4MOST Consortium Survey 3: Milky Way Disc and Bulge Low-Resolution Survey (4MIDABLE-LR)

The mechanisms of the formation and evolution of the Milky Way are encoded in the orbits, chemistry and ages of its stars. With the 4MOST MIlky way Disk And BuLgE Low-Resolution Survey (4MIDABLE-LR) we aim to study kinematic and chemical substructures in the Milky Way disc and bulge region with samples of unprecedented size out to larger distances and greater precision than conceivable with Gaia alone or any other ongoing or planned survey. Gaia gives us the unique opportunity for target selection based almost entirely on parallax and magnitude range, hence increasing the efficiency in sampling larger Milky Way volumes with well-defined and effective selection functions. Our main goal is to provide a detailed chrono-chemo-kinematical extended map of our Galaxy and the largest Gaia follow-up down to $G = 19$ magnitudes (Vega). The complex nature of the disc components (for example, large target densities and highly structured extinction distribution in the Milky Way bulge and disc area), prompted us to develop a survey strategy with five main sub-surveys that are tailored to answer the still open questions about the assembly and evolution of our Galaxy, while taking full advantage of the Gaia data.Comment: Part of the 4MOST issue of The Messenger, published in preparation of 4MOST Community Workshop, see http://www.eso.org/sci/meetings/2019/4MOST.htm

P E N G A R U H K O M P E N S A S I D A N D I S I P L I N K E R J A T E R H A D A P K I N E R J A G U R U D I S M A N 1 J A T I S A R I K A B U P A T E N K A R A W A N G

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Near-threshold production of omega mesons in the pn -> d omega reaction

The first measurement of the p n -> d omega total cross section has been achieved at mean excess energies of Q = 28 and 57 MeV by using a deuterium cluster-jet target. The momentum of the fast deuteron was measured in the ANKE spectrometer at COSY-Juelich and that of the slow "spectator" proton p(sp) from the p d -> p(sp) d omega reaction in a silicon telescope placed close to the target. The cross sections lie above those measured for p p -> p p omega but seem to be below theoretical predictions.Comment: 7 pages, 8 figures; second approach to describe the background has been added; results changed insignificantly, EPJ in pres

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

Medaka piwi is Essential for Primordial Germ Cell Migration

Piwi controls the number of primordial germ cells (PGCs) via protecting maternal mRNA from decay and adult germ stem cell division in Drosophila. In mouse and zebrafish, piwi controls maintenance and differentiation of adult germ stem cell during gametogenesis. Whether piwi plays a role in PGC development of vertebrates remains unsolved. We addressed this issue by using medaka (Oryzias latipes) as a vertebrate model. Molecular cloning, sequence comparison and analyses of genomic organization and chromosome synteny led to the identification in this fish of a single piwi gene, called Opiwi. By RT-PCR analyses and in situ hybridization, the Opiwi transcript is maternally supplied and becomes restricted to PGCs and the central nervous system (CNS). Opiwi knockdown did not prevent PGC formation even in the absence of any somatic structures but did significantly reduce the number of PGCs in vivo and in vitro and affect the distribution of PGCs in developing embryos. Surprisingly, depletion of zygotic Opiwi severely and specifically affected PGC migration. We conclude that Opiwi is required not only for determining the PGC number but also for controlling PGC migration. Our results demonstrate that piwi plays a generally conserved role in germ cell development from Drosophila to vertebrate and a specific role in PGC migration.Piwi controls the number of primordial germ cells (PGCs) via protecting maternal mRNA from decay and adult germ stem cell division in Drosophila. In mouse and zebrafish, piwi controls maintenance and differentiation of adult germ stem cell during gametogenesis. Whether piwi plays a role in PGC development of vertebrates remains unsolved. We addressed this issue by using medaka (Oryzias latipes) as a vertebrate model. Molecular cloning, sequence comparison and analyses of genomic organization and chromosome synteny led to the identification in this fish of a single piwi gene, called Opiwi. By RT-PCR analyses and in situ hybridization, the Opiwi transcript is maternally supplied and becomes restricted to PGCs and the central nervous system (CNS). Opiwi knockdown did not prevent PGC formation even in the absence of any somatic structures but did significantly reduce the number of PGCs in vivo and in vitro and affect the distribution of PGCs in developing embryos. Surprisingly, depletion of zygotic Opiwi severely and specifically affected PGC migration. We conclude that Opiwi is required not only for determining the PGC number but also for controlling PGC migration. Our results demonstrate that piwi plays a generally conserved role in germ cell development from Drosophila to vertebrate and a specific role in PGC migration

Class I major histocompatibility complexes loaded by a periodate trigger

Class I major histocompatibility complexes (MHCs) present peptide ligands on the cell surface for recognition by appropriate cytotoxic T cells. The unstable nature of unliganded MHC necessitates the production of recombinant class I complexes through in vitro refolding reactions in the presence of an added excess of peptides. This strategy is not amenable to high-throughput production of vast collections of class I complexes. To address this issue, we recently designed photocaged MHC ligands that can be cleaved by a UV light trigger in the MHC bound state under conditions that do not affect the integrity of the MHC structure. The results obtained with photocaged MHC ligands demonstrate that conditional MHC ligands can form a generally applicable concept for the creation of defined peptide−MHCs. However, the use of UV exposure to mediate ligand exchange is unsuited for a number of applications, due to the lack of UV penetration through cell culture systems and due to the transfer of heat upon UV irradiation, which can induce evaporation. To overcome these limitations, here, we provide proof-of-concept for the generation of defined peptide−MHCs by chemical trigger-induced ligand exchange. The crystal structure of the MHC with the novel chemosensitive ligand showcases that the ligand occupies the expected binding site, in a conformation where the hydroxyl groups should be reactive to periodate. We proceed to validate this technology by producing peptide−MHCs that can be used for T cell detection. The methodology that we describe here should allow loading of MHCs with defined peptides in cell culture devices, thereby permitting antigen-specific T cell expansion and purification for cell therapy. In addition, this technology will be useful to develop miniaturized assay systems for performing high-throughput screens for natural and unnatural MHC ligands

Dynamical Supersymmetry Breaking

Supersymmetry is one of the most plausible and theoretically motivated frameworks for extending the Standard Model. However, any supersymmetry in Nature must be a broken symmetry. Dynamical supersymmetry breaking (DSB) is an attractive idea for incorporating supersymmetry into a successful description of Nature. The study of DSB has recently enjoyed dramatic progress, fueled by advances in our understanding of the dynamics of supersymmetric field theories. These advances have allowed for direct analysis of DSB in strongly coupled theories, and for the discovery of new DSB theories, some of which contradict early criteria for DSB. We review these criteria, emphasizing recently discovered exceptions. We also describe, through many examples, various techniques for directly establishing DSB by studying the infrared theory, including both older techniques in regions of weak coupling, and new techniques in regions of strong coupling. Finally, we present a list of representative DSB models, their main properties, and the relations between them.Comment: 113 pages, Revtex. Minor changes, references added and corrected. To appear in Reviews of Modern Physic

Structure and mechanism of acetolactate decarboxylase

Acetolactate decarboxylase catalyzes the conversion of both enantiomers of acetolactate to the (R)-enantiomer of acetoin, via a mechanism that has been shown to involve a prior rearrangement of the non-natural (R)-enantiomer substrate to the natural (S)-enantiomer. In this paper, a series of crystal structures of ALDC complex with designed transition state mimics are reported. These structures, coupled with inhibition studies and site-directed mutagenesis provide an improved understanding of the molecular processes involved in the stereoselective decarboxylation/protonation events. A mechanism for the transformation of each enantiomer of acetolactate is proposed

Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes. The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.Bio-organic Synthesi