Phenotypic characteristics of early Wolfram syndrome

BACKGROUND: Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions. METHODS: Eighteen subjects (ages 5.9–25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging. RESULTS: Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 ± 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 ± 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume. CONCLUSIONS: WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression

Neuregulin and BDNF Induce a Switch to NMDA Receptor-Dependent Myelination by Oligodendrocytes

<div><p>Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. <i>In vivo</i>, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.</p></div

Natural variation in flavonol accumulation in Arabidopsis is determined by the flavonol glucosyltransferase BGLU6.

Flavonols are colourless secondary metabolites, primarily regarded as UV-protection pigments that are deposited in plants in their glycosylated forms. The glycosylation of flavonols is mainly catalysed by UDP-sugar-dependent glycosyltransferases (UGTs). Although the structures of flavonol glycosides accumulating in Arabidopsis thaliana are known, many genes involved in the flavonol glycosylation pathway are yet to be discovered. The flavonol glycoside profiles of seedlings from 81 naturally occurring A. thaliana accessions were screened using high performance thin layer chromatography. A qualitative variation in flavonol 3-O-gentiobioside 7-O-rhamnoside (F3GG7R) content was identified. Ler × Col-0 recombinant inbred line mapping and whole genome association mapping led to the identification of a glycoside hydrolase family 1-type gene, At1g60270/BGLU6, that encodes a homolog of acyl-glucose-dependent glucosyltransferases involved in the glycosylation of anthocyanins, possibly localized in the cytoplasm, and that is co-expressed with genes linked to phenylpropanoid biosynthesis. A causal single nucleotide polymorphism introducing a premature stop codon in non-producer accessions was found to be absent in the producers. Several other naturally occurring loss-of-function alleles were also identified. Two independent bglu6 T-DNA insertion mutants from the producer accessions showed loss of F3GG7R. Furthermore, bglu6 mutant lines complemented with the genomic Ler BGLU6 gene confirmed that BGLU6 is essential for production of F3GGR7. We have thus identified an accession-specific gene that causes a qualitative difference in flavonol glycoside accumulation in A. thaliana strains. This gene encodes a flavonol 3-O-glucoside: 6″-O-glucosyltransferase that does not belong to the large canonical family of flavonol glycosyltransferases that use UDP-conjugates as the activated sugar donor substrate

Fault Tolerance in Massively Parallel Systems

In massively parallel systems (MPS), fault tolerance is indispensable to obtain proper completion of long-running computation-intensive applications . To achieve this at reasonable low cost, we present a global approach . A flexible and powerful backbone is provided through the combination ofhardware and software error detection techniques, fault diagnosis and operator-site software together with reconfiguration of the system. Application recovery is based on checkpointing and rollback . The red line (i.e. applicability for a massively parallel system) comprises scalability as well as simplicity. A unifying system model is introduced that allows the mapping of a global concept for fault tolerance to a wide variety of MPS. The framework for implementation in an existing MPS is discussed .'This work is partially supported by the EU as ESPRIT project 6731 (ITMPS