Search

We prove the finite dimensionality of the global attractor and estimate the numbers of the determining modes for the 2D Boussinesq system in a periodic domain with fractional Laplacian in the subcritical case.

Hepatocellular carcinoma (HCC) formation is a multi‐step pathological process that involves evolution of a heterogeneous immunosuppressive tumor microenvironment. However, the specific cell populations involved and their origins and contribution to HCC development remain largely unknown. Here, comprehensive single‐cell transcriptome sequencing was applied to profile rat models of toxin‐induced liver tumorigenesis and HCC patients. Specifically, we identified three populations of hepatic parenchymal cells emerging during HCC progression, termed metabolic hepatocytes (HCMeta), Epcam+ population with differentiation potential (EP+Diff) and immunosuppressive malignant transformation subset (MTImmu). These distinct subpopulations form an oncogenic trajectory depicting a dynamic landscape of hepatocarcinogenesis, with signature genes reflecting the transition from EP+Diff to MTImmu. Importantly, GPNMB+Gal‐3+ MTImmu cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 is required for the generation and malignant transformation of GPNMB+Gal‐3+ MTImmu cells. Enrichment of the GPNMB+Gal‐3+ MTImmu subset was found to be associated with poor prognosis and a higher rate of recurrence in patients. Collectively, we unraveled the single‐cell HCC progression atlas and uncovered GPNMB+Gal‐3+ parenchymal cells as a major subset contributing to the immunosuppressive microenvironment thus malignance in HCC. Synopsis: Malignant transformation is the major driver of liver cancer, but the molecular and cellular bases for its induction remain poorly understood. Here, in‐depth profiling of hepatocellular carcinoma (HCC) initiation and progression defines new molecular markers involved and emerging malignant cell populations counteracting immune surveillance. Longitudinal single‐cell RNA‐sequencing of toxin‐induced liver tumorigenesis in rats reveals a dynamic composition and transformation of hepatic parenchymal cells.Complementary analyses of four HCC patients show conservation of HCC cell dynamics.GPNMB+Gal‐3+ parenchymal cells arise from EPCAM+ cells during HCC progression and exhibit immunosuppressive and malignant properties in vivo.The transcription factor SOX18 is required for the GPNMB+Gal‐3+ cell stemness and immunosuppressive capacity.Enrichment of GPNMB+Gal‐3+ cells is associated with poor prognosis in HCC patients. [ABSTRACT FROM AUTHOR]

[CD4.sup.+] T cell interactions with B cells play a critical role in the pathogenesis of systemic autoimmune diseases such as systemic lupus and chronic graft-versus-host disease (cGVHD). Extrafollicular [CD44.sup.hi][CD62L.sup.lo][PSGL1.sup.lo][CD4.sup.+] T cells ([PSGL1.sup.lo][CD4.sup.+] T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized [MHC.sup.-/-][HLA-A2.sup.+][DR4.sup.+] murine models of cGVHD, we showed that murine and human [PSGL1.sup.lo][CD4.sup.+] T cells from GVHD target tissues have features of B cell helpers with upregulated expression of programmed cell death protein 1 (PD1) and inducible T cell costimulator (ICOS) and production of IL-21. They reside in nonlymphoid tissues without circulating in the blood and have features of tissue-resident memory T cells with upregulated expression of CD69. Murine [PSGL1.sup.lo][CD4.sup.+] T cells from GVHD target tissues augmented B cell differentiation into plasma cells and production of autoantibodies via their PD1 interaction with PD-L2 on B cells. Human [PSGL1.sup.lo][CD4.sup.+] T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human [PSGL1.sup.lo][CD4.sup.+] T cells from humanized GVHD target tissues also augmented autologous memory B cell differentiation into plasma cells and antibody production in a PD1/PD- L2-dependent manner. Further preclinical studies targeting tissue-resident T cells to treat antibody-mediated features of autoimmune diseases are warranted., Introduction Systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and chronic graft-versus-host disease (cGVHD) are mediated by abnormal [CD4.sup.+] T cell interaction with B cells and autoantibody deposition in [...]