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Browsing by Author "Zhang, Zhiwei"

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    Interaction of α Carboxyl Terminus 1 Peptide With the Connexin 43 Carboxyl Terminus Preserves Left Ventricular Function After Ischemia‐Reperfusion Injury
    Jiang, Jingbo; Hoagland, Daniel T.; Palatinus, Joseph A.; He, Huamei; Iyyathurai, Jegan; Jourdan, L. Jane; Bultynck, Geert; Wang, Zhen; Zhang, Zhiwei; Schey, Kevin; Poelzing, Steven; McGowan, Francis X.; Gourdie, Robert G. (American Heart Association, 2019-08-19)
    Background α Carboxyl terminus 1 (αCT1) is a 25–amino acid therapeutic peptide incorporating the zonula occludens‐1 (ZO‐1)–binding domain of connexin 43 (Cx43) that is currently in phase 3 clinical testing on chronic wounds. In mice, we reported that αCT1 reduced arrhythmias after cardiac injury, accompanied by increases in protein kinase Cε phosphorylation of Cx43 at serine 368. Herein, we characterize detailed molecular mode of action of αCT1 in mitigating cardiac ischemia‐reperfusion injury. Methods and Results To study αCT1‐mediated increases in phosphorylation of Cx43 at serine 368, we undertook mass spectrometry of protein kinase Cε phosphorylation assay reactants. This indicated potential interaction between negatively charged residues in the αCT1 Asp‐Asp‐Leu‐Glu‐Iso sequence and lysines (Lys345, Lys346) in an α‐helical sequence (helix 2) within the Cx43‐CT. In silico modeling provided further support for this interaction, indicating that αCT1 may interact with both Cx43 and ZO‐1. Using surface plasmon resonance, thermal shift, and phosphorylation assays, we characterized a series of αCT1 variants, identifying peptides that interacted with either ZO‐1–postsynaptic density‐95/disks large/zonula occludens‐1 2 or Cx43‐CT, but with limited or no ability to bind both molecules. Only peptides competent to interact with Cx43‐CT, but not ZO‐1–postsynaptic density‐95/disks large/zonula occludens‐1 2 alone, prompted increased pS368 phosphorylation. Moreover, in an ex vivo mouse model of ischemia‐reperfusion injury, preischemic infusion only with those peptides competent to bind Cx43 preserved ventricular function after ischemia‐reperfusion. Interestingly, a short 9–amino acid variant of αCT1 (αCT11) demonstrated potent cardioprotective effects when infused either before or after ischemic injury. Conclusions Interaction of αCT1 with the Cx43, but not ZO‐1, is correlated with cardioprotection. Pharmacophores targeting Cx43‐CT could provide a translational approach to preserving heart function after ischemic injury.
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    A Longitudinal Study of Alcohol and Drug Use in the Workplace
    Zhang, Zhiwei (Virginia Tech, 1999-04-15)
    Alcohol abuse and illicit drug use in the United States are major concerns of American households, as well as of the White House. This dissertation research evaluates alcohol abuse and controlled drug use by American workers in the context of various individual, organizational, and occupational settings. It tests the importation and organizational stress perspectives, the occupation subculture perspective, and the lifecycle wage compensation theory. The analyses are developed utilizing (1) logistic regression, (2) generalized linear modeling, including Poisson regression and negative binomial regression, (3) weighted modeling estimation, taking the clustering effects of complex survey design into account, and (4) the hierarchical growth curve modeling of intra- and inter-individual differences. Using data from the National Longitudinal Survey of Youth 1979—1993, the 1997 National Household Survey on Drug Abuse, and the 1998 National Occupational Information Network (O*NET 98), I find that employees' drinking and controlled drug use behavior are predicted by a number of individual background characteristics, as well as workplace-environment variables. I also find that occupational characteristics influence alcohol and drug using behaviors of workers, although in more complex ways than suggested by much of the organizational stress and occupational subculture literature. It appears that occupations with higher levels of steady employment prospects exert the most significant negative effect on employees' alcohol use, marijuana use, and any illicit drug use, regardless of an employee's age, gender, race, education, and income. It also appears that the etiology of cocaine use is different from that of either alcohol use or other drugs, such as marijuana. Finally, I find that when education and years employed are held constant, employees' current marijuana use is negatively associated with their earnings. No evidence has been found that current alcohol use, current marijuana use, or lifetime cocaine use predicts future growth rates on earnings. Having examined the factors of occupational, organizational, and individual social/demographic characteristics as they influence patterns of alcohol abuse and controlled drug use in multiple large representative samples of the labor force, discussions on the research findings, the implications, the limitations, and the future study directions are presented.