Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses

Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell-mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti-PD1 treatment. In vitro results show that Ptpn6/11-deleted CD8(+) T cells exhibit impaired expansion due to a survival defect and proteomics analyses reveal substantial alterations, including in apoptosis-related pathways. These data indicate that concomitant ablation of Ptpn6/11 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches

TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene-targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive (Tyk2K923E) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein’s stability. An inhibitory function was only observed upon over-expression of TYK2K923E in vitro. Tyk2K923E mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors

Pleiotropic Effects of Sox2 during the Development of the Zebrafish Epithalamus

The zebrafish epithalamus is part of the diencephalon and encompasses three major components: the pineal, the parapineal and the habenular nuclei. Using sox2 knockdown, we show here that this key transcriptional regulator has pleiotropic effects during the development of these structures. Sox2 negatively regulates pineal neurogenesis. Also, Sox2 is identified as the unknown factor responsible for pineal photoreceptor prepatterning and performs this function independently of the BMP signaling. The correct levels of sox2 are critical for the functionally important asymmetrical positioning of the parapineal organ and for the migration of parapineal cells as a coherent structure. Deviations from this strict control result in defects associated with abnormal habenular laterality, which we have documented and quantified in sox2 morphants

Nickel-based super-alloy Inconel 600 morphological modifications by high repetition rate femtosecond Ti:sapphire laser

The interaction of Ti:sapphire laser, operating at high repetition rate of 75 MHz, with nickel-based super-alloy Inconel 600 was studied. The laser was emitting at 800 nm and ultrashort pulse duration was 160 fs. Nickel-based super-alloy surface modification was studied in a low laser energy/fluence regime of maximum 20 nJ-15 mJ/cm(2), for short (10 s) and long irradiation times (range of minutes). Surface damage threshold of this material was estimated to be 1.46 nJ, i.e., 0.001 J/cm(2) in air. The radiation absorbed from Ti:sapphire laser beam under these conditions generates at the surface a series of effects. such as direct material vaporization, plasma creation, formation of nano-structures and their larger aggregates, damage accumulation, etc. Laser induced surface morphological changes observed on Inconel 600 were: (1) intensive removal Of Surface material with crater like features; (2) material deposition at near and farther periphery and creation of nano-aggregates/nano-structures; (3) sporadic micro-cracking of the inner and outer damage area. Generally. features created on nickel-based super-alloy surface by high repetition rate femtosecond pulses are characterized by low inner/outer damage diameter of less than 11 mu m/30 mu m and relatively large depth on the order of 150 mu m, in both low (10 s) and high (minutes) irradiation time regimes

A classification of built forms

A classification of built forms is presented. It is based on a study of buildings surveyed at 3350 addresses in four English towns and has been designed for use in the national Non-Domestic Building Stock (NDBS) database developed for the Department of Environment, Transport and the Regions. As the prime use of the database is in energy analysis, the classification focuses on the external envelopes of buildings. (Materials of construction, servicing systems, and activities are classified separately.) Built forms are distinguished according to two main criteria: the broad 'texture' of their internal subdivision; and whether they are daylit or artificially lit.