No abstract

N-methyl-D-aspartate receptors (NMDARs) mediate slow excitatory postsynaptic transmission in the central nervous system, thereby exerting a critical role in neuronal development and brain function. Rare genetic variants in the GRIN genes encoding NMDAR subunits segregated with neurological disorders. Here, we summarize the clinical presentations for 18 patients harboring 12 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M2 re-entrant loop, a region that lines the pore and is intolerant to missense variation. These de novo variants were identified in children with a set of neurological and neuropsychiatric conditions. Evaluation of the receptor cell surface expression, pharmacological properties, and biophysical characteristics show that these variants can have modest changes in agonist potency, proton inhibition, and surface expression. However, voltage-dependent magnesium inhibition is significantly reduced in all variants. The NMDARs hosting a single copy of a mutant subunit showed a dominant reduction in magnesium inhibition for some variants. These variant NMDARs also show reduced calcium permeability and single-channel conductance, as well as altered open probability. The data suggest that M2 missense variants increase NMDAR charge

ABSTRACTThis study explores microbial community structure in managed aquifer recharge (MAR) systems across both laboratory and field scales. Two field sites, the Taif River (Taif, Saudi Arabia) and South Platte River (Colorado), were selected as geographically distinct MAR systems. Samples derived from unsaturated riverbed, saturated-shallow-infiltration (depth, 1 to 2 cm), and intermediate-infiltration (depth, 10 to 50 cm) zones were collected. Complementary laboratory-scale sediment columns representing low (0.6 mg/liter) and moderate (5 mg/liter) dissolved organic carbon (DOC) concentrations were used to further query the influence of DOC and depth on microbial assemblages. Microbial density was positively correlated with the DOC concentration, while diversity was negatively correlated at both the laboratory and field scales. Microbial communities derived from analogous sampling zones in each river were not phylogenetically significantly different on phylum, class, genus, and species levels, as determined by 16S rRNA gene pyrosequencing, suggesting that geography and season exerted less sway than aqueous geochemical properties. When field-scale communities derived from the Taif and South Platte River sediments were grouped together, principal coordinate analysis revealed distinct clusters with regard to the three sample zones (unsaturated, shallow, and intermediate saturated) and, further, with respect to DOC concentration. An analogous trend as a function of depth and corresponding DOC loss was observed in column studies. Canonical correspondence analysis suggests that microbial classesBetaproteobacteriaandGammaproteobacteriaare positively correlated with DOC concentration. Our combined analyses at both the laboratory and field scales suggest that DOC may exert a strong influence on microbial community composition and diversity in MAR saturated zones.

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.

While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney p < .001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney p < .0001). We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH.

No abstract

Fresh water resources within the Kingdom of Saudi Arabia are a rare and precious commodity that must be managed within a context of integrated water management. Wadi aquifers contain a high percentage of the naturally occurring fresh groundwater in the Kingdom. This resource is currently overused and has become depleted or contaminated at many locations. One resource that could be used to restore or enhance the fresh water resources within wadi aquifers is treated municipal waste water (reclaimed water). Each year about 80 percent of the country's treated municipal waste water is discharged to waste without any beneficial use. These discharges not only represent a lost water resource, but also create a number of adverse environmental impacts, such as damage to sensitive nearshore marine environments and creation of high-salinity interior surface water areas. An investigation of the hydrogeology of wadi aquifers in Saudi Arabia revealed that these aquifers can be used to develop aquifer recharge and recovery (ARR) systems that will be able to treat the impaired-quality water, store it until needed, and allow recovery of the water for transmittal to areas in demand. Full-engineered ARR systems can be designed at high capacities within wadi aquifer systems that can operate in concert with the natural role of wadis, while providing the required functions of additional treatment, storage and recovery of reclaimed water, while reducing the need to develop additional, energy-intensive desalination to meet new water supply demands.

Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region of GFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect the levels of GFAP in brain parenchyma, we have assayed GFAP levels in two body fluids in humans that are readily accessible as biopsy sites: CSF and blood. We find that GFAP levels are consistently elevated in the CSF of patients with Alexander disease, but only occasionally and modestly elevated in blood. These results provide the foundation for future studies that will explore whether GFAP levels can serve as a convenient means to monitor the progression of disease and the response to treatment.