Biology subjects

Sands, M.

Publications and source records attributed to Sands, M..

7 recordsLinked to original sources

bioRxiv2024

Haploinsufficiency of lysosomal enzyme genes in Alzheimers disease

There is growing evidence suggesting that the lysosome or lysosome dysfunction is associated with Alzheimers disease (AD). Pathway analysis of post mortem brain-derived proteomic data from AD patients shows that the lysosomal system is perturbed relative to similarly aged unaffected controls. However, it is unclear if these changes contributed to the pathogenesis or are a response to the disease. Consistent with the hypothesis that lysosome dysfunction contributes to AD pathogenesis, whole genome sequencing data indicate that heterozygous pathogenic mutations and predicted protein-damaging variants in multiple lysosomal enzyme genes are enriched in AD patients compared to matched controls. Heterozygous loss-of-function mutations in the palmitoyl protein thioesterase-1 (PPT1), -L-iduronidase (IDUA), {beta}-glucuronidase (GUSB), N-acetylglucosaminidase (NAGLU), and galactocerebrosidase (GALC) genes have a gene-dosage effect on A{beta}40 levels in brain interstitial fluid in C57BL/6 mice and significantly increase A{beta} plaque formation in the 5xFAD mouse model of AD, thus providing in vivo validation of the human genetic data. A more detailed analysis of PPT1 heterozygosity in 18-month-old mice revealed changes in -, {beta}-, and {gamma}-secretases that favor an amyloidogenic pathway. Proteomic changes in brain tissue from aged PPT1 heterozygous sheep are consistent with both the mouse data and the potential activation of AD pathways. Finally, CNS-directed, AAV-mediated gene therapy significantly decreased A{beta} plaques, increased life span, and improved behavioral performance in 5xFAD/PPT1+/- mice. Collectively, these data strongly suggest that heterozygosity of multiple lysosomal enzyme genes represent risk factors for AD and may identify precise therapeutic targets for a subset of genetically-defined AD patients. Significance StatementLysosomes play a role in the degradation of aggregation-prone proteins such as amyloid {beta} (A{beta}). Homozygous lysosomal enzyme gene defects result in fatal pediatric lysosomal storage diseases and, historically, carriers were considered normal. However, a human genetic analysis identified deleterious heterozygous variants in multiple lysosomal enzyme genes that are enriched in Alzheimers disease (AD) patients. Those findings were validated in vivo by demonstrating that heterozygous loss-of-function (LoF) mutations in five different lysosomal enzyme genes affect A{beta} processing and exacerbate A{beta} plaque formation. CNS-directed gene therapy ameliorated the effects of a heterozygous LoF mutation in one of those genes in a mouse model of AD. These findings provide insights into the role of lysosomes in AD and have important therapeutic implications.

neuroscience↗

bioRxiv2024

The role of phosphorylation and dephosphorylation in the regulation of Rubisco activase

Rubisco activase is an ATP-dependent chaperone that facilitates dissociation of inhibitory sugar phosphates from the catalytic sites of ribulose-1,5-bisphosphate carboxylase/oxygenase during photosynthesis. In Arabidopsis, Rubisco activase is negatively regulated by dark-dependent phosphorylation of threonine 78. The prevalence of threonine 78 in Rubisco activase was investigated across sequences from 91 plant species, finding 29 ([~]32%) species shared a threonine in the same position. Analysis of seven C3 species with an antibody raised against a threonine 78 phospho-peptide demonstrated that this position is phosphorylated in multiple genera. However, light-dependent dephosphorylation of threonine 78 was observed only in Arabidopsis. Further, phosphorylation of threonine 78 could not be detected in any of the four C4 grass species examined. The results suggest that despite conservation of threonine 78 in Rubisco activase from a wide range of species, a regulatory role for phosphorylation at this site is more limited. This provides a case study for how variation in post-translational regulation can amplify functional divergence across the phylogeny of plants beyond what is explained by sequence variation in a metabolically important protein.

plant biology↗

bioRxiv2024

MicroRNAs and PFAS: A Pilot Study in Blood Collected from Firefighters

Per- and polyfluoroalkyl substances (PFAS) are chemicals with widespread industrial and consumer applications, and firefighters are known to be at risk of elevated PFAS exposure due to their occupational activities. This study aims to assess PFAS exposure and explore potential mechanistic insights through miRNA sequencing of plasma exosomes, in relation to PFAS levels in the general population. The study included 34 firefighter participants. PFAS levels in plasma were analyzed, and miRNA sequencing of plasma exosomes was conducted. The findings were compared with the general population data from the National Health and Nutrition Examination Survey (NHANES). While total PFAS levels did not significantly differ between firefighters and the general population in the cohort considered, variations in individual PFAS compounds were observed. MiRNA sequencing revealed substantial heterogeneity in miRNA expression patterns. Associations between serum PFAS levels and biochemical indicators suggested potential health implications, although further mechanistic insights need to be explored.

pharmacology and toxicology↗

bioRxiv2024

Kidney toxicology of a novel compound Lithium Bis(trifluoromethanesulfonyl)imide (LiTFSI, ie. HQ-115) used in energy applications: an Epigenetic evaluation

Exposure to emerging energy-based environmental contaminants such as lithium bis(trifluoromethanesulfonyl)imide (LiTFSI), more commonly known as HQ-115, poses a significant threat to human health, yet its impact on kidney function and epigenetic regulation remains poorly understood. Here, we investigated the effects of LiTFSI exposure on kidney-related biochemical parameters, renal injuries, and epigenetic alterations in male CD-1 mice under both 14-day and 30-day exposure durations. Our study revealed that LiTFSI exposure led to changes in kidney-related biochemical indicators, notably affecting serum bicarbonate levels, while relative kidney weight remained unaffected. Histological analysis unveiled tubule dilation, inflammation, and loss of kidney structure in LiTFSI-exposed mice, alongside dysregulated expression of genes associated with inflammation, renal function, and uric acid metabolism. Epigenetic analysis further identified widespread DNA methylation changes in the two exposure regimes. Functional analysis revealed that differentially methylated regions are implicated in cell apoptosis and cancer-related pathways and are enriched with development-related transcription factor binding motifs, suggesting a potential mechanism of action that can lead to kidney injury. These findings underscore the intricate interplay between environmental exposures, epigenetic modulation, and kidney health, emphasizing the need for additional research to unravel precise mechanisms that can help in the development of targeted interventions to mitigate the adverse effects of LiTFSI exposure on human health. SYNOPSISLiTFSI (HQ-115), an emerging environmental contaminant, impacts kidney health in male CD-1 mice by altering biochemical indicators, to result in renal injuries, and inducing epigenetic changes, highlighting environmental health concerns.

pharmacology and toxicology↗

bioRxiv2023

PFAS assessment in fish: samples from Illinois waters

Per- and Polyfluoroalkyl substances (PFAS) have been widely used in various industries, including pesticide production, electroplating, packaging, paper making, and the manufacturing of water-resistant clothes. This study investigates the levels of PFAS in fish tissues collected from four target waterways (15 sampling points) in the northwestern part of Illinois during 2021-2022. To assess accumulation, concentrations of 17 PFAS compounds were evaluated in nine fish species to potentially inform on exposure risks to local sport fishing population via fish consumption. At least four PFAS (PFHxA, PFHxS, PFOS, and PFBS) were detected at each sampling site. The highest concentrations of PFAS were consistently found in samples from the Rock River, particularly in areas near urban and industrial activities. PFHxA emerged as the most accumulated PFAS in the year 2022, while PFBS and PFOS dominated in 2021. Channel Catfish exhibited the highest PFAS content across different fish species, indicating its bioaccumulation potential across the food chain. Elevated levels of PFOS were observed in nearly all fish, indicating the need for careful consideration of fish consumption. Additional bioaccumulation data in the future years is needed to shed light on the sources and PFAS accumulation potential in aquatic wildlife in relation to exposures for potential health risk assessment.

pharmacology and toxicology↗

bioRxiv2023

In vitro toxicity of LiTFSI on Human Renal and Hepatoma Cells

We evaluate the cytotoxicity, intracellular redox conditions, apoptosis, and methylation of DNMTs/TETs upon exposure to LiTFSI, a novel PFAS compound commonly found in lithium-ion batteries, on human renal carcinoma cells (A498) and hepatoma cells (HepG2). The MTT assay showed both PFOS and LiTFSI had a dose-dependent effect on A498 and HepG2, with LiTFSI being less toxic. Intracellular redox conditions were assessed with a microplate reader and confocal, which showed a significant decrease in ROS levels and an increase in SOD content in both cells. Exposure to LiTFSI enhanced cell apoptosis, with HepG2 being more susceptible than A498. Quantitative analysis of mRNA expression levels of 19 genes associated with kidney injury, methylation, lipid metabolism and transportation was performed. LiTFSI exposure impacted kidney function by downregulating Acta2 and upregulating Tgfb1, Bcl2l1, Harvcr1, Nfe2l2, and Hes1 expression. LiTFSI exposure also affected the abundance of transcripts associated with DNA methylation by the expression of TET and DNMT genes. Furthermore, LiTFSI exposure induced an increase in lipid anabolism and alterations in lipid catabolism in HepG2. Our results provide new insight on the potential role of a new contaminant, LiTFSI in the regulation of oxidative stress, apoptosis and methylation in human renal carcinoma and hepatoma cells.

pharmacology and toxicology↗

bioRxiv2016

HOMINID: A framework for identifying associations between host genetic variation and microbiome composition

Recent studies have uncovered a strong effect of host genetic variation on the composition of host-associated microbiota. Here, we present HOMINID, a computational approach based on Lasso linear regression, that given host genetic variation and microbiome composition data, identifies host SNPs that are correlated with microbial taxa abundances. Using simulated data we show that HOMINID has accuracy in identifying associated SNPs, and performs better compared to existing methods. We also show that HOMINID can accurately identify the microbial taxa that are correlated with associated SNPs. Lastly, by using HOMINID on real data of human genetic variation and microbiome composition, we identified 13 human SNPs in which genetic variation is correlated with microbiome taxonomic composition across body sites. In conclusion, HOMINID is a powerful method to detect host genetic variants linked to microbiome composition, and can facilitate discovery of mechanisms controlling host-microbiome interactions.\n\nAvailability and implementationSoftware, code, tutorial, installation and setup details, and synthetic data are available in the project homepage: https://github.com/blekhmanlab/hominid.\n\nReal dataset used here is from Blekhman et al. (Blekhman et al. 2015); 16S rRNA gene sequence data and OTU tables are available on the HMP DACC website (www.hmpdacc.org), and host genetic data are deposited in dbGaP under project number phs000228.

genomics↗