Biology subjects

Friedman, E.

Publications and source records attributed to Friedman, E..

5 recordsLinked to original sources

bioRxiv2026

Liver Fatty Acid Binding Protein (FABP1) Affects Cytochrome P450 2C9 (CYP2C9)-Mediated Metabolism in Human Liver Models

Metabolic clearance of drugs is often systematically over- or underpredicted from human liver microsomes (HLM). We hypothesized that lack of consideration of interactions of cytosolic liver fatty acid binding protein (FABP1) with drugs and cytochrome P450s (CYPs) explains the off-prediction. We used two CYP2C9 probe substrates, diclofenac and tolbutamide, to test this hypothesis. We found that presence of FABP1 alters the kinetics of metabolite formation in HLM. The model that best fit the kinetic data included FABP1-CYP2C9 protein-protein interactions. Statistical modeling of proteomic expression and drug hydroxylation across a panel of 61 human liver S9 fractions (HLS9) showed that CYP2C9 and FABP1 expression together best predicted probe substrate hydroxylation. Incorporation of FABP1 expression and protein-protein interactions into novel physiologically based liver models significantly improved the quantitative accuracy of in vivo hepatic clearance prediction. Together, our data demonstrate the importance of taking FABP1 into consideration for CYP2C9-mediated metabolism.

pharmacology and toxicology↗

bioRxiv2025

In vivo human embryonic spinal cord atlas validates stem cell-derived human dorsal interneurons and reveals ASD spinal signatures

Restoring somatosensory function after spinal cord injury (SCI) faces fundamental challenges: neuronal subtypes must match both axial position and circuit identity, yet the developmental patterning of human dorsal spinal interneurons (dIs) remains incompletely defined. Here, we integrate six single-cell transcriptomics datasets derived from human embryonic spinal cord tissue spanning gestational weeks 4-25 to generate a reference atlas of early human somatosensory circuit development. The atlas reveals molecular signatures underlying expansion and specialization of dI4 and dI5 interneuron populations associated with mechanosensory and nociceptive processing. Guided by this resource, we established a neuromesodermal progenitor-based differentiation approach that generates dorsal interneurons spanning anterior-posterior identities. Comparison of in vivo and in vitro dI4/dI5 subclasses identified conserved gene networks associated with sensory modalities and revealed enrichment of autism spectrum disorder-associated genes within mechanosensory interneuron populations. Together, these findings clarify how human dorsal spinal interneuron diversity is established.

neuroscience↗

bioRxiv2022

Optical Genome and Epigenome Mapping of Clear Cell Renal Cell Carcinoma

Cancer cells display complex genomic aberrations that include large-scale genetic rearrangements and epigenetic modulation that are not easily characterized by short-read sequencing. We present a method for simultaneous profiling of long-range genetic/epigenetic changes in matched cancer samples. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. Most ccRCC cases demonstrate somatic genomic alterations involving the short arm of chromosome 3 (3p), most often targeting the von Hippel-Lindau (VHL) gene. Aiming to identify somatic alterations that characterize early stage ccRCC, we performed comprehensive genetic, cytogenetic and epigenetic analyses comparing ccRCC tumor to adjacent non-tumorous tissue. Optical genome mapping identified genomic aberrations such as structural and copy number variations, complementing exome-sequencing results. Single-molecule methylome and hydroxymethylome mapping revealed multiple differential regions, some of them known to be associated with ccRCC pathogenesis. Among them, metabolic pathways were significantly enriched. Moreover, significant global epigenetic differences were detected between the tumor and the adjacent non-tumorous tissue, and a correlation between epigenetic signals and gene expression was found. This is the first reported comparison of a human tumor and a matched tissue by optical genome/epigenome mapping, revealing well-established and novel somatic aberrations.

genomics↗

bioRxiv2022

Variable Number Tandem Repeats (VNTRs) as modifiers of breast cancer risk in carriers of BRCA1 185delAG

Despite substantial efforts in identifying both rare and common variants affecting disease risk, in the majority of diseases, a large proportion of unexplained genetic risk remains. We propose that variable number tandem repeats (VNTRs) may explain a proportion of the missing genetic risk. Herein, we tested whether VNTRs are causal modifiers of breast cancer risk in 347 female carriers of BRCA1 185delAG, an important group given their high risk of developing breast cancer. We performed targeted-capture to sequence VNTRs, called genotypes with adVNTR, and tested the association of VNTRs and breast cancer risk using Cox regression models. Of 303 VNTRs that passed quality control checks, 4 VNTRs were significantly associated with risk to develop breast cancer at false discovery rate [FDR] < 0.05 and an additional 4 VNTRs had FDR < 0.25. After determining the specific risk alleles, there was a significantly earlier age at development of breast cancer in carriers of the risk genotypes compared to those without the risk genotypes for seven of eight VNTRs. Results from this first systematic study of VNTRs demonstrate that VNTRs may explain a proportion of the unexplained genetic risk for disease and have larger effects than SNPs.

cancer biology↗

bioRxiv2020

Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Expression of Abnormal Involuntary Movements

L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinsons Disease. The mechanistic underpinnings of LID remain obscure. Here we report that diminshed sonic hedgehog (Shh) signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons (DANs) facilitates the formation and expression of LID. We demonstrate that augmenting Shh signaling with agonists of the Shh effector Smoothened attenuates LID in mouse and macaque models of PD. Employing conditional genetic loss-of-function approaches, we show that reducing Shh secretion from DANs or Smo activity in cholinergic interneurons (CINs) promotes LID. Conversely, the selective expression of constitutively active Smo (SmoM2) in CINs is sufficient to render the sensitized aphakia model of PD resistant to LID. Furthermore, acute depletion of Shh from DANs through prolonged optogenetic stimulation in otherwise intact mice and in the absence of L-Dopa produces LID-like involuntary movements. These findings indicate that augmenting Shh signaling in the L-Dopa treated brain may be a promising and unexpected novel therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-Dopa

neuroscience↗