Determining the effects of training duration on the behavioral expression of habitual control in humans: a multi-laboratory investigation

It has been suggested that there are two distinct and parallel mechanisms for controlling instrumental behavior in mammals: goal-directed actions and habits. To gain an understanding of how these two systems interact to control behavior, it is essential to characterize the mechanisms by which the balance between these systems is influenced by experience. Studies in rodents have shown that the amount of training governs the relative expression of these two systems: behavior is goal-directed following moderate training, but the more extensively an instrumental action is trained, the more it becomes habitual. It is less clear whether humans exhibit similar training effects on the expression of goal-directed and habitual behavior, as human studies have reported contradictory findings. To tackle these contradictory findings, we formed a consortium, where four laboratories undertook a pre-registered experimental induction of habits by manipulating the amount of training. There was no statistical evidence for a main effect of the amount of training on the formation and expression of habits. However, exploratory analyses suggest a moderating effect of the affective component of stress on the impact of training over habit expression. Participants who were lower in affective stress appeared to be initially goal-directed, but became habitual with increased training, whereas participants who were high in affective stress were already habitual even after moderate training, thereby manifesting insensitivity to overtraining effects. Our findings highlight the importance of the role of moderating variables such as individual differences in stress and anxiety when studying the experimental induction of habits in humans

A unifying mathematical framework for experimental TCR-pMHC kinetic constants

Receptor binding and triggering are central in Immunology as T cells activated through their T cell receptors (TCR) by protein antigens orchestrate immune responses. In order to understand receptor-ligand interactions, many groups working with different experimental techniques and assays have generated a vast body of knowledge during the last decades. However, in recent years a type of assays, referred to as two-dimensional or membrane-to-membrane, has questioned our current understanding of the role of different kinetic constants (for instance, on- versus off-rate constants) on TCR-ligand interaction and subsequent T cell activation. Here we present a general mathematical framework that provides a unifying umbrella to relate fundamental and effective (or experimentally determined) kinetic constants, as well as describe and compare state-of-the-art experimental methods. Our framework is able to predict the correlations between functional output, such as 1/EC50, and effective kinetic constants for a range of different experimental assays (in two and three dimensions). Furthermore, our approach can be applied beyond Immunology, and serve as a “translation method” for the biochemical characterization of receptor-ligand interactions

The major upgrade of the MAGIC telescopes, Part II: A performance study using observations of the Crab Nebula

MAGIC is a system of two Imaging Atmospheric Cherenkov Telescopes located in the Canary island of La Palma, Spain. During summer 2011 and 2012 it underwent a series of upgrades, involving the exchange of the MAGIC-I camera and its trigger system, as well as the upgrade of the readout system of both telescopes. We use observations of the Crab Nebula taken at low and medium zenith angles to assess the key performance parameters of the MAGIC stereo system. For low zenith angle observations, the standard trigger threshold of the MAGIC telescopes is ~50GeV. The integral sensitivity for point-like sources with Crab Nebula-like spectrum above 220GeV is (0.66+/-0.03)% of Crab Nebula flux in 50 h of observations. The angular resolution, defined as the sigma of a 2-dimensional Gaussian distribution, at those energies is < 0.07 degree, while the energy resolution is 16%. We also re-evaluate the effect of the systematic uncertainty on the data taken with the MAGIC telescopes after the upgrade. We estimate that the systematic uncertainties can be divided in the following components: < 15% in energy scale, 11-18% in flux normalization and +/-0.15 for the energy spectrum power-law slope.Comment: 21 pages, 25 figures, accepted for publication in Astroparticle Physic

The 2009 multiwavelength campaign on Mrk 421: Variability and correlation studies

Aims: We perform an extensive characterization of the broadband emission of Mrk 421, as well as its temporal evolution, during the non-flaring (low) state. The high brightness and nearby location (z = 0.031) of Mrk 421 make it an excellent laboratory to study blazar emission. The goal is to learn about the physical processes responsible for the typical emission of Mrk 421, which might also be extended to other blazars that are located farther away and hence are more difficult to study. Methods: We performed a 4.5-month multi-instrument campaign on Mrk 421 between January 2009 and June 2009, which included VLBA, F-GAMMA, GASP-WEBT, Swift, RXTE, Fermi-LAT, MAGIC, and Whipple, among other instruments and collaborations. This extensive radio to very-high-energy (VHE; E> 100 GeV) γ-ray dataset provides excellent temporal and energy coverage, which allows detailed studies of the evolution of the broadband spectral energy distribution. Results: Mrk421 was found in its typical (non-flaring) activity state, with a VHE flux of about half that of the Crab Nebula, yet the light curves show significant variability at all wavelengths, the highest variability being in the X-rays. We determined the power spectral densities (PSD) at most wavelengths and found that all PSDs can be described by power-laws without a break, and with indices consistent with pink/red-noise behavior. We observed a harder-when-brighter behavior in the X-ray spectra and measured a positive correlation between VHE and X-ray fluxes with zero time lag. Such characteristics have been reported many times during flaring activity, but here they are reported for the first time in the non-flaring state. We also observed an overall anti-correlation between optical/UV and X-rays extending over the duration of the campaign. Conclusions: The harder-when-brighter behavior in the X-ray spectra and the measured positive X-ray/VHE correlation during the 2009 multi-wavelength campaign suggests that the physical processes dominating the emission during non-flaring states have similarities with those occurring during flaring activity. In particular, this observation supports leptonic scenarios as being responsible for the emission of Mrk 421 during non-flaring activity. Such a temporally extended X-ray/VHE correlation is not driven by any single flaring event, and hence is difficult to explain within the standard hadronic scenarios. The highest variability is observed in the X-ray band, which, within the one-zone synchrotron self-Compton scenario, indicates that the electron energy distribution is most variable at the highest energies.Fil: Aleksic, J.. IFAE; EspañaFil: Ansoldi, S.. Università di Udine; ItaliaFil: Antonelli, L. A.. INAF National Institute for Astrophysics; ItaliaFil: Antoranz, P.. Università di Siena; ItaliaFil: Babic, A.. University of Rijeka; CroaciaFil: Bangale, P.. Max-Planck-Institut für Physik; AlemaniaFil: Barres de Almeida, U.. Max-Planck-Institut für Physik; AlemaniaFil: Barrio, J. A.. Universidad Complutense de Madrid; EspañaFil: Becerra Gonzalez, J.. Inst. de Astrofísica de Canarias; EspañaFil: Bednarek, W.. University of Lodz; PoloniaFil: Berger, K.. Inst. de Astrofísica de Canarias; EspañaFil: Bernardini, E.. Deutsches Elektronen-Synchrotron (DESY); AlemaniaFil: Bijand, A.. ETH Zurich; SuizaFil: Blanch, O.. IFAE; EspañaFil: Bock, R. K.. Max-Planck-Institut für Physik; AlemaniaFil: Bonnefoy, S.. Universidad Complutense; EspañaFil: Bonnoli, G.. INAF National Institute for Astrophysics; ItaliaFil: Borracci, F.. Max-Planck-Institut für Physik; AlemaniaFil: Bretz, T.. Universität Würzburg,; AlemaniaFil: Carmona, E.. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas; EspañaFil: Carosi, A.. INAF National Institute for Astrophysics; EspañaFil: Carreto Fidalgo, D.. Universität Würzburg; AlemaniaFil: Colin, P.. Max-Planck-Institut für Physik; AlemaniaFil: Colombo, E.. Inst. de Astrofísica de Canarias; EspañaFil: Contreras, J. L.. Universidad Complutense; EspañaFil: Cortina, J.. IFAE; EspañaFil: Covino, S.. INAF National Institute for Astrophysics; ItaliaFil: Pichel, Ana Carolina. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Rovero, Adrian Carlos. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: The Magic Collaboration.Fil: The Veritas Collaboration

Unprecedented study of the broadband emission of Mrk 421 during flaring activity in March 2010

Context. Because of its proximity, Mrk 421 is one of the best sources on which to study the nature of BL Lac objects. Its proximity allows us to characterize its broadband spectral energy distribution (SED). Aims. The goal is to better understand the mechanisms responsible for the broadband emission and the temporal evolution of Mrk 421. These mechanisms may also apply to more distant blazars that cannot be studied with the same level of detail. Methods. A flare occurring in March 2010 was observed for 13 consecutive days (from MJD 55 265 to MJD 55 277) with unprecedented wavelength coverage from radio to very high energy (VHE; E> 100 GeV) γ-rays with MAGIC, VERITAS, Whipple, Fermi-LAT, MAXI, RXTE, Swift, GASP-WEBT, and several optical and radio telescopes. We modeled the day-scale SEDs with one-zone and two-zone synchrotron self-Compton (SSC) models, investigated the physical parameters, and evaluated whether the observed broadband SED variability can be associated with variations in the relativistic particle population. Results. The activity of Mrk 421 initially was high and then slowly decreased during the 13-day period. The flux variability was remarkable at the X-ray and VHE bands, but it was minor or not significant at the other bands. The variability in optical polarization was also minor. These observations revealed an almost linear correlation between the X-ray flux at the 2–10 keV band and the VHE γ-ray flux above 200 GeV, consistent with the γ-rays being produced by inverse-Compton scattering in the Klein-Nishina regime in the framework of SSC models. The one-zone SSC model can describe the SED of each day for the 13 consecutive days reasonably well, which once more shows the success of this standard theoretical scenario to describe the SEDs of VHE BL Lacs such as Mrk 421. This flaring activity is also very well described by a two-zone SSC model, where one zone is responsible for the quiescent emission, while the other smaller zone, which is spatially separated from the first, contributes to the daily variable emission occurring at X-rays and VHE γ-rays. The second blob is assumed to have a smaller volume and a narrow electron energy distribution with 3 × 104<γ< 6 × 105, where γ is the Lorentz factor of the electrons. Such a two-zone scenario would naturally lead to the correlated variability at the X-ray and VHE bands without variability at the optical/UV band, as well as to shorter timescales for the variability at the X-ray and VHE bands with respect to the variability at the other bands. Conclusions. Both the one-zone and the two-zone SSC models can describe the daily SEDs via the variation of only four or five model parameters, under the hypothesis that the variability is associated mostly with the underlying particle population. This shows that the particle acceleration and cooling mechanism that produces the radiating particles might be the main mechanism responsible for the broadband SED variations during the flaring episodes in blazars. The two-zone SSC model provides a better agreement with the observed SED at the narrow peaks of the low- and high-energy bumps during the highest activity, although the reported one-zone SSC model could be further improved by varying the parameters related to the emitting region itself (δ, B and R), in addition to the parameters related to the particle population.Fil: Aleksic, J.. IFAE; EspañaFil: Ansoldi, S.. Università di Udine; ItaliaFil: Antonelli, L. A.. INAF National Institute for Astrophysics; ItaliaFil: Antoranz, P.. Università di Siena; ItaliaFil: Babic, A.. University of Rijeka; CroaciaFil: Bangale, P.. Max-Planck-Institut für Physik; AlemaniaFil: Barres de Almeida, U.. Max-Planck-Institut für Physik; AlemaniaFil: Barrio, J. A.. Universidad Complutense de Madrid; EspañaFil: Becerra Gonzalez, J.. Inst. de Astrofísica de Canarias; EspañaFil: Bednarek, W.. University of Łódź,; PoloniaFil: Bernardini, E.. Deutsches Elektronen-Synchrotron (DESY); AlemaniaFil: Biasuzzi, B.. Università di Udine; ItaliaFil: Biland, A.. ETH Zurich; SuizaFil: Blanch, O.. IFAE; EspañaFil: Boller, A.. ETH Zurich; SuizaFil: Bonnefoy, S.. Universidad Complutense de Madrid; EspañaFil: Bonnoli, G.. INAF National Institute for Astrophysics ; ItaliaFil: Borracci, F.. Max-Planck-Institut für Physik; AlemaniaFil: Bretz, T.. Universität Würzburg ; AlemaniaFil: Carmona, E.. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas ; EspañaFil: Carosi, A.. INAF National Institute for Astrophysics; ItaliaFil: Colin, P.. Max-Planck-Institut für Physik; AlemaniaFil: Colombo, E.. Inst. de Astrofísica de Canarias; EspañaFil: Contreras, J. L.. Universidad Complutense; EspañaFil: Cortina, J.. IFAE; EspañaFil: Covino, S.. INAF National Institute for Astrophysics; ItaliaFil: Da Vela, P.. Università di Siena; ItaliaFil: Dazzi, F.. Max-Planck-Institut für Physik; AlemaniaFil: Pichel, Ana Carolina. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Rovero, Adrian Carlos. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: The Veritas Collaboration.Fil: The MAGIC Collaboration

Multiwavelength observations of Mrk 501 in 2008

Context. Blazars are variable sources on various timescales over a broad energy range spanning from radio to very high energy (>100 GeV, hereafter VHE). Mrk 501 is one of the brightest blazars at TeV energies and has been extensively studied since its first VHE detection in 1996. However, most of the γ-ray studies performed on Mrk 501 during the past years relate to flaring activity, when the source detection and characterization with the available γ-ray instrumentation was easier toperform. Aims: Our goal is to characterize the source γ-ray emission in detail, together with the radio-to-X-ray emission, during the non-flaring (low) activity, which is less often studied than the occasional flaring (high) activity. Methods: We organized a multiwavelength (MW) campaign on Mrk 501 between March and May 2008. This multi-instrument effort included the most sensitive VHE γ-ray instruments in the northern hemisphere, namely the imaging atmospheric Cherenkov telescopes MAGIC and VERITAS, as well as Swift, RXTE, the F-GAMMA, GASP-WEBT, and other collaborations and instruments. This provided extensive energy and temporal coverage of Mrk 501 throughout the entire campaign. Results: Mrk 501 was found to be in a low state of activity during the campaign, with a VHE flux in the range of 10%-20% of the Crab nebula flux. Nevertheless, significant flux variations were detected with various instruments, with a trend of increasing variability with energy and a tentative correlation between the X-ray and VHE fluxes. The broadband spectral energy distribution during the two different emission states of the campaign can be adequately described within the homogeneous one-zone synchrotron self-Compton model, with the (slightly) higher state described by an increase in the electron number density. Conclusions: The one-zone SSC model can adequately describe the broadband spectral energy distribution of the source during the two months covered by the MW campaign. This agrees with previous studies of the broadband emission of this source during flaring and non-flaring states. We report for the first time a tentative X-ray-to-VHE correlation during such a low VHE activity. Although marginally significant, this positive correlation between X-ray and VHE, which has been reported many times during flaring activity, suggests that the mechanisms that dominate the X-ray/VHE emission during non-flaring-activity are not substantially different from those that are responsible for the emission during flaring activity.Fil: Aleksic, J.. IFAE; EspañaFil: Ansoldi, S.. Università di Udine; ItaliaFil: Antonelli, L. A.. INAF National Institute for Astrophysics; ItaliaFil: Antoranz, P.. Università di Siena; ItaliaFil: Babic, A.. University of Rijeka ; Croacia. University of Split; CroaciaFil: Bangale, P.. Max-Planck-Institut für Physik; AlemaniaFil: Barres de Almeida, U.. Max-Planck-Institut für Physik; AlemaniaFil: Barrio, J. A.. Universidad Complutense de Madrid; EspañaFil: Becerra Gonzalez, J.. Inst. de Astrofísica de Canarias; EspañaFil: Bednarek, W.. University of Lodz; PoloniaFil: Berger, K.. Inst. de Astrofísica de Canarias; EspañaFil: Bernardini, E.. Deutsches Elektronen-Synchrotron (DESY); AlemaniaFil: Biland, A.. ETH Zurich; SuizaFil: Blanch, O.. IFAE; EspañaFil: Bock, R. K.. Max-Planck-Institut für Physik; AlemaniaFil: Bonnefoy, S.. Universidad Complutense de Madrid; EspañaFil: Bonnoli, G.. INAF National Institute for Astrophysics; ItaliaFil: Borracci, F.. Max-Planck-Institut für Physik; AlemaniaFil: Bretz, T.. Universität Würzburg; Alemania. Now at École polytechnique fédérale de Lausanne (EPFL); SuizaFil: Carmona, E.. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas; EspañaFil: Carosi, A.. INAF National Institute for Astrophysics; ItaliaFil: Carreto Fidalgo, D.. Universität Würzburg; AlemaniaFil: Colin, P.. Max-Planck-Institut für Physik; AlemaniaFil: Colombo, E.. Inst. de Astrofísica de Canarias; EspañaFil: Contreras, J. L.. Universidad Complutense de Madrid; EspañaFil: Cortina, J.. IFAE; EspañaFil: Covino, S.. INAF National Institute for Astrophysics; ItaliaFil: Da Vela, P.. Università di Siena; ItaliaFil: Dazzi, F.. Università di Udine; ItaliaFil: Pichel, Ana Carolina. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: The MAGIC collaboration.Fil: The VERITAS collaboration

Unilateral congenital elongation of the cervical part of the internal carotid artery with kinking and looping: two case reports and review of the literature

Unilateral and bilateral variation in the course and elongation of the cervical (extracranial) part of the internal carotid artery (ICA) leading to its tortuosity, kinking and coiling or looping is not a rare condition, which could be caused by both embryological and acquired factors. Patients with such variations may be asymptomatic in some cases; in others, they can develop cerebrovascular symptoms due to carotid stenosis affecting cerebral circulation. The risk of transient ischemic attacks in patients with carotid stenosis is high and its surgical correction is indicated for the prevention of ischemic stroke. Detection of developmental variations of the ICA and evaluation of its stenotic areas is very important for surgical interventions and involves specific diagnostic imaging techniques for vascular lesions including contrast arteriography, duplex ultrasonography and magnetic resonance angiography. Examination of obtained images in cases of unusual and complicated variations of vascular pattern of the ICA may lead to confusion in interpretation of data. Awareness about details and topographic anatomy of variations of the ICA may serve as a useful guide for both radiologists and vascular surgeons. It may help to prevent diagnostic errors, influence surgical tactics and interventional procedures and avoid complications during the head and neck surgery. Our present study was conducted with a purpose of updating data about developmental variations of the ICA. Dissections of the main neurovascular bundle of the head and neck were performed on a total 14 human adult cadavers (10 – Africans: 7 males & 3 females and 4 – East Indians: all males). Two cases of unilateral congenital elongation of the cervical part of the ICA with kinking and looping and carotid stenoses were found only in African males. Here we present their detailed case reports with review of the literature

Heterogeneity assessment of functional T cell avidity.

The potency of cellular immune responses strongly depends on T cell avidity to antigen. Yet, functional avidity measurements are rarely performed in patients, mainly due to the technical challenges of characterizing heterogeneous T cells. The mean functional T cell avidity can be determined by the IFN-γ Elispot assay, with titrated amounts of peptide. Using this assay, we developed a method revealing the heterogeneity of functional avidity, represented by the steepness/hillslope of the peptide titration curve, documented by proof of principle experiments and mathematical modeling. Our data show that not only natural polyclonal CD8 T cell populations from cancer patients, but also monoclonal T cells differ strongly in their heterogeneity of functional avidity. Interestingly, clones and polyclonal cells displayed comparable ranges of heterogeneity. We conclude that besides the mean functional avidity, it is feasible and useful to determine its heterogeneity (hillslope) for characterizing T cell responses in basic research and patient investigation

Igf1r Signaling Is Indispensable for Preimplantation Development and Is Activated via a Novel Function of E-cadherin

Insulin-like growth factor I receptor (Igf1r) signaling controls proliferation, differentiation, growth, and cell survival in many tissues; and its deregulated activity is involved in tumorigenesis. Although important during fetal growth and postnatal life, a function for the Igf pathway during preimplantation development has not been described. We show that abrogating Igf1r signaling with specific inhibitors blocks trophectoderm formation and compromises embryo survival during murine blastocyst formation. In normal embryos total Igf1r is present throughout the membrane, whereas the activated form is found exclusively at cell contact sites, colocalizing with E-cadherin. Using genetic domain switching, we show a requirement for E-cadherin to maintain proper activation of Igf1r. Embryos expressing exclusively a cadherin chimera with N-cadherin extracellular and E-cadherin intracellular domains (NcEc) fail to form a trophectoderm and cells die by apoptosis. In contrast, homozygous mutant embryos expressing a reverse-structured chimera (EcNc) show trophectoderm survival and blastocoel cavitation, indicating a crucial and non-substitutable role of the E-cadherin ectodomain for these processes. Strikingly, blastocyst formation can be rescued in homozygous NcEc embryos by restoring Igf1r signaling, which enhances cell survival. Hence, perturbation of E-cadherin extracellular integrity, independent of its cell-adhesion function, blocked Igf1r signaling and induced cell death in the trophectoderm. Our results reveal an important and yet undiscovered function of Igf1r during preimplantation development mediated by a unique physical interaction between Igf1r and E-cadherin indispensable for proper receptor activation and anti-apoptotic signaling. We provide novel insights into how ligand-dependent Igf1r activity is additionally gated to sense developmental potential in utero and into a bifunctional role of adhesion molecules in contact formation and signaling