Precision medicine最新文献

It is a reality that globally opioid deaths have soared for men and women of all social, economic status and age from heroin and fentanyl overdoses. Specifically, in the United States, deaths from narcotic overdoses have reached alarming metrics since 2010. In fact, the Fentanyl rise is driven by drug dealers who sell it as heroin or who use it to lace cocaine or to make illegal counterfeit prescription opioids. The President's Commission on the crisis has linked the death toll as equivalent to "September 11th every three weeks." In fact, The U.S. Centre for Disease Control (CDC) released data showing that opioid-related overdoses were up 15% in the first three quarters of 2016 compared to 2015. Various governmental organizations including NIDA, are actively seeking solutions. However, we argue that unless the scientific community embraces genetic addiction risk coupled with potential precision or personalized medicine to induce "dopamine homeostasis" it will fail. We now have evidence that a ten-gene and eleven single nucleotide polymorphism (SNP) panel predicts Addiction Severity Index (ASI) for both alcohol and drugs of abuse (e.g., Opioids). In a large multi-addiction centre study involving seven diverse treatment programs, the genetic addiction risk score (GARS^™) was shown to have a predictive relationship with ASI-MV derived alcohol (≥ seven alleles), and other drugs (≥ 4 alleles) severity risk scores. In a number of neuroimaging studies, we also display that in both animal (bench) and abstinent Chinese severe heroin-dependent patients (bedside), BOLD dopamine activation across the brain reward circuitry revealed increases in resting state functional connectivity as well volume connectivity. It is also known that published nutrigenomic (coupling gene polymorphisms with altered KB220z) studies reveal improved clinical outcomes related to obesity.

It has been realized in recent years that non-coding RNAs are playing important roles in genome functions and human diseases. Here we developed a new technology and observed a new pattern of gene expression. We observed that over 72% of RNAs in human genome are expressed in forward-reverse pairs, just like mirror images of each other between forward expression and reverse expression; the overview showed that it cannot be simply described as transcript overlapping, so we designated it as mirror expression. Furthermore, we found that the mirror expression is gene-specific and tissue-specific, and less common in the proximal promoter regions. The size of the shadows varies between different genes, different tissues and different classes. The shadow expression is most significant in the Alu element, it was also observed among L1, Simple Repeats and LTR elements, but rare in other repeats such as low-complexity, LINE/L2, DNA and MIRs. Although there is no evidence yet about the relationship of this mirror pattern and double-strand RNA (dsRNA), this new striking pattern provides a new clue and a new direction to unveil the role of RNAs in the genome functions and diseases.

We recently discovered a dynamic copy number variation on the NCF1 (neutrophil cytosolic factor 1) pseudogenes in human populations. In this study, we investigated whether these pseudogenes are functional or junk as described before. We sequenced the RNAs transcribed from the genome of this locus, and discovered over 10 splicing isoforms from the NCF1 pseudogenes. We cloned 4 splicing isoforms into expression vectors and introduced them into human vascular endothelial cells by transient transfection. We then used two chemical approaches to measure the superoxide production in the cells with and without these pseudogene overexpression. Our data showed that three pseudogene splicing products remarkably reduced the superoxide production after the GFP (Green fluorescent protein) normalization. We used an anti-HA (Hemagglutinin A) tag antibody to stain the cells and confirmed that the proteins transcribed from the NCF1 pseudogene were exclusively localized in the cytoplasm in the perinuclear area in the transient transfection assays. We further examined the tissue distribution of these splicing isoforms of NCF1 pseudogenes in human tissues by quantitative real-time PCR analysis. Our data showed that although these splicing variants are ubiquitously expressed in non-immune tissues in human, they seem to be under a tight control of transcription regulation and show a non-random distribution pattern across tissues. This study challenges the concept that pseudogenes in human genome are only junks without biological functions. Moreover, it suggests that those pseudogenes in human genome may serve as a natural resource for novel drug discovery.