Biology subjects

Segal, J. P.

Publications and source records attributed to Segal, J. P..

4 recordsLinked to original sources

bioRxiv2026

Disease progression shapes circadian and locomotor disruption in a model of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system featuring a wide range of debilitating symptoms. Wearable activity recording devices have recently been adopted to improve symptom monitoring in MS, capturing symptoms related to sleep/wake cycles, circadian disruption, and fatigue. However, comparable measures of activity have yet been established in pre-clinical models of MS, the most widely used being experimental autoimmune encephalomyelitis (EAE). We therefore sought to characterize changes in continual home-cage activity over the course of EAE, and establish whether home-cage monitoring can be used as an observer-independent measure of disease progression. Our results showed that locomotor activity in the mid-active/dark phase was most severely affected by EAE. Disrupted circadian (24-hour) activity was observed during the peak and onset stages of disease. Bout activity analysis revealed >40-minute long activity bouts as a sensitive indicator of non-motor symptoms independent of clinical score-based motor deficits. Current assessment of disease progression in EAE relies on clinical scores, which primarily assess motor deficits through visual observation prone to observer bias. Various computed activity parameters were found to be altered during key disease stages, suggesting that a combination of activity measures can serve as objective indicators of disease progression. Overall, our results show that home-cage activity effectively captures signs of non-motor symptoms in the EAE model of MS and can serve as an observer-independent measure of EAE disease progression.

animal behavior and cognition↗

bioRxiv2021

Clonal hematopoiesis in individuals with ANKRD26 or ETV6 germline mutations

Currently, there are at least a dozen recognized hereditary hematopoietic malignancies (HHMs), some of which phenocopy others. Among these, three HHMs driven by germline mutations in ANKRD26, ETV6, or RUNX1 share a phenotype of thrombocytopenia, qualitative platelet defects, and an increased lifetime risk of hematopoietic malignancies (HMs). Prior work has demonstrated that RUNX1 germline mutation carriers experience an elevated lifetime risk (66%) for developing clonal hematopoiesis (CH) prior to age 50. Germline mutations in ANKRD26 or ETV6 phenocopy RUNX1 germline mutations, but no studies have focused on the risk of CH in individuals with germline mutations in ANKRD26 or ETV6. To determine the prevalence of CH in individuals with germline mutations in ANKRD26 or ETV6, we performed next generation sequencing on hematopoietic tissue from twelve individuals with either germline ANKRD26 or germline ETV6 mutations. Each patient had thrombocytopenia but had not developed HMs. Among the seven individuals with germline ANKRD26 mutations, one patient had a CH clone driven by a somatic SF3B1 mutation (p.Lys700Glu). This mutation increased from a variant allele frequency (VAF) of 9.4% at age 56 to 17.4% at age 60. None of the germline ETV6 mutation carriers had evidence of CH at the limits of detection of the NGS assay (5% VAF). Unlike individuals with germline mutations in RUNX1, no individuals under the age of 50 with germline mutations in ANKRD26 or ETV6 had detectable CH. This work demonstrates that ANKRD26 germline mutation carriers, but not ETV6 mutation carriers, experience elevated risk for CH.

genetics↗

bioRxiv2018

γδ T cells do not contribute to peripheral inflammatory pain

Circulating immune cells, which are recruited to the site of injury/disease, secrete various inflammatory mediators that are critical to nociception and pain. The role of tissue-resident immune cells, however, remains poorly characterized. One of the first cells to be activated in peripheral tissues following injury are {gamma}{delta} T cells, which serve important roles in infection and disease. Using a transgenic mouse line lacking these cells, we sought to identify their contribution to inflammatory pain. Three distinct models of inflammatory pain were used: intraplantar injection of formalin and incisional wound (as models of acute inflammatory pain) and intraplantar injection of complete Freunds adjuvant (as a model of chronic inflammatory pain). Our results show that absence of these cells does not alter baseline sensitivity, nor does it result in changes to mechanical or thermal hypersensitivity after tissue injury. These results were consistent in both male and female mice, suggesting that there are no sex differences in these outcomes. This comprehensive characterization suggests that {gamma}{delta} T cells do not contribute to basal sensitivity or the development and maintenance of inflammatory pain.

neuroscience↗

bioRxiv2018

Pancreatic adenocarcinoma human organoids share structural and genetic features with primary tumors

Patient-derived pancreatic ductal adenocarcinoma (PDAC) organoid systems show great promise for understanding the biological underpinnings of disease and advancing therapeutic precision medicine. Despite the increased use of organoids, the fidelity of molecular features, genetic heterogeneity, and drug response to the tumor of origin remain important unanswered questions limiting their utility. To address this gap in knowledge, we created primary tumor- and PDX-derived organoids, and 2D cultures for in-depth genomic and histopathological comparisons to the primary tumor. Histopathological features and PDAC representative protein markers showed strong concordance. DNA and RNA sequencing of single organoids revealed patient-specific genomic and transcriptomic consistency. Single-cell RNAseq demonstrated that organoids are primarily a clonal population. In drug response assays, organoids displayed patient-specific sensitivities. Additionally, we examined the in vivo PDX response to FOLFIRINOX and Gemcitabine/Abraxane treatments, which was recapitulated in vitro by organoids. The patient-specific molecular and histopathological fidelity of organoids indicate that they can be used to understand the etiology of the patients tumor and the differential response to therapies and suggests utility for predicting drug responses.

cancer biology↗