Stemness Analysis Uncovers That The Peroxisome Proliferator-Activated Receptor Signaling Pathway Can Mediate Fatty Acid Homeostasis In Sorafenib-Resistant Hepatocellular Carcinoma Cells

Hepatocellular carcinoma (HCC) stem cells are regarded as an important part of individualized HCC treatment and sorafenib resistance. However, there is lacking systematic assessment of stem-like indices and associations with a response of sorafenib in HCC. Our study thus aimed to evaluate the status of tumor dedifferentiation for HCC and further identify the regulatory mechanisms under the condition of resistance to sorafenib. Datasets of HCC, including messenger RNAs (mRNAs) expression, somatic mutation, and clinical information were collected. The mRNA expression-based stemness index (mRNAsi), which can represent degrees of dedifferentiation of HCC samples, was calculated to predict drug response of sorafenib therapy and prognosis. Next, unsupervised cluster analysis was conducted to distinguish mRNAsi-based subgroups, and gene/geneset functional enrichment analysis was employed to identify key sorafenib resistance-related pathways. In addition, we analyzed and confirmed the regulation of key genes discovered in this study by combining other omics data. Finally, Luciferase reporter assays were performed to validate their regulation. Our study demonstrated that the stemness index obtained from transcriptomic is a promising biomarker to predict the response of sorafenib therapy and the prognosis in HCC. We revealed the peroxisome proliferator-activated receptor signaling pathway (the PPAR signaling pathway), related to fatty acid biosynthesis, that was a potential sorafenib resistance pathway that had not been reported before. By analyzing the core regulatory genes of the PPAR signaling pathway, we identified four candidate target genes, retinoid X receptor beta (RXRB), nuclear receptor subfamily 1 group H member 3 (NR1H3), cytochrome P450 family 8 subfamily B member 1 (CYP8B1) and stearoyl-CoA desaturase (SCD), as a signature to distinguish the response of sorafenib. We proposed and validated that the RXRB and NR1H3 could directly regulate NR1H3 and SCD, respectively. Our results suggest that the combined use of SCD inhibitors and sorafenib may be a promising therapeutic approach

Disruption of splicing-regulatory elements using CRISPR/Cas9 to rescue spinal muscular atrophy in human iPSCs and mice

We here report a genome-editing strategy to correct spinal muscular atrophy (SMA). Rather than directly targeting the pathogenic exonic mutations, our strategy employed Cas9 and guide-sgRNA for the targeted disruption of intronic splicing-regulatory elements. We disrupted intronic splicing silencers (ISSs, including ISS-N1 and ISS + 100) of survival motor neuron (SMN) 2, a key modifier gene of SMA, to enhance exon 7 inclusion and full-length SMN expression in SMA iPSCs. Survival of splicing-corrected iPSC-derived motor neurons was rescued with SMN restoration. Furthermore, co-injection of Cas9 mRNA from Streptococcus pyogenes (SpCas9) or Cas9 from Staphylococcus aureus (SaCas9) alongside their corresponding sgRNAs targeting ISS-N1 into zygotes rescued 56% and 100% of severe SMA transgenic mice (Smn , SMN2 ). The median survival of the resulting mice was extended to >400 days. Collectively, our study provides proof-of-principle for a new strategy to therapeutically intervene in SMA and other RNA-splicing-related diseases. -/- tg/

Rationale for a Singapore Transthyretin Amyloidosis Registry

10.47102/annals-acadmedsg.202089ANNALS ACADEMY OF MEDICINE SINGAPORE496411-41

Synthesis of Rosin Acid Starch Catalyzed by Lipase

Rosin, an abundant raw material from pine trees, was used as a starting material directly for the synthesis of rosin acid starch. The esterification reaction was catalyzed by lipase (Novozym 435) under mild conditions. Based on single factor experimentation, the optimal esterification conditions were obtained as follows: rosin acid/anhydrous glucose unit in the molar ratio 2 : 1, reaction time 4 h at 45°C, and 15% of lipase dosage. The degree of substitution (DS) reaches 0.098. Product from esterification of cassava starch with rosin acid was confirmed by FTIR spectroscopy and iodine coloration analysis. Scanning electron microscopy and X-ray diffraction analysis showed that the morphology and crystallinity of the cassava starch were largely destroyed. Thermogravimetric analysis indicated that thermal stability of rosin acid starch decreased compared with native starch

Genome Sequencing and Assembly by Long Reads in Plants

Plant genomes generated by Sanger and Next Generation Sequencing (NGS) have provided insight into species diversity and evolution. However, Sanger sequencing is limited in its applications due to high cost, labor intensity, and low throughput, while NGS reads are too short to resolve abundant repeats and polyploidy, leading to incomplete or ambiguous assemblies. The advent and improvement of long-read sequencing by Third Generation Sequencing (TGS) methods such as PacBio and Nanopore have shown promise in producing high-quality assemblies for complex genomes. Here, we review the development of sequencing, introducing the application as well as considerations of experimental design in TGS of plant genomes. We also introduce recent revolutionary scaffolding technologies including BioNano, Hi-C, and 10× Genomics. We expect that the informative guidance for genome sequencing and assembly by long reads will benefit the initiation of scientists’ projects

Coordinated power-water optimization for precision irrigation among distribution network and agricultural parks

With more and more agricultural parks are integrated to the electrical distribution network, the disordered characteristics of farmers’ irrigation water consumption will not only increase the cost of water and electricity, but also cause security problems in traditional term of rural distribution network, such as large short-term load fluctuation, overload and transformer load imbalance. In this context, this paper proposes a double-layer master–slave game model of power-water interaction and coordination between distribution network and agricultural irrigation park under photovoltaic (PV) assisted agricultural precision irrigation. The upper layer (electrical distribution network) plays an interactive game with the lower layer (agricultural irrigation parks) by establishing effective time-of-use (TOU) price. On the one hand, the electrical distribution network takes the operation security as the optimization objective, it could optimize line loss by network configuration and guides agricultural irrigation parks to consume electricity orderly by formulating electricity prices. On the other hand, agricultural irrigation parks take satisfaction and cost as the optimization objective after receiving TOU price from upper layer, and regulates the operation time and intensity of irrigation pumps to realize precise irrigation. Finally, an example is given to verify the model on the modified 148-node system. It is determined that the model can effectively support the safe and reliable operation of rural distribution network while realizing the transformation of agricultural irrigation water use from low efficiency to economical and high efficiency, so as to achieve win–win between agricultural irrigation park and distribution network