Biology subjects

William, N.

Publications and source records attributed to William, N..

3 recordsLinked to original sources

bioRxiv2026

Enhancing Supercooled Red Blood Cell Storage: The Membrane-Stabilizing Effect of Ethanol

Hypothermic storage is constrained by the progressive depletion of energy reserves, curtailing the shelf-life of organs, cell therapies, and blood products. High sub-zero supercooling helps preserve energy homeostasis by slowing catabolic processes; however, the resulting injury in this setting is not primarily driven by energy depletion. Here, we investigated whether low-dose ethanol could prevent forms of injury that arise independently of disrupted energy homeostasis and remain unaddressed in supercooled storage. Human red blood cells treated with 4% (v/v) ethanol were stored 4 {degrees}C, -4 {degrees}C, or -8 {degrees}C and subject to a series of functional assessments and integrated metabolomic/lipidomic profiling after 21 and 42 days of storage. Metabolomics data showed that energy homeostasis was better preserved at lower temperatures, yet these supercooled conditions simultaneously intensified hemolysis and caused a marked depletion of lysophospholipid species that did not occur at 4 {degrees}C. Ethanol blunted these effects, cutting hemolysis by [~]50 % at -4 {degrees}C, by [~]85 % at -8 {degrees}C, and attenuating lysophospholipid depletion. These results uncover a previously unrecognized, lipid-centric injury that arises during supercooled storage and establish low-dose ethanol as a simple, readily deployable countermeasure that could help extend storage intervals of diverse biological systems. SUMMARYCellular preservation has traditionally focused on maintaining energy metabolism during hypothermic storage, but whether this is sufficient at high sub-zero temperatures remains unclear. Human red blood cells were stored for up to 42 days at 4{degrees}C, -4{degrees}C, or -8{degrees}C with or without 4% ethanol and evaluated using functional assays and integrated metabolomic and lipidomic profiling. Although supercooling preserved energy homeostasis, it increased hemolysis and caused pronounced lysophospholipid depletion. Ethanol reduced hemolysis by approximately 50% at -4{degrees}C and 85% at -8{degrees}C, attenuated lysophospholipid loss, and produced comparatively modest changes in cellular metabolism. These findings identify membrane integrity as a critical determinant of preservation outcome and support strategies that protect membrane stability alongside metabolic homeostasis.

cell biology↗

bioRxiv2020

Rare protein coding variants implicate genes involved in risk of suicide death

Suicide death is a worldwide health crisis, claiming close to 800,000 lives per year. Recent evidence suggests that prediction and prevention challenges may be aided by discoveries of genetic risk factors. Here we focus on the role of rare (MAF <1%), putatively functional single nucleotide polymorphisms (SNPs) in suicide death using the large genetic resources available in the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of 30,377 rare putatively functional SNPs present on the PsychArray genotyping array in 2,672 USGRS suicides of non-Finnish European (NFE) ancestry and 51,583 publicly available NFE controls from gnomAD, with additional follow-up analyses using an independent control sample of 21,324 NFE controls from the Psychiatric Genomics Consortium. SNPs underwent rigorous quality control, and among SNPs meeting significance thresholds, we considered only those that were validated in sequence data. We identified five novel, high-impact, rare SNPs with significant associations with suicide death (SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and an association with bipolar disorder has been reported for PER1 and with schizophrenia for PER1, TNKS1BP1, and ESS2. Three genes (PER1, TNKS1BP1, and ADGRF5), with additional genes implicated by GWAS studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. Pain, depression, and accidental trauma were the most prevalent phenotypes in electronic medical record data for the categories assessed. These findings suggest an important role for rare variants in suicide risk and provide new insights into the genetic architecture of suicide death. Furthermore, we demonstrate the added utility of careful assessment of genotyping arrays in rare variant discovery.

genetics↗

bioRxiv2017

Identification of genome-wide significant shared genomic segments in large extended Utah families at high risk for completed suicide

Suicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests genetic factors play a significant role in completed suicide. We linked a resource of >4,500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over 8 million individuals. This linking has resulted in the identification of high-risk extended families (7-9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p=2.02E-07 to 1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk. While PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact in ~1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory. However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.

genetics↗