The N-terminal Phosphodegron Targets TAZ/WWTR1 Protein for SCF β-TrCP -dependent Degradation in Response to Phosphatidylinositol 3-Kinase Inhibition

The Hippo tumor suppressor pathway plays a major role in development and organ size control, and its dysregulation contributes to tumorigenesis. TAZ (transcriptional co-activator with PDZ-binding motif; also known as WWTR1) is a transcription co-activator acting downstream of the Hippo pathway, and increased TAZ protein levels have been associated with human cancers, such as breast cancer. Previous studies have shown that TAZ is inhibited by large tumor suppressor (LATS)-dependent phosphorylation, leading to cytoplasmic retention and ubiquitin-dependent degradation. The LATS kinase, a core component of the Hippo pathway, phosphorylates the C-terminal phosphodegron in TAZ to promote its degradation. In this study, we have found that the N-terminal phosphodegron of TAZ also plays a role in TAZ protein level regulation, particularly in response to different status of cellular PI3K signaling. GSK3, which can be inhibited by high PI3K via AKT-dependent inhibitory phosphorylation, phosphorylates the N-terminal phosphodegron in TAZ, and the phosphorylated TAZ binds to β-TrCP subunit of the SCFβ-TrCP E3 ubiquitin ligase, thereby leading to TAZ ubiquitylation and degradation. We observed that the TAZ protein level is elevated in tumor cells with high PI3K signaling, such as in PTEN mutant cancer cells. This study provides a novel mechanism of TAZ regulation and suggests a role of TAZ in modulating tissue growth and tumor development in response to PI3K signaling

Design & Optimization of the HV divider for JUNO 20-inch PMT

The Jiangmen Underground Observatory (JUNO) is a 20-kton liquid scintillator detector that employs 20,000 20-inch photomultiplier tubes (PMTs) as photon sensors, with 5,000 dynode-PMTs from HAMAMATSU Photonics K.K. (HPK), and 15,000 MCP-PMTs from North Night Vision Technology (NNVT) installed in pure water. JUNO aims to provide long-lasting and the best performance operation by utilizing a high-transparency liquid scintillator, high detection efficiency PMTs, and specially designed electronics including water-proof potting for the high voltage (HV) dividers of PMTs. In this paper, we present a summary of the design and optimization of HV dividers for both types of 20-inch PMTs, which includes collection efficiency, charge resolution, HV divider current, pulse shape, and maximum amplitude restriction. We have developed and finalized four schemes of the HV divider for different scenarios, including the final version selected by JUNO. All 20,000 20-inch PMTs have successfully undergone production and burning tests.Comment: 14pages,28figure

Acetylation Targets the M2 Isoform of Pyruvate Kinase for Degradation through Chaperone-Mediated Autophagy and Promotes Tumor Growth

Most tumor cells take up more glucose than normal cells but metabolize glucose via glycolysis even in the presence of normal levels of oxygen, a phenomenon known as the Warburg effect. Tumor cells commonly express the embryonic M2 isoform of pyruvate kinase (PKM2) that may contribute to the metabolism shift from oxidative phosphorylation to aerobic glycolysis and tumorigenesis. Here we show that PKM2 is acetylated on lysine 305 and that this acetylation is stimulated by high glucose concentration. PKM2 K305 acetylation decreases PKM2 enzyme activity and promotes its lysosomal-dependent degradation via chaperone-mediated autophagy (CMA). Acetylation increases PKM2 interaction with HSC70, a chaperone for CMA, and association with lysosomes. Ectopic expression of an acetylation mimetic K305Q mutant accumulates glycolytic intermediates and promotes cell proliferation and tumor growth. These results reveal an acetylation regulation of pyruvate kinase and the link between lysine acetylation and CMA

Single-molecule level control of host-guest interactions in metallocycle-C60 complexes

Host−guest interactions are of central importance in many biological and chemical processes. However, the investigation of the formation and decomplexation of host−guest systems at the single-molecule level has been a challenging task. Here we show that the single-molecule conductance of organoplatinum(II) metallocycle hosts can be enhanced by an order of magnitude by the incorporation of a C60 guest molecule. Mechanically stretching the metallocycle-C60 junction with a scanning tunneling microscopy break junction technique causes the release of the C60 guest from the metallocycle, and consequently the conductance switches back to the free-host level. Metallocycle hosts with different shapes and cavity sizes show different degrees of flexibility to accommodate the C60 guest in response to mechanical stretching. DFT calculations provide further insights into the electronic structures and charge transport properties of the molecular junctions based on metallocycles and the metallocycle-C60 complexes

Detecting 22q11.2 deletion in Chinese children with conotruncal heart defects and single nucleotide polymorphisms in the haploid TBX1 locus

<p>Abstract</p> <p>Background</p> <p>Conotruncal heart defects (CTDs) are present in 75-85% of patients suffering from the 22q11.2 deletion syndrome. To date, no consistent phenotype has been consistently correlated with the 22q11.2 deletions. Genetic studies have implicated <it>TBX1 </it>as a critical gene in the pathogenesis of the syndrome. The aim of study was to determine the incidence of the 22q11.2 deletion in Chinese patients with CTDs and the possible mechanism for pathogenesis of CTDs.</p> <p>Methods</p> <p>We enrolled 212 patients with CTDs and 139 unrelated healthy controls. Both karyotypic analysis and multiplex ligation-dependent probe amplification were performed for all CTDs patients. Fluorescence <it>in situ </it>hybridization was performed for the patients with genetic deletions and their relatives. The <it>TBX1 </it>gene was sequenced for all patients and healthy controls. The <it>χ</it>²and Fisher's exact test were used in the statistical analysis.</p> <p>Results</p> <p>Thirteen of the 212 patients with CTDs (6.13%) were found to have the 22q11.2 deletion syndrome. Of the 13 cases, 11 presented with a hemizygous interstitial microdeletion from <it>CLTCL1 </it>to <it>LZTR1</it>; one presented with a regional deletion from <it>CLTCL1 </it>to <it>DRCR8</it>; and one presented with a regional deletion from <it>CDC45L </it>to <it>LZTR1</it>. There were eight sequence variants in the haploid <it>TBX1 </it>genes of the del22q11 CTDs patients. The frequency of one single nucleotide polymorphism (SNP) in the del22q11 patients was different from that of the non-del patients (<it>P </it>< 0.05), and the frequencies of two other SNPs were different between the non-del CTDs patients and controls (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>CTDs, especially pulmonary atresia with ventricular septal defect and tetralogy of Fallot, are the most common disorders associated with the 22q11.2 deletion syndrome. Those patients with both CTDs and 22q11.2 deletion generally have a typical or atypical deletion region within the <it>TBX1 </it>gene. Our results indicate that <it>TBX1 </it>genetic variants may be associated with CTDs.</p