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Biomedical subjects

Michael McManus

Publications and source records attributed to Michael McManus.

6 recordsLinked to original sources

Duox2 exhibits potent heme peroxidase activity in human respiratory tract epithelium.

The dual oxidase isozymes Duox1 and Duox2 exhibit functional NADPH:O(2) oxidoreductase activity in thyroid and respiratory tract cells and are thought to be essential for H(2)O(2) generation in these tissues. However, it is not universally accepted that the heme peroxidase domains of the Duox isozymes are functional. To address this question, we modulated Duox2 expression in human tracheobronchial epithelial (TBE) cell culture systems and quantified peroxidase activity. We discovered that interferon-gamma (IFN-gamma) induced robust peroxidase activity in TBE cells that paralleled Duox2 expression. IFN-gamma-induced peroxidase activity was abolished in the presence of sodium azide, which implicated the activation of a heme peroxidase. IFN-gamma-induced peroxidase activity was abolished in TBE cell lines expressing anti-Duox2 short hairpin RNA transcripts. Together, these data unequivocally demonstrated that Duox2 contains a functional heme peroxidase in intact respiratory tract epithelium.

Antineoplastic Agents↗

Hippocampal atrophy in the healthy is initially linear and independent of age.

Patients with minimal cognitive impairment (MCI) or Alzheimer's disease (AD) have smaller hippocampal volumes (HV) and increased rates of HV loss (rHVL). A 6-year study was conducted to assess rHVL in healthy aging subjects (HC) in which four MRI scans, each 2 years apart, were obtained on 26 HC with a mean age of 58.8 years when entering the study. rHVLs were linear and significantly differed among subjects, even those sharing an identical apoliporotein E genotype, ranging from .027 to .191 cc/year (S.D. = .022 cc/year), and were not affected by age or sex. rHVL, but not HV, at time of subject entry, was found to predict performance on the delayed recall measure of the Selective Reminder Task obtained 6 years after subject entry into study. Although the molecular events underlying rHVL are unclear, the significance of rHVL in subjects in their sixth and seventh decades of life for predicting age-related cognitive trajectories and whether changes in rHVLs foreshadow the development of MCI are the subject of ongoing study.

Age Factors↗

Cre-lox-regulated conditional RNA interference from transgenes.

We have generated two lentiviral vectors for conditional, Cre-lox-regulated, RNA interference. One vector allows for conditional activation, whereas the other permits conditional inactivation of short hairpin RNA (shRNA) expression. The former is based on a strategy in which the mouse U6 promoter has been modified by including a hybrid between a LoxP site and a TATA box. The ability to efficiently control shRNA expression by using these vectors was shown in cell-based experiments by knocking down p53, nucleophosmin and DNA methyltransferase 1. We also demonstrate the usefulness of this approach to achieve conditional, tissue-specific RNA interference in Cre-expressing transgenic mice. Combined with the growing array of Cre expression strategies, these vectors allow spatial and temporal control of shRNA expression in vivo and should facilitate functional genetic analysis in mammals.

Amino Acid Sequence↗

Occurrence of spruce bark beetles in forest stands at different levels of air pollution stress.

The spruce bark beetle, Ips typographus (L.) is the most serious pest of mature spruce stands, mainly Norway spruce, Picea abies (L.) Karst. throughout Eurasia. A complex of weather-related events and other environmental stresses are reported to predispose spruce stands to bark beetle attack and subsequent tree mortality; however the possible role of industrial pollution as a predisposing factor to attack by this species is poorly understood. The abundance and dynamics of I. typographus populations was evaluated in 60-80 year old Norway spruce stands occurring on 10 x 50 ha sites in five countries within the Carpathian range that were selected in proximity to established ozone measurement sites. Data were recorded on several parameters including the volume of infested trees, captures of adult beetles in pheromone traps, number of attacks, and the presence and relative abundance of associated bark beetle species. In several cases, stands adjacent to sites with higher ozone values were associated with higher bark beetle populations. The volume of sanitary cuttings, a reflection of tree mortality, and the mean daily capture of beetles in pheromone traps were significantly higher at sites where the O(3) level was higher. However, the mean infestation density on trees was higher in plots associated with lower O(3) levels. Captures of beetles in pheromone traps and infestation densities were higher in the zone above 800 m. However, none of the relationships was conclusive, suggesting that spruce bark beetle dynamics are driven by a complex interaction of biotic and abiotic factors and not by a single parameter such as air pollution.

Air Pollution↗

New international long-term ecological research on air pollution effects on the Carpathian Mountain forests, Central Europe.

An international cooperative project on distribution of ozone in the Carpathian Mountains, Central Europe was conducted from 1997 to 1999. Results of that project indicated that in large parts of the Carpathian Mountains, concentrations of ozone were elevated and potentially phytotoxic to forest vegetation. That study led to the establishment of new long-term studies on ecological changes in forests and other ecosystems caused by air pollution in the Retezat Mountains, Southern Carpathians, Romania and in the Tatra Mountains, Western Carpathians on the Polish-Slovak border. Both of these important mountain ranges have the status of national parks and are Man & the Biosphere Reserves. In the Retezat Mountains, the primary research objective was to evaluate how air pollution may affect forest health and biodiversity. The main research objective in the Tatra Mountains was to evaluate responses of natural and managed Norway spruce forests to air pollution and other stresses. Ambient concentrations of ozone (O(3)), sulfur dioxide (SO(2)), nitrogen oxides (NO(x)) as well as forest health and biodiversity changes were monitored on densely distributed research sites. Initial monitoring of pollutants indicated low levels of O(3), SO(2), and NO(x) in the Retezat Mountains, while elevated levels of O(3) and high deposition of atmospheric sulfur (S) and nitrogen (N) have characterized the Tatra Mountains. In the Retezat Mountains, air pollution seems to have little effect on forest health; however, there was concern that over a long time, even low levels of pollution may affect biodiversity of this important ecosystem. In contrast, severe decline of Norway spruce has been observed in the Tatra Mountains. Although bark beetle seems to be the immediate cause of that decline, long-term elevated levels of atmospheric N and S depositions and elevated O(3) could predispose trees to insect attacks and other stresses. European and US scientists studied pollution deposition, soil and plant chemistry, O(3)-sensitive plant species, forest insects, and genetic changes in the Retezat and Tatra Mountains. Results of these investigations are presented in a GIS format to allow for a better understanding of the changes and the recommendations for effective management in these two areas.

Air Pollutants↗

CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells.

Centrosome duplication and separation are linked inextricably to certain cell cycle events, in particular activation of cyclin-dependent kinases (CDKs). However, relatively few CDK targets driving these events have been uncovered. Here, we have performed a screen for CDK substrates and have isolated a target, CP110, which is phosphorylated by CDKs in vitro and in vivo. Human CP110 localizes to centrosomes. Its expression is strongly induced at the G1-to-S phase transition, coincident with the initiation of centrosome duplication. RNAi-mediated depletion of CP110 indicates that this protein plays an essential role in centrosome duplication. Long-term disruption of CP110 phosphorylation leads to unscheduled centrosome separation and overt polyploidy. Our data suggest that CP110 is a physiological centrosomal CDK target that promotes centrosome duplication, and its deregulation may contribute to genomic instability.

Amino Acid Motifs↗