Jasamplexoside A

23220583

Therapeutic agents that suppress apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP) levels/activity are being developed in the clinic to benefit patients who are unable to reach target LDL-C levels with maximally tolerated lipid-lowering drugs. To compare and contrast the metabolic consequences of reducing these targets, murine-specific apoB or MTP antisense oligonucleotides (ASOs) were administered to chow-fed and high fat-fed C57BL/6 or to chow-fed and Western diet-fed LDLr−/− mice for periods ranging from 2 to 12 weeks, and detailed analyses of various factors affecting fatty acid metabolism were performed. Administration of these drugs significantly reduced target hepatic mRNA and protein, leading to similar reductions in hepatic VLDL/triglyceride secretion. MTP ASO treatment consistently led to increases in hepatic triglyceride accumulation and biomarkers of hepatotoxicity relative to apoB ASO due in part to enhanced expression of peroxisome proliferator activated receptor γ target genes and the inability to reduce hepatic fatty acid synthesis. Thus, although both drugs effectively lowered LDL-C levels in mice, the apoB ASO produced a more positive liver safety profile.

Ric microsomal triglyceride transfer protein, dyslipidemia, steatosis, lipoprotein metabolism, lipid droplets, familial hypercholesterolemiahard G. Lee,1 Wuxia Fu, Mark J. Graham, Adam E. Mullick, Donna Sipe, Danielle Gattis, Thomas A. Bell, Sheri Booten, and Rosanne M. Crooke

Comparison of the pharmacological profiles of murine antisense oligonucleotides targeting apolipoprotein B and microsomal triglyceride transfer protein

Richard G. Lee, Wuxia Fu, Mark J. Graham, Adam E. Mullick, Donna Sipe, Danielle Gattis, Thomas A. Bell, Sheri Booten, Rosanne M. Crooke

2013 Mar;

23741504

To tackle the exponentially increasing throughput of Next-Generation Sequencing (NGS), most of the existing short-read aligners can be configured to favor speed in trade of accuracy and sensitivity. SOAP3-dp, through leveraging the computational power of both CPU and GPU with optimized algorithms, delivers high speed and sensitivity simultaneously. Compared with widely adopted aligners including BWA, Bowtie2, SeqAlto, CUSHAW2, GEM and GPU-based aligners BarraCUDA and CUSHAW, SOAP3-dp was found to be two to tens of times faster, while maintaining the highest sensitivity and lowest false discovery rate (FDR) on Illumina reads with different lengths. Transcending its predecessor SOAP3, which does not allow gapped alignment, SOAP3-dp by default tolerates alignment similarity as low as 60%. Real data evaluation using human genome demonstrates SOAP3-dp’s power to enable more authentic variants and longer Indels to be discovered. Fosmid sequencing shows a 9.1% FDR on newly discovered deletions. SOAP3-dp natively supports BAM file format and provides the same scoring scheme as BWA, which enables it to be integrated into existing analysis pipelines. SOAP3-dp has been deployed on Amazon-EC2, NIH-Biowulf and Tianhe-1A.

SOAP3-dp: Fast, Accurate and Sensitive GPU-Based Short Read Aligner

Ruibang Luo, Thomas Wong, Jianqiao Zhu, Chi-Man Liu, Xiaoqian Zhu, Edward Wu, Lap-Kei Lee, Haoxiang Lin, Wenjuan Zhu, David W. Cheung, Hing-Fung Ting, Siu-Ming Yiu, Shaoliang Peng, Chang Yu, Yingrui Li, Ruiqiang Li, Tak-Wah Lam

2013