Design, synthesis and biological evaluation of new RNF126-based p300/CBP degraders.

Histone acetyltransferase CREB-binding protein (CBP) and its homologous protein p300 are key transcriptional activators that can activate oncogene transcription, which present promising targets for cancer therapy. Here, we designed and synthesized a series of p300/CBP targeted low molecular weight PROTACs by assembling the covalent ligand of RNF126 E3 ubiquitin ligase and the bromodomain ligand of the p300/CBP. The optimal molecule A8 could effectively degrade p300 and CBP through the ubiquitin-proteasome system in time- and concentration-dependent manners, with half-maximal degradation (DC50) concentrations of 208.35/454.35 nM and 82.24/79.45 nM for p300/CBP in MV4-11 and Molm13 cell lines after 72 h of treatment. And the degradation of p300/CBP by A8 is dependent on the ubiquitin-proteasome pathway and its simultaneous interactions with the target proteins and RNF126. A8 exhibits good antiproliferative activity in a series of p300/CBP-dependent cancer cells. It could transcriptionally inhibit the expression of c-Myc, induce cell cycle arrest in the G0/G1 phase and apoptosis in MV4-11 cells. This study thus provided us a new chemotype for the development of drug-like PROTACs targeting p300/CBP, which is expected to be applied in cancer therapy.

Improved Resolution and Cost Performance of Low-Cost MEMS Seismic Sensor through Parallel Acquisition.

In earthquake monitoring, an important aspect of the operational effect of earthquake intensity rapid reporting and earthquake early warning networks depends on the density and performance of the deployed seismic sensors. To improve the resolution of seismic sensors as much as possible while keeping costs low, in this article the use of multiple low-cost and low-resolution digital MEMS accelerometers is proposed to increase the resolution through the correlation average method. In addition, a cost-effective MEMS seismic sensor is developed. With ARM and Linux embedded computer technology, this instrument can cyclically store the continuous collected data on a built-in large-capacity SD card for approximately 12 months. With its real-time seismic data processing algorithm, this instrument is able to automatically identify seismic events and calculate ground motion parameters. Moreover, the instrument is easy to install in a variety of ground or building conditions. The results show that the RMS noise of the instrument is reduced from 0.096 cm/s2 with a single MEMS accelerometer to 0.034 cm/s2 in a bandwidth of 0.1-20 Hz by using the correlation average method of eight low-cost MEMS accelerometers. The dynamic range reaches more than 90 dB, the amplitude-frequency response of its input and output within -3 dB is DC -80 Hz, and the linearity is better than 0.47%. In the records from our instrument, earthquakes with magnitudes between M2.2 and M5.1 and distances from the epicenter shorter than 200 km have a relatively high SNR, and are more visible than they were prior to the joint averaging.

Whole-Genome Sequencing Reveals Large ATP8B1 Deletion/Duplications as Second Mutations Missed by Exome-Based Sequencing.

Progressive familial intrahepatic cholestasis type 1 (PFIC1) results from biallelic pathogenic variants in ATP8B1. This study sought second pathogenic variants in ATP8B1 by whole-genome sequencing (WGS) in four unrelated low γ-glutamyl transpeptidase cholestasis patients in whom clinical suspicion of PFIC1 was high and gene-panel or Sanger sequencing had identified only one pathogenic variant in ATP8B1. Sanger sequencing confirmed WGS findings and determined the origin of each variant. Novel nonrecurrent structural variants in three patients (patient 1 to patient 3) were identified in trans: g.55396652_55403080del (6427-bp deletion), g.55335906_55346620dup (10,715-bp duplication), and g.55362063_55364293dup (2231-bp duplication). One synonymous variant in patient 4 was recognized in trans (c.1029G>A, p. Thr343Thr) and demonstrated as deleterious. In conclusion, WGS improves genetic diagnostic yield in PFIC1. These findings expand the gene-variant spectrum associated with familiar intrahepatic cholestasis 1 (FIC1) disease and for the first time report tandem duplication in ATP8B1 associated with cholestasis.

Nucleotide polymorphism in ARDS outcome: a whole exome sequencing association study.

BACKGROUND: Genetic locus were identified associated with acute respiratory distress syndrome (ARDS). Our goal was to explore the associations between genetic variants and ARDS outcome, as well as subphenotypes. METHODS: This was a single-center, prospective observational trial enrolling adult ARDS patients. After baseline data were collected, blood samples were drawn to perform whole exome sequencing, single nucleotide polymorphism (SNP)/insertion-deletion to explore the quantitative and functional associations between genetic variants and ICU outcome, clinical subphenotypes. Then the lung injury burden (LIB), which was defined as the ratio of nonsynonymous SNP number per megabase of DNA, was used to evaluate its value in predicting ARDS outcome. RESULTS: A total of 105 ARDS patients were enrolled in the study, including 70 survivors and 35 nonsurvivors. Based on the analysis of a total of 65,542 nonsynonymous SNP, LIB in survivors was significantly higher than nonsurvivors [1,892 (1,848-1,942)/MB versus 1,864 (1,829-1,910)/MB, P=0.018], while GO analysis showed that 60 functions were correlated with ARDS outcome, KEGG enrichment analysis showed that SNP/InDels were enriched in 13 pathways. Several new SNPs were found potentially associated with ARDS outcome. Analysis of LIB was used to determine its outcome predicting ability, the area under the ROC curve of which was only 0.6103, and increase to 0.712 when combined with APACHE II score. CONCLUSIONS: Genetic variants are associated with ARDS outcome and subphenotypes; however, their prognostic value still need to be verified by larger trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT02644798. Registered 20 April 2015.

[Screening and identification of 36 new STR loci in human Y chromosome].

133 candidate Y-STR loci were selected from NCBI STS database or by bioinformatics analysis in human Y-chromosome sequence, and were screened among 48 DNA samples around the world. Forty-one Y-STRs with high allelic frequency were validated, 36 of which were first reported. Two hundred haplotypes of the 41 STRs were identified among 200 randomly sampled male individuals in Shanghai, indicating 100% inter-individual discrimination. By network analysis of haplotypes of the 41 STRs among nine Jiang-surname male individuals with no consanguinity within 5 generations from a Jiang-surname individual gathering at Jiangshan, Zhejiang Province, and 7 Jiang-surname male individuals from the random shanghai population, 6 Jiang-surname individuals from Jiangshan were close with only 2-4 STR locus difference. These 41 Y-STR loci provide enough information by which individuals from each other with different early modern family origin can be effectively distinguished. This will promote studies on identification of non-lineal relationship in forensics, ancestry location of oversea Chinese, the surname origin and evolution, origin and migration of modern humans and many other studies of Contemporary Anthropology.