Holmwestergaard3533

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF's role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.HDAC inhibitors are efficacious for treating lymphoma, but display limited efficacy in treating solid tumors. Here, we investigated the relationship between HDAC inhibitor resistance and the tumor immune environment in colorectal cancer. Our data indicated that among the investigated immune factors, B7x expression was enhanced in HDAC inhibitor-resistant colorectal cancer models in vitro and in vivo. In addition, gene manipulation results demonstrated that xenograft mice with tumors derived from a B7x-overexpressing CT-26 colorectal cancer cell line were resistant to HDAC inhibitor treatment. Notably, we found that there is a negative relationship between HDAC and B7x expression in both colorectal cancer cell lines and patients' tumors. Furthermore, our data indicated that elevated expression of B7x was related to a poor prognosis in colorectal tumor patients. Interestingly, treatment with a specific inhibitor or siRNA of HDAC3, but not HDAC2, 6, and 8, resulted in obvious upregulation of B7x expression in colorectal cancer cells. In addition, our data showed that a cell line with high HDAC3 expression and low B7x expression had decreased enrichment of acetylated histone H3 in the promoter region of the gene encoding B7x. This pattern was reversed by addition of HDAC3 inhibitors. selleck chemical Mechanistically, we found that HDAC3 regulated B7x transcription by promoting the binding of the transcription activator C/EBP-α with the B7x promoter region. Importantly, our data indicated that an antibody neutralizing B7x augmented the response to HDAC inhibitor in the colorectal cancer xenograft model and the lung metastasis model by increasing the ratios of both CD4-positive and CD8-positive T cells. In summary, we demonstrated a role of B7x in HDAC inhibitor resistance and identified the mechanism that dysregulates B7x in colorectal cancer. Our work provides a novel strategy to overcome HDAC inhibitor resistance.Extreme polar vortex events known as sudden stratospheric warmings can influence surface winter weather conditions, but their timing is difficult to predict. Here, we examine factors that influence their occurrence, with a focus on their timing and vertical extent. We consider the roles of the troposphere and equatorial stratosphere separately, using a split vortex event in January 2009 as the primary case study. This event cannot be reproduced by constraining wind and temperatures in the troposphere alone, even when the equatorial lower stratosphere is in the correct phase of the quasi biennial oscillation. When the flow in the equatorial upper stratosphere is also constrained, the timing and spatial evolution of the vortex event is captured remarkably well. This highlights an influence from this region previously unrecognised by the seasonal forecast community. We suggest that better representation of the flow in this region is likely to improve predictability of extreme polar vortex events and hence their associated impacts at the surface.Frequent mutation of the tumour suppressor RNF43 is observed in many cancers, particularly colon malignancies. RNF43, an E3 ubiquitin ligase, negatively regulates Wnt signalling by inducing degradation of the Wnt receptor Frizzled. In this study, we discover that RNF43 activity requires phosphorylation at a triplet of conserved serines. This phospho-regulation of RNF43 is required for zebrafish development and growth of mouse intestinal organoids. Cancer-associated mutations that abrogate RNF43 phosphorylation cooperate with active Ras to promote tumorigenesis by abolishing the inhibitory function of RNF43 in Wnt signalling while maintaining its inhibitory function in p53 signalling. Our data suggest that RNF43 mutations cooperate with KRAS mutations to promote multi-step tumorigenesis via the Wnt-Ras-p53 axis in human colon cancers. Lastly, phosphomimetic substitutions of the serine trio restored the tumour suppressive activity of extracellular oncogenic mutants. Therefore, harnessing phospho-regulation of RNF43 might be a potential therapeutic strategy for tumours with RNF43 mutations.Hematite has a great potential as a photoanode for photoelectrochemical (PEC) water splitting by converting solar energy into hydrogen fuels, but the solar-to-hydrogen conversion efficiency of state-of-the-art hematite photoelectrodes are still far below the values required for practical hydrogen production. Here, we report a core-shell formation of gradient tantalum-doped hematite homojunction nanorods by combination of hydrothermal regrowth strategy and hybrid microwave annealing, which enhances the photocurrent density and reduces the turn-on voltage simultaneously. The unusual bi-functional effects originate from the passivation of the surface states and intrinsic built-in electric field by the homojunction formation. The additional driving force provided by the field can effectively suppress charge-carrier recombination both in the bulk and on the surface of hematite, especially at lower potentials. Moreover, the synthesized homojunction shows a remarkable synergy with NiFe(OH)x cocatalyst with significant additional improvements of photocurrent density and cathodic shift of turn-on voltage.