Development of Organic Carbon Monoxide prodrugs

Carbon monoxide (CO) is an endogenously produced gasotransmitter in mammals and may have signaling roles in bacteria as well. It has many recognized therapeutic effects. A significant challenge in this field is the development of pharmaceutically acceptable forms of CO delivery with controllable and tunable release rates. Our lab has designed a series of organic CO prodrugs as prototypes of “carbon monoxide in a pill.” In the first project, a series of such CO prodrugs was synthesized to examine the structure-release rate in aqueous solution at neutral pH. CO prodrugs with triggered release mechanisms are highly desirable for targeted delivery. In the second project, we focused on the development of reactive oxygen species ROS-sensitive CO prodrugs, which selectively deliver CO to cells with elevated ROS levels and sensitize cancer cells to chemotherapy. CO prodrugs as such could serve as powerful tools for targeted delivery to disease sites with elevated ROS levels and for exploring the therapeutic applications of CO. In the third project, we focused on metal-free CO prodrugs with dual-responsive endogenous triggers, which have the advantage of controlled activation at the desired site of action. These CO prodrugs afford highly selective release profiles as compared to others with no or a single trigger. In addition, one representative CO prodrug showed significant anti-inflammatory effects both in vitro and in a LPS-simulated systemic inflammation models, suggesting its possible application in treating systemic inflammatory conditions. The prodrug also conferred very pronounced protective effects against LPS-induced acute liver injury. These results firmly established such CO prodrugs as either research tools or candidate compounds for the treatment of systemic inflammation or other inflammation-related organ injuries

Does enterprise risk management benefit manufacturing firms? Evidence from China

It is observed that Enterprise risk management (ERM) framework has been adopted by some manufacturing firms in China in the past years. To investigate the effectiveness of ERM, data of A-share listed manufacturing firms in Shanghai and Shenzhen stock exchange during 2010-2019 are adopted from Wind database and CSMAR database, two large domestic databases, to examine the impact of ERM on value of manufacturing firms. Treatment effects model and genenralised method of moments (GMM) are employed to derive the empirical results. Our results show that adoption of ERM can add value to the firms, and firms benefitmore from high-quality ERM program. Furthermore, the impact of ERM seems to be more significant among the manufacturing firms with smaller scale, or stronger institutional shareholding, or international business. Our findings encourage the manufacturing firms to implement ERM program and improve the program to achieve its targets

Numerical simulation and experimental investigation of diesel fuel reforming over a Pt/CeO₂-Al₂O₃ catalyst

In order to benefit from a realistic hydrogen production device equipped on a vehicle, issues with the effects of the process parameters on H2 and CO yield need to be resolved. In this study, a reduced mechanism for n-heptane (as a surrogate diesel) reforming over a Pt/CeO2-Al2O3 catalyst is adopted to investigate the effects of the process parameters on H2 and CO yield, and the preferred process parameters are concluded. In addition, the comparison of reforming bench tests of diesel fuel and n-heptane under typical diesel engine operating conditions is conducted. The n-heptane reforming simulation results show that the maximum H2 and CO yield moves toward unity with the decreased GHSV and increased reaction temperature, and the GHSV of 10,000 1/h, O2/C ratio of 0.6 and reaction temperature of 500 °C is preferable. The contrast experiments reveal that the change trend of H2 and CO yield displays consistence, although the difference of the average H2 and CO yield results is obvious. The characteristics of n-heptane reforming can represent H2 and CO yield features of diesel fuel reforming at typical reaction temperatures in a way

Developmental trajectories of reading development and impairment from ages 3 to 8 years in Chinese children

Early prediction of reading disabilities in Chinese is important for early remediation efforts. In this 6-year longitudinal study, we investigated the early cognitive predictors of reading skill in a statistically representative sample of Chinese children from Beijing.Two hundred sixty-one (261) native Chinese children were administered seven language-related skills over three years between the ages of 3 and 6 years. Performances on these skills were then examined in relation to subsequent word reading accuracy and fluency. Individual differences in developmental profiles across tasks were then estimated using growth mixture modeling.Four developmental trajectories were classified – the typical (control), catch-up (with low initial cognitive performances but adequate subsequent reading), literacy-related-cognitive-delay (with difficulties in morphological awareness, phonological awareness, and speeded naming and subsequent word recognition), and language-delay (relatively low across all tasks) groups.Findings suggest that the combination of phonological awareness, rapid naming and morphological awareness are essential in the early prediction of later reading difficulties in Chinese children.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79090/1/j.1469-7610.2010.02311.x.pd

A Global View of Cancer-Specific Transcript Variants by Subtractive Transcriptome-Wide Analysis

BACKGROUND: Alternative pre-mRNA splicing (AS) plays a central role in generating complex proteomes and influences development and disease. However, the regulation and etiology of AS in human tumorigenesis is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: A Basic Local Alignment Search Tool database was constructed for the expressed sequence tags (ESTs) from all available databases of human cancer and normal tissues. An insertion or deletion in the alignment of EST/EST was used to identify alternatively spliced transcripts. Alignment of the ESTs with the genomic sequence was further used to confirm AS. Alternatively spliced transcripts in each tissue were then subtractively cross-screened to obtain tissue-specific variants. We systematically identified and characterized cancer/tissue-specific and alternatively spliced variants in the human genome based on a global view. We identified 15,093 cancer-specific variants of 9,989 genes from 27 types of human cancers and 14,376 normal tissue-specific variants of 7,240 genes from 35 normal tissues, which cover the main types of human tumors and normal tissues. Approximately 70% of these transcripts are novel. These data were integrated into a database HCSAS (http://202.114.72.39/database/human.html, pass:68756253). Moreover, we observed that the cancer-specific AS of both oncogenes and tumor suppressor genes are associated with specific cancer types. Cancer shows a preference in the selection of alternative splice-sites and utilization of alternative splicing types. CONCLUSIONS/SIGNIFICANCE: These features of human cancer, together with the discovery of huge numbers of novel splice forms for cancer-associated genes, suggest an important and global role of cancer-specific AS during human tumorigenesis. We advise the use of cancer-specific alternative splicing as a potential source of new diagnostic, prognostic, predictive, and therapeutic tools for human cancer. The global view of cancer-specific AS is not only useful for exploring the complexity of the cancer transcriptome but also widens the eyeshot of clinical research