Platelets Recognize Brain-Specific Glycolipid Structures, Respond to Neurovascular Damage and Promote Neuroinflammation

Platelets respond to vascular damage and contribute to inflammation, but their role in the neurodegenerative diseases is unknown. We found that the systemic administration of brain lipid rafts induced a massive platelet activation and degranulation resulting in a life-threatening anaphylactic-like response in mice. Platelets were engaged by the sialated glycosphingolipids (gangliosides) integrated in the rigid structures of astroglial and neuronal lipid rafts. The brain-abundant gangliosides GT1b and GQ1b were specifically recognized by the platelets and this recognition involved multiple receptors with P-selectin (CD62P) playing the central role. During the neuroinflammation, platelets accumulated in the central nervous system parenchyma, acquired an activated phenotype and secreted proinflammatory factors, thereby triggering immune response cascades. This study determines a new role of platelets which directly recognize a neuronal damage and communicate with the cells of the immune system in the pathogenesis of neurodegenerative diseases

Variations of the ISM Compactness Across the Main Sequence of Star-Forming Galaxies: Observations and Simulations

(abridged) The majority of star-forming galaxies follow a simple empirical correlation in the star formation rate (SFR) versus stellar mass ($M_*$) plane, usually referred to as the star formation Main Sequence (MS). Here we combine a set of hydro-dynamical simulations of interacting galactic disks with state-of-the-art radiative transfer codes to analyze how the evolution of mergers is reflected upon the properties of the MS. We present \textsc{Chiburst}, a Markov Chain Monte Carlo (MCMC) Spectral Energy Distribution (SED) code that fits the multi-wavelength, broad-band photometry of galaxies and derives stellar masses, star formation rates, and geometrical properties of the dust distribution. We apply this tool to the SEDs of simulated mergers and compare the derived results with the reference output from the simulations. Our results indicate that changes in the SEDs of mergers as they approach coalescence and depart from the MS are related to an evolution of dust geometry in scales larger than a few hundred parsecs. This is reflected in a correlation between the specific star formation rate (sSFR), and the compactness parameter $\mathcal{C}$, that parametrizes this geometry and hence the evolution of dust temperature ($T_{\rm{dust}}$) with time. As mergers approach coalescence, they depart from the MS and increase their compactness, which implies that moderate outliers of the MS are consistent with late-type mergers. By further applying our method to real observations of Luminous Infrared Galaxies (LIRGs), we show that the merger scenario is unable to explain these extreme outliers of the MS. Only by significantly increasing the gas fraction in the simulations are we able to reproduce the SEDs of LIRGs.Comment: 18 pages, 10 figures, accepted in Ap

The AGN Luminosity Fraction in Merging Galaxies

Galaxy mergers are key events in galaxy evolution, often causing massive starbursts and fueling active galactic nuclei (AGN). In these highly dynamic systems, it is not yet precisely known how much starbursts and AGN respectively contribute to the total luminosity, at what interaction stages they occur, and how long they persist. Here we estimate the fraction of the bolometric infrared (IR) luminosity that can be attributed to AGN by measuring and modeling the full ultraviolet to far-infrared spectral energy distributions (SEDs) in up to 33 broad bands for 24 merging galaxies with the Code for Investigating Galaxy Emission. In addition to a sample of 12 confirmed AGN in late-stage mergers, found in the $Infrared$ $Array$ $Satellite$ Revised Bright Galaxy Sample or Faint Source Catalog, our sample includes a comparison sample of 12 galaxy mergers from the $Spitzer$ Interacting Galaxies Survey, mostly early-stage. We perform identical SED modeling of simulated mergers to validate our methods, and we supplement the SED data with mid-IR spectra of diagnostic lines obtained with $Spitzer$ InfraRed Spectrograph. The estimated AGN contributions to the IR luminosities vary from system to system from 0% up to 91% but are significantly greater in the later-stage, more luminous mergers, consistent with what is known about galaxy evolution and AGN triggering.Comment: 26 pages, 10 figure

Adaptive Autoimmunity and Foxp3-Based Immunoregulation in Zebrafish

Background: Jawed vertebrates generate their immune-receptor repertoire by a recombinatorial mechanism that has the potential to produce harmful autoreactive lymphocytes. In mammals, peripheral tolerance to self-antigens is enforced by Foxp3+ regulatory T cells. Recombinatorial mechanisms also operate in teleosts, but active immunoregulation is thought to be a late incorporation to the vertebrate lineage. Methods/Principal Findings: Here we report the characterization of adaptive autoimmunity and Foxp3-based immunoregulation in the zebrafish. We found that zebrafish immunization with an homogenate of zebrafish central nervous system (zCNS) triggered CNS inflammation and specific antibodies. We cloned the zebrafish ortholog for mammalian Foxp3 (zFoxp3) which induced a regulatory phenotype on mouse T cells and controlled IL-17 production in zebrafish embryos. Conclusions/Significance: Our findings demonstrate the acquisition of active mechanisms of self-tolerance early in vertebrate evolution, suggesting that active regulatory mechanisms accompany the development of the molecular potential for adaptive autoimmunity. Moreover, they identify the zebrafish as a tool to study the molecular pathways controlling adaptive immunity

Evaluation of an Online Platform for Multiple Sclerosis Research: Patient Description, Validation of Severity Scale, and Exploration of BMI Effects on Disease Course

Objectives: To assess the potential of an online platform, PatientsLikeMe.com (PLM), for research in multiple sclerosis (MS). An investigation of the role of body mass index (BMI) on MS disease course was conducted to illustrate the utility of the platform. Methods: First, we compared the demographic characteristics of subjects from PLM and from a regional MS center. Second, we validated PLM’s patient-reported outcome measure (MS Rating Scale, MSRS) against standard physician-rated tools. Finally, we analyzed the relation of BMI to the MSRS measure. Results: Compared with 4,039 MS Center patients, the 10,255 PLM members were younger, more educated, and less often male and white. Disease course was more often relapsing remitting, with younger symptom onset and shorter disease duration. Differences were significant because of large sample sizes but small in absolute terms. MSRS scores for 121 MS Center patients revealed acceptable agreement between patient-derived and physician-derived composite scores (weighted kappa = 0.46). The Walking domain showed the highest weighted kappa (0.73) and correlation (rs = 0.86) between patient and physician scores. Additionally, there were good correlations between the patient-reported MSRS composite and walking scores and physician-derived measures: Expanded Disability Status Scale (composite rs = 0.61, walking rs = 0.74), Timed 25 Foot Walk (composite rs = 0.70, walking rs = 0.69), and Ambulation Index (composite rs = 0.81, walking rs = 0.84). Finally, using PLM data, we found a modest correlation between BMI and cross-sectional MSRS (rho = 0.17) and no association between BMI and disease course. Conclusions: The PLM population is comparable to a clinic population, and its patient-reported MSRS is correlated with existing clinical instruments. Thus, this online platform may provide a venue for MS investigations with unique strengths (frequent data collection, large sample sizes). To illustrate its applicability, we assessed the role of BMI in MS disease course but did not find a clinically meaningful role for BMI in this setting

The Impact of Lesion In-Painting and Registration Methods on Voxel-Based Morphometry in Detecting Regional Cerebral Gray Matter Atrophy in Multiple Sclerosis

Background and Purpose: VBM has been widely used to study GM atrophy in MS. MS lesions lead to segmentation and registration errors that may affect the reliability of VBM results. Improved segmentation and registration have been demonstrated by WM LI before segmentation. DARTEL appears to improve registration versus the USM. Our aim was to compare the performance of VBM-DARTEL versus VBM-USM and the effect of LI in the regional analysis of GM atrophy in MS. Materials and Methods: 3T T1 MR imaging scans were acquired from 26 patients with RRMS and 28 age-matched NC. LI replaced WM lesions with normal-appearing WM intensities before image segmentation. VBM analysis was performed in SPM8 by using DARTEL and USM with and without LI, allowing the comparison of 4 VBM methods (DARTEL + LI, DARTEL − LI, USM + LI, and USM − LI). Accuracy of VBM was assessed by using NMI, CC, and a simulation analysis. Results: Overall, DARTEL + LI yielded the most accurate GM maps among the 4 methods (highest NMI and CC, P < .001). DARTEL + LI showed significant GM loss in the bilateral thalami and caudate nuclei in patients with RRMS versus NC. The other 3 methods overestimated the number of regions of GM loss in RRMS versus NC. LI improved the accuracy of both VBM methods. Simulated data suggested the accuracy of the results provided from patient MR imaging analysis. Conclusions: We introduce a pipeline that shows promise in limiting segmentation and registration errors in VBM analysis in MS

Evaluating more naturalistic outcome measures:A 1-year smartphone study in multiple sclerosis

Objective: In this cohort of individuals with and without multiple sclerosis (MS), we illustrate some of the novel approaches that smartphones provide to monitor patients with chronic neurologic disorders in their natural setting. Methods: Thirty-eight participant pairs (MS and cohabitant) aged 18–55 years participated in the study. Each participant received an Android HTC Sensation 4G smartphone containing a custom application suite of 19 tests capturing participant performance and patient-reported outcomes (PROs). Over 1 year, participants were prompted daily to complete one assigned test. Results: A total of 22 patients with MS and 17 cohabitants completed the entire study. Among patients with MS, low scores on PROs relating to mental and visual function were associated with dropout (p < 0.05). We illustrate several novel features of a smartphone platform. First, fluctuations in MS outcomes (e.g., fatigue) were assessed against an individual's ambient environment by linking responses to meteorological data. Second, both response accuracy and speed for the Ishihara color vision test were captured, highlighting the benefits of both active and passive data collection. Third, a new trait, a person-specific learning curve in neuropsychological testing, was identified using spline analysis. Finally, averaging repeated measures over the study yielded the most robust correlation matrix of the different outcome measures. Conclusions: We report the feasibility of, and barriers to, deploying a smartphone platform to gather useful passive and active performance data at high frequency in an unstructured manner in the field. A smartphone platform may therefore enable large-scale naturalistic studies of patients with MS or other neurologic diseases

Reward, learning and games

The link between reward and learning has chiefly been studied scientifically in the context of reinforcement learning. This type of learning, which relies upon midbrain dopaminergic response, differs greatly from the learning valued by educators, which typically involves declarative memory formation. However, with recent insights regarding the modulation of hippocampal function by midbrain dopamine, scientific understanding of the midbrain response to reward may be becoming more relevant to education. Here, we consider the potential for our current understanding of reward to inform educational learning, and consider its implications for game-like interventions in the classroom

IL-27 Imparts Immunoregulatory Function to Human NK Cell Subsets

Interleukin-27 (IL-27) is a cytokine with multiple roles in regulating the immune response, but its effect on human CD56bright and CD56dim NK cell subsets is unknown. NK cell subsets interact with other components of the immune system, leading to cytotoxicity or immunoregulation depending on stimulating factors. We found that IL-27 treatment results in increased IL-10 and IFN-γ expression, increased viability and decreased proliferation in both CD56bright and CD56dim NK cell subsets. More importantly, IL-27 treatment imparts regulatory activity to CD56bright NK cells, which mediates its suppressive function on T cells in a contact-dependent manner. There is growing evidence that CD56bright NK cell-mediated immunoregulation plays an important role in the control of autoimmunity. Thus, understanding the role of IL-27 in NK cell function has important implications for treatment of autoimmune disorders

Drug-tubulin interactions interrogated by transient absorption spectroscopy

[EN] Colchicine (COL) is a bioactive molecule with antitumor properties. When COL binds to tubulin (TU), it inhibits microtubule assembly dynamics. We have investigated COL-TU interactions using laser flash photolysis (LFP) technique and performing fully flexible molecular dynamics simulations. Excitation of COL at 355 nm in aqueous medium did not lead to any transient absorption spectrum. By contrast, in the presence of TU a transient peaking at lambda(max) ca. 420 nm was registered and assigned as triplet excited COL complexed with TU ((COL)-C-3*@TU). In aerated medium, the lifetime was tau ca. 160 mu s and the quantum yield was 0.138. Likewise, when the bicyclic COL analog MTC was submitted to LFP in the presence of TU, (MTC)-M-3@TU* was detected with a lifetime of ca. 62 ms and a quantum yield of 0.296, Aqueous solutions of MTC did not produce any signal in the microsecond timescale. The triplet energy of MTC was obtained by means of emission measurements and found to be ca. 200 kJ mol(-1), a value that matches with that previously reported for COL (188 kJ mol(-1)). Molecular dynamic simulations, both with the ground and triplet excited state, reveal a strong interaction between COL and TU to give stabilized complexes with restricted mobility inside the protein binding site. These results demonstrate that LFP is a useful methodology to study the binding of COL derivatives to TU and open a new way to evaluate the interactions of non-fluorescent anticancer drugs with this protein.Financial support from the Spanish Government (grants CTQ2010-19909; BFU2011-23416 and SEV 2012-0267), the Generalitat Valenciana (Prometeo II/2013/005) and Comunidad de Madrid (S2010/BMD-2353) is gratefully acknowledged. G.S. thanks ASIC-UPV for computing time.Bosca Mayans, F.; Sastre Navarro, GI.; Andreu, JM.; Jornet, D.; Tormos Faus, RE.; Miranda Alonso, MÁ. (2015). 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