Dissociating the Role of the Orbitofrontal Cortex and the Striatum in the Computation of Goal Values and Prediction Errors

To make sound economic decisions, the brain needs to compute several different value-related signals. These include goal values that measure the predicted reward that results from the outcome generated by each of the actions under consideration, decision values that measure the net value of taking the different actions, and prediction errors that measure deviations from individuals' previous reward expectations. We used functional magnetic resonance imaging and a novel decision-making paradigm to dissociate the neural basis of these three computations. Our results show that they are supported by different neural substrates: goal values are correlated with activity in the medial orbitofrontal cortex, decision values are correlated with activity in the central orbitofrontal cortex, and prediction errors are correlated with activity in the ventral striatum

Insights into the particle acceleration of a peculiar gamma -ray radio galaxy IC 310

IC 310 has recently been identified as a gamma-ray emitter based on observations at GeV energies with Fermi-LAT and at very high energies (VHE, E > 100 GeV) with the MAGIC telescopes. Despite IC 310 having been classified as a radio galaxy with the jet observed at an angle > 10 degrees, it exhibits a mixture of multiwavelength properties of a radio galaxy and a blazar, possibly making it a transitional object. On the night of 12/13th of November 2012 the MAGIC telescopes observed a series of violent outbursts from the direction of IC 310 with flux-doubling time scales faster than 5 min and a peculiar spectrum spreading over 2 orders of magnitude. Such fast variability constrains the size of the emission region to be smaller than 20% of the gravitational radius of its central black hole, challenging the shock acceleration models, commonly used in explanation of gamma-ray radiation from active galaxies. Here we will show that this emission can be associated with pulsar-like particle acceleration by the electric field across a magnetospheric gap at the base of the jet.Comment: 2014 Fermi Symposium proceedings - eConf C14102.

Effect of diaminopropionic acid (Dap) on the biophysical properties of a modified synthetic channel-forming peptide

Citation: Bukovnik, U., Sala-Rabanal, M., Francis, S., Frazier, S. J., Schultz, B. D., Nichols, C. G., & Tomich, J. M. (2013). Effect of diaminopropionic acid (Dap) on the biophysical properties of a modified synthetic achannel-forming peptide. Molecular Pharmaceutics, 10(10), 3959-3966.Channel replacement therapy, based on synthetic channel-forming peptides (CFPs) with the ability to supersede defective endogenous ion channels, is a novel treatment modality that may augment existing interventions against multiple diseases. Previously, we derived CFPs from the second transmembrane segment of the α-subunit of the glycine receptor, M2GlyR, which forms chloride-selective channels in its native form. The best candidate, NK₄-M2GlyR T19R, S22W (p22-T19R, S22W), was water-soluble, incorporated into cell membranes and was nonimmunogenic, but lacked the structural properties for high conductance and anion selectivity when assembled into a pore. Further studies suggested that the threonine residues at positions 13, 17, and 20 line the pore of assembled p22-T19R, S22W, and here we used 2,3-diaminopropionic acid (Dap) substitutions to introduce positive charges to the pore-lining interface of the predicted p22-T19R, S22W channel. Dap-substituted p22-T19R, S22W peptides retained the α-helical secondary structure characteristic of their parent peptide, and induced short-circuit transepithelial currents when exposed to the apical membrane of Madin-Darby canine kidney (MDCK) cells; the sequences containing multiple Dap-substituted residues induced larger currents than the peptides with single or no Dap substitutions. To gain further insights into the effects of Dap residues on the properties of the putative pore, we performed two-electrode voltage clamp electrophysiology on Xenopus oocytes exposed to p22-T19R, S22W or its Dap-modified analogues. We observed that Dap-substituted peptides also induced significantly larger voltage-dependent currents than the parent compound, but there was no apparent change in reversal potential upon replacement of external Na⁺, Cl⁻ or K⁺, indicating that these currents remained nonselective. These results suggest that the introduction of positively charged side chains in predicted pore-lining residues does not improve anion-to-cation selectivity, but results in higher conductance, perhaps due to higher oligomerization numbers

Minimum Information about a Neuroscience Investigation (MINI) Electrophysiology

This module represents the formalized opinion of the authors and the CARMEN consortium, which identifies the minimum information required to report the use of electrophysiology in a neuroscience study, for submission to the CARMEN system (www.carmen.org.uk).
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Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

Cost-effectiveness of Implementing Low-Tidal Volume Ventilation in Patients With Acute Lung Injury

Background: Despite widespread guidelines recommending the use of lung-protective ventilation (LPV) in patients with acute lung injury (ALI), many patients do not receive this lifesaving therapy. We sought to estimate the incremental clinical and economic outcomes associated with LPV and determined the maximum cost of a hypothetical intervention to improve adherence with LPV that remained cost-effective. Methods: Adopting a societal perspective, we developed a theoretical decision model to determine the cost-effectiveness of LPV compared to non-LPV care. Model inputs were derived from the literature and a large population-based cohort of patients with ALI. Cost-effectiveness was determined as the cost per life saved and the cost per quality-adjusted life-years (QALYs) gained. Results: Application of LPV resulted in an increase in QALYs gained by 15% (4.21 years for non-LPV vs 4.83 years for LPV), and an increase in lifetime costs of $7,233 per patient with ALI ($99,588 for non-LPV vs $106,821 for LPV). The incremental cost-effectiveness ratios for LPV were$22,566 per life saved at hospital discharge and $11,690 per QALY gained. The maximum, cost-effective, per patient investment in a hypothetical program to improve LPV adherence from 50 to 90$9,482. Results were robust to a wide range of economic and patient parameter assumptions. Conclusions: Even a costly intervention to improve adherence with low-tidal volume ventilation in patients with ALI reduces death and is cost-effective by current societal standards.NIH F32HL090220.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/84154/1/Cooke - CEA LPV.pd

Investigating the peculiar emission from the new VHE gamma-ray source H1722+119

The MAGIC (Major Atmospheric Gamma-ray Imaging Cherenkov) telescopes observed the BL Lac object H1722+119 (redshift unknown) for six consecutive nights between 2013 May 17 and 22, for a total of 12.5 h. The observations were triggered by high activity in the optical band measured by the KVA (Kungliga Vetenskapsakademien) telescope. The source was for the first time detected in the very high energy (VHE, $E > 100$ GeV) $\gamma$-ray band with a statistical significance of 5.9 $\sigma$. The integral flux above 150 GeV is estimated to be $(2.0\pm 0.5)$ per cent of the Crab Nebula flux. We used contemporaneous high energy (HE, 100 MeV $< E < 100$ GeV) $\gamma$-ray observations from Fermi-LAT (Large Area Telescope) to estimate the redshift of the source. Within the framework of the current extragalactic background light models, we estimate the redshift to be $z = 0.34 \pm 0.15$. Additionally, we used contemporaneous X-ray to radio data collected by the instruments on board the Swift satellite, the KVA, and the OVRO (Owens Valley Radio Observatory) telescope to study multifrequency characteristics of the source. We found no significant temporal variability of the flux in the HE and VHE bands. The flux in the optical and radio wavebands, on the other hand, did vary with different patterns. The spectral energy distribution (SED) of H1722+119 shows surprising behaviour in the $\sim 3\times10^{14} - 10^{18}$ Hz frequency range. It can be modelled using an inhomogeneous helical jet synchrotron self-Compton model.Comment: 12 pages, 5 figures, 2 table

The Cherenkov Telescope Array Large Size Telescope

The two arrays of the Very High Energy gamma-ray observatory Cherenkov Telescope Array (CTA) will include four Large Size Telescopes (LSTs) each with a 23 m diameter dish and 28 m focal distance. These telescopes will enable CTA to achieve a low-energy threshold of 20 GeV, which is critical for important studies in astrophysics, astroparticle physics and cosmology. This work presents the key specifications and performance of the current LST design in the light of the CTA scientific objectives.Comment: 4 pages, 5 figures, In Proceedings of the 33rd International Cosmic Ray Conference (ICRC2013), Rio de Janeiro (Brazil). All CTA contributions at arXiv:1307.223