A large ozone-circulation feedback and its implications for global warming assessments.

State-of-the-art climate models now include more climate processes which are simulated at higher spatial resolution than ever1. Nevertheless, some processes, such as atmospheric chemical feedbacks, are still computationally expensive and are often ignored in climate simulations1,2. Here we present evidence that how stratospheric ozone is represented in climate models can have a first order impact on estimates of effective climate sensitivity. Using a comprehensive atmosphere-ocean chemistry-climate model, we find an increase in global mean surface warming of around 1°C (~20%) after 75 years when ozone is prescribed at pre-industrial levels compared with when it is allowed to evolve self-consistently in response to an abrupt 4×CO2 forcing. The difference is primarily attributed to changes in longwave radiative feedbacks associated with circulation-driven decreases in tropical lower stratospheric ozone and related stratospheric water vapour and cirrus cloud changes. This has important implications for global model intercomparison studies1,2 in which participating models often use simplified treatments of atmospheric composition changes that are neither consistent with the specified greenhouse gas forcing scenario nor with the associated atmospheric circulation feedbacks3-5.We thank the European Research Council for funding through the ACCI project, project number 267760. The model development was part of the QESM-ESM project supported by the UK Natural Environment Research Council (NERC) under contract numbers RH/H10/19 and R8/H12/124. We acknowledge use of the MONSooN system, a collaborative facility supplied under the Joint Weather and Climate Research Programme, which is a strategic partnership between the UK Met Office and NERC. A.C.M. acknowledges support from an AXA Postdoctoral Research Fellowship.This is the accepted manuscript. The final version is available from Nature Publishing at http://www.nature.com/nclimate/journal/v5/n1/full/nclimate2451.html

Dobutamine stress cardiovascular magnetic resonance at 3 Tesla

<p>Abstract</p> <p>Purpose</p> <p>The assessment of inducible wall motion abnormalities during high-dose dobutamine-stress cardiovascular magnetic resonance (DCMR) is well established for the identification of myocardial ischemia at 1.5 Tesla. Its feasibility at higher field strengths has not been reported. The present study was performed to prospectively determine the feasibility and diagnostic accuracy of DCMR at 3 Tesla for depicting hemodynamically significant coronary artery stenosis (≥ 50% diameter stenosis) in patients with suspected or known coronary artery disease (CAD).</p> <p>Materials and methods</p> <p>Thirty consecutive patients (6 women) (66 ± 9.3 years) were scheduled for DCMR between January and May 2007 for detection of coronary artery disease. Patients were examined with a Philips Achieva 3 Tesla system (Philips Healthcare, Best, The Netherlands), using a spoiled gradient echo cine sequence. Technical parameters were: spatial resolution 2 × 2 × 8 mm³, 30 heart phases, spoiled gradient echo TR/TE: 4.5/2.6 msec, flip angle 15°. Images were acquired at rest and stress in accordance with a standardized high-dose dobutamine-atropine protocol during short breath-holds in three short and three long-axis views. Dobutamine was administered using a standard protocol (10 μg increments every 3 minutes up to 40 μg dobutamine/kg body weight/minute plus atropine if required to reach target heart rate). The study protocol included administration of 0.1 mmol/kg/body weight Gd-DTPA before the cine images at rest were acquired to improve the image quality. The examination was terminated if new or worsening wall-motion abnormalities or chest pain occurred or when > 85% of age-predicted maximum heart rate was reached. Myocardial ischemia was defined as new onset of wall-motion abnormality in at least one segment. In addition, late gadolinium enhancement (LGE) was performed. Images were evaluated by two blinded readers. Diagnostic accuracy was determined with coronary angiography as the reference standard. Image quality and wall-motion at rest and maximum stress level were evaluated using a four-point scale.</p> <p>Results</p> <p>In 27 patients DCMR was performed successfully, no patient had to be excluded due to insufficient image quality. Twenty-two patients were examined by coronary angiography, which depicted significant stenosis in 68.2% of the patients. Patient-based sensitivity and specificity were 80.0% and 85.7% respectively and accuracy was 81.8%. Interobserver variability for assessment of wall motion abnormalities was 88% (κ = 0.760; p < 0.0001). Negative and positive predictive values were 66.7% and 92.3%, respectively. No significant differences in average image quality at rest versus stress for short or long-axis cine images were found.</p> <p>Conclusion</p> <p>High-dose DCMR at 3T is feasible and an accurate method to depict significant coronary artery stenosis in patients with suspected or known CAD.</p

Defining the expression hierarchy of latent T-cell epitopes in Epstein-Barr virus infection with TCR-like antibodies

Epstein-Barr virus (EBV) is a gamma herpesvirus that causes a life-long latent infection in human hosts. The latent gene products LMP1, LMP2A and EBNA1 are expressed by EBV-associated tumors and peptide epitopes derived from these can be targeted by CD8 Cytotoxic T-Lymphocyte (CTL) lines. Whilst CTL-based methodologies can be utilized to infer the presence of specific latent epitopes, they do not allow a direct visualization or quantitation of these epitopes. Here, we describe the characterization of three TCR-like monoclonal antibodies (mAbs) targeting the latent epitopes LMP1[subscript 125–133], LMP2A[subscript 426–434] or EBNA1[subscript 562–570] in association with HLA-A0201. These are employed to map the expression hierarchy of endogenously generated EBV epitopes. The dominance of EBNA1[subscript 562–570] in association with HLA-A0201 was consistently observed in cell lines and EBV-associated tumor biopsies. These data highlight the discordance between MHC-epitope density and frequencies of associated CTL with implications for cell-based immunotherapies and/or vaccines for EBV-associated disease

Cholinergic Interneurons Mediate Fast VGluT3-Dependent Glutamatergic Transmission in the Striatum

The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity

Effects of perceived cocaine availability on subjective and objective responses to the drug

<p>Abstract</p> <p>Rationale</p> <p>Several lines of evidence suggest that cocaine expectancy and craving are two related phenomena. The present study assessed this potential link by contrasting reactions to varying degrees of the drug's perceived availability.</p> <p>Method</p> <p>Non-treatment seeking individuals with cocaine dependence were administered an intravenous bolus of cocaine (0.2 mg/kg) under 100% ('unblinded'; N = 33) and 33% ('blinded'; N = 12) probability conditions for the delivery of drug. Subjective ratings of craving, high, rush and low along with heart rate and blood pressure measurements were collected at baseline and every minute for 20 minutes following the infusions.</p> <p>Results</p> <p>Compared to the 'blinded' subjects, their 'unblinded' counterparts had similar craving scores on a multidimensional assessment several hours before the infusion, but reported higher craving levels on a more proximal evaluation, immediately prior to the receipt of cocaine. Furthermore, the 'unblinded' subjects displayed a more rapid onset of high and rush cocaine responses along with significantly higher cocaine-induced heart rate elevations.</p> <p>Conclusion</p> <p>These results support the hypothesis that cocaine expectancy modulates subjective and objective responses to the drug. Provided the important public health policy implications of heavy cocaine use, health policy makers and clinicians alike may favor cocaine craving assessments performed in the settings with access to the drug rather than in more neutral environments as a more meaningful marker of disease staging and assignment to the proper level of care.</p