Age-related delay in information accrual for faces: Evidence from a parametric, single-trial EEG approach

Background: In this study, we quantified age-related changes in the time-course of face processing by means of an innovative single-trial ERP approach. Unlike analyses used in previous studies, our approach does not rely on peak measurements and can provide a more sensitive measure of processing delays. Young and old adults (mean ages 22 and 70 years) performed a non-speeded discrimination task between two faces. The phase spectrum of these faces was manipulated parametrically to create pictures that ranged between pure noise (0% phase information) and the undistorted signal (100% phase information), with five intermediate steps. Results: Behavioural 75% correct thresholds were on average lower, and maximum accuracy was higher, in younger than older observers. ERPs from each subject were entered into a single-trial general linear regression model to identify variations in neural activity statistically associated with changes in image structure. The earliest age-related ERP differences occurred in the time window of the N170. Older observers had a significantly stronger N170 in response to noise, but this age difference decreased with increasing phase information. Overall, manipulating image phase information had a greater effect on ERPs from younger observers, which was quantified using a hierarchical modelling approach. Importantly, visual activity was modulated by the same stimulus parameters in younger and older subjects. The fit of the model, indexed by R2, was computed at multiple post-stimulus time points. The time-course of the R2 function showed a significantly slower processing in older observers starting around 120 ms after stimulus onset. This age-related delay increased over time to reach a maximum around 190 ms, at which latency younger observers had around 50 ms time lead over older observers. Conclusion: Using a component-free ERP analysis that provides a precise timing of the visual system sensitivity to image structure, the current study demonstrates that older observers accumulate face information more slowly than younger subjects. Additionally, the N170 appears to be less face-sensitive in older observers

Principles for transformative ocean governance

With a focus on oceans, we collaborated across ecological, social and legal disciplines to respond to the United Nations call for transformation in the ‘2030 Agenda for Sustainable Development’. We developed a set of 13 principles that strategically and critically connect transformative ocean research to transformative ocean governance (complementing the UN Decade for Ocean Science). We used a rigorous, iterative and transparent consensus-building approach to define the principles, which can interact in supporting, neutral or sometimes conflicting ways. We recommend that the principles could be applied as a comprehensive set and discuss how to learn from their interactions, particularly those that reveal hidden tensions. The principles can bring and keep together partnerships for innovative ocean action. This action must respond to the many calls to reform current ocean-use practices which are based on economic growth models that have perpetuated inequities and fuelled conflict and environmental decline

Deconvoluting kinase inhibitor induced cardiotoxicity

Many drugs designed to inhibit kinases have their clinical utility limited by cardiotoxicity-related label warnings or prescribing restrictions. While this liability is widely recognized, designing safer kinase inhibitors (KI) requires knowledge of the causative kinase(s). Efforts to unravel the kinases have encountered pharmacology with nearly prohibitive complexity. At therapeutically relevant concentrations, KIs show promiscuity distributed across the kinome. Here, to overcome this complexity, 65 KIs with known kinome-scale polypharmacology profiles were assessed for effects on cardiomyocyte (CM) beating. Changes in human iPSC-CM beat rate and amplitude were measured using label-free cellular impedance. Correlations between beat effects and kinase inhibition profiles were mined by computation analysis (Matthews Correlation Coefficient) to identify associated kinases. Thirty kinases met criteria of having (1) pharmacological inhibition correlated with CM beat changes, (2) expression in both human-induced pluripotent stem cell-derived cardiomyocytes and adult heart tissue, and (3) effects on CM beating following single gene knockdown. A subset of these 30 kinases were selected for mechanistic follow up. Examples of kinases regulating processes spanning the excitation–contraction cascade were identified, including calcium flux (RPS6KA3, IKBKE) and action potential duration (MAP4K2). Finally, a simple model was created to predict functional cardiotoxicity whereby inactivity at three sentinel kinases (RPS6KB1, FAK, STK35) showed exceptional accuracy in vitro and translated to clinical KI safety data. For drug discovery, identifying causative kinases and introducing a predictive model should transform the ability to design safer KI medicines. For cardiovascular biology, discovering kinases previously unrecognized as influencing cardiovascular biology should stimulate investigation of underappreciated signaling pathways

Assessing Communities of Practice in health policy : A conceptual framework as a first step towards empirical research

Peer reviewe

Effect of chloroquine on gene expression of Plasmodium yoelii nigeriensis during its sporogonic development in the mosquito vector

<p>Abstract</p> <p>Background</p> <p>The anti-malarial chloroquine can modulate the outcome of infection during the <it>Plasmodium </it>sporogonic development, interfering with <it>Plasmodium </it>gene expression and subsequently, with transmission. The present study sets to identify <it>Plasmodium </it>genes that might be regulated by chloroquine in the mosquito vector.</p> <p>Methods</p> <p>Differential display RT-PCR (DDRT-PCR) was used to identify genes expressed during the sporogonic cycle that are regulated by exposure to chloroquine. <it>Anopheles stephensi </it>mosquitoes were fed on <it>Plasmodium yoelii nigeriensis</it>-infected mice. Three days post-infection, mosquitoes were fed a non-infectious blood meal from mice treated orally with 50 mg/kg chloroquine. Two differentially expressed <it>Plasmodium </it>transcripts (Pyn_chl091 and Pyn_chl055) were further characterized by DNA sequencing and real-time PCR analysis.</p> <p>Results</p> <p>Both transcripts were represented in <it>Plasmodium </it>EST databases, but displayed no homology with any known genes. Pyn_chl091 was upregulated by day 18 post infection when the mosquito had a second blood meal. However, when the effect of chloroquine on that transcript was investigated during the erythrocytic cycle, no significant differences were observed. Although slightly upregulated by chloroquine exposure the expression of Pyn_chl055 was more affected by development, increasing towards the end of the sporogonic cycle. Transcript abundance of Pyn_chl055 was reduced when erythrocytic stages were treated with chloroquine.</p> <p>Conclusion</p> <p>Chloroquine increased parasite load in mosquito salivary glands and interferes with the expression of at least two <it>Plasmodium </it>genes. The transcripts identified contain putative signal peptides and transmembrane domains suggesting that these proteins, due to their location, are targets of chloroquine (not as an antimalarial) probably through cell trafficking and recycling.</p

A search for point sources of EeV photons

Measurements of air showers made using the hybrid technique developed with the fluorescence and surface detectors of the Pierre Auger Observatory allow a sensitive search for point sources of EeV photons anywhere in the exposed sky. A multivariate analysis reduces the background of hadronic cosmic rays. The search is sensitive to a declination band from -85{\deg} to +20{\deg}, in an energy range from 10^17.3 eV to 10^18.5 eV. No photon point source has been detected. An upper limit on the photon flux has been derived for every direction. The mean value of the energy flux limit that results from this, assuming a photon spectral index of -2, is 0.06 eV cm^-2 s^-1, and no celestial direction exceeds 0.25 eV cm^-2 s^-1. These upper limits constrain scenarios in which EeV cosmic ray protons are emitted by non-transient sources in the Galaxy.Comment: 28 pages, 10 figures, accepted for publication in The Astrophysical Journa

Reconstruction of inclined air showers detected with the Pierre Auger Observatory

We describe the method devised to reconstruct inclined cosmic-ray air showers with zenith angles greater than $60^\circ$ detected with the surface array of the Pierre Auger Observatory. The measured signals at the ground level are fitted to muon density distributions predicted with atmospheric cascade models to obtain the relative shower size as an overall normalization parameter. The method is evaluated using simulated showers to test its performance. The energy of the cosmic rays is calibrated using a sub-sample of events reconstructed with both the fluorescence and surface array techniques. The reconstruction method described here provides the basis of complementary analyses including an independent measurement of the energy spectrum of ultra-high energy cosmic rays using very inclined events collected by the Pierre Auger Observatory.Comment: 27 pages, 19 figures, accepted for publication in Journal of Cosmology and Astroparticle Physics (JCAP

Benefits and barriers among volunteer teaching faculty: comparison between those who precept and those who do not in the core pediatrics clerkship

Background: Community-based outpatient experiences are a core component of the clinical years in medical school. Central to the success of this experience is the recruitment and retention of volunteer faculty from the community. Prior studies have identified reasons why some preceptors volunteer their time however, there is a paucity of data comparing those who volunteer from those who do not. Methods: A survey was developed following a review of previous studies addressing perceptions of community-based preceptors. A non-parametric, Mann&#x2013;Whitney U test was used to compare active preceptors (APs) and inactive preceptors (IPs) and all data were analyzed in SPSS 20.0. Results: There was a 28% response rate. Preceptors showed similar demographic characteristics, valued intrinsic over extrinsic benefits, and appreciated Continuing Medical Education (CME)/Maintenance of Certification (MOC) opportunities as the highest extrinsic reward. APs were more likely to also precept at the M1/M2 level and value recognition and faculty development opportunities (p&#x3C;0.05). IPs denoted time as the most significant barrier and, in comparison to APs, rated financial compensation as more important (p&#x3C;0.05). Conclusions: Community preceptors are motivated by intrinsic benefits of teaching. Efforts to recruit should initially focus on promoting awareness of teaching opportunities and offering CME/MOC opportunities. Increasing the pool of preceptors may require financial compensation

Azimuthal asymmetry in the risetime of the surface detector signals of the Pierre Auger Observatory

The azimuthal asymmetry in the risetime of signals in Auger surface detector stations is a source of information on shower development. The azimuthal asymmetry is due to a combination of the longitudinal evolution of the shower and geometrical effects related to the angles of incidence of the particles into the detectors. The magnitude of the effect depends upon the zenith angle and state of development of the shower and thus provides a novel observable, $(\sec \theta)_\mathrm{max}$, sensitive to the mass composition of cosmic rays above $3 \times 10^{18}$ eV. By comparing measurements with predictions from shower simulations, we find for both of our adopted models of hadronic physics (QGSJETII-04 and EPOS-LHC) an indication that the mean cosmic-ray mass increases slowly with energy, as has been inferred from other studies. However, the mass estimates are dependent on the shower model and on the range of distance from the shower core selected. Thus the method has uncovered further deficiencies in our understanding of shower modelling that must be resolved before the mass composition can be inferred from $(\sec \theta)_\mathrm{max}$.Comment: Replaced with published version. Added journal reference and DO