Recruitment of Activation Receptors at Inhibitory NK Cell Immune Synapses

Natural killer (NK) cell activation receptors accumulate by an actin-dependent process at cytotoxic immune synapses where they provide synergistic signals that trigger NK cell effector functions. In contrast, NK cell inhibitory receptors, including members of the MHC class I-specific killer cell Ig-like receptor (KIR) family, accumulate at inhibitory immune synapses, block actin dynamics, and prevent actin-dependent phosphorylation of activation receptors. Therefore, one would predict inhibition of actin-dependent accumulation of activation receptors when inhibitory receptors are engaged. By confocal imaging of primary human NK cells in contact with target cells expressing physiological ligands of NK cell receptors, we show here that this prediction is incorrect. Target cells included a human cell line and transfected Drosophila insect cells that expressed ligands of NK cell activation receptors in combination with an MHC class I ligand of inhibitory KIR. The two NK cell activation receptors CD2 and 2B4 accumulated and co-localized with KIR at inhibitory immune synapses. In fact, KIR promoted CD2 and 2B4 clustering, as CD2 and 2B4 accumulated more efficiently at inhibitory synapses. In contrast, accumulation of KIR and of activation receptors at inhibitory synapses correlated with reduced density of the integrin LFA-1. These results imply that inhibitory KIR does not prevent CD2 and 2B4 signaling by blocking their accumulation at NK cell immune synapses, but by blocking their ability to signal within inhibitory synapses

Preferencia por el olor del etanol tras la interacción social con un congénere intoxicado en ratas adolescentes expuestas a la droga in-útero

Background: Prenatal exposure to ethanol and later socially mediated exposure predicts ethanol intake in human adolescents. Animal rat models indicate that brief interactions with an ethanol-intoxicated peer result in heightened preference for ethanol odor and ethanol intake. Methods: This study assessed preference for ethanol odor in adolescent male rats (observers) following social interaction with an ethanol intoxicated peer (demonstrators) as a function of prenatal ethanol exposure (gestational days 17-20, 1.0 g/kg, intragastric). Social behavior and locomotion during social interaction was also measured. Results: Social investigation was greater in observers that interacted with an intoxicated demonstrator in comparison to those that interacted with a sober peer. Social contact increased when the demonstrator was under the effects of ethanol, but only if the observer had experienced ethanol prenatally. Ethanol inhibited locomotion in the demonstrators. Finally, social interaction with an intoxicated peer during adolescence as well as prenatal ethanol experience increased preference for ethanol odor. Conclusions: Fetal exposure to ethanol mediated by maternal intoxication at late gestation or by interaction with an intoxicated peer at adolescence heightens preference for the chemosensory cues of the drug.Antecedentes: la exposición prenatal al alcohol y la exposición postnatal en contextos sociales predice el consumo de alcohol durante la adolescencia en humanos. Modelos animales indican que la interacción con un congéner intoxicado aumenta la preferencia por el olor del alcohol y su consumo. Método: se analizó la preferencia hacia el olor del etanol en ratas macho adolescentes (observadores) que interactuaron con un compañero intoxicado con alcohol (demostrador), en función de la exposición prenatal al alcohol (días gestacionales 17-20, 1,0 g/kg, intragástrica). Durante la interacción social, se evaluó la conducta social y la locomoción. Resultados: la investigación social fue mayor en los observadores que interactuaron con un sujeto intoxicado en comparación con aquellos que interactuaron con un sujeto sobrio. El contacto social aumentó cuando el demostrador estaba intoxicado, solo si el observador había sido expuesto al alcohol prenatalmente. El alcohol inhibió la locomoción en los demostradores. Finalmente, tanto la interacción social con un congéner intoxicado como la exposición prenatal incrementaron la preferencia por el olor a etanol. Conclusiones: el contacto con etanol durante la vida fetal, así como mediante la exposición a un par intoxicado durante la adolescencia, incrementa la preferencia por las claves quimiosensoriales de la droga.Fil: March, Samanta Mabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Nizhnikov, Michael. University Of Binghamton; Estados UnidosFil: Fernandez Vidal, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra; ArgentinaFil: Spear, Norman E.. University Of Binghamton; Estados UnidosFil: Molina, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba; Argentin

Olfactory preference for ethanol following social interaction with an intoxicated peer in adolescent rats exposed to ethanol in-utero

Background: Prenatal exposure to ethanol and later socially mediated exposure predicts ethanol intake in human adolescents. Animal rat models indicate that brief interactions with an ethanol-intoxicated peer result in heightened preference for ethanol odor and ethanol intake. Methods: This study assessed preference for ethanol odor in adolescent male rats (observers) following social interaction with an ethanol intoxicated peer (demonstrators) as a function of prenatal ethanol exposure (gestational days 17-20, 1.0 g/kg, intragastric). Social behavior and locomotion during social interaction was also measured. Results: Social investigation was greater in observers that interacted with an intoxicated demonstrator in comparison to those that interacted with a sober peer. Social contact increased when the demonstrator was under the effects of ethanol, but only if the observer had experienced ethanol prenatally. Ethanol inhibited locomotion in the demonstrators. Finally, social interaction with an intoxicated peer during adolescence as well as prenatal ethanol experience increased preference for ethanol odor. Conclusions: Fetal exposure to ethanol mediated by maternal intoxication at late gestation or by interaction with an intoxicated peer at adolescence heightens preference for the chemosensory cues of the drug

Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells

The relative contribution to cytotoxicity of each of the multiple NK cell activation receptors has been difficult to assess. Using Drosophila insect cells, which express ligands of human NK cell receptors, we show that target cell lysis by resting NK cells is controlled by different receptor signals for cytolytic granule polarization and degranulation. Intercellular adhesion molecule (ICAM)-1 on insect cells was sufficient to induce polarization of granules, but not degranulation, in resting NK cells. Conversely, engagement of the Fc receptor CD16 by rabbit IgG on insect cells induced degranulation without specific polarization. Lysis by resting NK cells occurred when polarization and degranulation were induced by the combined presence of ICAM-1 and IgG on insect cells. Engagement of receptor 2B4 by CD48 on insect cells induced weak polarization and no degranulation. However, coengagement of 2B4 and CD16 by their respective ligands resulted in granule polarization and cytotoxicity in the absence of leukocyte functional antigen-1–mediated adhesion to target cells. These data show that cytotoxicity by resting NK cells is controlled tightly by separate or cooperative signals from different receptors for granule polarization and degranulation

GREAT3 results I: systematic errors in shear estimation and the impact of real galaxy morphology

We present first results from the third GRavitational lEnsing Accuracy Testing (GREAT3) challenge, the third in a sequence of challenges for testing methods of inferring weak gravitational lensing shear distortions from simulated galaxy images. GREAT3 was divided into experiments to test three specific questions, and included simulated space- and ground-based data with constant or cosmologically-varying shear fields. The simplest (control) experiment included parametric galaxies with a realistic distribution of signal-to-noise, size, and ellipticity, and a complex point spread function (PSF). The other experiments tested the additional impact of realistic galaxy morphology, multiple exposure imaging, and the uncertainty about a spatially-varying PSF; the last two questions will be explored in Paper II. The 24 participating teams competed to estimate lensing shears to within systematic error tolerances for upcoming Stage-IV dark energy surveys, making 1525 submissions overall. GREAT3 saw considerable variety and innovation in the types of methods applied. Several teams now meet or exceed the targets in many of the tests conducted (to within the statistical errors). We conclude that the presence of realistic galaxy morphology in simulations changes shear calibration biases by $\sim 1$ per cent for a wide range of methods. Other effects such as truncation biases due to finite galaxy postage stamps, and the impact of galaxy type as measured by the S\'{e}rsic index, are quantified for the first time. Our results generalize previous studies regarding sensitivities to galaxy size and signal-to-noise, and to PSF properties such as seeing and defocus. Almost all methods' results support the simple model in which additive shear biases depend linearly on PSF ellipticity.Comment: 32 pages + 15 pages of technical appendices; 28 figures; submitted to MNRAS; latest version has minor updates in presentation of 4 figures, no changes in content or conclusion

Dark Matter from Minimal Flavor Violation

We consider theories of flavored dark matter, in which the dark matter particle is part of a multiplet transforming nontrivially under the flavor group of the Standard Model in a manner consistent with the principle of Minimal Flavor Violation (MFV). MFV automatically leads to the stability of the lightest state for a large number of flavor multiplets. If neutral, this particle is an excellent dark matter candidate. Furthermore, MFV implies specific patterns of mass splittings among the flavors of dark matter and governs the structure of the couplings between dark matter and ordinary particles, leading to a rich and predictive cosmology and phenomenology. We present an illustrative phenomenological study of an effective theory of a flavor SU(3)_Q triplet, gauge singlet scalar.Comment: 10 pages, 2 figures; v2: references added, minor changes to collider analysis, conclusions unchange

Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

Complementary Embryonic and Adult Cell Populations Enhance Myocardial Repair in Rat Myocardial Injury Model

We compared the functional outcome of Isl-1+ cardiac progenitors, CD90+ bone marrow-derived progenitor cells, and the combination of the two in a rat myocardial infarction (MI) model. Isl-1+ cells were isolated from embryonic day 12.5 (E12.5) rat hearts and expanded in vitro. Thy-1+/CD90+ cells were isolated from the bone marrow of adult Sprague-Dawley rats by immunomagnetic cell sorting. Six-week-old female Sprague-Dawley rats underwent permanent left anterior descending (LAD) coronary artery ligation and received intramyocardial injection of either saline, Isl-1+ cells, CD90+ cells, or a combination of Isl-1+ and CD90+ cells, at the time of infarction. Cells were delivered transepicardially to the peri-infarct zone. Left ventricular function was assessed by transthoracic echocardiography at 1- and 4-week post-MI and by Millar catheterization (-dP/dt and +dP/dt) at 4-week post-MI. Fluorescence in situ hybridization (Isl-1+cells) and monochrystalline iron oxide nanoparticles labeling (MION; CD90+ cells) were performed to assess biodistribution of transplanted cells. Only the combination of cells demonstrated a significant improvement of cardiac function as assessed by anterior wall contractility, dP/dt (max), and dP/dt (min), compared to Isl-1+ or CD90+ cell monotherapies. In the combination cell group, viable cells were detected at week 4 when anterior wall motion was completely restored. In conclusion, the combination of Isl-1+ cardiac progenitors and adult bone marrow-derived CD90+ cells shows prolonged and robust myocardial tissue repair and provides support for the use of complementary cell populations to enhance myocardial repair

International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered