In Situ Patrolling of Regulatory T Cells Is Essential for Protecting Autoimmune Exocrinopathy

BACKGROUND: Migration of T cells, including regulatory T (Treg) cells, into the secondary lymph organs is critically controlled by chemokines and adhesion molecules. However, the mechanisms by which Treg cells regulate organ-specific autoimmunity via these molecules remain unclear. Although we previously reported autoimmune exocrinopathy resembling Sjögren's syndrome (SS) in the lacrimal and salivary glands from C-C chemokine receptor 7 (CCR7)-deficient mice, it is still unclear whether CCR7 signaling might specifically affect the dynamics and functions of Treg cells in vivo. We therefore investigated the cellular mechanism for suppressive function of Treg cells via CCR7 in autoimmunity using mouse models and human samples. METHODS AND FINDINGS: Patrolling Treg cells were detected in the exocrine organs such as lacrimal and salivary glands from normal mice that tend to be targets for autoimmunity while the Treg cells were almost undetectable in the exocrine glands of CCR7(-/-) mice. In addition, we found the significantly increased retention of CD4(+)CD25(+)Foxp3(+) Treg cells in the lymph nodes of CCR7(-/-) mice with aging. Although Treg cell egress requires sphingosine 1-phosphate (S1P), chemotactic function to S1P of CCR7-/- Treg cells was impaired compared with that of WT Treg cells. Moreover, the in vivo suppression activity was remarkably diminished in CCR7(-/-) Treg cells in the model where Treg cells were co-transferred with CCR7(-/-) CD25(-)CD4(+) T cells into Rag2(-/-) mice. Finally, confocal analysis showed that CCR7(+)Treg cells were detectable in normal salivary glands while the number of CCR7(+)Treg cells was extremely decreased in the tissues from patients with Sjögren's syndrome. CONCLUSIONS: These results indicate that CCR7 essentially governs the patrolling functions of Treg cells by controlling the traffic to the exocrine organs for protecting autoimmunity. Characterization of this cellular mechanism could have clinical implications by supporting development of new diagnosis or treatments for the organ-specific autoimmune diseases such as Sjögren's syndrome and clarifying how the local immune system regulates autoimmunity

Mouse SPNS2 Functions as a Sphingosine-1-Phosphate Transporter in Vascular Endothelial Cells

Sphingosine-1-phosphate (S1P), a sphingolipid metabolite that is produced inside the cells, regulates a variety of physiological and pathological responses via S1P receptors (S1P1–5). Signal transduction between cells consists of three steps; the synthesis of signaling molecules, their export to the extracellular space and their recognition by receptors. An S1P concentration gradient is essential for the migration of various cell types that express S1P receptors, such as lymphocytes, pre-osteoclasts, cancer cells and endothelial cells. To maintain this concentration gradient, plasma S1P concentration must be at a higher level. However, little is known about the molecular mechanism by which S1P is supplied to extracellular environments such as blood plasma. Here, we show that SPNS2 functions as an S1P transporter in vascular endothelial cells but not in erythrocytes and platelets. Moreover, the plasma S1P concentration of SPNS2-deficient mice was reduced to approximately 60% of wild-type, and SPNS2-deficient mice were lymphopenic. Our results demonstrate that SPNS2 is the first physiological S1P transporter in mammals and is a key determinant of lymphocyte egress from the thymus

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

Approaches in biotechnological applications of natural polymers

Natural polymers, such as gums and mucilage, are biocompatible, cheap, easily available and non-toxic materials of native origin. These polymers are increasingly preferred over synthetic materials for industrial applications due to their intrinsic properties, as well as they are considered alternative sources of raw materials since they present characteristics of sustainability, biodegradability and biosafety. As definition, gums and mucilages are polysaccharides or complex carbohydrates consisting of one or more monosaccharides or their derivatives linked in bewildering variety of linkages and structures. Natural gums are considered polysaccharides naturally occurring in varieties of plant seeds and exudates, tree or shrub exudates, seaweed extracts, fungi, bacteria, and animal sources. Water-soluble gums, also known as hydrocolloids, are considered exudates and are pathological products; therefore, they do not form a part of cell wall. On the other hand, mucilages are part of cell and physiological products. It is important to highlight that gums represent the largest amounts of polymer materials derived from plants. Gums have enormously large and broad applications in both food and non-food industries, being commonly used as thickening, binding, emulsifying, suspending, stabilizing agents and matrices for drug release in pharmaceutical and cosmetic industries. In the food industry, their gelling properties and the ability to mold edible films and coatings are extensively studied. The use of gums depends on the intrinsic properties that they provide, often at costs below those of synthetic polymers. For upgrading the value of gums, they are being processed into various forms, including the most recent nanomaterials, for various biotechnological applications. Thus, the main natural polymers including galactomannans, cellulose, chitin, agar, carrageenan, alginate, cashew gum, pectin and starch, in addition to the current researches about them are reviewed in this article.. }To the Conselho Nacional de Desenvolvimento Cientfíico e Tecnológico (CNPq) for fellowships (LCBBC and MGCC) and the Coordenação de Aperfeiçoamento de Pessoal de Nvíel Superior (CAPES) (PBSA). This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, the Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462) and COMPETE 2020 (POCI-01-0145-FEDER-006684) (JAT)

In search of tools for the use of Country-Image (CI) in the brand

Existing country image (CI) literature tends to focus on consumer behaviour. In contrast, this paper approaches CI from the point of view of the firm. In doing so, it seeks to identify the means by which international companies associate a brand with a specific country of origin in order to build brand values. In particular, it looks at the use of CI cues in brand strategies. The paper is based on exploratory research comprising a case study of two contrasting companies from the cosmetics industry, Natura, a domestic company, and the French-owned L’Occitane, both of which draw on images of Brazil to build their brands. Specific elements of CI used in branding are identified, and the extent to which the use of these differs depending on the origin of the owning company is explored. The cases suggest that CI can be exploited in different contexts. Through analysis of the elements used by both companies to build strong brands associated with the Brazilian CI—Natura Cosméticos and L’Occitane au Brésil—six tools are identified that can be combined by firms to deliver brand values, derived from any country, through the use of CI

International expansion of Chinese emerging market multinational corporations to developed markets: A qualitative analysis of post-acquisition and integration strategies

Since the end of Great Recession about a decade ago, the 20 biggest emerging market economies have become the drivers for global outward foreign direct investments (OFDI) (Casanova and Miroux in Emerging Market Multinational Report, 2017), and these capital outflows are increasingly directed toward developed countries in form of international mergers and acquisitions (Thomson Reuters in Mergers and acquisition review, 2018; UNCTAD in World investment report: investment and new industrial policies. United Nations 646 Publications, New York, 2018). Particularly China has become a key player in the global market for corporate takeovers since the turn of the century. The country already constitutes the world’s second largest economy (and largest emerging economy) for OFDI through international mergers and acquisitions, second only to the United States. In fact, the total transaction value of outbound international mergers and acquisitions of emerging market multinational corporations (EMNCs) from China amounted to nearly US$256 billion in 2016, with particular focus on target companies in developed economies (Casanova and Miroux in Emerging Market Multinational Report, 2017). Due to the significant capabilities gap between EMNCs from China and developed market companies, however, international acquisitions of the latter by the former require a unique post-acquisition integration approach that differs from those prescribed by extant research. In addition, due to the unique institutional environment of China, which is characterized by a considerable oversight and influence of the central government on the foreign market entry and location decisions by Chinese companies that are conducting outward foreign direct investments, a better understanding about the specific institutional demands and legitimacy pressures is needed for this context. This chapter aims to address these issues by examining the unique institutional environment of China in the context of the internationalization strategies of indigenous firms through acquisitions in developed markets, and the related, context-specific integration approaches Chinese EMNCs employ for these transactions

Synergistic effects of substrate-induced conformational changes in phosphoglycerate kinase activation

Phosphoglycerate kinase (PGK), a key enzyme in glycolysis, catalyses the transfer of a phosphoryl-group from 1,3-bis-phosphoglycerate to ADP to form 3-phosphoglycerate and ATP. Despite extensive kinetic and structural investigations over more than two decades, the conformation assumed by this enzyme during catalysis remained unknown. Here we present the 2.8 Angstrom crystal structure of a ternary complex of PGK from Trypanosoma brucei, the causative agent of sleeping sickness. This structure determination relied on a procedure in which fragments containing less than 10% of the scattering mass were successively positioned in the unit cell to obtain phases. The PGK ternary complex exhibits a dramatic dosing of the large cleft between the two domains seen in all previous studies(1-6), thereby bringing the two ligands, 3-phosphoglycerate and ADP into dose proximity. Our results demonstrate that PGK is a hinge-bending enzyme, reveal a novel mechanism in which substrate-induced effects combine synergistically to induce major conformational changes and, to our knowledge, afford the first observation of the PGK active site in a catalytic conformation