Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic

Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, δ, κ and μ (δ-OR, κ-OR and μ-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes (～60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors κ (ref. 5) and μ (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.     

Domain structure and function of matrix metalloprotease 23 (MMP23): role in potassium channel trafficking

MMP23 is a member of the matrix metalloprotease family of zinc- and calcium-dependent endopeptidases, which are involved in a wide variety of cellular functions. Its catalytic domain displays a high degree of structural homology with those of other metalloproteases, but its atypical domain architecture suggests that it may possess unique functional properties. The N-terminal MMP23 pro-domain contains a type-II transmembrane domain that anchors the protein to the plasma membrane and lacks the cysteine-switch motif that is required to maintain other MMPs in a latent state during passage to the cell surface. Instead of the C-terminal hemopexin domain common to other MMPs, MMP23 contains a small toxin-like domain (TxD) and an immunoglobulin-like cell adhesion molecule (IgCAM) domain. The MMP23 pro-domain can trap Kv1.3 but not closely-related Kv1.2 channels in the endoplasmic reticulum, preventing their passage to the cell surface, while the TxD can bind to the channel pore and block the passage of potassium ions. The MMP23 C-terminal IgCAM domain displays some similarity to Ig-like C2-type domains found in IgCAMs of the immunoglobulin superfamily, which are known to mediate protein–protein and protein–lipid interactions. MMP23 and Kv1.3 are co-expressed in a variety of tissues and together are implicated in diseases including cancer and inflammatory disorders. Further studies are required to elucidate the mechanism of action of this unique member of the MMP family.     

The Impact of Bela H. Banathy's Research on an Educational Scholar-Practitioner

This remembrance is a narrative of how Bela H. Banathy's work involving the idealized design approach to educational change mediated and informed the author's attempt to understand the complexity of educational change. In addition, commentary is provided about the influence on the author's students of Banathy's ideas regarding systems thinking, design culture, design conversation, conscious evolution, and evolutionary guidance systems.     

Glycoprotein misfolding in the endoplasmic reticulum: identification of released oligosaccharides reveals a second ER-associated degradation pathway for Golgi-retrieved proteins

Endoplasmic reticulum-associated degradation (ERAD) is a key cellular process whereby misfolded proteins are removed from the endoplasmic reticulum (ER) for subsequent degradation by the ubiquitin/proteasome system. In the present work, analysis of the released, free oligosaccharides (FOS) derived from all glycoproteins undergoing ERAD, has allowed a global estimation of the mechanisms of this pathway rather than following model proteins through degradative routes. Examining the FOS produced in endomannosidase-compromised cells following α-glucosidase inhibition has revealed a mechanism for clearing Golgi-retrieved glycoproteins that have failed to enter the ER quality control cycle. The Glc₃Man₇GlcNAc₂ FOS species has been shown to be produced in the ER lumen by a mechanism involving a peptide: N-glycanase-like activity, and its production was sensitive to disruption of Golgi-ER trafficking. The detection of this oligosaccharide was unaffected by the overexpression of EDEM1 or cytosolic mannosidase, both of which increased the production of previously characterised cytosolically localised FOS. The lumenal FOS identified are therefore distinct in their production and regulation compared to FOS produced by the conventional route of misfolded glycoproteins directly removed from the ER. The production of such lumenal FOS is indicative of a novel degradative route for cellular glycoproteins that may exist under certain conditions.     

Impacts of black-tailed prarie dog rodenticides on nontarget passerines

In 1983 zinc phosphide, strychnine with prebait, and strychnine without prebait were applied to black-tailed prairie dog ( Cynomys ludovicianus ) colonies in west central South Dakota. Short-term (four days later) and long-term (one year later) impacts of the rodenticides on Horned Larks ( Eremophila alpestris ) and other granivorous birds inhabiting prairie dog colonies were evaluated. Hrned Larks and 49 other bird species were observed. Immediate impacts reduced Horned Lark relative densities 66% with strychnine only and 55% with prebaited strychnine. Zinc phosphide caused no measurable reduction. Horned Larks showed no long-term direct impacts. Indirect negative impacts occurred through habitat changes following prairie dog control. The granivorous guild showed no short- or long-term effects.     

Dry-year grazing and Nebraska sedge ( Carex nebraskensis )

In 1984 (a dry year), Tule Meadow, in the Sierra National Forest, California, was well grazed after several years of light use. This situation provided the opportunity to study responses of Nebraska sedge ( Carex nebraskensis ), an important forage species in mountain meadows, to protection and grazing. Rooted shoot frequencies and densities in fall 1984 and spring 1985 were the same within an exclosure and on the grazed area. Residual herbage (shoot weight) in fall and shoot heights in spring were greater within the exclosure. Lower spring shoot heights on the grazed area may relate to fall regrowth and reduced insulation induced by grazing. Nitrogen and potassium content of fall herbage was greater on the grazed area. Phosphorus content was the same both inside and outside the exclosure.     

PDGF signaling specificity is mediated through multiple immediate early genes

Growth factor signaling leads to the induction or repression of immediate early genes, but how these genes act collectively as effectors of downstream processes remains unresolved. We have used gene trap-coupled microarray analysis to identify and mutate multiple platelet-derived growth factor (PDGF) intermediate early genes in mice. Mutations in these genes lead to a high frequency of phenotypes that affect the same cell types and processes as those controlled by the PDGF pathway. We conclude that these genes form a network that controls specific processes downstream of PDGF signaling.     

Profit Guided or Statistical Error Guided? A Study of Stock Index Forecasting Using Support Vector Regression

Stock index forecasting has been one of the most widely investigated topics in the field of financial forecasting. Related studies typically advocate for tuning the parameters of forecasting models by minimizing learning errors measured using statistical metrics such as the mean squared error or mean absolute percentage error. The authors argue that statistical metrics used to guide parameter tuning of forecasting models may not be meaningful, given the fact that the ultimate goal of forecasting is to facilitate investment decisions with expected profits in the future. The authors therefore introduce the Sharpe ratio into the process of model building and take it as the profit metric to guide parameter tuning rather than using the commonly adopted statistical metrics. The authors consider three widely used trading strategies, which include a na¨?ve strategy, a filter strategy and a dual moving average strategy, as investment scenarios. To verify the effectiveness of the proposed profit guided approach, the authors carry out simulation experiments using three global mainstream stock market indices. The results show that profit guided forecasting models are competitive, and in many cases produce significantly better performances than statistical error guided models. This implies thatprofit guided stock index forecasting is a worthwhile alternative over traditional stock index forecasting practices.