Hypothalamo-hypophyseal-gonadal function in the rat following administration of the novel and selective D-1 agonist CY 208-243

Summary The effects of the novel and selective dopamine D-1 agonist CY 208-243 on the rat hypothalamo-hypophyseal-gonadal (HHG) axis were studied. CY 208-243 did not modify the concentration of luteinizing hormone (LH) in serum from female or male rats, and had no effect upon opiate antagonist-induced stimulation of LH secretion in male rats. CY 208-243 did not inhibit ovulation in cycling female rats. Thus, D-1 receptor activation by systemic drug administration does not alter HHG function in rats.     

Differential alterations in branched-chain amino acid decarboxylation in liver of hypophysectomized rats

Summary Valine decarboxylation was significantly increased and leucine decarboxylation was significantly decreased in rat liver slices following hypophysectomy. In both normal and hypophysectomized rats decarboxylation of leucine exceeded that of valine in slices whereas the reverse was observed with the respective keto acids and mitochondria.Acknowledgments. This study was supported by the National Institutes of Health and the Samuel A. Berger Foundation.     

Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect

Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 x 10(-6)) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 x 10(-5)). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.     

Lack of long-term cortical reorganization after macaque retinal lesions

Several aspects of cortical organization are thought to remain plastic into adulthood, allowing cortical sensorimotor maps to be modified continuously by experience. This dynamic nature of cortical circuitry is important for learning, as well as for repair after injury to the nervous system. Electrophysiology studies suggest that adult macaque primary visual cortex (V1) undergoes large-scale reorganization within a few months after retinal lesioning, but this issue has not been conclusively settled. Here we applied the technique of functional magnetic resonance imaging (fMRI) to detect changes in the cortical topography of macaque area V1 after binocular retinal lesions. fMRI allows non-invasive, in vivo, long-term monitoring of cortical activity with a wide field of view, sampling signals from multiple neurons per unit cortical area. We show that, in contrast with previous studies, adult macaque V1 does not approach normal responsivity during 7.5 months of follow-up after retinal lesions, and its topography does not change. Electrophysiology experiments corroborated the fMRI results. This indicates that adult macaque V1 has limited potential for reorganization in the months following retinal injury.     

Structural insights into mRNA recognition from a PIWI domain-siRNA guide complex

RNA interference and related RNA silencing phenomena use short antisense guide RNA molecules to repress the expression of target genes. Argonaute proteins, containing amino-terminal PAZ (for PIWI/Argonaute/Zwille) domains and carboxy-terminal PIWI domains, are core components of these mechanisms. Here we show the crystal structure of a Piwi protein from Archaeoglobus fulgidus (AfPiwi) in complex with a small interfering RNA (siRNA)-like duplex, which mimics the 5' end of a guide RNA strand bound to an overhanging target messenger RNA. The structure contains a highly conserved metal-binding site that anchors the 5' nucleotide of the guide RNA. The first base pair of the duplex is unwound, separating the 5' nucleotide of the guide from the complementary nucleotide on the target strand, which exits with the 3' overhang through a short channel. The remaining base-paired nucleotides assume an A-form helix, accommodated within a channel in the PIWI domain, which can be extended to place the scissile phosphate of the target strand adjacent to the putative slicer catalytic site. This study provides insights into mechanisms of target mRNA recognition and cleavage by an Argonaute-siRNA guide complex.