ABSTRACT
The dorsoventral (DV) patterning of the early Drosophila embryo depends on Dorsal, a maternal sequence-specific transcription factor related to mammalian NF-kappaB. Dorsal controls DV patterning through the differential regulation of approximately 50 target genes in a concentration-dependent manner. Whole-genome methods, including ChIP-chip and ChIP-seq assays, have identified approximately 100 Dorsal target enhancers, and more than one-third of these have been experimentally confirmed via transgenic embryo assays. Despite differences in DV patterning among divergent insects, a number of the Dorsal target enhancers are located in conserved positions relative to the associated transcription units. Thus, the evolution of novel patterns of gene expression might depend on the modification of old enhancers, rather than the invention of new ones. As many as half of all Dorsal target genes appear to contain "shadow" enhancers: a second enhancer that directs the same or similar expression pattern as the primary enhancer. Preliminary studies suggest that shadow enhancers might help to ensure resilience of gene expression in response to environmental and genetic perturbations. Finally, most Dorsal target genes appear to contain RNA polymerase II (pol II) prior to their activation. Stalled pol II fosters synchronous patterns of gene activation in the early embryo. In contrast, DV patterning genes lacking stalled pol II are initially activated in an erratic or stochastic fashion. It is possible that stalled pol II confers fitness to a population by ensuring coordinate deployment of the gene networks controlling embryogenesis.
Subject(s)
Biological Evolution , Body Patterning/genetics , Insecta/embryology , Insecta/genetics , Animals , Drosophila/embryology , Drosophila/genetics , Drosophila Proteins/genetics , Enhancer Elements, Genetic , Gene Expression Regulation, Developmental , Genes, Insect , Nuclear Proteins/genetics , Phosphoproteins/genetics , Transcription Factors/geneticsABSTRACT
A novel series of potent blockers of the monocarboxylate transporter, MCT1, is disclosed. From very potent but lipophilic lead compounds, systematic changes to all parts of the molecule, targeting reduction in log D, afforded compounds with significantly improved overall properties. These compounds show potent immunomodulatory activity.
Subject(s)
Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 Enzyme System/metabolism , Herpesviridae/drug effects , Immunologic Factors/pharmacology , Monocarboxylic Acid Transporters/antagonists & inhibitors , Symporters/antagonists & inhibitors , T-Lymphocytes/drug effects , Animals , Aryl Hydrocarbon Hydroxylases/immunology , Cytochrome P-450 CYP2C9 , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/immunology , Graft vs Host Disease/immunology , Herpesviridae/immunology , Herpesviridae/metabolism , Humans , Immunologic Factors/chemistry , Monocarboxylic Acid Transporters/immunology , Monocarboxylic Acid Transporters/metabolism , Symporters/immunology , Symporters/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
BACKGROUND AND OBJECTIVE: The purpose of this study is to summarize our use of the Holmium laser as a tool in performing chondroplasties of the knee and to determine whether any untoward affects developed at the site of laser application. STUDY DESIGN/MATERIALS AND METHODS: A retrospective review of 504 laser chondroplasties of the medial femoral condyle was done. Laser parameters and the average number of joules to perform the chondroplasties were recorded. The average follow-up was 11 months. RESULTS: Preoperative MRI interpretation indicated that 8% of the patients had osteonecrosis prior to surgery. 88% of the patients were satisfied with the procedure. All failures were evaluated by X-ray, MRI, bone scan, or biopsy of the medial femoral condyle. No new cases of osteonecrosis were determined. CONCLUSION: No new cases of osteonecrosis were documented of the medial femoral condyle following laser chondroplasty utilizing the parameters in this study. The Holmium laser remains a safe and efficacious tool in performing chondroplasty.
