Developmental hypomyelination in Wolfram syndrome: New insights from neuroimaging and gene expression analyses

Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging studies showed marked alteration in early brain development, primarily characterized by abnormal white matter myelination. Interestingly, ER stress and the UPR pathway are implicated in the pathogenesis of some inherited myelin disorders like Pelizaeus-Merzbacher disease, and Vanishing White Matter disease. In addition, exploratory gene-expression network-based analyses suggest that WFS1 expression occurs preferentially in oligodendrocytes during early brain development. Therefore, we propose that Wolfram syndrome could belong to a category of neurodevelopmental disorders characterized by ER stress-mediated myelination impairment. Further studies of myelination and oligodendrocyte function in Wolfram syndrome could provide new insights into the underlying mechanisms of the Wolfram syndrome-associated brain changes and identify potential connections between neurodevelopmental disorders and neurodegeneration

Water-Moderated and -Reflected Slabs of Uranium Oxyfluoride

A series of ten experiments were conducted at the Oak Ridge National Laboratory Critical Experiment Facility in December 1955, and January 1956, in an attempt to determine critical conditions for a slab of aqueous uranium oxyfluoride (UO2F2). These experiments were recorded in an Oak Ridge Critical Experiments Logbook and results were published in a journal of the American Nuclear Society, Nuclear Science and Engineering, by J. K. Fox, L. W. Gilley, and J. H. Marable (Reference 1). The purpose of these experiments was to obtain the minimum critical thickness of an effectively infinite slab of UO2F2 solution by extrapolation of experimental data. To do this the slab thickness was varied and critical solution and water-reflector heights were measured using two different fuel solutions. Of the ten conducted experiments eight of the experiments reached critical conditions but the results of only six of the experiments were published in Reference 1. All ten experiments were evaluated from which five critical configurations were judged as acceptable criticality safety benchmarks. The total uncertainty in the acceptable benchmarks is between 0.25 and 0.33 % ?k/keff. UO2F2 fuel is also evaluated in HEU-SOL-THERM-043, HEU-SOL-THERM-011, and HEU-SOL-THERM-012, but these those evaluation reports are for large reflected and unreflected spheres. Aluminum cylinders of UO2F2 are evaluated in HEU-SOL-THERM-050

Benchmarking of Graphite Reflected Critical Assemblies of UO2

A series of experiments were carried out in 1963 at the Oak Ridge National Laboratory Critical Experiments Facility (ORCEF) for use in space reactor research programs. A core containing 93.2% enriched UO2 fuel rods was used in these experiments. The first part of the experimental series consisted of 253 tightly-packed fuel rods (1.27 cm triangular pitch) with graphite reflectors [1], the second part used 253 graphite-reflected fuel rods organized in a 1.506 cm triangular pitch [2], and the final part of the experimental series consisted of 253 beryllium-reflected fuel rods with a 1.506 cm triangular pitch. [3] Fission rate distribution and cadmium ratio measurements were taken for all three parts of the experimental series. Reactivity coefficient measurements were taken for various materials placed in the beryllium reflected core. The first part of this experimental series has been evaluated for inclusion in the International Reactor Physics Experiment Evaluation Project (IRPhEP) [4] and the International Criticality Safety Benchmark Evaluation Project (ICSBEP) Handbooks, [5] and is discussed below. These experiments are of interest as benchmarks because they support the validation of compact reactor designs with similar characteristics to the design parameters for a space nuclear fission surface power systems. [6

Benchmark Evaluation of the NRAD Reactor LEU Core Startup Measurements

The Neutron Radiography (NRAD) reactor is a 250-kW TRIGA-(Training, Research, Isotope Production, General Atomics)-conversion-type reactor at the Idaho National Laboratory; it is primarily used for neutron radiography analysis of irradiated and unirradiated fuels and materials. The NRAD reactor was converted from HEU to LEU fuel with 60 fuel elements and brought critical on March 31, 2010. This configuration of the NRAD reactor has been evaluated as an acceptable benchmark experiment and is available in the 2011 editions of the International Handbook of Evaluated Criticality Safety Benchmark Experiments (ICSBEP Handbook) and the International Handbook of Evaluated Reactor Physics Benchmark Experiments (IRPhEP Handbook). Significant effort went into precisely characterizing all aspects of the reactor core dimensions and material properties; detailed analyses of reactor parameters minimized experimental uncertainties. The largest contributors to the total benchmark uncertainty were the 234U, 236U, Er, and Hf content in the fuel; the manganese content in the stainless steel cladding; and the unknown level of water saturation in the graphite reflector blocks. A simplified benchmark model of the NRAD reactor was prepared with a keff of 1.0012 {+-} 0.0029 (1s). Monte Carlo calculations with MCNP5 and KENO-VI and various neutron cross section libraries were performed and compared with the benchmark eigenvalue for the 60-fuel-element core configuration; all calculated eigenvalues are between 0.3 and 0.8% greater than the benchmark value. Benchmark evaluations of the NRAD reactor are beneficial in understanding biases and uncertainties affecting criticality safety analyses of storage, handling, or transportation applications with LEU-Er-Zr-H fuel

Early presentation of gait impairment in Wolfram Syndrome

BACKGROUND: Classically characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities, Wolfram syndrome (WFS) is also associated with atypical brainstem and cerebellar findings in the first decade of life. As such, we hypothesized that gait differences between individuals with WFS and typically developing (TD) individuals may be detectable across the course of the disease. METHODS: Gait was assessed for 13 individuals with WFS (min 6.4 yrs, max 25.8 yrs) and 29 age-matched, typically developing individuals (min 5.6 yrs, max 28.5 yrs) using a GAITRite ® walkway system. Velocity, cadence, step length, base of support and double support time were compared between groups. RESULTS: Across all tasks, individuals with WFS walked slower (p = 0.03), took shorter (p ≤ 0.001) and wider (p ≤ 0.001) steps and spent a greater proportion of the gait cycle in double support (p = 0.03) compared to TD individuals. Cadence did not differ between groups (p = 0.62). Across all tasks, age was significantly correlated with cadence and double support time in the TD group but only double support time was correlated with age in the WFS group and only during preferred pace forward (r(s)= 0.564, p = 0.045) and dual task forward walking (r(s)= 0.720, p = 0.006) tasks. Individuals with WFS also had a greater number of missteps during tandem walking (p ≤ 0.001). Within the WFS group, spatiotemporal measures of gait did not correlate with measures of visual acuity. Balance measures negatively correlated with normalized gait velocity during fast forward walking (rs = −0.59, p = 0.03) and percent of gait cycle in double support during backward walking (rs = −0.64, p = 0.03). CONCLUSIONS: Quantifiable gait impairments can be detected in individuals with WFS earlier than previous clinical observations suggested. These impairments are not fully accounted for by the visual or balance deficits associated with WFS, and may be a reflection of early cerebellar and/or brainstem abnormalities. Effective patient-centered treatment paradigms could benefit from a more complete understanding of the progression of motor and other neurological symptom presentation in individuals with WFS

Water-Moderated and -Reflected Slabs of Uranium Oxyfluoride

A series of ten experiments were conducted at the Oak Ridge National Laboratory Critical Experiment Facility in December 1955, and January 1956, in an attempt to determine critical conditions for a slab of aqueous uranium oxyfluoride (UO2F2). These experiments were recorded in an Oak Ridge Critical Experiments Logbook and results were published in a journal of the American Nuclear Society, Nuclear Science and Engineering, by J. K. Fox, L. W. Gilley, and J. H. Marable (Reference 1). The purpose of these experiments was to obtain the minimum critical thickness of an effectively infinite slab of UO2F2 solution by extrapolation of experimental data. To do this the slab thickness was varied and critical solution and water-reflector heights were measured using two different fuel solutions. Of the ten conducted experiments eight of the experiments reached critical conditions but the results of only six of the experiments were published in Reference 1. All ten experiments were evaluated from which five critical configurations were judged as acceptable criticality safety benchmarks. The total uncertainty in the acceptable benchmarks is between 0.25 and 0.33 % ?k/keff. UO2F2 fuel is also evaluated in HEU-SOL-THERM-043, HEU-SOL-THERM-011, and HEU-SOL-THERM-012, but these those evaluation reports are for large reflected and unreflected spheres. Aluminum cylinders of UO2F2 are evaluated in HEU-SOL-THERM-050

Fresh-Core Reload of the Neutron Radiography (NRAD) Reactor with Uranium(20)-Erbium-Zirconium-Hydride Fuel

The neutron radiography (NRAD) reactor is a 250 kW TRIGA® (Training, Research, Isotopes, General Atomics) Mark II , tank-type research reactor currently located in the basement, below the main hot cell, of the Hot Fuel Examination Facility (HFEF) at the Idaho National Laboratory (INL). It is equipped with two beam tubes with separate radiography stations for the performance of neutron radiography irradiation on small test components. The 60-fuel-element operational core configuration of the NRAD LEU TRIGA reactor has been evaluated as an acceptable benchmark experiment. The initial critical configuration developed during the fuel loading process, which contains only 56 fuel elements, has not been evaluated as it is very similar to the evaluated core configuration. The benchmark eigenvalue is 1.0012 ± 0.0029. Calculated eigenvalues differ significantly (~±1%) from the benchmark eigenvalue and have demonstrated sensitivity to the thermal scattering treatment of hydrogen in the U-Er-Zr-H fuel

Reliability and validity of the Wolfram Unified Rating Scale (WURS)

BACKGROUND: Wolfram syndrome (WFS) is a rare, neurodegenerative disease that typically presents with childhood onset insulin dependent diabetes mellitus, followed by optic atrophy, diabetes insipidus, deafness, and neurological and psychiatric dysfunction. There is no cure for the disease, but recent advances in research have improved understanding of the disease course. Measuring disease severity and progression with reliable and validated tools is a prerequisite for clinical trials of any new intervention for neurodegenerative conditions. To this end, we developed the Wolfram Unified Rating Scale (WURS) to measure the severity and individual variability of WFS symptoms. The aim of this study is to develop and test the reliability and validity of the Wolfram Unified Rating Scale (WURS). METHODS: A rating scale of disease severity in WFS was developed by modifying a standardized assessment for another neurodegenerative condition (Batten disease). WFS experts scored the representativeness of WURS items for the disease. The WURS was administered to 13 individuals with WFS (6-25 years of age). Motor, balance, mood and quality of life were also evaluated with standard instruments. Inter-rater reliability, internal consistency reliability, concurrent, predictive and content validity of the WURS were calculated. RESULTS: The WURS had high inter-rater reliability (ICCs>.93), moderate to high internal consistency reliability (Cronbach’s α = 0.78-0.91) and demonstrated good concurrent and predictive validity. There were significant correlations between the WURS Physical Assessment and motor and balance tests (r(s)>.67, p<.03), between the WURS Behavioral Scale and reports of mood and behavior (r(s)>.76, p<.04) and between WURS Total scores and quality of life (r(s)=-.86, p=.001). The WURS demonstrated acceptable content validity (Scale-Content Validity Index=0.83). CONCLUSIONS: These preliminary findings demonstrate that the WURS has acceptable reliability and validity and captures individual differences in disease severity in children and young adults with WFS

Sharing and Connecting Our Stories through “Archival Drama”

This session presents a collaborative sociology-library-theatre project that uses devised performance as a tool for qualitative research into individuals’ experiences with family immigrant stories. The team created two original dramatic pieces from archival materials, and used audience reactions to explore deeply-held feelings linked to personal objects. The project uses Johnny Saldaña’s work on ethnodrama to articulate “archival drama”, a bridge between arts, humanities, and social sciences