Single-cell transcriptome analysis of fish immune cells provides insight into the evolution of vertebrate immune cell types

The immune system of vertebrate species consists of many different cell types that have distinct functional roles and are subject to different evolutionary pressures. Here, we first analyzed conservation of genes specific for all major immune cell types in human and mouse. Our results revealed higher gene turnover and faster evolution of trans-membrane proteins in NK cells compared with other immune cell types, and especially T cells, but similar conservation of nuclear and cytoplasmic protein coding genes. To validate these findings in a distant vertebrate species, we used single-cell RNA sequencing of lck:GFP cells in zebrafish and obtained the first transcriptome of specific immune cell types in a nonmammalian species. Unsupervised clustering and single-cell TCR locus reconstruction identified three cell populations, T cells, a novel type of NK-like cells, and a smaller population of myeloid-like cells. Differential expression analysis uncovered new immune-cell–specific genes, including novel immunoglobulin-like receptors, and neofunctionalization of recently duplicated paralogs. Evolutionary analyses confirmed the higher gene turnover of trans-membrane proteins in NK cells compared with T cells in fish species, suggesting that this is a general property of immune cell types across all vertebrates.This work was supported by SystemsX (MelanomX grant for S.J.C.), Cancer Research UK grant number C45041/A14953 to A.C. and L.F., European Research Council project 677501–ZF_Blood to A.C., and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute

Systemic Risk and Default Clustering for Large Financial Systems

As it is known in the finance risk and macroeconomics literature, risk-sharing in large portfolios may increase the probability of creation of default clusters and of systemic risk. We review recent developments on mathematical and computational tools for the quantification of such phenomena. Limiting analysis such as law of large numbers and central limit theorems allow to approximate the distribution in large systems and study quantities such as the loss distribution in large portfolios. Large deviations analysis allow us to study the tail of the loss distribution and to identify pathways to default clustering. Sensitivity analysis allows to understand the most likely ways in which different effects, such as contagion and systematic risks, combine to lead to large default rates. Such results could give useful insights into how to optimally safeguard against such events.Comment: in Large Deviations and Asymptotic Methods in Finance, (Editors: P. Friz, J. Gatheral, A. Gulisashvili, A. Jacqier, J. Teichmann) , Springer Proceedings in Mathematics and Statistics, Vol. 110 2015

The Effective Lagrangian for Bulk Fermions in Models with Extra Dimensions

We compute the dimension 6 effective Lagrangian arising from the tree level integration of an arbitrary number of bulk fermions in models with warped extra dimensions. The coefficients of the effective operators are written in terms of simple integrals of the metric and are valid for arbitrary warp factors, with or without an infrared brane, and for a general Higgs profile. All relevant tree level fermion effects in electroweak and flavor observables can be computed using this effective Lagrangian.Comment: 22 pages. V2: typos corrected, matches published versio

Neutrino Mixing from Wilson Lines in Warped Space

We consider the generation of the hierarchical charged lepton spectrum and anarchic neutrino masses and mixing angles in warped extra dimensional models with Randall-Sundrum metric. We have classified all possible cases giving rise to realistic spectra for both Dirac and Majorana neutrinos. An anarchic neutrino spectrum requires a convenient bulk symmetry broken by boundary conditions on both UV and IR branes. We have in particular considered the case of Majorana neutrinos with a continuous bulk symmetry. To avoid unwanted massless extra gauge bosons the 4D group should be empty. If the 4D coset is not vanishing it can provide a Wilson Line description of the neutrino Majorana mass matrix. We have studied an example based on the bulk gauge group U(3)_{L} \otimes U(3)_{N} \otimes_{i} U(1)_{E^i} with the Wilson Line in SO(3)_{N} satisfying all required conditions. A \chi^2-fit to experimental data exhibits the 95% CL region in the parameter space with no fine-tuning. As a consequence of the symmetries of the theory there is no tree-level induced lepton flavor violation and so one-loop processes are consistent with experimental data for KK-modes about a few TeV. The model is easily generalizable to models with IR deformed metrics with similar conclusions.Comment: 28 pages, 9 eps plots, uses axodraw; v2 Title changed, comments on phenomenology added, version to be published in JHE

Projected WIMP sensitivity of the LUX-ZEPLIN dark matter experiment

LUX-ZEPLIN (LZ) is a next-generation dark matter direct detection experiment that will operate 4850 feet underground at the Sanford Underground Research Facility (SURF) in Lead, South Dakota, USA. Using a two-phase xenon detector with an active mass of 7 tonnes, LZ will search primarily for low-energy interactions with weakly interacting massive particles (WIMPs), which are hypothesized to make up the dark matter in our galactic halo. In this paper, the projected WIMP sensitivity of LZ is presented based on the latest background estimates and simulations of the detector. For a 1000 live day run using a 5.6-tonne fiducial mass, LZ is projected to exclude at 90% confidence level spin-independent WIMP-nucleon cross sections above 1.4×10-48 cm2 for a 40 GeV/c2 mass WIMP. Additionally, a 5σ discovery potential is projected, reaching cross sections below the exclusion limits of recent experiments. For spin-dependent WIMP-neutron(-proton) scattering, a sensitivity of 2.3×10-43 cm2 (7.1×10-42 cm2) for a 40 GeV/c2 mass WIMP is expected. With underground installation well underway, LZ is on track for commissioning at SURF in 2020

Simulations of events for the LUX-ZEPLIN (LZ) dark matter experiment

The LUX-ZEPLIN dark matter search aims to achieve a sensitivity to the WIMP-nucleon spin-independent cross-section down to (1–2)×10−12 pb at a WIMP mass of 40 GeV/c2. This paper describes the simulations framework that, along with radioactivity measurements, was used to support this projection, and also to provide mock data for validating reconstruction and analysis software. Of particular note are the event generators, which allow us to model the background radiation, and the detector response physics used in the production of raw signals, which can be converted into digitized waveforms similar to data from the operational detector. Inclusion of the detector response allows us to process simulated data using the same analysis routines as developed to process the experimental data

Projected sensitivity of the LUX-ZEPLIN experiment to the 0νββ decay of Xe 136

The LUX-ZEPLIN (LZ) experiment will enable a neutrinoless double β decay search in parallel to the main science goal of discovering dark matter particle interactions. We report the expected LZ sensitivity to Xe136 neutrinoless double β decay, taking advantage of the significant (>600 kg) Xe136 mass contained within the active volume of LZ without isotopic enrichment. After 1000 live-days, the median exclusion sensitivity to the half-life of Xe136 is projected to be 1.06×1026 years (90% confidence level), similar to existing constraints. We also report the expected sensitivity of a possible subsequent dedicated exposure using 90% enrichment with Xe136 at 1.06×1027 years

Pre-hospital antibiotic treatment and mortality caused by invasive meningococcal disease, adjusting for indication bias

<p>Abstract</p> <p>Background</p> <p>Mortality from invasive meningococcal disease (IMD) has remained stable over the last thirty years and it is unclear whether pre-hospital antibiotherapy actually produces a decrease in this mortality. Our aim was to examine whether pre-hospital oral antibiotherapy reduces mortality from IMD, adjusting for indication bias.</p> <p>Methods</p> <p>A retrospective analysis was made of clinical reports of all patients (n = 848) diagnosed with IMD from 1995 to 2000 in Andalusia and the Canary Islands, Spain, and of the relationship between the use of pre-hospital oral antibiotherapy and mortality. Indication bias was controlled for by the propensity score technique, and a multivariate analysis was performed to determine the probability of each patient receiving antibiotics, according to the symptoms identified before admission. Data on in-hospital death, use of antibiotics and demographic variables were collected. A logistic regression analysis was then carried out, using death as the dependent variable, and pre-hospital antibiotic use, age, time from onset of symptoms to parenteral antibiotics and the propensity score as independent variables.</p> <p>Results</p> <p>Data were recorded on 848 patients, 49 (5.72%) of whom died. Of the total number of patients, 226 had received oral antibiotics before admission, mainly betalactams during the previous 48 hours. After adjusting the association between the use of antibiotics and death for age, time between onset of symptoms and in-hospital antibiotic treatment, pre-hospital oral antibiotherapy remained a significant protective factor (Odds Ratio for death 0.37, 95% confidence interval 0.15–0.93).</p> <p>Conclusion</p> <p>Pre-hospital oral antibiotherapy appears to reduce IMD mortality.</p

Gapped continuum Kaluza-Klein spectrum

We consider a warped ve-dimensional model with an ultraviolet (UV) brane and, on top of the Standard Model isolated modes, continua of KK modes with different mass gaps for all particles: gauge bosons, fermions, graviton, radion and Higgs boson. The model can be considered as a modelization in ve dimensions of gapped unparticles. The ve dimensional metric has a singularity, at a finite (infinite) value of the proper (conformal) coordinate, which is admissible as it supports finite temperature in the form of a black hole horizon. An infrared (IR) brane, with particular jumping conditions, is introduced to trigger correct electroweak breaking. The gravitational metric is AdS5 near the UV brane, to solve the hierarchy problem with a fundamental Planck scale, and linear, in conformal coordinates, near the IR, as in the linear dilaton and ve-dimensional clockwork models. The branes, and singularity, distances are fixed, à la Goldberger-Wise, by a bulk scalar field with brane potentials explicitly breaking the conformal symmetry. The bosonic continuum of KK modes with the smallest mass gap are those of gauge bosons, and so they are the most likely produced at the LHC. Mass gaps of the continuum of KK fermions do depend on their localization in the extra dimension. We have computed the spectral functions, and arbitrary Green's functions, and shown how they can modify some Standard Model processes.The work of EM is supported by the Spanish MINEICO under Grant FIS2017-85053-C2-1-P, by the Junta de Andalucía under Grant FQM-225, by the Consejería de Conocimiento, Investigación y Universidad of the Junta de Andalucía and European Regional Development Fund (ERDF) under Grant SOMM17/6105/UGR, and by the Spanish Consolider Ingenio 2010 Programme CPAN under Grant CSD2007-00042. The research of EM is also supported by the Ramón y Cajal Program of the Spanish MINEICO under Grant RYC-2016-20678. The work of MQ is partly supported by Spanish MINEICO (Grant FPA2017-88915-P), by the Catalan Government under Grant 2017SGR1069, and by Severo Ochoa Excellence Program of MINEICO (Grant SEV-2016-0588)

Methamphetamine withdrawal induces activation of CRF neurons in the brain stress system in parallel with an increased activity of cardiac sympathetic pathways.

Methamphetamine (METH) addiction is a major public health problem in some countries. There is evidence to suggest that METH use is associated with increased risk of developing cardiovascular problems. Here, we investigated the effects of chronic METH administration and withdrawal on the activation of the brain stress system and cardiac sympathetic pathways. Mice were treated with METH (2 mg/kg, i.p.) for 10 days and left to spontaneous withdraw for 7 days. The number of corticotrophin-releasing factor (CRF), c-Fos, and CRF/c-Fos neurons was measured by immunohistochemistry in the paraventricular nucleus of the hypothalamus (PVN) and the oval region of the bed nucleus of stria terminalis (ovBNST), two regions associated with cardiac sympathetic control. In parallel, levels of catechol-o-methyl-transferase (COMT), tyrosine hydroxylase (TH), and heat shock protein 27 (Hsp27) were measured in the heart. In the brain, chronic-METH treatment enhanced the number of c-Fos neurons and the CRF neurons with c-Fos signal (CRF+/c-Fos+) in PVN and ovBNST. METH withdrawal increased the number of CRF+neurons. In the heart, METH administration induced an increase in soluble (S)-COMT and membrane-bound (MB)-COMT without changes in phospho (p)-TH, Hsp27, or pHsp27. Similarly, METH withdrawal increased the expression of S- and MB-COMT. In contrast to chronic treatment, METH withdrawal enhanced levels of (p)TH and (p)Hsp27 in the heart. Overall, our results demonstrate that chronic METH administration and withdrawal activate the brain CRF systems associated with the heart sympathetic control and point towards a METH withdrawal induced activation of sympathetic pathways in the heart. Our findings provide further insight in the mechanism underlining the cardiovascular risk associated with METH use and proposes targets for its treatment