Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma

Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically,THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.

NONLINEAR STABILITY OF VISCOUS SHOCK WAVES FOR ONE-DIMENSIONAL NONISENTROPIC COMPRESSIBLE NAVIER–STOKES EQUATIONS WITH A CLASS OF LARGE INITIAL PERTURBATION

We study the nonlinear stability of viscous shock waves for the Cauchy problem of one-dimensional nonisentropic compressible Navier–Stokes equations for a viscous and heat conducting ideal polytropic gas. The viscous shock waves are shown to be time asymptotically stable under large initial perturbation with no restriction on the range of the adiabatic exponent provided that the strengths of the viscous shock waves are assumed to be sufficiently small.The proofs are based on the nonlinear energy estimates and the crucial step is to obtain the positive lower and upper bounds of the density and the temperature which are uniformly in time and space.

Effects of Various Environmental Factors on Biological Characteristics of Azolla

This study was conducted to screen and breed Azolla varieties with strong resistance.Four Azolla samples( CD,XT,HY,YZ) were collected from Hunan Province,and the growth characteristics such as propagation coefficient,temperature,light intensity,pH value and humidity were analyzed using artificial culture method.The results showed the four Azolla varieties all had the largest reproduction coefficients after cultured for 21 d,and the optimum culture conditions were temperature at 24-28 ℃,illumination intensity of 15 000-20 000 lx,pH 6.0,and humidity of 60%-80%.Among the four Azolla varieties,YZ has strong reproductive performance and high temperature resistance,and XT has strong acid resistance.

SARS-CoV-2 Spike Protein Post-Translational Modification Landscape and Its Impact on Protein Structure and Function via Computational Prediction

To elucidate the role of post-translational modifications(PTMs)in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike protein’s structure and virulence,we generated a high-resolution map of 87 PTMs using liquid chromatography with tandem mass spectrometry data on the extracted spike protein from SARS-CoV-2 virions and then reconstituted its structure heterogeneity caused by PTMs.Nonetheless,Alphafold2,a high-accuracy artificial intelligence tool to perform protein structure prediction,relies solely on primary amino acid sequence,whereas the impact of PTM,which often modulates critical protein structure and function,is much ignored.To overcome this challenge,we proposed the mutagenesis approach—an in silico,site-directed amino acid substitution to mimic the influence of PTMs on protein structure due to altered physicochemical properties in the post-translationally modified amino acids—and then reconstituted the spike protein’s structure from the substituted sequences by Alphafold2.For the first time,the proposed method revealed predicted protein structures resulting from PTMs,a problem that Alphafold2 has yet to address.As an example,we performed computational analyses of the interaction of the post-translationally modified spike protein with its host factors such as angiotensin-converting enzyme 2 to illuminate binding affinity.Mechanistically,this study suggested the structural analysis of post-translationally modified protein via mutagenesis and deep learning.To summarize,the reconstructed spike protein structures showed that specific PTMs can be used to modulate host factor binding,guide antibody design,and pave the way for new therapeutic targets.The code and Supplementary Materials are freely available at https://github.com/LTZHKUSTGZ/SARS-CoV-2-spike-protein-PTM.