The receptor-interacting protein kinase 3 (RIPK3) plays crucial roles in programmed necrosis and innate inflammatory responses. However, a little is known about the involvement of RIPK3 in NKT cell-mediated immune responses. Here, we demonstrate that RIPK3 plays an essential role in NKT cell function via activation of the mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5). RIPK3-mediated activation of PGAM5 promotes the expression of cytokines by facilitating nuclear translocation of NFAT and dephosphorylation of dynamin-related protein 1 (Drp1), a GTPase is essential for mitochondrial homoeostasis. Ripk3−/− mice show reduced NKT cell responses to metastatic tumour cells, and both deletion of RIPK3 and pharmacological inhibition of Drp1 protects mice from NKT cell-mediated induction of acute liver damage. Collectively, the results identify a crucial role for RIPK3-PGAM5-Drp1/NFAT signalling in NKT cell activation, and further suggest that RIPK3-PGAM5 signalling may mediate crosstalk between mitochondrial function and immune signalling.

We demonstrate a role of the vitamin D receptor (VDR) in reducing cerebral soluble and insoluble amyloid-␤ (A␤) peptides. Short-term treatment of two human amyloid precursor protein-expressing models, Tg2576 and TgCRND8 mice, with 1␣,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the endogenous active ligand of VDR, resulted in higher brain P-glycoprotein (P-gp) and lower soluble A␤ levels, effects negated with coadministration of elacridar, a P-gp inhibitor. Long-term treatment of TgCRND8 mice with 1,25(OH) 2 D 3 during the period of plaque formation reduced soluble and insoluble plaque-associated A␤, particularly in the hippocampus in which the VDR is abundant and P-gp induction is greatest after 1,25(OH) 2 D 3 treatment, and this led to improved conditioned fear memory. In mice fed a vitamin D-deficient diet, lower cerebral P-gp expression was observed, but levels were restored on replenishment with VDR ligands. The composite data suggest that the VDR is an important therapeutic target in the prevention and treatment of Alzheimer's disease.

The present study evaluated rate and extent of alveolar bone formation in dental implant dehiscence defects following guided bone regeneration(GBR) and implantation of xenogeneic freeze‐dried demineralized bone matrix (xDBM). A total of 16 titanium plasma‐sprayed (TPS) and 16 hydroxyapatite‐coated (HA) titanium cylinder implants were inserted in 4 mongrel dogs following extraction of the mandibular premolar teeth. Four implant sites per jaw quadrant (2 TPS and 2 HA implant sites) were prepared into extraction sockets in each dog. Buccal alveolar bone was removed to create 3 x 5 mm dehiscence defects. Two jaw quadrants in separate animals received GBR, GBR+xDBM, xDBM (control), or gingival flap surgery alone (GFS; control). Thus, four conditions were available for each implant type (TPS or HA): GBR, GBR+xDBM; xDBM and GFS. The animals received fluorescent bone labels to allow observations of rate and extent of bone formation. Animals were sacrificed at 12 weeks postsurgery and block sections were harvested for histologic analysis. There were no apparent histologic differences between TPS and HA implant defects. GBR and GBR+xDBM resulted in almost complete bone closure of the dental implant dehiscence defect. Rate of bone formation appeared higher following GBR alone. Extent of bone formation appeared somewhat greater following GBR+xDBM; however, delayed. xDBM alone did not adequately resolve the bony defect. In conclusion, GBR results in rapid, clinically relevant bone closure of dental implant dehiscence defects. Adjunctive implantation of xDBM does not appear to significantly improve the healing response in the model used.

The multiplex RFMP assay is an accurate and sensitive means to detect entecavir and lamivudine resistance mutations, simultaneously. The method is expected to enable early and efficient diagnosis of multiple drug resistance mutations for optimal management of CHB.

The ubiquitin–proteasome system is an essential regulator of several cellular pathways involving oncogenes. Deubiquitination negatively regulates target proteins or substrates linked to both hereditary and sporadic forms of cancer. The deubiquitinating enzyme ubiquitin-specific protease 14 (USP14) is associated with proteasomes where it trims the ubiquitin chain on the substrate. Here, we found that USP14 is highly expressed in patients with lung cancer. We also demonstrated that USP14 inhibitors (IU1-47 and siRNA-USP14) significantly decreased cell proliferation, migration, and invasion in lung cancer. Remarkably, we found that USP14 negatively regulates lung tumorigenesis not only through apoptosis but also through the autophagy pathway. Our findings suggest that USP14 plays a crucial role in lung tumorigenesis and that USP14 inhibitors are potent drugs in lung cancer treatment.

No abstract

4-1BBL, a member of the TNF superfamily, regulates the sustained production of inflammatory cytokines in macrophages triggered by TLR signaling. In this study, we have investigated the role of 4-1BBL in macrophage metabolism and polarization and in skin inflammation using a model of imiquimod-induced psoriasis in mice. Genetic ablation or blocking of 4-1BBL signaling by Ab or 4-1BB–Fc alleviated the pathology of psoriasis by regulating the expression of inflammatory cytokines associated with macrophage activation and regulated the polarization of macrophages in vitro. We further linked this result with macrophage by finding that 4-1BBL expression during the immediate TLR response was dependent on glycolysis, mitochondrial oxidative phosphorylation, and fatty acid metabolism, whereas the late-phase 4-1BBL–mediated sustained inflammatory response was dependent on glycolysis and fatty acid synthesis. Correlating with this, administration of a fatty acid synthase inhibitor, cerulenin, also alleviated the pathology of psoriasis. We further found that 4-1BBL–mediated psoriasis development is independent of its receptor 4-1BB, as a deficiency of 4-1BB augmented the severity of psoriasis linked to a reduced regulatory T cell population and increased IL-17A expression in γδ T cells. Additionally, coblocking of 4-1BBL signaling and IL-17A activity additively ameliorated psoriasis. Taken together, 4-1BBL signaling regulates macrophage polarization and contributes to imiquimod-induced psoriasis by sustaining inflammation, providing a possible avenue for psoriasis treatment in patients.

Abstract. To date, most antibodies from combinatorial libraries have been selected purely on the basis of binding. However, new methods now allow selection on the basis of function in animal cells. These selected agonist antibodies have given new insights into the important problem of signal transduction. Remarkably, when some antibodies bind to a given receptor they induce a cell fate that is different than that induced by the natural agonist to the same receptor. The fact that receptors can be functionally pleiotropic may yield new insights into the important problem of signal transduction.