Biology subjects

Lee, E.

Publications and source records attributed to Lee, E..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Multidimensional characterization of cellular ecosystems in Hodgkin lymphoma

The tissue architecture of classic Hodgkin Lymphoma (CHL) is unique among cancers and characterized by rare malignant Hodgkin and Reed-Sternberg cells that co-evolve with a complex ecosystem of immune cells in the tumor microenvironment (TME). The lack of a comprehensive systems-level interrogation has hindered the description of disease heterogeneity and clinically relevant molecular subtypes. Here, we employed an integrative, multimodal approach to characterize CHL tumors using malignant cell sequencing, spatial transcriptomics and imaging mass cytometry. We identified four molecular subtypes (CST, CN913, STB, and CN2P), each characterized by distinct clinical features, mutational patterns, malignant cell gene expression profiles, and spatial architecture involving immune cell populations. Functional modeling of CSF2RB mutations, a characteristic feature of the CST subtype, revealed dysregulated oncogenic signaling and unique TME crosstalk. These findings highlight the significance of multi-dimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities.

cancer biology↗

bioRxiv2025

Critical Period Plasticity is Associated withResilience to Short Unpredictable Stress

Low resilience to stressful events can increase the risk of anxiety and depression. Resilience decreases with age, parallel to drastic changes in the quality of brain plasticity from juvenile to old age, suggesting that the type of plasticity found in the maturing brain promotes resilience. To indirectly test this, we administered short unpredictable stress to adult male and female wild type (WT) C57BL/6 mice, as well as to two groups of mice characterized by heightened cortical plasticity: adolescent C57BL/6 WT mice and adult mice that lack SynCAM 1 (Synaptic Cell Adhesion Molecule 1), a critical plasticity brake in the mature brain. We found that short unpredictable stress robustly increased core body temperature in all groups of mice, indicative of stress-induced hyperthermia (SIH) and confirming the efficacy of the stress paradigm. However, depressive-like behavior as measured though tail suspension test was increased in adult WT mice only, supporting that the type of plasticity found in the immature brains of adolescent WT and adult SynCAM 1 knockout (KO) mice promotes resilience to stress. All three groups of mice showed a mild increase in locomotor activity after stress, suggesting that the quality of plasticity does not correlate with resilience to anxiety-like phenotypes. Our study hence provides indirect evidence for the protective role of developmental plasticity during stress and points to new mechanisms that promote resilience to stress-induced depression.

neuroscience↗

bioRxiv2025

Lab-in-the-loop therapeutic antibody design with deep learning

Therapeutic antibody design is a complex multi-property optimization problem with substantial promise for improvement with the application of machine-learning methods. Towards realizing that promise, we introduce "Lab-in-the-loop," a new approach that orchestrates state-of-the-art repertoire mining methods, generative machine learning models, multi-task property predictors, active learning ranking and selection, and in vitro experimentation in a semi-autonomous, iterative optimization loop. By automating the design of antibody variants, property prediction, ranking and selection of designs to assay in the lab, and ingestion of in vitro data, we enable an end-to-end approach to developing computationally-informed therapeutic antibody design pipelines. We apply lab-in-the-loop to eleven seed antibodies obtained via animal immunization with four clinically relevant antigen targets: EGFR, IL-6, HER2, and OSM. Over 1,800 unique antibody variants are tested throughout four rounds of iterative optimization identifying 3-100x better binding variants for all targets and 10/11 seeds, with the best binders exceeding 100 pM affinity, demonstrating a process by which end-to-end machine learning can be developed for therapeutic antibody development.

bioengineering↗

bioRxiv2025

DyAb: sequence-based antibody design and property prediction in a low-data regime

Protein therapeutic design and property prediction are frequently hampered by data scarcity. Here we propose a new model, DyAb, that addresses these issues by leveraging a pair-wise representation to predict differences in protein properties, rather than absolute values. DyAb is built on top of a pre-trained protein language model and achieves a Spearman rank correlation of up to 0.85 on binding affinity prediction across molecules targeting three different antigens (EGFR, IL-6, and an internal target), given as few as 100 training data. We employ DyAb in two design contexts: as a ranking model to score combinations of known mutations, and combined with a genetic algorithm to generate new sequences. Our method consistently generates novel antibody candidates with high binding rates, including designs that improve on the binding affinity of the lead molecule by more than ten-fold. DyAb represents a powerful tool for engineering therapeutic protein properties in low data regimes common in early-stage drug development.

bioengineering↗

bioRxiv2025

deepNGS Navigator: Exploring antibody NGS datasets using deep contrastive learning

High-throughput sequencing uncovers how B-cells adapt and evolve in response to antigens by generating B-cell receptor (BCR) sequences at an unprecedented scale. As BCR datasets grow to be millions of sequences, using efficient computational methods becomes crucial for analyzing and understanding complex patterns within the data. One important aspect of antibody sequence analysis is detecting clonal families or clusters of related sequences, whether they come from immunization, synthetic libraries or even ML-generated datasets. Such analysis helps us to understand how sequences are evolutionarily connected, and how they might have been selected or evolved. Here we introduce deepNGS Navigator, a computational tool that leverages language models and contrastive learning to transform large datasets of antibody sequences into 2D representations. The resulting 2D maps offer an intuitive visualization of overall diversity of input datasets, which can be clustered based on the sequence distances and their densities across the map. Beyond grouping related sequences, the 2D maps can also point to evolutionary trajectories and capture mutational patterns among closely related sequences. By analyzing properties like charge, hydrophobicity, number of sequence neighbors, and read counts, the maps highlight which clusters are most promising for further investigation while also detecting anomalies or noisy sequences with higher risk. We demonstrate deepNGS Navigators utilities on various datasets, including: 1) a synthetic library from a yeast display targeting HER2, 2) a machine learning-generated dataset with a hierarchical tree structure, 3) NGS sequences from a llama immunized against COVID RBD, 4) human naive and memory B-cell sequences, and 5) an insilico dataset simulating B-cell clonal lineages.

bioinformatics↗

bioRxiv2025

Inhibition of EMT driver PTK6 enhances anti-tumor immune responses against triple-negative breast cancer

The non-receptor tyrosine kinase PTK6 is expressed in 70% of triple negative breast cancers (TNBC) and is an oncogenic driver of epithelial-mesenchymal transition (EMT). EMT promotes metastasis and immune evasion of TNBC. Therefore, targeting EMT drivers could reverse these properties and lead to more favorable outcomes. Treatment of TNBC tumors with a small molecule inhibitor of PTK6 kinase (P21d) suppressed their growth in vivo. Tumor inhibition by P21d is dependent on an induced immune response because: 1) inhibition is observed in immunocompetent, but not immunodeficient, mice; 2) P21d increases tumor-infiltrating CD8+ T and NK cells and decreases immunosuppressive myeloid-derived suppressor cells; and 3) tumor inhibition by P21d is abrogated by co-treatment with NK or CD8+ T cell-depleting antibodies. These effects on tumor growth and cytotoxic TILs are phenocopied by the knockdown of tumoral PTK6 or SNAIL, which supports EMT inhibition as a mechanism for enhanced anti-tumor immune response. RNA sequencing (RNA-seq) profiling of P21d-treated tumors also revealed changes consistent with activation of the immune response and identified CXCL10 as a critical chemokine induced intratumorally by P21d that promotes recruitment of NK/CD8+ T cells to the tumor site, leading to tumor growth inhibition. Our study highlights the novel tumor immune microenvironmental functions of PTK6 with important consequences for tumor growth that could lead to new immunotherapeutic approaches for TNBC.

cancer biology↗

bioRxiv2025

Anticancer synthetic arylsulfonamides with Wnt1-modulating activity

Dysregulation of the Wnt1/{beta}-catenin signaling pathway has been demonstrated to be a driving factor in the propagation of several human cancers. Previous studies have discovered methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate (MSAB) as a selective inhibitor of the Wnt1/{beta}-catenin signaling pathway, which putatively functions through direct engagement of {beta}-catenin. To understand how changes to the identity and position of the methyl ester affect the in vitro potency of this compound in Wnt1-driven mammalian cell lines, we prepared and evaluated three analogs of MSAB with 3- and 4-substituted methyl and ethyl esters. In MTT assays, analogs with methyl esters showed significantly more activity than their ethyl ester counterparts and both 4-substituted esters exhibited significantly attenuated antiproliferative activity, with MSAB exhibiting dose-dependent activity across cancerous cell lines. Further analysis by flow cytometry reveals low-Annexin V signal, suggesting that these compounds do not function via a pro-apoptotic pathway. Additionally, through a TCF/LEF-activated luciferase reporter cell assay, we observe that the 4-substituted methyl ester analogous to MSAB exhibits slightly diminished Wnt1-inhibitory activity, while 3- and 4-substituted ethyl esters exhibit minimal Wnt1-inhibitory activity. This difference in potency with a simple ester substitution might be attributed to several factors that ultimately drive antiproliferative activity, prompting the investigation of other potential substituents to further investigate the structure-activity relationship of these compounds as Wnt1-based antiproliferative agents.

cancer biology↗

bioRxiv2025

An integrated single-cell and spatial transcriptomic atlas of thyroid cancer progression identifies prognostic fibroblast subpopulations

Thyroid cancer progression from curable well-differentiated thyroid carcinoma to highly lethal anaplastic thyroid carcinoma is distinguished by tumor cell de-differentiation and recruitment of a robust stromal infiltrate. Combining an integrated thyroid cancer single-cell sequencing atlas with spatial transcriptomics and bulk RNA-sequencing, we define stromal cell subpopulations and tumor-stromal cross-talk occurring across the histologic and mutational spectrum of thyroid cancer. We identify distinct inflammatory and myofibroblastic cancer-associated fibroblast (iCAF and myCAF) populations and perivascular-like populations. The myCAF population is only found in malignant samples and is associated with tumor cell invasion, BRAFV600E mutation, lymph node metastasis, and disease progression. Tumor-adjacent myCAFs abut invasive tumor cells with a partial epithelial-to-mesenchymal phenotype. Tumor-distant iCAFs infiltrate inflammatory autoimmune thyroid lesions and anaplastic tumors. In summary, our study provides an integrated atlas of thyroid cancer fibroblast subtypes and spatial characterization at sites of tumor invasion and de-differentiation, defining the stromal reorganization central to disease progression.

cancer biology↗

bioRxiv2024

A hybrid machine learning model for predicting gene expression from epigenetics across fungal species

Understanding gene expression is crucial for optimizing biological processes in bioeconomic processes, human health, and environmental regulation. Epigenetic modifications significantly influence gene expression by altering chromatin structure and DNA accessibility. However, knowledge about the conservation of these mechanisms across species, especially in non-model organisms, is limited. This study predicts gene expression levels based on epigenetic modifications across fungal species, facilitating knowledge transfer from well-characterized to less understood species. We developed a deep learning model, MAPLE (Model predictions Across Phylogenetic distances by Learning Expression from Epigenetics), which integrates convolutional layers and multi-head attention to capture dependencies in epigenetic data. MAPLE shows strong cross-species performance in fungi, achieving up to 80% accuracy and 89% AUROC for intra-species validation, and 77% accuracy and 83% AUROC in cross-species tasks, outperforming benchmarks. SHAP analysis reveals key epigenetic features driving gene expression, providing insights for future experimental design. Our findings highlight MAPLEs potential to generalize across fungal species, offering a versatile tool for optimizing gene expression.

systems biology↗

bioRxiv2024

Tenascin-C potentiates Wnt signaling in thyroid cancer

Tenascin-C (TNC) is a secreted extracellular matrix protein that is highly expressed during embryonic development and re-expressed during wound healing, inflammation, and neoplasia. Studies in developmental models suggest that TNC may regulate the Wnt signaling pathway. Our lab has shown high levels of Wnt signaling and TNC expression in anaplastic thyroid cancer (ATC), a highly lethal cancer with an abysmal [~]3-5 month median survival. Here, we investigated the role of TNC in facilitating ligand-dependent Wnt signaling in thyroid cancer. We utilized bulk RNA-sequencing from three independent multi-institutional thyroid cancer patient cohorts. TNC expression was spatially localized in patient tumors with RNA in situ hybridization. The role of TNC was investigated in vitro using Wnt reporter assays and in vivo with a NOD.PrkdcscidIl2rg-/- mouse ATC xenograft tumor model. TNC expression was associated with aggressive thyroid cancer behavior, including anaplastic histology, extrathyroidal extension, and metastasis. Spatial localization of TNC in patient tissue demonstrated a dramatic increase in expression within cancer cells along the invasive edge, adjacent to Wnt ligand-producing fibroblasts. TNC expression was also increased in areas of intravascular invasion. In vitro, TNC bound Wnt ligands and potentiated Wnt signaling. Finally, in an ATC mouse model, TNC increased Wnt signaling, tumor burden, invasion, and metastasis. Altogether, TNC potentiated ligand driven Wnt signaling and promotes cancer cell invasion and metastasis in a mouse model of thyroid cancer. Understanding the role of TNC and its interaction with Wnt ligands could lead to the development of novel biomarkers and targeted therapeutics for thyroid cancer.

cancer biology↗

bioRxiv2024

Small mammals and their burrows shape the distribution of Coccidioides in soils: a long-term ecological experiment

BackgroundFor nearly all human fungal pathogens, the environmental constraints on their distributions remain poorly understood, hindering disease management. Here, we investigated the role of zoonotic host presence, soil conditions, and their interaction on the presence of Coccidioides immitis - an emerging fungal pathogen and causative agent of coccidioidomycosis. MethodsA long-term experimental study initiated in 2007 in the Carrizo Plain National Monument, California excluded rodents from certain areas (20 by 20-meter exclosures; n = 20) via the installation of submerged mesh fences, leaving emptied burrows intact. We collected 1,988 soil samples over four sampling periods spanning April 2021 to April 2022 using a factorial design that crossed burrows and surface soils (i.e., top 10 cm of soil) with exclosures (i.e., rodent absence) and non-exclosures (i.e., rodent presence). We measured in situ soil moisture, temperature, and vegetation, and analyzed soils for C. immitis DNA. ResultsThe proportion of samples containing C. immitis was significantly higher (p <0.0001) in burrow samples taken from outside rodent exclosures (i.e., rodents present; 28.5% positive) compared to burrow samples taken from within exclosures (i.e., rodents absent; 19.7%), surface soils outside of exclosures (3.6%) and surface soils within exclosures (0.5%). In generalized linear mixed models adjusting for soil conditions, rodent presence, and sample type (burrow vs. surface soil), we estimated that the odds of detecting C. immitis were 19.2 (95% CI: 11.3 - 36.7, p < 0.0001) times higher in soils taken from burrows compared to surface soils, and 2.6 (95% CI: 1.0 - 5.6, p = 0.049) times higher in soils where rodents were present compared to absent. Soil moisture was the only abiotic factor associated with C. immitis detection (odds ratio per 1% increase in water content: 0.83, 95% CI: 0.70 - 0.89, p = 0.0002). In mediation analyses, we estimated that 73.7% (95% CI: 68.9, 78.5) of the total association between rodents and Coccidioides detection effect was attributable to rodent creation of burrows. ConclusionsRodent creation and occupation of burrows substantially increases C. immitis detection. Synergy between reservoir host presence and environmental conditions may exist for other human fungal pathogens.

ecology↗

bioRxiv2024

The Conformational Space of the SARS-CoV-2 Main Protease Active Site Loops is Determined by Ligand Binding and Interprotomer Allostery

The main protease (Mpro) of SARS-CoV-2 is essential for viral replication and is, therefore, an important drug target. Here, we investigate two flexible loops in Mpro that play a role in catalysis. Using all-atom molecular dynamics simulations, we analyze the structural ensemble of Mpro in an apo state and substrate-bound state. We find that the flexible loops can adopt open, intermediate (partly open) and closed conformations in solution, which differs from the partially closed state observed in crystal structures of Mpro. When the loops are in closed or intermediate states, the catalytic residues are more likely to be in close proximity, which is crucial for catalysis. Additionally, we find that substrate binding to one protomer of the homodimer increases the frequency of intermediate states in the bound protomer, while also affecting the structural propensity of the apo protomers flexible loops. Using dynamic network analysis, we identify multiple allosteric pathways connecting the two active sites of the homodimer. Common to these pathways is an allosteric hotspot involving the N-terminus, a critical region that comprises part of the binding pocket. Taken together, the results of our simulation study provide detailed insight into the relationships between the flexible loops and substrate binding in a prime drug target for COVID-19.

biophysics↗

bioRxiv2024

Wolbachia introgression in Ae. aegypti is accompanied by variable loss - a multi-country assessment

The wMel and wAlbB strains of the bacterial endosymbiont Wolbachia are being introgressed into Aedes aegypti populations as a biocontrol method to reduce the transmission of medically important arboviruses. Successful introgression of Wolbachia relies on both persistence of Wolbachia throughout the host life cycle and a high fidelity of maternal transmission of Wolbachia between generations. wMel has been introgressed into field populations in 14 countries to date. Monitoring of field sites has shown that wMel prevalence can fluctuate substantially over time, prompting concerns this could lead to reduced efficacy of the biocontrol method. To explore the fidelity of wMel persistence and transmission, we developed molecular methods to measure the prevalence of Ae. aegypti negative for Wolbachia infection but carrying the "founder" mitochondrial haplotype of the single female first transinfected. As all released wMel-infected mosquitoes and any subsequent offspring will carry this founder mitochondrial haplotype, any mosquitoes with this mitochondrial haplotype and without wMel indicate that wMel was lost from this lineage at some point. We observed loss of wMel ranging from 0 to 20.4% measured at various time intervals after wMel-infected mosquito releases in five different countries. Despite some field sites showing Wolbachia loss, overall Wolbachia prevalence was sustained during the time periods studied. We then employed laboratory studies to explore factors that could contribute to the loss of wMel. Surprisingly, near-perfect maternal transmission was measured across laboratory conditions of early blood feeding, starvation, and salinity. Collectively, these findings underscore that although wMel transmission can be imperfect it does not necessarily undermine population-level establishment, providing encouragement that the intervention will be robust in most dengue-endemic environments.

ecology↗

bioRxiv2024

Dissecting human monoclonal antibody responses from mRNA- and protein-based XBB.1.5 COVID-19 monovalent vaccines

The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines to target those new variants specifically. While previous infections and booster vaccinations can enhance variant neutralization, it is unclear whether the monovalent version, administered using either mRNA or protein-based vaccine platforms, can elicit de novo B-cell responses specific for Omicron XBB.1.5 variants. Here, we dissected the genetic antibody repertoire of 603 individual plasmablasts derived from five individuals who received a monovalent XBB.1.5 vaccination either with mRNA (Moderna or Pfizer/BioNtech) or adjuvanted protein (Novavax). From these sequences, we expressed 100 human monoclonal antibodies and determined binding, affinity and protective potential against several SARS-CoV-2 variants, including JN.1. We then select two vaccine-induced XBB.1.5 mAbs, M2 and M39. M2 mAb was a de novo, antibody, i.e., specific for XBB.1.5 but not ancestral SARS-CoV-2. M39 bound and neutralized both XBB.1.5 and JN.1 strains. Our high-resolution cryo-electron microscopy (EM) structures of M2 and M39 in complex with the XBB.1.5 spike glycoprotein defined the epitopes engaged and revealed the molecular determinants for the mAbs specificity. These data show, at the molecular level, that monovalent, variant-specific vaccines can elicit functional antibodies, and shed light on potential functional and genetic differences of mAbs induced by vaccinations with different vaccine platforms. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=43 SRC="FIGDIR/small/602781v1_ufig1.gif" ALT="Figure 1000"> View larger version (16K): org.highwire.dtl.DTLVardef@7c4708org.highwire.dtl.DTLVardef@11b66acorg.highwire.dtl.DTLVardef@1f1cec7org.highwire.dtl.DTLVardef@3e72fe_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Polygenic architecture of brain structure and function, behaviors, and psychopathologies in children

The human brain undergoes structural and functional changes during childhood, a critical period in cognitive and behavioral development. Understanding the genetic architecture of the brain development in children can offer valuable insights into the development of the brain, cognition, and behaviors. Here, we integrated brain imaging-genetic-phenotype data from over 8,600 preadolescent children of diverse ethnic backgrounds using multivariate statistical techniques. We found a low-to-moderate level of SNP-based heritability in most IDPs, which is lower compared to the adult brain. Using sparse generalized canonical correlation analysis (SGCCA), we identified several covariation patterns among genome-wide polygenic scores (GPSs) of 29 traits, 7 different modalities of brain imaging-derived phenotypes (IDPs), and 266 cognitive and psychological phenotype data. In structural MRI, significant positive associations were observed between total grey matter volume, left ventral diencephalon volume, surface area of right accumbens and the GPSs of cognition-related traits. Conversely, negative associations were found with the GPSs of ADHD, depression and neuroticism. Additionally, we identified a significant positive association between educational attainment GPS and regional brain activation during the N-back task. The BMI GPS showed a positive association with fractional anisotropy (FA) of connectivity between the cerebellum cortex and amygdala in diffusion MRI, while the GPSs for educational attainment and cannabis use were negatively associated with the same IDPs. Our GPS-based prediction models revealed substantial genetic contributions to cognitive variability, while the genetic basis for many mental and behavioral phenotypes remained elusive. This study delivers a comprehensive map of the relationships between genetic profiles, neuroanatomical diversity, and the spectrum of cognitive and behavioral traits in preadolescence.

genetics↗

bioRxiv2024

Astrocytic hemoglobin is an H2O2-decomposing peroxidase and therapeutic target for Alzheimer's disease

Summary paragraphHemoglobin (Hb) is well-known for transporting oxygen in red blood cells within blood vessels1. Although Hb is also present in the brain2, its role remains poorly understood. Here, we show that Hb, found in astrocytes of neurodegenerative animal models and patients, displays significant antioxidant effects through its H2O2-decomposing peroxidase activity, and a small molecule enhancer boosts this activity, reducing aberrant H2O2 and mitigating H2O2-induced neurodegeneration. To counteract the harmful effects of aberrant H2O2-production in Alzheimers disease (AD), we developed KDS12025, a blood-brain barrier (BBB)-permeable small molecule that effectively enhances the peroxidase activity of Hb by a hundredfold, especially at a low level of Hb. KDS12025 and its analogs achieve this enhancement through its electron-donating amine group. KDS12025 reduces H2O2 levels in astrocytes, exhibits neuroprotective effects, and reverses memory impairment in AD models. Gene-silencing of Hb{beta} abrogates KDS12025s impact in both culture and animal models of AD. Moreover, KDS12025 prevented the death of dopaminergic neurons in a Parkinsons disease (PD) model without altering the oxygen-transporting function of Hb. KDS12025 extended survival and improved motor function even in the severe amyotrophic lateral sclerosis (ALS) mouse model. Our findings propose Hb as a new therapeutic target for neurodegenerative diseases, with KDS12025 emerging as a first-in-class drug candidate that enhances Hbs peroxidase activity to reduce H2O2. Boosting Hbs peroxidase activity with KDS12025 mitigates oxidative stress and alleviates neurodegeneration in AD, PD, and ALS with broad applicability for numerous oxidative-stress-driven diseases.

neuroscience↗

bioRxiv2024

Timing of treatment shapes the path to androgen receptor signaling inhibitor resistance in prostate cancer

There is optimism that cancer drug resistance can be addressed through appropriate combination therapy, but success requires understanding the growing complexity of resistance mechanisms, including the evolution and population dynamics of drug-sensitive and drug-resistant clones over time. Using DNA barcoding to trace individual prostate tumor cells in vivo, we find that the evolutionary path to acquired resistance to androgen receptor signaling inhibition (ARSI) is dependent on the timing of treatment. In established tumors, resistance occurs through polyclonal adaptation of drug-sensitive clones, despite the presence of rare subclones with known, pre-existing ARSI resistance. Conversely, in an experimental setting designed to mimic minimal residual disease, resistance occurs through outgrowth of pre-existing resistant clones and not by adaptation. Despite these different evolutionary paths, the underlying mechanisms responsible for resistance are shared across the two evolutionary paths. Furthermore, mixing experiments reveal that the evolutionary path to adaptive resistance requires cooperativity between subclones. Thus, despite the presence of pre-existing ARSI-resistant subclones, acquired resistance in established tumors occurs primarily through cooperative, polyclonal adaptation of drug-sensitive cells. This tumor ecosystem model of resistance has new implications for developing effective combination therapy.

cancer biology↗

bioRxiv2024

Estrogen deficiency reduces maximal running capacity and affects serotonin levels differently in the hippocampus and nucleus accumbens in response to acute exercise

ObjectiveEstrogen deficiency is associated with unfavorable changes in body composition and metabolic health. While physical activity ameliorates several of the negative effects, loss of ovarian function is associated with decreased physical activity levels. It has been proposed that the changes in brain neurochemical levels and /or impaired skeletal muscle function may underlie this phenomenon. MethodsWe studied the effect of estrogen deficiency induced via ovariectomy (OVX) in female Wistar rats (n=64). Rats underwent either sham or OVX surgery and were allocated thereafter into four groups matched for body mass and maximal running capacity: sham/control, sham/max, OVX/control, and OVX/max, of which the max groups had maximal running test before euthanasia to induce acute response to exercise. Metabolism, spontaneous activity, and maximal running capacity were measured before (PRE) and after (POST) the surgeries. Three months following the surgery, rats were euthanized, and blood and tissue samples harvested. Proteins were analyzed from gastrocnemius muscle and retroperitoneal adipose tissue via Western blot. Brain neurochemical markers were measured from nucleus accumbens (NA) and hippocampus (HC) using ultra-high performance liquid chromatography. ResultsOVX had lower basal energy expenditure and higher body mass and retroperitoneal adipose tissue mass compared with sham group (p[≤]0.005). OVX reduced maximal running capacity by 17% (p=0.005) with no changes in muscle mass or phosphorylated form of regulatory light chain (pRLC) in gastrocnemius muscle. OVX was associated with lower serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) level in the NA compared with sham (p=0.007). In response to acute exercise, OVX was associated with low serotonin level in the HC and high level in the NA (p[≤]0.024). ConclusionsOur results highlight that OVX reduces maximal running capacity and affects the response of brain neurochemical levels to acute exercise in a brain region-specific manner. These results may offer mechanistic insight into why OVX reduces willingness to exercise.

molecular biology↗