Paola Perez

Being Santa Claus is a grind, but Philly-area Santas love it and are in it for the holiday magic, not the money. Plus, wind gust advisory Friday, why you may be seeing more arches across Philadelphia.

What's the right neighborly approach to shoveling snow off the sidewalk? Philadelphia natives settle the debate. Plus, what Mayor Parker said in State of the City speech, and how to avoid norovirus.

Terrence Butler's family longs for answers two years after his untimely death. Plus, meet Philly's main caviar supplier, and it's the first day of winter. Will the city see a White Christmas?

Welcome to a brisk, mostly sunny Saturday. In todays edition, were addressing a seasonal situation: the neighborly approach to snow shoveling.

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And today's top stories The Morning Newsletter Start your day with the Philly news you need and the stories you want all in one easy-to-read newsletter

And U.S. seizes Maduro. The Morning Newsletter Start your day with the Philly news you need and the stories you want all in one easy-to-read newsletter

And today's top stories. The Morning Newsletter Start your day with the Philly news you need and the stories you want all in one easy-to-read newsletter

Objectives Inflammatory cytokines that signal through the Janus kinases–signal transducer and activator of transcription (JAK-STAT) pathway, especially interferons (IFNs), are implicated in Sjögren’s disease (SjD). Although inhibition of JAKs is effective in other autoimmune diseases, a systematic investigation of IFN-JAK-STAT signalling and the effect of JAK inhibitor (JAKi) therapy in SjD-affected human tissues has not been fully investigated.Methods Human minor salivary glands (MSGs) and peripheral blood mononuclear cells (PBMCs) were investigated using bulk or single-cell (sc) RNA sequencing (RNAseq), immunofluorescence (IF) microscopy and flow cytometry. Ex vivo culture assays on PBMCs and primary salivary gland epithelial cell (pSGEC) lines were performed to model changes in target tissues before and after JAKi.Results RNAseq and IF showed activated JAK-STAT pathway in SjD MSGs. Elevated IFN-stimulated gene (ISGs) expression associated with clinical variables (eg, focus scores, anti-SSA positivity). scRNAseq of MSGs exhibited cell type-specific upregulation of JAK-STAT and ISGs; PBMCs showed similar trends, including markedly upregulated ISGs in monocytes. Ex vivo studies showed elevated basal pSTAT levels in SjD MSGs and PBMCs that were corrected with JAKi. SjD-derived pSGECs exhibited higher basal ISG expressions and exaggerated responses to IFN-β, which were normalised by JAKi without cytotoxicity.Conclusions SjD patients’ tissues exhibit increased expression of ISGs and activation of the JAK-STAT pathway in a cell type-dependent manner. JAKi normalises this aberrant signalling at the tissue level and in PBMCs, suggesting a putative viable therapy for SjD, targeting both glandular and extraglandular symptoms. Predicated on these data, a phase Ib/IIa randomised controlled trial to treat SjD with tofacitinib was initiated.Data are available in a public, open access repository. Data and code are available upon reasonable request. The data that support the findings of this study are available on reasonable request from the corresponding author(s), SG, EY and BMW. The associated sequencing data are available through dbGAP, consistent with the consent groups of the participants: single-cell datasets are available at: dbGaP Study Accession: phs002446.v1.p1; bulk RNAseq datasets are available at: dbGaP Study Accession: phs001842.v1.p1.