Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein.

EBV is the major infectious environmental risk factor for multiple sclerosis (MS), but the underlying mechanisms remain obscure. Patient studies do not allow manipulation in vivo. We used the experimental autoimmune encephalomyelitis (EAE) models in the common marmoset and rhesus monkey to model the association of EBV and MS. We report that B cells infected with EBV-related lymphocryptovirus (LCV) are requisite APCs for MHC-E-restricted autoaggressive effector memory CTLs specific for the immunodominant epitope 40-48 of myelin oligodendrocyte glycoprotein (MOG). These T cells drive the EAE pathogenesis to irreversible neurologic deficit. The aim of this study was to determine why LCV infection is important for this pathogenic role of B cells. Transcriptome comparison of LCV-infected B cells and CD20(+) spleen cells from rhesus monkeys shows increased expression of genes encoding elements of the Ag cross-presentation machinery (i.e., of proteasome maturation protein and immunoproteasome subunits) and enhanced expression of MHC-E and of costimulatory molecules (CD70 and CD80, but not CD86). It was also shown that altered expression of endolysosomal proteases (cathepsins) mitigates the fast endolysosomal degradation of the MOG40-48 core epitope. Finally, LCV infection also induced expression of LC3-II(+) cytosolic structures resembling autophagosomes, which seem to form an intracellular compartment where the MOG40-48 epitope is protected against proteolytic degradation by the endolysosomal serine protease cathepsin G. In conclusion, LCV infection induces a variety of changes in B cells that underlies the conversion of destructive processing of the immunodominant MOG40-48 epitope into productive processing and cross-presentation to strongly autoaggressive CTLs

Topological String Amplitudes, Complete Intersection Calabi-Yau Spaces and Threshold Corrections

We present the most complete list of mirror pairs of Calabi-Yau complete intersections in toric ambient varieties and develop the methods to solve the topological string and to calculate higher genus amplitudes on these compact Calabi-Yau spaces. These symplectic invariants are used to remove redundancies in examples. The construction of the B-model propagators leads to compatibility conditions, which constrain multi-parameter mirror maps. For K3 fibered Calabi-Yau spaces without reducible fibers we find closed formulas for all genus contributions in the fiber direction from the geometry of the fibration. If the heterotic dual to this geometry is known, the higher genus invariants can be identified with the degeneracies of BPS states contributing to gravitational threshold corrections and all genus checks on string duality in the perturbative regime are accomplished. We find, however, that the BPS degeneracies do not uniquely fix the non-perturbative completion of the heterotic string. For these geometries we can write the topological partition function in terms of the Donaldson-Thomas invariants and we perform a non-trivial check of S-duality in topological strings. We further investigate transitions via collapsing D5 del Pezzo surfaces and the occurrence of free Z2 quotients that lead to a new class of heterotic duals.Comment: 117 pages, 1 Postscript figur

A function-based typology for Earth’s ecosystems

As the United Nations develops a post-2020 global biodiversity framework for the Convention on Biological Diversity, attention is focusing on how new goals and targets for ecosystem conservation might serve its vision of ‘living in harmony with nature’1,2. Advancing dual imperatives to conserve biodiversity and sustain ecosystem services requires reliable and resilient generalizations and predictions about ecosystem responses to environmental change and management3. Ecosystems vary in their biota4, service provision5 and relative exposure to risks6, yet there is no globally consistent classification of ecosystems that reflects functional responses to change and management. This hampers progress on developing conservation targets and sustainability goals. Here we present the International Union for Conservation of Nature (IUCN) Global Ecosystem Typology, a conceptually robust, scalable, spatially explicit approach for generalizations and predictions about functions, biota, risks and management remedies across the entire biosphere. The outcome of a major cross-disciplinary collaboration, this novel framework places all of Earth’s ecosystems into a unifying theoretical context to guide the transformation of ecosystem policy and management from global to local scales. This new information infrastructure will support knowledge transfer for ecosystem-specific management and restoration, globally standardized ecosystem risk assessments, natural capital accounting and progress on the post-2020 global biodiversity framework

Tau-Structure for the Double Ramification Hierarchies

In this paper we continue the study of the double ramification hierarchy of Buryak (Commun Math Phys 336(3):1085–1107, 2015). After showing that the DR hierarchy satisfies tau-symmetry we define its partition function as the (logarithm of the) tau-function of the string solution and show that it satisfies various properties (string, dilaton, and divisor equations plus some important degree constraints). We then formulate a stronger version of the conjecture from Buryak (2015): for any semisimple cohomological field theory, the Dubrovin–Zhang and double ramification hierarchies are related by a normal [i.e. preserving the tau-structure (Dubrovin et al. in Adv Math 293:382–435, 2016)] Miura transformation which we completely identify in terms of the partition function of the CohFT. In fact, using only the partition functions, the conjecture can be formulated even in the non-semisimple case (where the Dubrovin–Zhang hierarchy is not defined). We then prove this conjecture for various CohFTs (trivial CohFT, Hodge class, Gromov–Witten theory of CP¹, 3-, 4- and 5-spin classes) and in genus 1 for any semisimple CohFT. Finally we prove that the higher genus part of the DR hierarchy is basically trivial for the Gromov–Witten theory of smooth varieties with non-positive first Chern class and their analogue in Fan–Jarvis–Ruan–Witten quantum singularity theory (Fan et al. in Ann Math 178(1):1–106, 2013)

Allan Sandage and the Cosmic Expansion

This is an account of Allan Sandage's work on (1) The character of the expansion field. For many years he has been the strongest defender of an expanding Universe. He later explained the CMB dipole by a local velocity of 220 +/- 50 km/s toward the Virgo cluster and by a bulk motion of the Local supercluster (extending out to ~3500 km/s) of 450-500 km/s toward an apex at l=275, b=12. Allowing for these streaming velocities he found linear expansion to hold down to local scales (~300 km/s). (2) The calibration of the Hubble constant. Probing different methods he finally adopted - from Cepheid-calibrated SNe Ia and from independent RR Lyr-calibrated TRGBs - H_0 = 62.3 +/- 1.3 +/- 5.0 km/s/Mpc.Comment: 12 pages, 11 figures, 1 table, Submitted to Astrophysics and Space Science, Special Issue on the Fundamental Cosmic Distance Scale in the Gaia Er

Tides in colliding galaxies

Long tails and streams of stars are the most noticeable upshots of galaxy collisions. Their origin as gravitational, tidal, disturbances has however been recognized only less than fifty years ago and more than ten years after their first observations. This Review describes how the idea of galactic tides emerged, in particular thanks to the advances in numerical simulations, from the first ones that included tens of particles to the most sophisticated ones with tens of millions of them and state-of-the-art hydrodynamical prescriptions. Theoretical aspects pertaining to the formation of tidal tails are then presented. The third part of the review turns to observations and underlines the need for collecting deep multi-wavelength data to tackle the variety of physical processes exhibited by collisional debris. Tidal tails are not just stellar structures, but turn out to contain all the components usually found in galactic disks, in particular atomic / molecular gas and dust. They host star-forming complexes and are able to form star-clusters or even second-generation dwarf galaxies. The final part of the review discusses what tidal tails can tell us (or not) about the structure and content of present-day galaxies, including their dark components, and explains how tidal tails may be used to probe the past evolution of galaxies and their mass assembly history. On-going deep wide-field surveys disclose many new low-surface brightness structures in the nearby Universe, offering great opportunities for attempting galactic archeology with tidal tails.Comment: 46 pages, 13 figures, Review to be published in "Tidal effects in Astronomy and Astrophysics", Lecture Notes in Physics. Comments are most welcom

Heavy menstrual bleeding on direct factor Xa inhibitors: Rationale and design of the MEDEA study

Background: In premenopausal women, treatment with direct oral factor Xa inhibitors is associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists (VKA). Treatment with the direct oral thrombin inhibitor dabigatran appears to be associated with a reduced risk of HMB compared with VKA. These findings come from small observational studies or post hoc analyses of trials in which HMB was not a primary outcome. Use of tranexamic acid during the menstrual period may be effective in patients with HMB, but prospective data regarding efficacy and safety in patients on anticoagulant treatment are lacking. Rationale and Design: A direct comparison of a factor Xa inhibitor and a thrombin inhibitor with HMB as primary outcome, as well as an evaluation of the effects of adding tranexamic acid in women with anticoagulant-associated HMB is highly relevant for clinical practice. The MEDEA study is a randomized, open-label, pragmatic clinical trial to evaluate management strategies in premenopausal women with HMB associated with factor Xa inhibitor therapy. Outcomes: Women using factor Xa inhibitors with proven HMB, as assessed by a pictorial blood loss assessment chart (PBAC) score of >150, will be randomized to one of three study arms: (i) switch to dabigatran; (ii) continue factor Xa inhibitor with addition of tranexamic acid during the menstrual period; or (iii) continue factor Xa inhibitor without intervention. The primary outcome is the difference in PBAC score before and after randomization. Here, we present the rationale and highlight several unique features in the design of the study

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele