Biology subjects

Moaddel, R.

Publications and source records attributed to Moaddel, R..

6 recordsLinked to original sources

bioRxiv2025

SomaModules: a pathway enrichment approach tailored to SomaScan data

Motivated by the lack of adequate tools to perform pathway enrichment analysis, this work presents an approach specifically tailored to SomaScan data. Starting from annotated gene sets, we developed a greedy, top-down procedure to iteratively identify strongly intra-correlated SOMAmer modules, termed "SomaModules", based on 11K SomaScan data. We generated two repositories based on the latest MSigDB and MitoCarta releases, containing more than 40,000 SOMAmer-based gene sets combined. These repositories can be utilized by any unstructured pathway enrichment analysis tool. We validated our results with two case examples: (i) Alzheimers Disease specific pathways in a 7K SomaScan case-control study, and (ii) mitochondrial pathways using 11K SomaScan data linked to physical performance outcomes. Using Gene Set Enrichment Analysis (GSEA), we found that, in both examples, SomaModules had significantly higher enrichment than the original gene set counterparts. These findings were robust and not significantly affected by the choice of enrichment metric or the Kolmogorov enrichment statistic used in the GSEA procedure. We provide users with access to all code, documentation and data needed to reproduce our current repositories, which also will enable them to leverage our framework to analyze SomaModules derived from other sources, including custom, user-generated gene sets.

bioinformatics↗

bioRxiv2024

Effects of in vitro hemolysis and repeated freeze-thaw cycles in protein abundance quantification using the SomaScan and Olink assays

SomaScan and Olink are affinity-based platforms that aim to estimate the relative abundance of thousands of human proteins with a broad range of endogenous concentrations. In this study, we investigated the effects of in vitro hemolysis and repeated freeze-thaw cycles in protein abundance quantification across 10,776 (11K SomaScan) and 1472 (Olink Explore 1536) analytes, respectively. Using SomaScan, we found two distinct groups, each one consisting of 4% of all aptamers, affected by either hemolysis or freeze-thaw cycles. Using Olink, we found 6% of analytes affected by freeze-thaw cycles and nearly half of all measured probes significantly impacted by hemolysis. Moreover, we observed that Olink probes affected by hemolysis target proteins with a larger number of annotated protein-protein interactions. We found that Olink probes affected by hemolysis were significantly associated with the erythrocyte proteome, whereas SomaScan probes were not. Given the extent of the observed nuisance effects, we propose that unbiased, quantitative methods of evaluating hemolysis, such as the hemolysis index successfully implemented in many clinical laboratories, should be adopted in proteomics studies. We provide detailed results for each SomaScan and Olink probe in the form of extensive Supplementary Data files to be used as resources for the growing user communities of both platforms.

molecular biology↗

bioRxiv2024

Variability of 7K and 11K SomaScan plasma proteomics assays

SomaScan is an aptamer-based proteomics assay designed for the simultaneous measurement of thousands of human proteins with a broad range of endogenous concentrations. The 7K SomaScan assay has been recently expanded into the new 11K version. Following up on our previous assessment of the 7K assay, here we expand our work on technical replicates from donors enrolled in the Baltimore Longitudinal Study of Aging. By generating SomaScan data from a second batch of technical replicates in the 7K version, as well as additional intra- and inter-plate replicate measurements in the new 11K version using the same donor samples, this work provides useful precision benchmarks for the SomaScan user community. Beyond updating our previous technical assessment of the 7K assay with increased statistics, here we estimate inter-batch variability, we assess inter- and intra-plate variability in the new 11K assay, we compare the observed variability between the 7K and 11K assays (leveraging the use of overlapping pairs of technical replicates), and explore the potential effects of sample storage time (ranging from 2 to 30 years) in the assays precision.

systems biology↗

bioRxiv2024

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions.

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamines metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i.p.) 1 hour prior to ketamine or HNKs (10 mg/kg, i.p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 hours post-injection (t24h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration selectively rescued the antidepressant-like activity of ketamine in mice pretreated with fluconazole within 24 hours of treatment. Overall, these findings are consistent with an essential role of (6)-HNK in mediating the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.

neuroscience↗

bioRxiv2021

Unbiased Proteomics, Histochemistry, and Mitochondrial DNA Copy Number Reveal Better Mitochondrial Health in Muscle of High Functioning Octogenarians

BackgroundMaster athletes prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function remain unclear. MethodsWe performed muscle biopsies in 15 octogenarian world class track and field masters athletes (MA) and 14 non-athlete age/sex-matched controls (NA) to provide insights into mechanisms for preserving function in advanced age. Muscle samples were assessed for respiratory compromised fibers, mtDNA copy number, and proteomics by liquid-chromatography mass spectrometry. ResultsMost of the [~]800 differentially represented proteins in MA versus NA pertained to mitochondria structure/function such as electron transport capacity (ETC), cristae formation, mitochondrial biogenesis, and mtDNA-encoded proteins. In contrast, proteins from the spliceosome complex and nuclear pore were downregulated in MA. Consistent with proteomics data, MA had fewer respiratory compromised fibers, higher mtDNA copy number, and an increased protein ratio of the cristae-bound ETC subunits relative to the outer mitochondrial membrane protein voltage dependent anion channel. There was a substantial overlap of proteins overrepresented in MA versus NA with proteins that decline with aging and which are higher in physically active than sedentary individuals. However, we also found 176 proteins related to mitochondria that are uniquely differentially expressed in MA. DiscussionWe conclude that high function in advanced age is associated with preserving mitochondrial structure/function proteins, with under-representation of proteins involved in the spliceosome and nuclear pore complex. Whereas many of these differences in MA appear related to their physical activity habits, others may reflect unique biological (e.g., gene, environment) mechanisms that preserve muscle integrity and function with aging.

physiology↗

bioRxiv2018

Chemogenetic ligands for translational neurotheranostics

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for precision medicine-based clinical theranostics. DREADD ligands developed to date are not appropriate for such translational applications. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine. The second-generation DREADD agonist, Compound 21 (C21), was developed to overcome these limitations. We found that C21 has low brain penetrance, weak affinity, and low in vivo DREADD occupancy. To address these drawbacks, we developed two new DREADD agonists, JHU37152 and JHU37160, and the first dedicated positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons and at their long-range projections, enabling for the first time, noninvasive and longitudinal neuronal projection mapping and potential for neurotheranostic applications.

neuroscience↗