Competing endogenous RNA network analysis of Turner syndrome patient-specific iPSC-derived cardiomyocytes reveals dysregulation of autosomal heart development genes by altered dosages of X-inactivation escaping non-coding RNAs.

BACKGROUND: A 45,X monosomy (Turner syndrome, TS) is the only chromosome haploinsufficiency compatible with life. Nevertheless, the surviving TS patients still suffer from increased morbidity and mortality, with around one-third of them subjecting to heart abnormalities. How loss of one X chromosome drive these conditions remains largely unknown. METHODS: Here, we have generated cardiomyocytes (CMs) from wild-type and TS patient-specific induced pluripotent stem cells and profiled the mRNA, lncRNA and circRNA expression in these cells. RESULTS: We observed lower beating frequencies and higher mitochondrial DNA copies per nucleus in TS-CMs. Moreover, we have identified a global transcriptome dysregulation of both coding and non-coding RNAs in TS-CMs. The differentially expressed mRNAs were enriched of heart development genes. Further competing endogenous RNA network analysis revealed putative regulatory circuit of autosomal genes relevant with mitochondrial respiratory chain and heart development, such as COQ10A, RARB and WNT2, mediated by X-inactivation escaping lnc/circRNAs, such as lnc-KDM5C-4:1, hsa_circ_0090421 and hsa_circ_0090392. The aberrant expressions of these genes in TS-CMs were verified by qPCR. Further knockdown of lnc-KDM5C-4:1 in wild-type CMs exhibited significantly reduced beating frequencies. CONCLUSIONS: Our study has revealed a genomewide ripple effect of X chromosome halpoinsufficiency at post-transcriptional level and provided insights into the molecular mechanisms underlying heart abnormalities in TS patients.

Application of Induced Pluripotent Stem Cell-Derived Models for Investigating microRNA Regulation in Developmental Processes.

Advances in induced pluripotent stem cell (iPSC) techniques have opened up new perspectives in research on developmental biology. Compared with other sources of human cellular models, iPSCs present a great advantage in hosting the unique genotype background of donors without ethical concerns. A wide spectrum of cellular and organoid models can be generated from iPSCs under appropriate in vitro conditions. The pluripotency of iPSCs is orchestrated by external signalling and regulated at the epigenetic, transcriptional and posttranscriptional levels. Recent decades have witnessed the progress of studying tissue-specific expressions and functions of microRNAs (miRNAs) using iPSC-derived models. MiRNAs are a class of short non-coding RNAs with regulatory functions in various biological processes during development, including cell migration, proliferation and apoptosis. MiRNAs are key modulators of gene expression and promising candidates for biomarker in development; hence, research on the regulation of human development by miRNAs is expanding. In this review, we summarize the current progress in the application of iPSC-derived models to studies of the regulatory roles of miRNAs in developmental processes.

Generation of an induced pluripotent stem cell line GZHMCi008-A derived from a patient with SRY-positive 46,XX testicular disorder of sex development.

The testicular disorder of sex development (TDSD) is a rare condition characterized by a male appearance with a female karyotype. The most frequent cause of TDSD is misplacement of the sex determining region Y (SRY) gene on the X chromosome. Here, we report the generation of an induced pluripotent stem cell (iPSC) line from peripheral blood mononuclear cells of a patient with SRY-positive 46,XX TDSD. This cell line offers an unprecedented cellular model to investigate the profound manifestations like infertility of the male sex reversal patients, and serves as a useful tool to develop therapies for the disease.

Application of Human Induced Pluripotent Stem Cell-Derived Cellular and Organoid Models for COVID-19 Research.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its rapid international spread has caused the coronavirus disease 2019 (COVID-19) pandemics, which is a global public health crisis. Thus, there is an urgent need to establish biological models to study the pathology of SARS-CoV-2 infection, which not only involves respiratory failure, but also includes dysregulation of other organs and systems, including the brain, heart, liver, intestines, pancreas, kidneys, eyes, and so on. Cellular and organoid models derived from human induced pluripotent stem cells (iPSCs) are ideal tools for in vitro simulation of viral life cycles and drug screening to prevent the reemergence of coronavirus. These iPSC-derived models could recapitulate the functions and physiology of various human cell types and assemble the complex microenvironments similar with those in the human organs; therefore, they can improve the study efficiency of viral infection mechanisms, mimic the natural host-virus interaction, and be suited for long-term experiments. In this review, we focus on the application of in vitro iPSC-derived cellular and organoid models in COVID-19 studies.

Thermal Conductivity and Stability of Hydrocarbon-Based Nanofluids with Palladium Nanoparticles Dispersed by Modified Hyperbranched Polyglycerol.

Palladium nanoparticles, which were prepared by modified hyperbranched polyglycerol (mHPG) as stabilizers, can be dispersed well in nonpolar organic solvents and form highly stable nanofluids. The influences of three mHPG products modified with cyclohexanethiol (CSHPG), dodecanethiol (DSHPG), and octadecanethiol (OSHPG) on the preparation and stability of the palladium nanoparticles were investigated. The stability and thermal conductivity enhancement of the hydrocarbon-based nanofluids with Pd@mHPG (Pd@CSHPG, Pd@DSHPG, and Pd@OSHPG) compared to the corresponding base fluid were investigated at different temperatures. The average diameters of nanoparticles stabilized by CSHPG, DSHPG, and OSHPG are within 2.7-3.6 nm. The palladium nanoparticles could be dispersed well in the nonpolar base fluid such as decalin. The nanofluids with Pd@DSHPG and Pd@OSHPG could remain stable for up to 330 days at room temperature. The nanofluid with Pd@DSHPG or Pd@OSHPG could be stable for more than 24 h at 110 °C. The thermal conductivity of the nanofluids improved with increasing temperature and the mass fraction of nanoparticles compared to the corresponding base fluid. The long alkyl chain-modified HPG can give better protection for nanoparticles from agglomeration and assist metal nanoparticles in enhancing the thermal conductivity of nanofluids.

Relative down-regulation of apoptosis and autophagy genes in colorectal cancer.

BACKGROUND: Cancer is often caused by disturbance in the regulation and/or execution of programmed cell death (PCD, including apoptosis and autophagy). Our aim was to investigate these two pathways simultaneously in the same samples to understand further the pathological roles of PCDs in colorectal cancer. MATERIALS AND METHODS: Real time quantitative PCR (RT-qPCR) array was used to analyse the mRNA levels of 22 apoptosis and autophagy-related genes involved in pro- and anti-action of the pathways in 15 paired (tumour and non-cancerous part) colorectal samples using Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as the reference gene. RESULTS: GAPDH mRNA content was significantly higher (approximately 4·01 fold) in tumour tissue than that of paired non-cancerous part. The absolute mRNA levels for most of the 22 genes were higher in the tumour tissue also. However, after normalization with GAPDH Ct, the expressions of all the analysed genes were decreased in the tumour tissues, except for damage-regulated autophagy modulator (DRAM). The expression of most of the genes involved in the same pathway was closely correlated to each other in both tumour and non-cancerous tissues, and the correlation of tumour necrosis factor receptor (TNFR) and Akt to other genes in the same pathway was increased in tumour tissues. CONCLUSIONS: The high level expression of GAPDH might reflect the metabolic state of cancer cells, and PCDs were down-regulated in the tumour tissues when metabolic state was taken into consideration. This relative suppression of PCDs in tumour tissue is supposed to be in favour of cancer cell survival.