Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity

Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.     

Bayesian consensus forecasts of macroeconomic variables

Economists, like other forecasters, share knowledge, data and theories in common. Consequently, their forecast errors are likely to be highly dependent. This paper reports on an empirical study of 16 macroeconomic forecasters. Composite forecasts are computed using a sequential weighting scheme that takes dependence into account; these are compared to a simple average and median forecasts. A within-sample composite is also calculated. Both these methods perform significantly better than the average or median of the forecasts. This improvement in accuracy is apparently because the dependence between the forecasters' errors is so high that the optimal composite forecasts sometimes lie outside the range of the individual forecasts.     

Geographic patterns of ground-dwelling arthropods across an ecoregional transition in the North American Southwest

We examined the biogeographic patterns of ground-dwelling arthropod communities across a heterogeneous semiarid region of the Southern Rio Grande Rift Valley of New Mexico. Our 3 sites included portions of 5 ecoregions, with the middle site a transition area where all ecoregions converged. We addressed the following 3 questions: (1) Do the species assemblage patterns for ground arthropods across habitats and sites conform to recognized ecoregions? (2) Are arthropod assemblages in distinct vegetation-defined habitats within an ecoregion more similar to each other or to assemblages in similar vegetation-defined habitats in other ecoregions? (3) Is there a detectable edge effect with increased arthropod diversity in the area of converging ecoregions? We encountered 442 target arthropod species from pitfall traps operating continuously for 7 years over a series of different habitats at each of the 3 sites. We examined geographic distributions of spider and cricket/grasshopper species in detail, and they showed affinities for different ecoregions, respectively. Each habitat within a study site supported a unique overall arthropod assemblage; nevertheless, different habitats at the same site were more similar to each other than they were to similar habitats at other sites. Overall arthropod species richness was greatest in the area where all 5 ecoregions converged. Arthropod species and their geographic distributions are poorly known relative to vascular plants and vertebrate animals. Findings from this research indicate that ecoregional classification is a useful tool for understanding biogeographic patterns among arthropods.     

How successful are dynamic factor models at forecasting output and inflation? A meta‐analytic approach

This paper uses a meta‐analysis to survey existing factor forecast applications for output and inflation and assesses what causes large factor models to perform better or more poorly at forecasting than other models. Our results suggest that factor models tend to outperform small models, whereas factor forecasts are slightly worse than pooled forecasts. Factor models deliver better predictions for US variables than for UK variables, for US output than for euro‐area output and for euro‐area inflation than for US inflation. The size of the dataset from which factors are extracted positively affects the relative factor forecast performance, whereas pre‐selecting the variables included in the dataset did not improve factor forecasts in the past. Finally, the factor estimation technique may matter as well. Copyright © 2008 John Wiley & Sons, Ltd.     

The structural basis for membrane binding and pore formation by lymphocyte perforin

Natural killer cells and cytotoxic T lymphocytes accomplish the critically important function of killing virus-infected and neoplastic cells. They do this by releasing the pore-forming protein perforin and granzyme proteases from cytoplasmic granules into the cleft formed between the abutting killer and target cell membranes. Perforin, a 67-kilodalton multidomain protein, oligomerizes to form pores that deliver the pro-apoptopic granzymes into the cytosol of the target cell. The importance of perforin is highlighted by the fatal consequences of congenital perforin deficiency, with more than 50 different perforin mutations linked to familial haemophagocytic lymphohistiocytosis (type 2 FHL). Here we elucidate the mechanism of perforin pore formation by determining the X-ray crystal structure of monomeric murine perforin, together with a cryo-electron microscopy reconstruction of the entire perforin pore. Perforin is a thin 'key-shaped' molecule, comprising an amino-terminal membrane attack complex perforin-like (MACPF)/cholesterol dependent cytolysin (CDC) domain followed by an epidermal growth factor (EGF) domain that, together with the extreme carboxy-terminal sequence, forms a central shelf-like structure. A C-terminal C2 domain mediates initial, Ca(2+)-dependent membrane binding. Most unexpectedly, however, electron microscopy reveals that the orientation of the perforin MACPF domain in the pore is inside-out relative to the subunit arrangement in CDCs. These data reveal remarkable flexibility in the mechanism of action of the conserved MACPF/CDC fold and provide new insights into how related immune defence molecules such as complement proteins assemble into pores.     

The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia

Seven Fanconi anemia-associated proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) form a nuclear Fanconi anemia core complex that activates the monoubiquitination of FANCD2, targeting FANCD2 to BRCA1-containing nuclear foci. Cells from individuals with Fanconi anemia of complementation groups D1 and J (FA-D1 and FA-J) have normal FANCD2 ubiquitination. Using genetic mapping, mutation identification and western-blot data, we identify the defective protein in FA-J cells as BRIP1 (also called BACH1), a DNA helicase that is a binding partner of the breast cancer tumor suppressor BRCA1.     

Business Process Re-engineering in Practice—An Example of A Medium-Sized Slovenian Company in Difficulties

Among the contemporary and globally adopted management methods, Business Process Re-engineering (BPR) is the most influential one. Although it was developed in American social and economic environment, it has been widely practiced also in Europe. Experience has demonstrated though that uncritical application of the original American BPR substance to European entrepreneurial practice is as a rule inefficient, often even incompatible with the basic social values. The globally adopted BPR method of company re-engineering is aimed at an increase in competitiveness and must be specified expertly and in view of its substance or adapted to numerous social and economic factors, i.e., requisitely holistically. This article deals with the application of the BPR method in the case of a medium-sized Slovenian company in difficulties. It illustrates the criteria for the selection of a management method of an innovative business change management that is the most efficacious in the Slovenian economy. The BPR project realization is defined from the viewpoint of the given implementation projects and criteria, enabling continual evaluation of the attained results of company reorganization. It presents a good case of informal systemic, i.e., requisitely holistic thinking and action.