ABSTRACT
Discovering genetic biomarkers associated with disease resistance and enhanced immunity is critical to developing advanced strategies for controlling viral and bacterial infections in different species. Macrophages, important cells of innate immunity, are directly involved in cellular interactions with pathogens, the release of cytokines activating other immune cells and antigen presentation to cells of the adaptive immune response. IFNγ is a potent activator of macrophages and increased production has been associated with disease resistance in several species. This study characterizes the molecular basis for dramatically different nitric oxide production and immune function between the B2 and the B19 haplotype chicken macrophages.A large-scale RNA sequencing approach was employed to sequence the RNA of purified macrophages from each haplotype group (B2 vs. B19) during differentiation and after stimulation. Our results demonstrate that a large number of genes exhibit divergent expression between B2 and B19 haplotype cells both prior and after stimulation. These differences in gene expression appear to be regulated by complex epigenetic mechanisms that need further investigation.
Subject(s)
Adaptive Immunity/physiology , Gene Expression Regulation , Haplotypes , Macrophages/metabolism , Animals , Cell Differentiation/physiology , Chickens , Interferon-gamma/pharmacology , Macrophages/drug effects , Macrophages/immunology , Nitric Oxide/biosynthesis , Sequence Analysis, RNAABSTRACT
The SAR development is described for a series of N-acyl pyrrolidine inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase, NS5B, from tractable Delta21 enzyme inhibitors to an example with antiviral activity in a cellular assay (HCV replicon).
Subject(s)
Antiviral Agents/pharmacology , Chemistry, Pharmaceutical/methods , Hepacivirus/chemistry , Hepacivirus/genetics , Pyrrolidines/antagonists & inhibitors , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Replicon/genetics , Viral Nonstructural Proteins/pharmacology , Antiviral Agents/chemistry , Drug Design , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , RNA, Viral/chemistry , Viral Nonstructural Proteins/chemistry , Virus Replication/drug effectsABSTRACT
HTS of the compound collection for inhibition of the HCV RNA dependent RNA polymerase identified two 168 member N-acyl pyrrolidine combinatorial mixture hits. Deconvolution and expansion of these mixtures by solid phase synthesis to establish initial SAR and identify a potent inhibitor is reported.
Subject(s)
Hepacivirus/enzymology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Combinatorial Chemistry Techniques , Molecular StructureABSTRACT
BACKGROUND: Over the past few years there has been an interest in the use of magnetic resonance imaging (MRI) to study specific brain regions in bipolar disorder. The present study compared the grey matter volume in the subgenual prefrontal cortex in patients with familial and non-familial bipolar disorder and normal control subjects. METHODS: MRI brain scans were performed on 12 patients with bipolar I disorder including six patients with a positive family history of bipolar disorder as well as eight control subjects. RESULTS: There was a significant reduction in the grey matter volume in the right subgenual prefrontal cortex, but not in the left subgenual prefrontal cortex. A family history x sex interaction with right prefrontal cortex volume was also observed as a trend. For females, a positive family history was associated with reduced right prefrontal cortex volumes; for males, a positive family history was associated with increased right prefrontal cortex volumes. LIMITATIONS: Small sample size, reduced statistical power. CONCLUSION: These data add to the emerging literature on structural changes in the subgenual prefrontal cortex in bipolar disorder, especially in patients with a positive family history.
