Autoimmunity-Associated LYP-W620 Does Not Impair Thymic Negative Selection of Autoreactive T Cells.

A C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for human autoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays a role in thymic selection. However, the mechanism of action of the R620W variant in autoimmunity remains unclear. One model holds that LYP-W620 is a gain-of-function phosphatase that causes alterations in thymic negative selection and/or thymic output of regulatory T cells (Treg) through inhibition of thymic TCR signaling. To test this model, we generated mice in which the human LYP-W620 variant or its phosphatase-inactive mutant are expressed in developing thymocytes under control of the proximal Lck promoter. We found that LYP-W620 expression results in diminished thymocyte TCR signaling, thus modeling a "gain-of-function" of LYP at the signaling level. However, LYP-W620 transgenic mice display no alterations of thymic negative selection and no anomalies in thymic output of CD4(+)Foxp3(+) Treg were detected in these mice. Lck promoter-directed expression of the human transgene also causes no alteration in thymic repertoire or increase in disease severity in a model of rheumatoid arthritis, which depends on skewed thymic selection of CD4(+) T cells. Our data suggest that a gain-of-function of LYP is unlikely to increase risk of autoimmunity through alterations of thymic selection and that LYP likely acts in the periphery perhaps selectively in regulatory T cells or in another cell type to increase risk of autoimmunity

Land Law, Property Ideologies and the British-Irish relationship

English and Irish land law are deeply influenced by the historical context of the British-Irish relationship, yet property scholarship comparing the two jurisdictions is surprisingly rare. The current Brexit negotiations provide a timely reminder of the strategic importance of property and trade relations between the two countries; and of their related-but-different legal cultures. In this article we examine how the property cultures of England and Ireland were shaped by the politics and practices of land tenure, by competing economic and property ideologies, and by the influence of both on national identity and statehood in both jurisdictions. The article reveals the role of local contexts and events in shaping land reform, and demonstrates the fertile potential of the comparative frame to contextualise each jurisdiction’s doctrines and practices. As domestic land law systems are drawn together in the context of emerging EU jurisdiction over areas like mortgage credit, each jurisdiction’s underpinning ideological commitments have important implications for the ease – or not – of attempts to harmonize member state practices. We explain the alignments and divergences between domestic underpinnings of Irish and English law, and reflect on the implications of our findings for contemporary property problems in the context of evolving economic and political relationships between the UK and Ireland

Legislative requirements for milk quality in the Czech Republic

The aim of the thesis was to give a comprehensive review of literature dealing with legislative measures, milk production in terms of sales of milk and its storage. We used the most current Czech and European legislation. These sources have been supplemented thematically compliant scientific and professional publications. Milk is a primary since the Middle Ages and sought food which people consume every day. Along with dairy milk a deserved popularity mainly due to its rich composition and nutritional and health properties. The main components of milk include water, lactose, fat, protein and minerals. Milk however can also include foreign substances of organic and inorganic origin and unwanted microflora. Microorganisms are particularly dangerous to humans and are considered a major source of foodborne illnesses. To eliminate unwanted microflora, extending shelf life and maintain public safety is used heat treatment, including pasteurization and treatment of very high temperature (UHT). This treatment must be carried out according to established requirements and specifications. If a consumer buys a dairy product in the Czech Republic retains its quality as well. All animal products, including products imported to the Czech market, are compulsorily fitted with oval health mark, which ensures wholesomeness. The quality of the milk is influenced by many factors, most of which are closely linked, and therefore not always easy to identify the specific cause possible reduction in quality standards. Already during the production process, emphasis is put on prevention in the field of quality and safety. Security is guaranteed by a system of determining critical control points HACCP, which is in the Czech Republic and the EU compulsory by law. Among the optional systems include ISO. Most enterprises with good reputation has introduced both these systems. Simultaneous application of HACCP and ISO standards provides a guarantee for the security of the overall quality and safety of products. This connection is known as TQM system. The main indicators of quality of raw milk are total number of mesophilic microorganisms, somatic cell count, fat content, crude protein residues of inhibiting substances, the average herd size and the number of bred cows. The milk must not contain any preservatives or stabilizers. Meeting the requirements and quality criteria will be checked on the appropriate number of samples that are collected in enterprises producing milk, random checks. The basic quality criteria of raw milk, food business operators must ensure that: The content of microorganisms in 1 mL at 30 ° C must be < 100 000. It is found average values for two months for the collection of at least two samples per month. Somatic cells in 1 ml at 30 ° C must be < 400 000. It is obtained by moving the geometric mean for the three months, every month, evaluates at least one sample. Immediately before treating the milk must contain 1 ml 100,000 at 30 ° C