Probing the Production of Amidated Peptides following Genetic and Dietary Copper Manipulations

Amidated neuropeptides play essential roles throughout the nervous and endocrine systems. Mice lacking peptidylglycine α-amidating monooxygenase (PAM), the only enzyme capable of producing amidated peptides, are not viable. In the amidation reaction, the reactant (glycine-extended peptide) is converted into a reaction intermediate (hydroxyglycine-extended peptide) by the copper-dependent peptidylglycine-α-hydroxylating monooxygenase (PHM) domain of PAM. The hydroxyglycine-extended peptide is then converted into amidated product by the peptidyl-α-hydroxyglycine α-amidating lyase (PAL) domain of PAM. PHM and PAL are stitched together in vertebrates, but separated in some invertebrates such as Drosophila and Hydra. In addition to its luminal catalytic domains, PAM includes a cytosolic domain that can enter the nucleus following release from the membrane by γ-secretase. In this work, several glycine- and hydroxyglycine-extended peptides as well as amidated peptides were qualitatively and quantitatively assessed from pituitaries of wild-type mice and mice with a single copy of the Pam gene (PAM+/−) via liquid chromatography-mass spectrometry-based methods. We provide the first evidence for the presence of a peptidyl-α-hydroxyglycine in vivo, indicating that the reaction intermediate becomes free and is not handed directly from PHM to PAL in vertebrates. Wild-type mice fed a copper deficient diet and PAM+/− mice exhibit similar behavioral deficits. While glycine-extended reaction intermediates accumulated in the PAM+/− mice and reflected dietary copper availability, amidated products were far more prevalent under the conditions examined, suggesting that the behavioral deficits observed do not simply reflect a lack of amidated peptides

The effect of polytechnic reform on migration

This paper examines the effect of the polytechnic reform on geographical mobility. A polytechnic, higher education reform took place in Finland in the 1990s. It gradually transformed former vocational colleges into polytechnics and also brought higher education to regions that did not have a university before. This expansion of higher education provides exogenous variation in the regional supply of higher education. The reform raised the mobility of high school graduates across local labour markets in the years after they had completed their secondary studies, which indicated increased mobility between high school and post-secondary education. We estimate that the reform enhanced the annual migration rate of high school graduates by 1.2 percentage points over a three-year follow-up period. This represents a substantial increase, because their baseline migration rate is 3.7 per cent. The effect fades several years after the completion of secondary studies.peerReviewe

Schizopsychotic symptom-profiles and biomarkers: Beacons in diagnostic labyrinths

Several avenues of investigation through which the \u27labyrinths\u27 of schizopsychotic diagnosis may be examined, are offered by the consideration of the \u27beacons\u27 of symptom-profiles and biomarkers. Neurodevelopmental issues and risk assessment, neurocognitive factors of predictive necessity, supersensitivity in neurotransmitter systems, the implications of prodromal expressions of the disorder, functional dysconnectivity arising from prefrontal to diverse regional patterns and circuits with a neurodevelopmental origin, and heritable gene characteristics are viewed against the backdrop of the schizophrenia spectrum disorders. The associations between adolescent-adult use of cannabis, on the one hand, and, alternatively, the prevalence of chromosomal abnormalities, e.g., GRIK4 and NPAS3, and mental retardation, on the other hand, with the symptom-profiles of schizopsychosis provide further evidence of emerging biomarkers of biological inheritance factors. The involvement of dopamine D1 and D2 receptors, particularly in prefrontal region, with regard to functional integrity of cognitive systems is reviewed. It would appear that considerations of these disorders imply that one essential hub around which much of the neuropathology revolves may be observed in the various expressions of the cognitive and structural insufficiency

Alkane Functionalization via Electrophilic Activation

Electrophilic activation, which may be defined as the substitution of a transition metal center for a proton to generate a new metal–carbon bond, is the basis of a number of promising approaches to selective catalytic functionalization of alkanes. The field was introduced by the groundbreaking chemistry exhibited by aqueous chloroplatinum complexes, reported by Shilov in the early 1970s. Since then the field has expanded greatly, and electrophilic alkane activation has been demonstrated using a wide variety of species. These include ligand-supported platinum complexes; complexes of additional late transition metals, most commonly palladium but also iridium, gold and others; and even post-transition metals such as mercury. That body of work is surveyed here, with particular emphasis on mechanistic understanding, examples of actual functionalization at sp^3-hybridized C–H bonds in alkanes and related compounds, and assessment of the further development that will be needed for practical applications