TDP-43 is a predominantly nuclear RNA-binding protein that forms inclusion bodies in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Using individual nucleotide-resolution ultraviolet cross-linking and immunoprecipitation (iCLIP), we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo. Analysis of RNA binding by TDP-43 in brains from subjects with FTLD revealed that the greatest increases in binding were to the MALAT1 and NEAT1 noncoding RNAs. We also found that binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins. In addition, we identified unusually long clusters of TDP-43 binding at deep intronic positions downstream of silenced exons. Our results highlight the importance of TDP-43 for the regulation of splicing in the brain.
COBISS.SI-ID: 8278100
Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. We report that the establishment of positive feedback loop between prostaglandin E2 (PGE2) and COX2, the key regulator of PGE2 synthesis, represents the determining factor in redirecting the development of CD1a+ DCs to CD14+CD33+CD34+ monocytic MDSCs. The central role of COX2-PGE2 feedback in the induction and persistence of MDSCs highlights the potential for its manipulation to enhance or suppress immune responses in cancer, autoimmunity or transplantation.
COBISS.SI-ID: 3111793
The proinflammatory effects of bare and PEG)lated ORMOSIL-NPs, poly(lactic-co-glycolic acid) (PLGA)-NPs and small unilamellar vesicles (SUV) was tested. Bare ORMOSIL-NPs effectively stimulated the production of IL-1b/IL-6/TNF-a/IL-8 by monocytes and of IL-8 by polymorphonuclear leukocytes(PMNs). NP PEGylation inhibited such effects only partially. PEGylated SUV-NPs, bare and PEGylated ORMOSIL- and PLGA-NPs sensitize PMNs and monocytes to secrete O2- upon f-MLP stimulation. PEG-coating confers stealth effects but does not completely eliminate leukocyte activation.
COBISS.SI-ID: 3033713