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Roberts DC, Gabriele A, Zimmer BA.
Neurosci Biobehav Rev. 2013 May 10. [Epub ahead of print]
PMID: 23669047
IV drug self-administration is a special case of an operant task. In most operant experiments, the instrumental response that completes the schedule requirement is separate and distinct from the consumptive response (e.g. eating or drinking) that follows the delivery of the reinforcing stimulus. In most IV self-administration studies drug seeking and drug taking responses are conflated. The instrumental lever press or nose poke is also a consumptive response. The conflation of these two response classes has important implications for interpretation of the data as they are differentially regulated by dose and price. The types of pharmacological pretreatments that affect appetitive responses are not necessarily the same as those that affect consumptive responses suggesting that the neurobiology of the two response classes are to some extent controlled by different mechanisms. This review discusses how schedules of reinforcement and behavioral economic analyses can be used to assess the regulation of drug seeking and drug taking separately. New methods are described that allow the examination of appetitive or consumptive responding in isolation and provide subjects with greater control over the self-administered dose. These procedures provide novel insights into the regulation of drug intake. Cocaine intake patterns that result in large, intermittent spikes in cocaine levels are shown to produce increases in appetitive responding (i.e. drug seeking). The mechanisms that control drug intake should be considered distinct from appetitive and motivational processes and should be taken into consideration in future IV self-administration studies.
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Bharadwaj S, Liu G, Shi Y, Wu R, Yang B, He T, Fan Y, Lu X, Zhou X, Liu H, Atala A, Rohozinski J, Zhang Y.
Stem Cells. 2013 May 10. [Epub ahead of print]
PMID: 23666768
We sought to biologically characterize and identify a subpopulation of urine-derived stem cells (USCs) with the capacity for multipotent differentiation. We demonstrated that single USCs can expand to a large population with 60-70 population doublings. Nine of 15 individual USC clones expressed detectable levels of telomerase and have long telomeres. These cells expressed pericyte and mesenchymal stem cell markers. Upon induction with appropriate media in vitro, USCs differentiated into bladder-associated cell types, including functional urothelial and smooth muscle cell lineages. When the differentiated USCs were seeded onto a scaffold and subcutaneously implanted into nude mice, multilayered tissue-like structures formed consisting of urothelium and smooth muscle. Additionally, USCs were able to differentiate into endothelial, osteogenic, chondrogenic, adipogenic, skeletal myogenic and neurogenic lineages, but did not form teratomas during the 1-month study despite telomerase activity. USCs may be useful in cell-based therapies and tissue engineering applications, including urogenital reconstruction.
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Constantinidis C, Bucci DJ, Rugg MD.
Front Integr Neurosci. 2013;7():35.
PMID: 23675328
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Ashley-Ross MA, Hsieh ST, Gibb AC, Blob RW.
Integr Comp Biol. 2013 May 9. [Epub ahead of print]
PMID: 23660589
The transition from aquatic to terrestrial habitats was a seminal event in vertebrate evolution because it precipitated a sudden radiation of species as new land animals diversified in response to novel physical and biological conditions. However, the first stages of this environmental transition presented numerous challenges to ancestrally aquatic organisms, and necessitated changes in the morphological and physiological mechanisms that underlie most life processes, among them movement, feeding, respiration, and reproduction. How did solutions to these functional challenges evolve? One approach to this question is to examine modern vertebrate species that face analogous demands; just as the first tetrapods lived at the margins of bodies of water and likely moved between water and land regularly, many extant fishes and amphibians use their body systems in both aquatic and terrestrial habitats on a daily basis. Thus, studies of amphibious vertebrates elucidate the functional demands of two very different habitats and clarify our understanding of the initial evolutionary challenges of moving onto land. A complementary approach is to use studies of the fossil record and comparative development to gain new perspectives on form and function of modern amphibious and non-amphibious vertebrate taxa. Based on the synthetic approaches presented in the symposium, it is clear that our understanding of aquatic-to-terrestrial transitions is greatly improved by the reciprocal integration of paleontological and neontological perspectives. In addition, common themes and new insights that emerged from this symposium point to the value of innovative approaches, new model species, and cutting-edge research techniques to elucidate the functional challenges and evolutionary changes associated with vertebrates' invasion of the land.
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Ferluga S, Hantgan R, Goldgur Y, Himanen JP, Nikolov DB, Debinski W.
J Biol Chem. 2013 May 9. [Epub ahead of print]
PMID: 23661698
The EphA2 receptor tyrosine kinase is over-expressed in a number of malignancies and is activated by ephrin ligands, most commonly by ephrin-A1. The crystal structure of the ligand-receptor complex revealed a glycosylation on the Asn26 of ephrin-A1. Here we report for the first time the significance of the glycosylation in the biology of EphA2 and ephrin-A1. Ephrin-A1 was enzymatically deglycosylated and its activity was evaluated in several assays using glioblastoma (GBM) cells and recombinant EphA2. We found that deglycosylated ephrin-A1 does not efficiently induce EphA2 receptor internalization and degradation, and does not activate the downstream signaling pathways involved in cell migration and proliferation. Data obtained by surface plasmon resonance confirms that deglycosylated ephrin-A1 does not bind EphA2 with high affinity. Mutations in the glycosylation site on ephrin-A1 result in protein aggregation and mislocalization. Analysis of Eph/ephrin crystal structures reveals an interaction between the ligand carbohydrates and two residues of EphA2: Asp78 and Lys136. These findings suggest that the glycosylation on ephrin-A1 plays a critical role in the binding and activation of the EphA2 receptor.
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Simonds NI, Khoury MJ, Schully SD, Armstrong K, Cohn WF, Fenstermacher DA, Ginsburg GS, Goddard KA, Knaus WA, Lyman GH, Ramsey SD, Xu J, Freedman AN.
J Natl Cancer Inst. 2013 May 9. [Epub ahead of print]
PMID: 23661804
A major promise of genomic research is information that can transform health care and public health through earlier diagnosis, more effective prevention and treatment of disease, and avoidance of drug side effects. Although there is interest in the early adoption of emerging genomic applications in cancer prevention and treatment, there are substantial evidence gaps that are further compounded by the difficulties of designing adequately powered studies to generate this evidence, thus limiting the uptake of these tools into clinical practice. Comparative effectiveness research (CER) is intended to generate evidence on the "real-world" effectiveness compared with existing standards of care so informed decisions can be made to improve health care. Capitalizing on funding opportunities from the American Recovery and Reinvestment Act of 2009, the National Cancer Institute funded seven research teams to conduct CER in genomic and precision medicine and sponsored a workshop on CER on May 30, 2012, in Bethesda, Maryland. This report highlights research findings from those research teams, challenges to conducting CER, the barriers to implementation in clinical practice, and research priorities and opportunities in CER in genomic and precision medicine. Workshop participants strongly emphasized the need for conducting CER for promising molecularly targeted therapies, developing and supporting an integrated clinical network for open-access resources, supporting bioinformatics and computer science research, providing training and education programs in CER, and conducting research in economic and decision modeling.
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Kitzman DW, Brubaker PH, Herrington DM, Morgan TM, Stewart KP, Hundley WG, Abdelhamed A, Haykowsky MJ.
J Am Coll Cardiol. 2013 May 8. [Epub ahead of print]
PMID: 23665370
OBJECTIVES: To evaluate the effects of endurance exercise training (ET) on endothelial dependent flow-mediated arterial dilation (FMD) and carotid artery stiffness and their potential contributions to the training-related increase in peak exercise oxygen consumption (VO2) in older patients with heart failure with preserved ejection fraction (HFPEF). BACKGROUND: Elderly HFFEF patients have severely reduced peak VO2 which improves with ET, however the mechanisms of this improvement are unclear. FMD and arterial distensibility are critical components of the exercise response and are reduced with aging. However, it's unknown whether these improve with ET in elderly HFPEF or contribute to the training-related improvement in peak VO2. METHODS: 63 HFPEF patients (70±7 years) were randomized to 16 weeks of ET (walking, arm and leg ergometry, n=32) or attention control (CT; n=31). Peak VO2, brachial artery FMD in response to cuff ischemia, carotid artery distensibility by high-resolution ultrasound, LV function, and QOL were measured at baseline and follow-up. RESULTS: ET increased peak VO2 (ET: 15.8±3.3 vs. CT: 13.8±3.1 ml/kg/min, p=0.0001) and QOL. However, brachial artery FMD (ET: 3.8±3.0% vs. CT: 4.3±3.5%, p=0.88), and carotid arterial distensibility (ET: 0.97±0.56 vs. CT: 1.07±0.34 x10(-3)mm x mmHg(-1) p=0.65) were unchanged. Resting LV systolic and diastolic function were unchanged by ET. CONCLUSIONS: In elderly HFPEF patients, 16 weeks of ET improved peak VO2 without altering endothelial function or arterial stiffness. This suggests that other mechanisms, such as enhanced skeletal muscle perfusion and / or oxygen utilization, may be responsible for the ET-mediated increase in peak VO2 in older HFPEF patients.
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Walker FO.
Lancet Neurol. 2013 May 8. [Epub ahead of print]
PMID: 23664845
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Kavanagh K, Flynn DM, Jenkins KA, Wilson MD, Chilton FH.
Prostaglandins Leukot Essent Fatty Acids. 2013 May 7. [Epub ahead of print]
PMID: 23664597
Echium oil (EO) contains stearidonic acid (18:4), a n-3 polyunsaturated fatty acids (PUFAs), and gamma-linolenic acids (18:3), a n-6 PUFA that can be converted to long chain (LC)-PUFAs. We aimed to compare a safflower oil (SO)-enriched diet to EO- and fish oil (FO)-enriched diets on circulating and tissue PUFAs levels and glycemic, inflammatory, and cardiovascular health biomarkers in insulin resistant African green monkeys. In a Latin-square cross-over study, eight monkeys consumed matched diets for 6 weeks with 3-week washout periods. Monkeys consuming FO had significantly higher levels of n-3 LC-PUFAs and EO supplementation resulted in higher levels of circulating n-3 LC-PUFAs and a significant increase in dihomo-gamma linolenic acid (DGLA) in red blood cells and muscle. Glucose disposal was improved after EO consumption. These data suggest that PUFAs in EO supplementation have the capacity to alter circulating, RBC and muscle LC-PUFA levels and improve glucose tolerance in insulin-resistant monkeys.
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Ferris MJ, Calipari ES, Yorgason JT, Jones SR.
ACS Chem Neurosci. 2013 May 6. [Epub ahead of print]
PMID: 23581570
Fast scan cyclic voltammetry in brain slices (slice voltammetry) has been used over the last several decades to increase substantially our understanding of the complex local regulation of dopamine release and uptake in the striatum. This technique is routinely used for the study of changes that occur in the dopamine system associated with various disease states and pharmacological treatments, and to study mechanisms of local circuitry regulation of dopamine terminal function. In the context of this Review, we compare the relative advantages of voltammetry using striatal slice preparations versus in vivo preparations, and highlight recent advances in our understanding of dopamine release and uptake in the striatum specifically from studies that use slice voltammetry in drug-naïve animals and animals with a history of psychostimulant self-administration.
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Marcucci G, Maharry KS, Metzeler KH, Volinia S, Wu YZ, Mrózek K, Nicolet D, Kohlschmidt J, Whitman SP, Mendler JH, Schwind S, Becker H, Eisfeld AK, Carroll AJ, Powell BL, Kolitz JE, Garzon R, Caligiuri MA, Stone RM, Bloomfield CD.
J Clin Oncol. 2013 May 6. [Epub ahead of print]
PMID: 23650424
PURPOSETo evaluate the impact of miR-155 on the outcome of adults with cytogenetically normal (CN) acute myeloid leukemia (AML) in the context of other clinical and molecular prognosticators and to gain insight into the leukemogenic role of this microRNA. PATIENTS AND METHODSWe evaluated 363 patients with primary CN-AML. miR-155 levels were measured in pretreatment marrow and blood by NanoString nCounter assays that quantified the expression of the encoding gene MIR155HG. All molecular prognosticators were assessed centrally. miR-155-associated gene and microRNA expression profiles were derived using microarrays.ResultsConsidering all patients, high miR-155 expression was associated with a lower complete remission (CR) rate (P < .001) and shorter disease-free survival (P = .001) and overall survival (OS; P < .001) after adjusting for age. In multivariable analyses, high miR-155 expression remained an independent predictor for a lower CR rate (P = .007) and shorter OS (P < .001). High miR-155 expressers had approximately 50% reduction in the odds of achieving CR and 60% increase in the risk of death compared with low miR-155 expressers. Although high miR-155 expression was not associated with a distinct microRNA expression profile, it was associated with a gene expression profile enriched for genes involved in cellular mechanisms deregulated in AML (eg, apoptosis, nuclear factor-κB activation, and inflammation), thereby supporting a pivotal and unique role of this microRNA in myeloid leukemogenesis. CONCLUSIONmiR-155 expression levels are associated with clinical outcome independently of other strong clinical and molecular predictors. The availability of emerging compounds with antagonistic activity to microRNAs in the clinic provides the opportunity for future therapeutic targeting of miR-155 in AML.
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Hugenschmidt CE, Hsu FC, Hayasaka S, Carr JJ, Freedman BI, Nyenhuis DL, Williamson JD, Bowden DW.
J Diabetes Complications. 2013 May 6. [Epub ahead of print]
PMID: 23659774
We hypothesized that measures of coronary artery calcified plaque (CAC) collected at baseline from the Diabetes Heart Study (DHS) would explain associations between cognition and diabetes collected at follow-up approximately 7years later. The DHS is a sibling study of cardiovascular disease (CVD) in a cohort with a high prevalence of type 2 diabetes (~80%). Associations between baseline CAC and cognitive performance were tested using generalized estimating equations and mixed effects models to adjust for familial relationships. Diabetes status was associated (p<0.05) with poorer performance on tests of verbal memory, processing speed, and semantic fluency adjusting for age, sex, education, and hypertension status. As hypothesized, including CAC in the statistical model attenuated this association. Additionally, CAC and fasting glucose predicted performance in tasks not associated with diabetes status in this study (Stroop Task, Phonemic Fluency). These results confirm work attributing the heterogeneity of cognitive outcomes in type 2 diabetes to subclinical risk factors that combine to affect different aspects of brain function. Importantly, these results imply that risk factor intervention should begin before comorbidities, particularly CVD, become clinically apparent.
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Miller CD, Case LD, Little WC, Mahler SA, Burke GL, Harper EN, Lefebvre C, Hiestand B, Hoekstra JW, Hamilton CA, Hundley WG.
JACC Cardiovasc Imaging. 2013 May 6. [Epub ahead of print]
PMID: 23664718
OBJECTIVES: The aim of this study was to determine the effect of stress cardiac magnetic resonance (CMR) imaging in an observation unit (OU) on revascularization, hospital readmission, and recurrent cardiac testing in intermediate-risk patients with possible acute coronary syndromes (ACS). BACKGROUND: Intermediate-risk patients commonly undergo hospital admission with high rates of coronary revascularization. It is unknown whether OU-based care with CMR is a more efficient alternative. METHODS: One hundred five intermediate-risk participants with symptoms of ACS but without definite ACS on the basis of the first electrocardiogram and troponin were randomized to usual care provided by cardiologists and internists (n = 53) or to OU care with stress CMR (n = 52). The primary composite endpoint of coronary artery revascularization, hospital readmission, and recurrent cardiac testing at 90 days was determined. The secondary endpoint was length of stay from randomization to index visit discharge; safety was measured as ACS after discharge. RESULTS: The median age of participants was 56 years (range 35 to 91 years), 54% were men, and 20% had pre-existing coronary disease. Index hospital admission was avoided in 85% of the OU CMR participants. The primary outcome occurred in 20 usual care participants (38%) versus 7 OU CMR participants (13%) (hazard ratio: 3.4; 95% confidence interval: 1.4 to 8.0, p = 0.006). The OU CMR group experienced significant reductions in all components: revascularizations (15% vs. 2%, p = 0.03), hospital readmissions (23% vs. 8%, p = 0.03), and recurrent cardiac testing (17% vs. 4%, p = 0.03). Median length of stay was 26 h (interquartile range: 23 to 45 h) in the usual care group and 21 h (interquartile range: 15 to 25 h) in the OU CMR group (p < 0.001). ACS after discharge occurred in 3 usual care participants (6%) and no OU CMR participants. CONCLUSIONS: In this single-center trial, management of intermediate-risk patients with possible ACS in an OU with stress CMR reduced coronary artery revascularization, hospital readmissions, and recurrent cardiac testing, without an increase in post-discharge ACS at 90 days. (Randomized Investigation of Chest Pain Diagnostic Strategies; NCT01035047).
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Corcoran AJ, Wagner RD, Conner WE.
PLoS One. 2013;8(5):e63609.
PMID: 23671686
Nearly all animals face a tradeoff between seeking food and mates and avoiding predation. Optimal escape theory holds that an animal confronted with a predator should only flee when benefits of flight (increased survival) outweigh the costs (energetic costs, lost foraging time, etc.). We propose a model for prey risk assessment based on the predator's stage of attack. Risk level should increase rapidly from when the predator detects the prey to when it commits to the attack. We tested this hypothesis using a predator - the echolocating bat - whose active biosonar reveals its stage of attack. We used a prey defense - clicking used for sonar jamming by the tiger moth Bertholdia trigona- that can be readily studied in the field and laboratory and is enacted simultaneously with evasive flight. We predicted that prey employ defenses soon after being detected and targeted, and that prey defensive thresholds discriminate between legitimate predatory threats and false threats where a nearby prey is attacked. Laboratory and field experiments using playbacks of ultrasound signals and naturally behaving bats, respectively, confirmed our predictions. Moths clicked soon after bats detected and targeted them. Also, B. trigona clicking thresholds closely matched predicted optimal thresholds for discriminating legitimate and false predator threats for bats using search and approach phase echolocation - the period when bats are searching for and assessing prey. To our knowledge, this is the first quantitative study to correlate the sensory stimuli that trigger defensive behaviors with measurements of signals provided by predators during natural attacks in the field. We propose theoretical models for explaining prey risk assessment depending on the availability of cues that reveal a predator's stage of attack.
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Houle TT, Turner DP.
Anesthesiology. 2013 May 3. [Epub ahead of print]
PMID: 23648520
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Ali SM, Yosipovitch G.
Acta Derm Venereol. 2013 May 2;93(3):261-7.
PMID: 23322028
The "acid mantle" is a topic not only of historical interest, but also of clinical significance and has recently been linked to vital stratum corneum function. Despite compelling basic science evidence placing skin pH as a key factor in barrier homeostasis, stratum corneum integrity, and antimicrobial defense, application of the acid mantle concept in clinical care is lacking. We review recent basic science investigations into skin pH, discuss skin disorders characterized by aberrant pH, and finally discuss practical application for preservation of the acid mantle. Recognizing factors that alter skin pH and selecting products that preserve the acid mantle is of prime importance in treating dermatologic patients.
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Jasmin JN, Zeyl C.
J Evol Biol. 2013 May 2. [Epub ahead of print]
PMID: 23638686
The fitness of populations adapting to new environments is expected to decline in different environments, but empirical studies often do not lend support for such adaptation costs. We test the idea that the initial fitness of the selected populations in the environment where the cost is estimated is key for interpreting tests of ecological trade-offs. We isolated single clones of the yeast Saccharomyces cerevisiae every ~250 generations from replicate experimental lineages that had been selected during 5000 generations in a glucose-limited environment. We then selected these clones in a galactose-limited environment for ~120 generations. Finally, we estimated single-clone fitness in both environments, before and after selection on galactose. The pleiotropic effects on glucose of selection on galactose evolved from positive to negative as fitness in glucose increased, providing strong support for the importance of initial fitness for determining the sign and magnitude of pleiotropic effects. This demonstrates that the sign of pleiotropic effects for fitness following adaptation to a new environment can change during long-term adaptation to an original environment. We also found no relationship between the size of the fitness changes in galactose and glucose, such that pleiotropic effects in glucose became relatively smaller as the sizes of direct effects on galactose increased.
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Kolb B, Kertesz M, Thonhauser T.
J Phys Chem A. 2013 May 2;117(17):3642-9.
PMID: 23544786
Phenalenyl, an open-shell neutral radical that can form both π-stacked dimers and conducting molecular crystals, has gained attention for its interesting and potentially useful electrical and magnetic properties. The properties of this complex physical system are fairly well understood, making it an ideal testing ground for the newly developed van der Waals density functional (vdW-DF). We invoke a simple approximation, allowing the vdW-DF to be used within spin-polarized density functional theory and test this approximation on the π-stacked phenalenyl dimer. The results indicate that the vdW-DF is capable of qualitatively describing the interaction between two neutral radicals in the π-stacked configuration, producing, in line with experiment, binding distances that are significantly below the sum of the van der Waals radii. This is a nontypical distance range where most other theories fail. We then investigate two hypothetical closed-shell analogues of this dimer, one formed by replacing the central carbon of phenalenyl with a nitrogen atom and the other formed by replacing the central carbon with a boron atom. In these cases, relatively strong interaction energies are obtained at more typical equilibrium distances for van der Waals dimers. The nitrogen-substituted dimer shows an unexpected rotational barrier that is dictated by the electronic kinetic energy within the system. The torsional curve of the boron-substituted dimer also exhibits a rotational barrier, but this is found to disappear when exact exchange is used in place of a local or semilocal exchange functional.
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O'Flaherty JT, Wooten RE, Samuel MP, Thomas MJ, Levine EA, Case LD, Akman SA, Edwards IJ.
PLoS One. 2013;8(5):e63076.
PMID: 23658799
Breast cancers that over-express a lipoxygenase or cyclooxygenase are associated with poor survival possibly because they overproduce metabolites that alter the cancer's malignant behaviors. However, these metabolites and behaviors have not been identified. We here identify which metabolites among those that stimulate breast cancer cell proliferation in vitro are associated with rapidly proliferating breast cancer.
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Blumstein H, Singleton AH, Suttenfield CW, Hiestand BC.
Acad Emerg Med. 2013 May ;20(5):498-502.
PMID: 23672364
In the face of increasing volume of emergency department (ED) patients with primary psychiatric illness and increasing length of stay (LOS), a department of psychiatry initiated a program whereby faculty members of the department of psychiatry from a hospital conducted rounds in the ED each weekday on these patients.
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