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.     

Sequence analysis of peptides with biological activities using electrospray-Fourier trans form ion cyclotron resonance mass spectrometry

The mass spectra of five peptides with biological activities are reported. All mass spectra were recorded using a 4.7-T Fourier transform ion cyclotron resonance mass spectrometer equipped with an external electrospray source. The accurate molecular weights for the five peptides prepared by solid phase synthesis were measured as 1765.9013, 1063.5420, 1092.5254, 820.3804 and 1078.5193, respectively. All the data were obtained with the external calibration. Differences between observed and theoretical monoisotopic molecular weights were in the (0.2—1.0)×10^-6 range. The complete primary sequence for the five polypeptides were determined using the method of in-source electrospray ionization/collision induced dissociation (ESI/CID). All the intact y series ions and b series ions were obtained from various peptides respectively, thus determining the sequences of the five polypeptides. We found that the measured accurate molecular mass of sample 4 was not in agreement with that expected from the planned synthetic peptide. The sequences of sample 4 were determined through analysis. The corresponding accurate masses of b series ions and y series ions were gained, which proved that it was correct to re-determine the sequences.     

Extreme crustal oxygen isotope signatures preserved in coesite in diamond

The anomalously high and low oxygen isotope values observed in eclogite xenoliths from the upper mantle beneath cratons have been interpreted as indicating that the parent rock of the eclogites experienced alteration on the ancient sea floor. Recognition of this genetic lineage has provided the foundation for a model of the evolution of the continents whereby imbricated slabs of oceanic lithosphere underpin and promote stabilization of early cratons. Early crustal growth is thought to have been enhanced by the addition of slab-derived magmas, leaving an eclogite residuum in the upper mantle beneath the cratons. But the oxygen isotope anomalies observed in eclogite xenoliths are small relative to those in altered ocean-floor basalt and intermediate-stage subduction-zone eclogites, and this has hindered acceptance of the hypothesis that the eclogite xenoliths represent subducted and metamorphosed ocean-floor basalts. We present here the oxygen isotope composition of eclogitic mineral inclusions, analysed in situ in diamonds using an ion microprobe/secondary ion mass spectrometer. The oxygen isotope values of coesite (a polymorph of SiO2) inclusions are substantially higher than previously reported for xenoliths from the subcratonic mantle, but are typical of subduction-zone meta-basalts, and accordingly provide strong support for the link between altered ocean-floor basalts and mantle eclogite xenoliths.     

Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain

Modern pain-control theory predicts that a loss of inhibition (disinhibition) in the dorsal horn of the spinal cord is a crucial substrate for chronic pain syndromes. However, the nature of the mechanisms that underlie such disinhibition has remained controversial. Here we present evidence for a novel mechanism of disinhibition following peripheral nerve injury. It involves a trans-synaptic reduction in the expression of the potassium-chloride exporter KCC2, and the consequent disruption of anion homeostasis in neurons of lamina I of the superficial dorsal horn, one of the main spinal nociceptive output pathways. In our experiments, the resulting shift in the transmembrane anion gradient caused normally inhibitory anionic synaptic currents to be excitatory, substantially driving up the net excitability of lamina I neurons. Local blockade or knock-down of the spinal KCC2 exporter in intact rats markedly reduced the nociceptive threshold, confirming that the reported disruption of anion homeostasis in lamina I neurons was sufficient to cause neuropathic pain.     

The evolution of overconfidence

Confidence is an essential ingredient of success in a wide range of domains ranging from job performance and mental health to sports, business and combat. Some authors have suggested that not just confidence but overconfidence--believing you are better than you are in reality--is advantageous because it serves to increase ambition, morale, resolve, persistence or the credibility of bluffing, generating a self-fulfilling prophecy in which exaggerated confidence actually increases the probability of success. However, overconfidence also leads to faulty assessments, unrealistic expectations and hazardous decisions, so it remains a puzzle how such a false belief could evolve or remain stable in a population of competing strategies that include accurate, unbiased beliefs. Here we present an evolutionary model showing that, counterintuitively, overconfidence maximizes individual fitness and populations tend to become overconfident, as long as benefits from contested resources are sufficiently large compared with the cost of competition. In contrast, unbiased strategies are only stable under limited conditions. The fact that overconfident populations are evolutionarily stable in a wide range of environments may help to explain why overconfidence remains prevalent today, even if it contributes to hubris, market bubbles, financial collapses, policy failures, disasters and costly wars.     

Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum

Erythrocyte invasion by Plasmodium falciparum is central to the pathogenesis of malaria. Invasion requires a series of extracellular recognition events between erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. None of the few known receptor-ligand interactions involved are required in all parasite strains, indicating that the parasite is able to access multiple redundant invasion pathways. Here, we show that we have identified a receptor-ligand pair that is essential for erythrocyte invasion in all tested P. falciparum strains. By systematically screening a library of erythrocyte proteins, we have found that the Ok blood group antigen, basigin, is a receptor for PfRh5, a parasite ligand that is essential for blood stage growth. Erythrocyte invasion was potently inhibited by soluble basigin or by basigin knockdown, and invasion could be completely blocked using low concentrations of anti-basigin antibodies; importantly, these effects were observed across all laboratory-adapted and field strains tested. Furthermore, Ok(a-) erythrocytes, which express a basigin variant that has a weaker binding affinity for PfRh5, had reduced invasion efficiencies. Our discovery of a cross-strain dependency on a single extracellular receptor-ligand pair for erythrocyte invasion by P. falciparum provides a focus for new anti-malarial therapies.