2,792 research outputs found
Shadow Enhancers Foster Robustness of Drosophila Gastrulation
SummaryCritical developmental control genes sometimes contain “shadow” enhancers that can be located in remote positions, including the introns of neighboring genes [1]. They nonetheless produce patterns of gene expression that are the same as or similar to those produced by more proximal primary enhancers. It was suggested that shadow enhancers help foster robustness in gene expression in response to environmental or genetic perturbations [2, 3]. We critically tested this hypothesis by employing a combination of bacterial artificial chromosome (BAC) recombineering and quantitative confocal imaging methods [2, 4]. Evidence is presented that the snail gene is regulated by a distal shadow enhancer located within a neighboring locus. Removal of the proximal primary enhancer does not significantly perturb snail function, including the repression of neurogenic genes and formation of the ventral furrow during gastrulation at normal temperatures. However, at elevated temperatures, there is sporadic loss of snail expression and coincident disruptions in gastrulation. Similar defects are observed at normal temperatures upon reductions in the levels of Dorsal, a key activator of snail expression (reviewed in [5]). These results suggest that shadow enhancers represent a novel mechanism of canalization whereby complex developmental processes “bring about one definite end-result regardless of minor variations in conditions” [6]
Ariel - Volume 9 Number 6
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Apolipoprotein Mimetic Peptides: A New Approach for the Treatment of Asthma
New treatments are needed for severe asthmatics to improve disease control and avoid severe toxicities associated with oral corticosteroids. We have used a murine model of house dust mite (HDM)-induced asthma to identify steroid-unresponsive genes that might represent targets for new therapeutic approaches for severe asthma. This strategy identified apolipoprotein E as a steroid-unresponsive gene with increased mRNA expression in the lungs of HDM-challenged mice. Furthermore, apolipoprotein E functioned as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in experimental HDM-induced asthma. The ability of apolipoprotein E, which is expressed by lung macrophages, to attenuate AHR, and goblet cell hyperplasia is mediated by low density lipoprotein (LDL) receptors expressed by airway epithelial cells. Consistent with this, administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130–149 of the LDL receptor-binding domain of the holo-apoE protein, significantly reduced AHR and goblet cell hyperplasia in HDM-challenged apoE−/− mice. These findings identified the apolipoprotein E – LDL receptor pathway as a new druggable target for asthma that can be activated by administration of apoE-mimetic peptides. Similarly, apolipoprotein A-I may have therapeutic potential in asthma based upon its anti-inflammatory, anti-oxidative, and anti-fibrotic properties. Furthermore, administration of apolipoprotein A-I mimetic peptides has attenuated airway inflammation, airway remodeling, and airway hyperreactivity in murine models of experimental asthma. Thus, site-directed delivery of inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides may represent novel treatment approaches that can be developed for asthma, including severe disease
Etidronate prevents, but does not reverse, ectopic mineralization in a mouse model of pseudoxanthoma elasticum (
Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are heritable disorders manifesting with ectopic tissue mineralization. Most cases of PXE and some cases of GACI are caused by mutations in the ABCC6 gene, resulting in reduced plasma pyrophosphate (PPi) levels. There is no effective treatment for these disorders. It has been suggested that administration of bisphosphonates, stable and non-hydrolyzable PPi analogs, could counteract ectopic mineralization in these disorders. In this study we tested the potential efficacy of etidronate, a first generation bisphosphonate, on ectopic mineralization in the muzzle skin of Abcc6-/- mice, a model of PXE. The Abcc6-/- mice received subcutaneous injections of etidronate, 0.283 and 3.40 mg/kg per injection (0.01× and 0.12×), twice a week, in both prevention and reversal studies. Ectopic mineralization in the dermal sheath of vibrissae in muzzle skin was determined by histopathologic analysis and by direct chemical assay for calcium content. Subcutaneous injection of etidronate prevented ectopic mineralization but did not reverse existing mineralization. The effect of etidronate was accompanied by alterations in the trabecular bone microarchitecture, determined by micro-computed tomography. The results suggest that etidronate may offer a potential treatment modality for PXE and GACI caused by ABCC6 mutations. Etidronate therapy should be initiated in PXE patients as soon as the diagnosis is made, with careful monitoring of potential side effects
Activity-Based Cost Management Part I: Applied to Occupational and Environmental Health Organizations
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91960/1/Brandt1.pd
Activity-Based Cost Management Part II: Applied to a Respiratory Protection Program
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91961/1/Brandt2.pd
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