Subcellular location of L1 retrotransposon-encoded ORF1p, reverse transcription products, and DNA sensors in lupus granulocytes.

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p.

Results: Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS.

Regional economic costs of climate change: An interdisciplinary impact assessment for Upper Austria.

Region-specific meteorological data show that Upper Austria will mainly be affected by increasing temperatures (up to +2.7 °C in 2050) and decreasing precipitation (up to - 27 mm in 2050). Using an interdisciplinary framework, we derive climatic developments and quantify the resulting direct sectoral and macroeconomic impacts for Upper Austria.

Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279.

TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity.

Potent and selective TYK2-JH1 inhibitors highly efficacious in rodent model of psoriasis.

TYK2 is a member of the JAK family of kinases and a key mediator of IL-12, IL-23, and type I interferon signaling. These cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genetic association studies, TYK2 inhibition is an attractive therapeutic strategy for these diseases.