Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation

FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway

Coupled Multiphase Flow and Closure Analysis of Repository Response to Waste-Generated Gas at the Waste Isolation Pilot Plant (WIPP)

A long-term assessment of the Waste Isolation Pilot Plant (WIPP) repository performance must consider the impact of gas generation resulting from the corrosion and microbial degradation of the emplaced waste. A multiphase fluid flow code, TOUGH2/EOS8, was adapted to model the processes of gas generation, disposal room creep closure, and multiphase (brine and gas) fluid flow, as well as the coupling between the three processes. System response to gas generation was simulated with a single, isolated disposal room surrounded by homogeneous halite containing two anhydrite interbeds, one above and one below the room. The interbeds were assumed to have flow connections to the room through high-permeability, excavation-induced fractures. System behavior was evaluated by tracking four performance measures: (1) peak room pressure; (2) maximum brine volume in the room; (3) total mass of gas expelled from the room; and (4) the maximum gas migration distance in an interbed. Baseline simulations used current best estimates of system parameters, selected through an evaluation of available data, to predict system response to gas generation under best-estimate conditions. Sensitivity simulations quantified the effects of parameter uncertainty by evaluating the change in the performance measures in response to parameter variations. In the sensitivity simulations, a single parameter value was varied to its minimum and maximum values, representative of the extreme expected values, with all other parameters held at best-estimate values. Sensitivity simulations identified the following parameters as important to gas expulsion and migration away from a disposal room: interbed porosity; interbed permeability; gas-generation potential; halite permeability; and interbed threshold pressure. Simulations also showed that the inclusion of interbed fracturing and a disturbed rock zone had a significant impact on system performance

Modeling brine inflow to Room Q: A numerical investigation of flow mechanisms

A hydrologic modeling study was performed to gain insight into the flow mechanisms around Room Q. A summary of hydrologic and structural data and of predictive fluid flow models from Room Q are provided. Six years of measured data are available from the time of excavation. No brine accumulation in Room Q was measured in the first two years following excavation. However, there is considerable uncertainty associated with this early-time data due to inadequate sealing of the room. Brine may have been lost to evaporation or it may have flowed into newly created disturbed rock zone (DRZ) porosity resulting from excavation. Non-zero brine accumulation rates were measured from 2--5 years, but brine accumulation within the room dropped to zero after 5.5 years. A conceptual model for brine inflow to Room Q was developed which assumes far-field Darcy flow combined with an increasing DRZ pore volume. Numerical simulations employed TOUGH28W and used predictive DRZ porosity increase with time from SPECTROM-32 rock deformation simulations. Simulated brine inflow showed good agreement with measured brine accumulation rates for the first five years. Two important conclusions were drawn from the simulation results: (1) early-time brine inflow to the room can be reduced to zero if the DRZ pore volume increases with time, and (2) brine accumulation (inflow) rates from 2 to 5 years suggest a far-field permeability of 5 {times} 10{sup {minus}22} m{sup 2} with a bulk rock compressibility of 5.4 {times} 10{sup {minus}12} Pa{sup {minus}1}

On the generalized Davenport constant and the Noether number

Known results on the generalized Davenport constant related to zero-sum sequences over a finite abelian group are extended to the generalized Noether number related to the rings of polynomial invariants of an arbitrary finite group. An improved general upper bound is given on the degrees of polynomial invariants of a non-cyclic finite group which cut out the zero vector.Comment: 14 page

Using a multiphase flow code to model the coupled effects of repository consolidation and multiphase brine and gas flow at the Waste Isolation Pilot Plant

Long-term repository assessment must consider the processes of (1) gas generation, (2) room closure and expansions due to salt creep, and (3) multiphase (brine and gas) fluid flow, as well as the complex coupling between these three processes. The mechanical creep closure code SANCHO was used to simulate the closure of a single, perfectly sealed disposal room filled with water and backfill. SANCHO uses constitutive models to describe salt creep, waste consolidation, and backfill consolidation, Five different gas-generation rate histories were simulated, differentiated by a rate multiplier, f, which ranged from 0.0 (no gas generation) to 1.0 (expected gas generation under brine-dominated conditions). The results of the SANCHO f-series simulations provide a relationship between gas generation, room closure, and room pressure for a perfectly sealed room. Several methods for coupling this relationship with multiphase fluid flow into and out of a room were examined. Two of the methods are described

Using TOUGH2 to model the coupled effects of gas generation, repository consolidation, and multiphase brine and gas flow at the Waste Isolation Pilot Plant

The Waste Isolation Pilot Plant (WIPP) is a US Department of Energy facility designed to demonstrate the safe underground disposal of transuranic waste. Following waste emplacement, each room will be backfilled with crushed salt. Due to deviatoric stress introduced by excavation, the walls of the waste disposal rooms in the repository will deform over time, consolidating waste containers and salt backfill, thereby decreasing the void volume of the repository. Long-term repository assessment must consider the processes of gas generation, room closure and expansion due to salt creep, and multiphase (brine and gas) fluid flow, as well as the complex coupling between these three processes. Stone (1992) used the mechanical creep closure code SANCHO to simulate the closure of a single, perfectly sealed disposal room filled with waste and backfill. The results of the SANCHO f-series simulations provide a relationship between gas generation, room closure, and room pressure. Several methods for coupling this relationship with multiphase fluid flow into and out of a room were examined by Freeze et al. TOUGH2 was employed to couple the processes of gas generation, room closure/consolidation, and multiphase brine and gas flow. Two empirically-based methods for approximating salt creep and room consolidation were implemented in TOUGH2: the pressure-time-porosity line interpolation approach and the fluid-phase-salt approach. Both approaches utilized links to the SANCHO f-series simulation results to calculate room-void-volume changes with time during a simulation

Summary of applications of TOUGH2 to the evaluation of multiphase flow processes at the WIPP

The Waste Isolation Pilot Plant (WIPP) is a US Department of Energy (DOE) research and development facility for the underground disposal of transuranic waste in southeastern New Mexico. The WIPP repository is located 655 m below the land surface in the lower portion of the Salado Formation, which is comprised of beds of pure and impure halite with thin interbeds of anhydrite and related clay seams. The regional dip of the Salado Formation is approximately 1{degree} southeast in the vicinity of the repository. The proposed waste storage area has eight waste disposal panels, each of which will contain seven rooms. The repository is designed to follow a single stratigraphic horizon. Due to the dip, the north end of the repository will be about 10 meters higher than the south end. Waste that is emplaced in the disposal rooms will generate gas due to microbial degradation, anoxic corrosion, and radiolysis. Brine inflow to the rooms from the surrounding Salado Formation may significantly influence the gas generation rate and the total amount of gas generated. The salt surrounding the repository will creep in response to the excavation, reducing the room volume. Gas generation in the room may increase the pressure sufficiently to drive brine and gas into the surrounding Salado Formation. Migration of gas and brine in the Salado is an important factor in evaluating the performance of the repository. The studies summarized in this paper have. been performed to evaluate brine and gas flow processes in the WIPP disposal system and to identify some of the important processes. These studies are done in support of, but are not part of, the formal Performance Assessment (PA) effort. Because of probabilistic and system-scale requirements, the PA effort uses the Sandia-developed BRAGFLO (BRine And Gas FLOw) code for multiphase flow calculations

The effects of CO2, climate and land-use on terrestrial carbon balance, 1920-1992: An analysis with four process-based ecosystem models

The concurrent effects of increasing atmospheric CO2 concentration, climate variability, and cropland establishment and abandonment on terrestrial carbon storage between 1920 and 1992 were assessed using a standard simulation protocol with four process-based terrestrial biosphere models. Over the long-term(1920–1992), the simulations yielded a time history of terrestrial uptake that is consistent (within the uncertainty) with a long-term analysis based on ice core and atmospheric CO2 data. Up to 1958, three of four analyses indicated a net release of carbon from terrestrial ecosystems to the atmosphere caused by cropland establishment. After 1958, all analyses indicate a net uptake of carbon by terrestrial ecosystems, primarily because of the physiological effects of rapidly rising atmospheric CO2. During the 1980s the simulations indicate that terrestrial ecosystems stored between 0.3 and 1.5 Pg C yr−1, which is within the uncertainty of analysis based on CO2 and O2 budgets. Three of the four models indicated (in accordance with O2 evidence) that the tropics were approximately neutral while a net sink existed in ecosystems north of the tropics. Although all of the models agree that the long-term effect of climate on carbon storage has been small relative to the effects of increasing atmospheric CO2 and land use, the models disagree as to whether climate variability and change in the twentieth century has promoted carbon storage or release. Simulated interannual variability from 1958 generally reproduced the El Niño/Southern Oscillation (ENSO)-scale variability in the atmospheric CO2 increase, but there were substantial differences in the magnitude of interannual variability simulated by the models. The analysis of the ability of the models to simulate the changing amplitude of the seasonal cycle of atmospheric CO2 suggested that the observed trend may be a consequence of CO2 effects, climate variability, land use changes, or a combination of these effects. The next steps for improving the process-based simulation of historical terrestrial carbon include (1) the transfer of insight gained from stand-level process studies to improve the sensitivity of simulated carbon storage responses to changes in CO2 and climate, (2) improvements in the data sets used to drive the models so that they incorporate the timing, extent, and types of major disturbances, (3) the enhancement of the models so that they consider major crop types and management schemes, (4) development of data sets that identify the spatial extent of major crop types and management schemes through time, and (5) the consideration of the effects of anthropogenic nitrogen deposition. The evaluation of the performance of the models in the context of a more complete consideration of the factors influencing historical terrestrial carbon dynamics is important for reducing uncertainties in representing the role of terrestrial ecosystems in future projections of the Earth system

Mosaicism of the UDP-Galactose Transporter SLC35A2 Causes a Congenital Disorder of Glycosylation

Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses