As the demand for reliable and safe water supplies increases, both water quality and available quantity are being challenged by population growth and climate change. Greywater reuse is becoming a ...common practice worldwide; however, in remote locations of limited water supply, such as those encountered in military installations, it is desirable to expand its classification to include dishwashing water to maximize the conservation of fresh water. Given that no standards for dishwashing greywater reuse by the military are currently available, the current study determined a specific set of water quality standards for dishwater recycling systems for U.S. military field operations. A tentative water reuse standard for dishwashing water was developed based on federal and state regulations and guidelines for non-potable water, and the developed standard was cross-evaluated by monitoring water quality data from a full-scale dishwashing water recycling system using an innovative electrocoagulation and ultrafiltration process. Quantitative microbial risk assessment (QMRA) was also performed based on exposure scenarios derived from literature data. As a result, a specific set of dishwashing water reuse standards for field analysis (simple, but accurate) was finalized as follows: turbidity (<1NTU), Escherichia coli (<50cfumL−1), and pH (6–9). UV254 was recommended as a surrogate for organic contaminants (e.g., BOD5), but requires further calibration steps for validation. The developed specific water standard is the first for dishwashing water reuse and will be expected to ensure that water quality is safe for field operations, but not so stringent that design complexity, cost, and operational and maintenance requirements will not be feasible for field use. In addition the parameters can be monitored using simple equipment in a field setting with only modest training requirements and real-time or rapid sample turn-around. This standard may prove useful in future development of civilian guidelines.
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•A compact ultrafiltration system was developed for field dishwashing water reuse.•A review was conducted to recommend standards for dishwashing water reuse.•A specific dishwashing water reuse standard was developed for military use.•The water standard was cross-evaluated by monitoring reclaimed dishwashing water.
Decreased sequencing costs have led to an explosion of genetic and genomic data. These data have revealed thousands of candidate human disease variants. Establishing which variants cause phenotypes ...and diseases, however, has remained challenging. Significant progress has been made, including advances by the National Institutes of Health (NIH)-funded Undiagnosed Diseases Network (UDN). However, 6000-13,000 additional disease genes remain to be identified. The continued discovery of rare diseases and their genetic underpinnings provides benefits to affected patients, of whom there are more than 400 million worldwide, and also advances understanding the mechanisms of more common diseases. Platforms employing model organisms enable discovery of novel gene-disease relationships, help establish variant pathogenicity, and often lead to the exploration of underlying mechanisms of pathophysiology that suggest new therapies. The Model Organism Screening Center (MOSC) of the UDN is a unique resource dedicated to utilizing informatics and functional studies in model organisms, including worm (Caenorhabditis elegans), fly (Drosophila melanogaster), and zebrafish (Danio rerio), to aid in diagnosis. The MOSC has directly contributed to the diagnosis of challenging cases, including multiple patients with complex, multi-organ phenotypes. In addition, the MOSC provides a framework for how basic scientists and clinicians can collaborate to drive diagnoses. Customized experimental plans take into account patient presentations, specific genes and variant(s), and appropriateness of each model organism for analysis. The MOSC also generates bioinformatic and experimental tools and reagents for the wider scientific community. Two elements of the MOSC that have been instrumental in its success are (1) multidisciplinary teams with expertise in variant bioinformatics and in human and model organism genetics, and (2) mechanisms for ongoing communication with clinical teams. Here we provide a position statement regarding the central role of model organisms for continued discovery of disease genes, and we advocate for the continuation and expansion of MOSC-type research entities as a Model Organisms Network (MON) to be funded through grant applications submitted to the NIH, family groups focused on specific rare diseases, other philanthropic organizations, industry partnerships, and other sources of support.
Abstract
Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine ...palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive.
Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia. The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila.
Our results showed that two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals. The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila.
These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function.
Srivastava et al. identify monoallelic missense and biallelic frameshift variants in SPTSSA, encoding a subunit of serine palmitoyltransferase (SPT), in three individuals with a new complex hereditary spastic paraplegia. The variants disrupt ORMDL-mediated regulation of SPT resulting in excessive sphingolipid synthesis.
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