulation of betaine homocysteine methyltransferase-1, methionine adenosyl transferase-1, and glycine N-methyltransferase were the most visually prominent protein changes observed in livers of rats fed the betaine supplemented ethanol diet. We hypothesise that this concerted upregulation of these methionine metabolic pathway enzymes is the protective mechanism by which betaine restores a normal metabolic ratio of liver S-adenosylmethionine to S-adenosylhomocysteine. Ethanol also induced significant downregulation of carbonic anhydrase- III protein levels which was not restored by betaine supplementation. Carbonic anhydrase-III can function to resist oxidative stress, and we therefore hypothesise that carbonic anhydrase-III protein levels compromised by ethanol consumption, contribute to ethanol-induced redox stress

Implementing an electronic sideband offset lock for precision spectroscopy in radium

We demonstrate laser frequency stabilization with at least 6 GHz of offset tunability using an in-phase/quadrature (IQ) modulator to generate electronic sidebands (ESB) on a titanium sapphire laser at 714 nm and we apply this technique to the precision spectroscopy of $^{226}$Ra, and $^{225}$Ra. By locking the laser to a single resonance of a high finesse optical cavity and adjusting the lock offset, we determine the frequency difference between the magneto-optical trap (MOT) transitions in the two isotopes to be $2630.0\pm0.3$ MHz, a factor of 29 more precise than the previously available data. Using the known value of the hyperfine splitting of the $^{3}P_{1}$ level, we calculate the isotope shift for the $^{1}S_{0}$ to $^{3}P_{1}$ transition to be $2267.0\pm2.2$ MHz, which is a factor of 8 more precise than the best available value. Our technique could be applied to countless other atomic systems to provide unprecedented precision in isotope shift spectroscopy and other relative frequency comparisons

Simultaneous quantification of 12 different nucleotides and nucleosides released from renal epithelium and in human urine samples using ion-pair reversed-phase HPLC

Nucleotides and nucleosides are not only involved in cellular metabolism but also act extracellularly via P1 and P2 receptors, to elicit a wide variety of physiological and pathophysiological responses through paracrine and autocrine signalling pathways. For the first time, we have used an ion-pair reversed-phase high-performance liquid chromatography ultraviolet (UV)-coupled method to rapidly and simultaneously quantify 12 different nucleotides and nucleosides (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, adenosine, uridine triphosphate, uridine diphosphate, uridine monophosphate, uridine, guanosine triphosphate, guanosine diphosphate, guanosine monophosphate, guanosine): (1) released from a mouse renal cell line (M1 cortical collecting duct) and (2) in human biological samples (i.e., urine). To facilitate analysis of urine samples, a solid-phase extraction step was incorporated (overall recovery rate ? 98 %). All samples were analyzed following injection (100 ?l) into a Synergi Polar-RP 80 Å (250 × 4.6 mm) reversed-phase column with a particle size of 10 ?m, protected with a guard column. A gradient elution profile was run with a mobile phase (phosphate buffer plus ion-pairing agent tetrabutylammonium hydrogen sulfate; pH 6) in 2-30 % acetonitrile (v/v) for 35 min (including equilibration time) at 1 ml min(-1) flow rate. Eluted compounds were detected by UV absorbance at 254 nm and quantified using standard curves for nucleotide and nucleoside mixtures of known concentration. Following validation (specificity, linearity, limits of detection and quantitation, system precision, accuracy, and intermediate precision parameters), this protocol was successfully and reproducibly used to quantify picomolar to nanomolar concentrations of nucleosides and nucleotides in isotonic and hypotonic cell buffers that transiently bathed M1 cells, and urine samples from normal subjects and overactive bladder patients

Probing the Heterogeneous Ozonolysis of Squalene Nanoparticles by Photoemission

The heterogeneous reaction of ozone (O3) with 200 nm squalene nanoparticles is studied using near-edge X-ray absorption fine structure (NEXAFS) and ultraviolet (UPS) and X-ray photoelectron spectroscopy (XPS). Photoelectrons are detected from free nanoparticle beams using a velocity map imaging (VMI) spectrometer capable of detecting photoelectrons with up to 40 eV of kinetic energy. Heterogeneous kinetics are quantified using changes in the UPS, XPS, and NEXAFS spectrum, yielding uptake coefficients for the decay of the double bonds in squalene of (3.1 ± 0.7) × 10-4, (2.6 ± 0.6) × 10-4, and (2.9 ± 0.7) × 10-4, respectively. When comparing these values with the uptake coefficient, (1.0 ± 0.2) × 10-3, determined by the molecular decay of squalene measured with aerosol mass spectrometry, it is found that on average 1.6 ± 0.2 double bonds are removed for each ozone-squalene reactive collision, suggesting the importance of evaporation of small molecular weight reaction products from the aerosol. From further analysis of the nanoparticle XPS spectrum, it is found that ozonolysis increases the oxygen-to-carbon (O:C) ratio of the aerosol to 0.43 ± 0.03 and produces 16 ± 4% and 84 ± 4% secondary ozonides and carbonyls, respectively. The methods developed here show how aerosol photoemission can be used to quantify heterogeneous reaction on free nanoparticles

Linking water age and solute dynamics in streamflow at the Hubbard Brook Experimental Forest, NH, USA

We combine experimental and modeling results from a headwater catchment at the Hubbard Brook Experimental Forest (HBEF), New Hampshire, USA, to explore the link between stream solute dynamics and water age. A theoretical framework based on water age dynamics, which represents a general basis for characterizing solute transport at the catchment scale, is here applied to conservative and weathering-derived solutes. Based on the available information about the hydrology of the site, an integrated transport model was developed and used to compute hydrochemical fluxes. The model was designed to reproduce the deuterium content of streamflow and allowed for the estimate of catchment water storage and dynamic travel time distributions (TTDs). The innovative contribution of this paper is the simulation of dissolved silicon and sodium concentration in streamflow, achieved by implementing first-order chemical kinetics based explicitly on dynamic TTD, thus upscaling local geochemical processes to catchment scale. Our results highlight the key role of water stored within the subsoil glacial material in both the short-term and long-term solute circulation. The travel time analysis provided an estimate of streamflow age distributions and their evolution in time related to catchment wetness conditions. The use of age information to reproduce a 14 year data set of silicon and sodium stream concentration shows that, at catchment scales, the dynamics of such geogenic solutes are mostly controlled by hydrologic drivers, which determine the contact times between the water and mineral interfaces. Justifications and limitations toward a general theory of reactive solute circulation at catchment scales are discussed

'A mockery of equality': An exploratory investigation into disabled activists' views of the Paralympic Games

This article offers an exploratory analysis of the opinions of disabled activists towards the Paralympic Games. With the use of a qualitative online survey, the work focuses on the perceptions of disabled individuals (n = 32) who are not Paralympic athletes but are affiliated to the disability rights group, the United Kingdom Disabled People's Council. Working on the premise that the views of disabled activists have been excluded from Paralympic sports discourse to date, the results illustrate a nuanced yet negative view of the Games to contrast with an existing, yet overly positive, academic narrative. Participants were particularly cynical of the portrayal and production of the Games and its Paralympic athletes as they perceived that the wider population of disabled people is misrepresented. The overwhelming perception in this preliminary analysis suggests that the Paralympic Games can be counterproductive to disability rights beyond sport