Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness

Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking.     

Do Experts’ SKU Forecasts Improve after Feedback?

We analyze the behavior of experts who quote forecasts for monthly SKU‐level sales data, where we compare data before and after the moment that experts received different kinds of feedback on their behavior. We have data for 21 experts located in as many countries who make SKU‐level forecasts for a variety of pharmaceutical products for October 2006 to September 2007. We study the behavior of the experts by comparing their forecasts with those from an automated statistical program, and we report the forecast accuracy over these 12 months. In September 2007 these experts were given feedback on their behavior and they received training at the headquarters office, where specific attention was given to the ins and outs of the statistical program. Next, we study the behavior of the experts for the 3 months after the training session, i.e. October 2007 to December 2007. Our main conclusion is that in the second period the experts’ forecasts deviated less from the statistical forecasts and that their accuracy improved substantially. Copyright © 2013 John Wiley & Sons, Ltd.     

Mutations in the pre-replication complex cause Meier-Gorlin syndrome

Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears1?3. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.     

Lung cancer susceptibility locus at 5p15.33

We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.     

Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin

Gerodermia osteodysplastica is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that gerodermia osteodysplastica is caused by loss-of-function mutations in SCYL1BP1, which is highly expressed in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues.     

Multi-step forecast error variances for periodically integrated time series

A periodically integrated (PI) time series process assumes that the stochastic trend can be removed using a seasonally varying differencing filter. In this paper the multi-step forecast error variances are derived for a quarterly PI time series when low-order periodic autoregressions adequately describe the data. The forecast error variances display seasonal variation, indicating that observations in some seasons can be forecast more precise than those in others. Two examples illustrate the empirical relevance of calculating forecast error variances. A by-product of the analysis is an expression for the seasonally varying impact of the stochastic trend.     

Amplitudes, rates, periodicities and causes of temperature variations in the past 2485 years and future trends over the central-eastern Tibetan Plateau

Amplitudes, rates, periodicities, causes and future trends of temperature variations based on tree rings for the past 2485 years on the central-eastern Tibetan Plateau were analyzed. The results showed that extreme climatic events on the Plateau, such as the Medieval Warm Period, Little Ice Age and 20th Century Warming appeared synchronously with those in other places worldwide. The largest amplitude and rate of temperature change occurred during the Eastern Jin Event (343?C425 AD), and not in the late 20th century. There were significant cycles of 1324 a, 800 a, 199 a, 110 a and 2?C3 a in the 2485-year temperature series. The 1324 a, 800 a, 199 a and 110 a cycles are associated with solar activity, which greatly affects the Earth surface temperature. The long-term trends (>1000 a) of temperature were controlled by the millennium-scale cycle, and amplitudes were dominated by multi-century cycles. Moreover, cold intervals corresponded to sunspot minimums. The prediction indicated that the temperature will decrease in the future until to 2068 AD and then increase again.     

On SETAR non‐linearity and forecasting

We compare linear autoregressive (AR) models and self‐exciting threshold autoregressive (SETAR) models in terms of their point forecast performance, and their ability to characterize the uncertainty surrounding those forecasts, i.e. interval or density forecasts. A two‐regime SETAR process is used as the data‐generating process in an extensive set of Monte Carlo simulations, and we consider the discriminatory power of recently developed methods of forecast evaluation for different degrees of non‐linearity. We find that the interval and density evaluation methods are unlikely to show the linear model to be deficient on samples of the size typical for macroeconomic data. Copyright © 2003 John Wiley & Sons, Ltd.     

Hypoxanthin,ein Zusatzwachstumsfaktor für Mucorineen

Summary In case ofAbsidia coerulea, Mucor mucedo, Rhizopus nodosus, Rhizopus oryzae andRhizopus suinus (auxoautotroph), Hypoxanthine effects, as well as in case ofPhycomyces Blakesleeanus (auxo-heterotroph), by acceleration of the germinating of the spores a temporary increased growth in contrary to controls without this additional growth factor.     

Über die Ursache des gegensätzlichen geotropischen Verhaltens von Sproß und Wurzel

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