Aversive Stimuli Drive Drug Seeking in a State of Low Dopamine Tone

Background Stressors negatively impact emotional state and drive drug seeking, in part, by modulating the activity of the mesolimbic dopamine system. Unfortunately, the rapid regulation of dopamine signaling by the aversive stimuli that cause drug seeking is not well characterized. In a series of experiments, we scrutinized the subsecond regulation of dopamine signaling by the aversive stimulus, quinine, and tested its ability to cause cocaine seeking. Additionally, we examined the midbrain regulation of both dopamine signaling and cocaine seeking by the stress-sensitive peptide, corticotropin releasing factor (CRF). Methods Combining fast-scan cyclic voltammetry with behavioral pharmacology, we examined the effect of intraoral quinine administration on nucleus accumbens dopamine signaling and hedonic expression in 21 male Sprague-Dawley rats. We tested the role of CRF in modulating aversion-induced changes in dopamine concentration and cocaine seeking by bilaterally infusing the CRF antagonist, CP-376395, into the ventral tegmental area (VTA). Results We found that quinine rapidly reduced dopamine signaling on two distinct time scales. We determined that CRF acted in the VTA to mediate this reduction on only one of these time scales. Further, we found that the reduction of dopamine tone and quinine-induced cocaine seeking were eliminated by blocking the actions of CRF in the VTA during the experience of the aversive stimulus. Conclusions These data demonstrate that stress-induced drug seeking can occur in a terminal environment of low dopamine tone that is dependent on a CRF-induced decrease in midbrain dopamine activity

Verification and Validation for Flight-Critical Systems (VVFCS)

On March 31, 2009 a Request for Information (RFI) was issued by NASA s Aviation Safety Program to gather input on the subject of Verification and Validation (V & V) of Flight-Critical Systems. The responses were provided to NASA on or before April 24, 2009. The RFI asked for comments in three topic areas: Modeling and Validation of New Concepts for Vehicles and Operations; Verification of Complex Integrated and Distributed Systems; and Software Safety Assurance. There were a total of 34 responses to the RFI, representing a cross-section of academic (26%), small & large industry (47%) and government agency (27%)

An integrated Rotorcraft Avionics/Controls Architecture to support advanced controls and low-altitude guidance flight research

Salient design features of a new NASA/Army research rotorcraft--the Rotorcraft-Aircrew Systems Concepts Airborne Laboratory (RASCAL) are described. Using a UH-60A Black Hawk helicopter as a baseline vehicle, the RASCAL will be a flying laboratory capable of supporting the research requirements of major NASA and Army guidance, control, and display research programs. The paper describes the research facility requirements of these programs together with other critical constraints on the design of the research system. Research program schedules demand a phased development approach, wherein specific research capability milestones are met and flight research projects are flown throughout the complete development cycle of the RASCAL. This development approach is summarized, and selected features of the research system are described. The research system includes a real-time obstacle detection and avoidance system which will generate low-altitude guidance commands to the pilot on a wide field-of-view, color helmet-mounted display and a full-authority, programmable, fault-tolerant/fail-safe, fly-by-wire flight control system

Asymmetries in the perception of synthesized speech

It was previously observed [1] that the order of presentation of paired stimuli influenced the number of different responses in same-different tasks in speech synthesis evaluation. This paper investigates this phenomenon within the context of cognitive psychology and demonstrates that, as the cognitive psychology literature suggests, there is an effect relating to the prototypicality of the stimulus. Index Terms: speech synthesis, evaluation, perception, Blizzard Challeng

Preliminary design features of the RASCAL: A NASA /Army rotorcraft in-flight simulator

Salient design features of a new NASA/Army research rotorcraft - the Rotorcraft-Aircrew Systems Concepts Airborne Laboratory (RASCAL) - are described. Using a UH-60A Black Hawk helicopter as a baseline vehicle, the RASCAL will be a flying laboratory capable of supporting the research requirements of major NASA and Army guidance, control, and display research programs. The paper describes the research facility requirements of these programs together with other critical constraints on the design of the research system, including safety-of-flight. Research program schedules demand a phased development approach, wherein specific research capability milestones are met and flight research projects are flown throughout the complete development cycle of the RASCAL. This development approach is summarized, and selected features of the research system are described. The research system includes a full-authority, programmable, fault-tolerant/fail-safe, fly-by-wire flight control system and a real-time obstacle detection and avoidance system which will generate low-altitude guidance commands to the pilot on a wide field-of-view, color helmet-mounted display

Baseline urinary metabolites predict albuminuria response to spironolactone in type 2 diabetes

The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in subjects with diabetic kidney disease, albeit with a large variability between individuals. Identifying novel biomarkers that predict response to therapy may help to tailor spironolactone therapy. We aimed to identify a set of metabolites for prediction of albuminuria response to spironolactone in subjects with type 2 diabetes. Systems biology molecular process analysis was performed a priori to identify metabolites linked to molecular disease processes and drug mechanism of action. Individual subject data and urine samples were used from 2 randomized placebo controlled double blind clinical trials (NCT01062763, NCT00381134). A urinary metabolite score was developed to predict albuminuria response to spironolactone therapy using penalized ridge regression with leave-one-out cross validation. Bioinformatic analysis identified a set of 18 metabolites linked to a diabetic kidney disease molecular model and potentially affected by spironolactone mechanism of action. Spironolactone reduced UACR relative to placebo by median -42% (25th to 75% percentile -65 to 6) and -29% (25th to 75% percentile -37 to -1) in the test and replication cohorts, respectively. In the test cohort, UACR reduction was higher in the lowest tertile of the baseline urinary metabolite score compared with middle and upper tertiles -58% (25th to 75% percentile -78 to 33), -28% (25th to 75% percentile -46 to 8), -40% (25th to 75% percentile -52% to 31), respectively, P= 0.001 for trend). In the replication cohort, UACR reduction was -54% (25th to 75% percentile -65 to -50), -41 (25th to 75% percentile -46% to 30), and -17% (25th to 75% percentile -36 to 5), respectively, P= 0.010 for trend). We identified a set of 18 urinary metabolites through systems biology to predict albuminuria response to spironolactone in type 2 diabetes. These data suggest that urinary metabolites may be used as a tool to tailor optimal therapy and move in the direction of personalized medicine

Specificity of the osmotic stress response in Candida albicans highlighted by quantitative proteomics

We are grateful to the BBSRC for funding the CRISP Consortium (Combinatorial Responses in Stress Pathways) under the SABR Initiative (Systems Approaches to Biological Research) (BB/F00513X/1; BB/F005210/1). AJPB was also funded by the BBSRC (BB/K017365/1), the ERC (C-2009-AdG-249793), the Wellcome Trust (097377), the MRC (MR/M026663/1), and the MRC Centre for Medical Mycology and the University of Aberdeen (MR/M026663/1).Peer reviewedPublisher PD

Coronary atherosclerosis in diabetes mellitus A population-based autopsy study

AbstractObjectivesThe study was conducted to test the hypothesis that the prevalence of coronary atherosclerosis is greater among diabetic than among nondiabetic individuals and is similar for diabetic individuals without clinical coronary artery disease (CAD) and nondiabetics with clinical CAD.BackgroundPersons with diabetes but without clinical CAD encounter cardiovascular mortality similar to nondiabetic individuals with clinical CAD. This excess mortality is not fully explained. We examined the association between diabetes and coronary atherosclerosis in a geographically defined autopsied population, while capitalizing on the autopsy rate and medical record linkage system available via the Rochester Epidemiology Project, which allows rigorous ascertainment of coronary atherosclerosis, clinical CAD, and diabetes.MethodsUsing two measures, namely a global coronary score and high-grade stenoses, the prevalence of atherosclerosis was analyzed in a cohort of autopsied residents of Rochester, Minnesota, age 30 years or older at death, while stratifying on diabetes, clinical CAD diagnosis, age, and gender.ResultsIn this cohort, diabetes was associated with a higher prevalence of atherosclerosis. Among diabetic decedents without clinical CAD, almost three-fourths had high-grade coronary atherosclerosis and more than half had multivessel disease. Without diabetes, women had less atherosclerosis than men, but this female advantage was lost with diabetes. Among those without clinical CAD, diabetes was associated with a global coronary disease burden and a prevalence of high-grade atherosclerosis similar to that observed among nondiabetic subjects with clinical CAD.ConclusionsThese findings provide mechanistic insights into the excess risk of clinical CAD among diabetic individuals, thereby supporting the need for aggressive prevention of atherosclerosis in all diabetic individuals, irrespective of clinical CAD symptoms

Evidence for an FU Orionis-like Outburst from a Classical T Tauri Star

We present pre- and post-outburst observations of the new FU Orionis-like young stellar object PTF 10qpf (also known as LkHa 188-G4 and HBC 722). Prior to this outburst, LkHa 188-G4 was classified as a classical T Tauri star on the basis of its optical emission-line spectrum superposed on a K8-type photosphere, and its photometric variability. The mid-infrared spectral index of LkHa 188-G4 indicates a Class II-type object. LkHa 188-G4 exhibited a steady rise by ~1 mag over ~11 months starting in Aug. 2009, before a subsequent more abrupt rise of > 3 mag on a time scale of ~2 months. Observations taken during the eruption exhibit the defining characteristics of FU Orionis variables: (i) an increase in brightness by > 4 mag, (ii) a bright optical/near-infrared reflection nebula appeared, (iii) optical spectra are consistent with a G supergiant and dominated by absorption lines, the only exception being Halpha which is characterized by a P Cygni profile, (iv) near-infrared spectra resemble those of late K--M giants/supergiants with enhanced absorption seen in the molecular bands of CO and H_2O, and (v) outflow signatures in H and He are seen in the form of blueshifted absorption profiles. LkHa 188-G4 is the first member of the FU Orionis-like class with a well-sampled optical to mid-infrared spectral energy distribution in the pre-outburst phase. The association of the PTF 10qpf outburst with the previously identified classical T Tauri star LkHa 188-G4 (HBC 722) provides strong evidence that FU Orionis-like eruptions represent periods of enhanced disk accretion and outflow, likely triggered by instabilities in the disk. The early identification of PTF 10qpf as an FU Orionis-like variable will enable detailed photometric and spectroscopic observations during its post-outburst evolution for comparison with other known outbursting objects.Comment: 14 pages, 11 figures, ApJ accepte