Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects.

Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient's mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient's mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification.

Enhanced Gasdermin-E-mediated Pyroptosis in Alzheimer's Disease.

Amyloid ß protein (Aß) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Aß induces apoptosis, and gasdermin-E (GSDME) expression can switch apoptosis to pyroptosis. In this study, we demonstrated that GSDME was highly expressed in the hippocampus of APP23/PS45 mouse models compared to that in age-matched wild-type mice. Aß treatment induced pyroptosis by active caspase-3/GSDME in SH-SY5Y cells. Furthermore, the knockdown of GSDME improved the cognitive impairments of APP23/PS45 mice by alleviating inflammatory response. Our findings reveal that GSDME, as a modulator of Aß and pyroptosis, plays a potential role in Alzheimer's disease pathogenesis and shows that GSDME is a therapeutic target for AD.

Spatio-temporal evolution law of gas-temperature coupling field in "110 method" goaf and prevention of spontaneous combustion.

To investigate the distribution characteristics of spontaneous combustion disaster (SCD) zones in the goaf of "110" mining method with U + L ventilation system and formulate corresponding fire prevention measures, enclosed coal oxidation experiments were carried out to measure the oxidation characteristics of Dongrong Coal Mine bituminous coal sample. A coupled 3DEC-CFD (3 dimensional Distinct Element Code) model was established. The 3D transient distribution characteristics of SCD zones in the "110" mining goaf under U+L ventilation condition were analyzed. Nitrogen injection in the tailgate was proposed for coal spontaneous combustion prevention. The results show that air leakage changed the distribution of oxygen and temperature fields in the "110" goaf, causing the region 20~60 m parallel to the retained roadway to remain in the oxidation zone for spontaneous combustion. As the working face advanced, the area change curve of SCD zones in the "110" goaf exhibited a "double inflection point" pattern. Eliminating the "retained roadway oxidation zone" can effectively reduce the spontaneous combustion risks in the "110" goaf and ensure mining safety. This study enriches the mechanisms of coal spontaneous combustion.

Inhibition of cystathionine ß-synthase promotes apoptosis and reduces cell proliferation in chronic myeloid leukemia.

Increased endogenous hydrogen sulfide (H2S) level by cystathionine ß-synthase (CBS) has been shown to closely relate tumorigenesis. H2S promotes angiogenesis, stimulates bioenergy metabolism and inhibits selective phosphatases. However, the role of CBS and H2S in chronic myeloid leukemia (CML) remains elusive. In this study, we found that CBS and H2S levels were increased in the bone marrow mononuclear cells of pediatric CML patients, as well as in the CML-derived K562 cells and CBS expression levels were correlated with different disease phases. Inhibition of CBS reduced the proliferation of the CML primary bone marrow mononuclear cells and induced growth inhibition, apoptosis, cell cycle arrest, and migration suppression in K562 cells and tumor xenografts. The knockdown of CBS expression by shRNA and inhibiting CBS activity by AOAA decreased the endogenous H2S levels, promoted mitochondrial-related apoptosis and inhibited the NF-κB-mediated gene expression. Our study suggests that inhibition of CBS induces cell apoptosis, as well as limits cell proliferation and migration, a potential target for the treatment of chronic myeloid leukemia.