Neuroimaging the consciousness of self: Review, and conceptual-methodological framework

We review neuroimaging research investigating self-referential processing (SRP), that is, how we respond to stimuli that reference ourselves, prefaced by a lexical-thematic analysis of words indicative of “self-feelings”. We consider SRP as occurring verbally (V-SRP) and non-verbally (NV-SRP), both in the controlled, “top-down” form of introspective and interoceptive tasks, respectively, as well as in the “bottom-up” spontaneous or automatic form of “mind wandering” and “body wandering” that occurs during resting state. Our review leads us to outline a conceptual and methodological framework for future SRP research that we briefly apply toward understanding certain psychological and neurological disorders symptomatically associated with abnormal SRP. Our discussion is partly guided by William James’ original writings on the consciousness of self

Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy

Iron regulatory proteins (IRPs) are iron-regulated RNA binding proteins that, along with iron-responsive elements (IREs), control the translation of a diverse set of mRNA with 5′ IRE. Dysregulation of IRP action causes disease with etiology that may reflect differential control of IRE-containing mRNA. IREs are defined by a conserved stem–loop structure including a midstem bulge at C8 and a terminal CAGUGH sequence that forms an AGU pseudo-triloop and N19 bulge. C8 and the pseudo-triloop nucleotides make the majority of the 22 identified bonds with IRP1. We show that IRP1 binds 5′ IREs in a hierarchy extending over a ninefold range of affinities that encompasses changes in IRE binding affinity observed with human L-ferritin IRE mutants. The limits of this IRE binding hierarchy are predicted to arise due to small differences in binding energy (e.g., equivalent to one H-bond). We demonstrate that multiple regions of the IRE stem not predicted to contact IRP1 help establish the binding hierarchy with the sequence and structure of the C8 region displaying a major role. In contrast, base-pairing and stacking in the upper stem region proximal to the terminal loop had a minor role. Unexpectedly, an N20 bulge compensated for the lack of an N19 bulge, suggesting the existence of novel IREs. Taken together, we suggest that a regulatory binding hierarchy is established through the impact of the IRE stem on the strength, not the number, of bonds between C8 or pseudo-triloop nucleotides and IRP1 or through their impact on an induced fit mechanism of binding

Effects of Bovine Somatotropin and Revalor-S® on Growth Performance and Carcass Leanness in Beef Cattle

Twenty crossbred steers were used to evaluate bovine somatotropin (bST) and an anabolic steroid implant, Revalor-S® (REV), to improve growth and increase carcass leanness. During the first 70 days on feed, bST-treated steers tended to improve live weight gains, consume more feed, and numerically improve feed utilization for growth. The implanted steers grew faster and utilized feed better than steers not implanted with REV. The improvement in gain and feed utilization for growth was maintained throughout the feeding period for REV-implanted steers. At slaughter, REV steers had heavier carcasses which resulted in more pounds of muscle, bone, and fat. When adjusted for hot carcass weight, bST increased leanness of the carcass as evident by the increased weight of the semitendinosus muscle, more pounds of dissected lean, and fewer pounds of dissected fat. Thus, REV and bST can be used to improve growth performance and increase carcass leanness.</p

Effects of Bovine Somatotropin and Revalor-S® on Growth Performance and Carcass Leanness in Beef Cattle

Twenty crossbred steers were used to evaluate bovine somatotropin (bST) and an anabolic steroid implant, Revalor-S® (REV), to improve growth and increase carcass leanness. During the first 70 days on feed, bST-treated steers tended to improve live weight gains, consume more feed, and numerically improve feed utilization for growth. The implanted steers grew faster and utilized feed better than steers not implanted with REV. The improvement in gain and feed utilization for growth was maintained throughout the feeding period for REV-implanted steers. At slaughter, REV steers had heavier carcasses which resulted in more pounds of muscle, bone, and fat. When adjusted for hot carcass weight, bST increased leanness of the carcass as evident by the increased weight of the semitendinosus muscle, more pounds of dissected lean, and fewer pounds of dissected fat. Thus, REV and bST can be used to improve growth performance and increase carcass leanness

Selective Inhibition of Collagen Prolyl 4‑Hydroxylase in Human Cells

Collagen is the most abundant protein in animals. Its overproduction is associated with fibrosis and cancer metastasis. The stability of collagen relies on post-translational modifications, the most prevalent being the hydroxylation of collagen strands by collagen prolyl 4-hydroxylases (CP4Hs). Catalysis by CP4Hs enlists an iron cofactor to convert proline residues to 4-hydroxyproline residues, which are essential for the conformational stability of mature collagen. Ethyl 3,4-dihydroxybenzoate (EDHB) is commonly used as a “P4H” inhibitor in cells, but suffers from low potency, poor selectivity, and off-target effects that cause iron deficiency. Dicarboxylates of 2,2′-bipyridine are among the most potent known CP4H inhibitors but suffer from a high affinity for free iron. A screen of biheteroaryl compounds revealed that replacing one pyridyl group with a thiazole moiety retains potency and enhances selectivity. A diester of 2-(5-carboxythiazol-2-yl)­pyridine-5-carboxylic acid is bioavailable to human cells and inhibits collagen biosynthesis at concentrations that neither cause general toxicity nor disrupt iron homeostasis. These data anoint a potent and selective probe for CP4H and a potential lead for the development of a new class of antifibrotic and antimetastatic agents

Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein

Recent studies demonstrate a pivotal role for bone morphogenic protein-6 (BMP6) and matriptase-2, a protein encoded by the TMPRSS6 gene, in the induction and suppression of hepatic hepcidin expression, respectively. We examined their expression profiles in the liver and showed a predominant localization of BMP6 mRNA in nonparenchymal cells and exclusive expression of TMPRSS6 mRNA in hepatocytes. In rats fed an iron-deficient (ID) diet for 24 hours, the rapid decrease of transferrin saturation from 71% to 24% (control vs ID diet) was associated with a 100-fold decrease in hepcidin mRNA compared with the corresponding controls. These results indicated a close correlation of low transferrin saturation with decreased hepcidin mRNA. The lower phosphorylated Smad1/5/8 detected in the ID rat livers suggests that the suppressed hepcidin expression results from the inhibition of BMP signaling. Quantitative real-time reverse transcription polymerase chain reaction analysis revealed no significant change in either BMP6 or TMPRSS6 mRNA in the liver. However, an increase in matriptase-2 protein in the liver from ID rats was detected, suggesting that suppression of hepcidin expression in response to acute iron deprivation is mediated by an increase in matriptase-2 protein levels