Aguirreortiz3498

The demethylation of histone lysine residues, one of the most important modifications in transcriptional regulation, is associated with various physiological states. read more KDM2B is a demethylase of histones H3K4, H3K36, and H3K79 and is associated with the repression of transcription. Here, we present a novel mechanism by which KDM2B demethylates serum response factor (SRF) K165 to negatively regulate muscle differentiation, which is counteracted by the histone methyltransferase SET7. We show that KDM2B inhibited skeletal muscle differentiation by inhibiting the transcription of SRF-dependent genes. Both KDM2B and SET7 regulated the balance of SRF K165 methylation. SRF K165 methylation was required for the transcriptional activation of SRF and for the promoter occupancy of SRF-dependent genes. SET7 inhibitors blocked muscle cell differentiation. Taken together, these data indicate that SRF is a nonhistone target of KDM2B and that the methylation balance of SRF as maintained by KDM2B and SET7 plays an important role in muscle cell differentiation.Prolongation of the picosecond Raman pump laser pulse in the femtosecond stimulated Raman spectroscopy (FSRS) setup is essential for achieving the high spectral resolution of the time-resolved vibrational Raman spectra. In this work, the 2nd-order diffraction has been firstly employed in the double-pass grating filter technique for realizing the FSRS setup with the sub-5 cm-1 spectral resolution. It has been experimentally demonstrated that our new FSRS setup gives rise to a highly-resolved Raman spectrum of the excited trans-stilbene, which is much improved from those reported in the literatures. The spectral resolution of the present FSRS system has been estimated to be the lowest value ever reported to date, giving Δν = 2.5 cm-1.Glycoproteins and glycolipids at the plasma membrane contribute to a range of functions from growth factor signaling to cell adhesion and migration. Glycoconjugates undergo endocytic trafficking. According to the glycolipid-lectin (GL-Lect) hypothesis, the construction of tubular endocytic pits is driven in a glycosphingolipid-dependent manner by sugar-binding proteins of the galectin family. Here, we provide evidence for a function of the GL-Lect mechanism in transcytosis across enterocytes in the mouse intestine. We show that galectin-3 (Gal3) and its newly identified binding partner lactotransferrin are transported in a glycosphingolipid-dependent manner from the apical to the basolateral membrane. Transcytosis of lactotransferrin is perturbed in Gal3 knockout mice and can be rescued by exogenous Gal3. Inside enterocytes, Gal3 is localized to hallmark structures of the GL-Lect mechanism, termed clathrin-independent carriers. These data pioneer the existence of GL-Lect endocytosis in vivo and strongly suggest that polarized trafficking across the intestinal barrier relies on this mechanism.Hepatocellular carcinoma highly occurs in chronic hepatitis livers, where hepatocyte apoptosis is frequently detected. Apoptosis is a mechanism that eliminates mutated cells. Hepatocyte apoptosis induces compensatory liver regeneration, which is believed to contribute to tumor formation. Hepatocyte-specific Mcl-1 knockout mice (Mcl-1Δhep mice) developed persistent hepatocyte apoptosis and compensatory liver regeneration with increased oxidative stress in adulthood but had not yet developed hepatocyte apoptosis at the age of 2 weeks. When diethylnitrosamine (DEN) was administered to 2-week-old Mcl-1Δhep mice, multiple liver tumors were formed at 4 months, while wild-type mice did not develop any tumors. These tumors contained the B-Raf V637E mutation, indicating that DEN-initiated tumorigenesis was promoted by persistent hepatocyte apoptosis. When N-acetyl-L-cysteine was given from 6 weeks of age, DEN-administered Mcl-1Δhep mice had reduced oxidative stress and suppressed tumorigenesis in the liver but showed no changes in hepatocyte apoptosis or proliferation. In conclusion, enhanced tumor formation from DEN-transformed hepatocytes by persistent hepatocyte apoptosis is mediated by increased oxidative stress, independent of compensatory liver regeneration. For patients with livers harboring transformed cells, the control of oxidative stress may suppress hepatocarcinogenesis based on chronic liver injury.Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-negative MPNs) such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis are characterized by abnormal proliferation of mature bone marrow cell lineages. Since various non-hematologic disorders can also cause leukocytosis, thrombocytosis and polycythemia, the detection of abnormal peripheral blood cells is essential for the diagnostic screening of Ph-negative MPNs. We sought to develop an automated diagnostic support system of Ph-negative MPNs. Our strategy was to combine the complete blood cell count and research parameters obtained by an automated hematology analyzer (Sysmex XN-9000) with morphological parameters that were extracted using a convolutional neural network deep learning system equipped with an Extreme Gradient Boosting (XGBoost)-based decision-making algorithm. The developed system showed promising performance in the differentiation of PV, ET, and MF with high accuracy when compared with those of the human diagnoses, namely > 90% sensitivity and > 90% specificity. The calculated area under the curve of the ROC curves were 0.990, 0.967, and 0.974 for PV, ET, MF, respectively. This study is a step toward establishing a universal automated diagnostic system for all types of hematology disorders.SARS-CoV-2 Nsp15 is a uridine-specific endoribonuclease with C-terminal catalytic domain belonging to the EndoU family that is highly conserved in coronaviruses. As endoribonuclease activity seems to be responsible for the interference with the innate immune response, Nsp15 emerges as an attractive target for therapeutic intervention. Here we report the first structures with bound nucleotides and show how the enzyme specifically recognizes uridine moiety. In addition to a uridine site we present evidence for a second base binding site that can accommodate any base. The structure with a transition state analog, uridine vanadate, confirms interactions key to catalytic mechanisms. In the presence of manganese ions, the enzyme cleaves unpaired RNAs. This acquired knowledge was instrumental in identifying Tipiracil, an FDA approved drug that is used in the treatment of colorectal cancer, as a potential anti-COVID-19 drug. Using crystallography, biochemical, and whole-cell assays, we demonstrate that Tipiracil inhibits SARS-CoV-2 Nsp15 by interacting with the uridine binding pocket in the enzyme's active site.