PTPN22.6, a Dominant Negative Isoform of PTPN22 and Potential Biomarker of Rheumatoid Arthritis

PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis

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

Measurement of the muon flux at the SND@LHC experiment

The Scattering and Neutrino Detector at the LHC (SND@LHC) started taking data at the beginning of Run 3 of the LHC. The experiment is designed to perform measurements with neutrinos produced in proton-proton collisions at the LHC in an energy range between 100 GeV and 1 TeV. It covers a previously unexplored pseudo-rapidity range of 7.2 < η< 8.4 . The detector is located 480 m downstream of the ATLAS interaction point in the TI18 tunnel. It comprises a veto system, a target consisting of tungsten plates interleaved with nuclear emulsion and scintillating fiber (SciFi) trackers, followed by a muon detector (UpStream, US and DownStream, DS). In this article we report the measurement of the muon flux in three subdetectors: the emulsion, the SciFi trackers and the DownStream Muon detector. The muon flux per integrated luminosity through an 18 × 18 cm 2 area in the emulsion is: 1.5±0.1(stat)×104fb/cm2. The muon flux per integrated luminosity through a 31 × 31 cm 2 area in the centre of the SciFi is: 2.06±0.01(stat)±0.12(sys)×104fb/cm2 The muon flux per integrated luminosity through a 52 × 52 cm 2 area in the centre of the downstream muon system is: 2.35±0.01(stat)±0.10(sys)×104fb/cm2 The total relative uncertainty of the measurements by the electronic detectors is 6 % for the SciFi and 4 % for the DS measurement. The Monte Carlo simulation prediction of these fluxes is 20–25 % lower than the measured values

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets

Development of a clinical information tool for the electronic medical record: A case study

Question: What is the process of developing a clinical information tool to be embedded in the electronic health record of a very large and diverse academic medical center? &Setting: The development took place at the University of Pittsburgh Health Sciences Library System. &Method: The clinical information tool developed is a search box with subject tabs to provide quick access to designated full-text information resources. Each subject tab offers a federated search of a different pool of resources. Search results are organized ''on the fly'' into meaningful categories using clustering technology and are directly accessible from the results page. &Results: After more than a year of discussion and planning, a clinical information tool was embedded in the academic medical center's electronic health record. &Conclusion: The library successfully developed a clinical information tool, called Clinical-e, for use at the point of care. Future development will refine the tool and evaluate its impact and effectiveness

A Hierarchical Model for the Rocca di Sciara Northeastern Slope Instabilities (Sicily, Italy)

In this chapter, an object-oriented hierarchical approach for the study of landslides is proposed. The model has been applied on the instabilities that affected the northeastern slope of the Rocca di Sciara relief on the left slope of the Imera river valley in northern Sicily. The last reactivation of the lower portion of this slope dates to April 2015; the event caused severe damages to the road network, also involving the Palermo – Catania highway leading to the failure of the Imera viaduct. The hierarchical model of landslides has been built considering the spatiotemporal relations of all the inventoried landslides along the slope in order to reconstruct the event series; it includes four levels of detail: the focal level composed by the landslides themselves, one level of decomposition storing their components and two levels of generalization. The last generalization defines the Rocca di Sciara landslide system, which groups all the landslides spatially connected and their corresponding evolution phases. This methodological approach for studying nested and superimposed landslide events can be useful for the reconstruction of the landsliding history of a slope and its evolution both in spatial and in temporal terms