ABSTRACT
The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000-5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3'UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.
ABSTRACT
<p><b>OBJECTIVE</b>To assess the data quality and estimate the provincial infant mortality rate (1q0) from China's sixth census.</p><p><b>METHODS</b>A log-quadratic model is applied to under-fifteen data. We analyze and compare the average relative errors (AREs) for 1q0 between the estimated and reported values using the leave-one-out cross-validation method.</p><p><b>RESULTS</b>For the sixth census, the AREs are more than 100% for almost all provinces. The estimated average 1q0 level for 31 provinces is 12.3‰ for males and 10.7‰ for females.</p><p><b>CONCLUSION</b>The data for the provincial 1q0 from China's sixth census have a serious data quality problem. The actual levels of 1q0 for each province are significantly higher than the reported values.</p>
Subject(s)
Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Male , Young Adult , Censuses , China , Infant MortalityABSTRACT
Turn-over of messenger ribonucleic acid ( mRNA) is a major control point in gene expres-sion.In mammals,many mRNAs encode inflammatory cytokines ,oncoproteins,and G-protein-coupled receptors are destabilized by the presence of AU -rich elements ( AREs ) in their 3′-untranslated regions .Association of ARE-binding proteins(AUBPs)with these mRNAs promotes rapid mRNA degradation .ARE/poly(U)-binding factor 1(AUF1),one of the best-characterized AUBPs,binds to many ARE-mRNAs and assembles other fac-tors to recruit the mRNA degradation machinery .Most studies support an mRNA -destabilizing role for AUF1,al-though other findings suggest additional functions for this factor .However,several lines of evidence also support a role for AUF1 in the initiation and/or development of cancer .Many AUF1-targeted transcripts encode products that control pro-or anti-oncogenic processes .Numerous signaling pathways alter the composition of this AUF 1 complex of proteins to affect changes in ARE -mRNA degradation rates .This review briefly describes the roles of mRNA decay in gene expression in general and ARE -mediated decay ( AMD) in particular ,with a focus on AUF1 and the different modes of regulation that govern AUF 1 involvement in AMD.In the end,we discuss how changes in AUF1 isoform distribution,subcellular localization,and post-translational protein modifications can influence the metabolism of targeted mRNAs .