Biology subjects

Hart, W. S.

Publications and source records attributed to Hart, W. S..

7 recordsLinked to original sources

bioRxiv2026

End-of-outbreak determination under seasonal transmission

At the apparent end of an infectious disease outbreak, policymakers must decide when to relax interventions, balancing epidemiological safety and economic efficiency. Here, we extend a renewal equation framework for estimating the risk of additional cases to scenarios with seasonal transmission, such as Aedes-borne virus transmission in temperate settings. In simulations, we demonstrate that the time of year is key to when it is safe to relax interventions under seasonal transmission: measures can be relaxed sooner if the last observed case occurs towards the end of the transmission season. We apply our framework to the 2017 chikungunya outbreak in Italy, integrating incidence data with estimates of temperature suitability for transmission, and further extend our approach to account for case under-reporting. Our model incorporating an end-of-season decline in transmission indicates a lower risk of additional cases late in the outbreak than a model based on incidence alone: assuming 60% case reporting, the seasonal model reaches a 1% risk threshold 22 days after the last observed case, compared with 39 days for the incidence-only model. Incorporating seasonality in model-based assessments of transmission risks at the end of an outbreak can therefore support more timely and reliable decision making.

ecology↗

bioRxiv2026

Demographic changes and behavioural responses shape vulnerability to infectious disease outbreaks

Demographic shifts are reshaping population age structures worldwide, with implications for infectious disease dynamics. Since contact patterns, susceptibility and infectiousness often vary by age, the risk that pathogen introductions initiate a substantial outbreak depends on the population's age distribution and associated behavioural characteristics. We develop an age-structured mathematical model to estimate the risk that a single pathogen introduction leads to sustained transmission (the probability of a major outbreak) under long-term demographic transitions, incorporating changes in age-specific contact patterns and behavioural adaptation (specifically, extended workforce participation in an ageing society). Using the Republic of Korea (projected to become the world's oldest population by 2050) as a case study, we show that population ageing may reduce the probability of a major outbreak due to older individuals' lower contact rates. However, this effect is attenuated for pathogens with increasing susceptibility or infectiousness with age, and by factors such as later retirement that increase contacts among older individuals. These findings demonstrate that, while outbreak risks are affected by demographic changes, they are further modified by associated behavioural responses, highlighting the importance of accounting for demographic and socio-behavioural context when assessing future infectious disease outbreak risks.

ecology↗

bioRxiv2026

Systems modeling identifies phenotype-determining signaling pathways controlled by phosphatase PTPRJ in diverse receptor tyrosine kinase activation settings

Protein tyrosine phosphatase receptor J (PTPRJ) restrains cell proliferation and migration by dephosphorylating receptor tyrosine kinases (RTKs) including the epidermal growth factor receptor (EGFR). PTPRJ is a purported tumor suppressor, and alterations to its expression and/or function are associated with colorectal, breast, lung, and other cancers. While there is interest in controlling PTPRJ-regulated phenotypes, efforts are limited by the complexity of PTPRJ-mediated signaling. PTPRJ dephosphorylates multiple RTKs, and the degree to which PTPRJ control of signaling and phenotypes depends on local cellular RTK activation profiles is unknown. To probe the context dependence of PTPRJ signaling regulation, we collected signaling measurements across 16 pathway nodes at two time points in a panel of HSC3 carcinoma cells engineered with different PTPRJ expression profiles. Cells were treated with three different RTK ligands, and paired phenotype measurements (viability, wound healing, xCELLigence cell index) were made. Partial least squares regression models were developed to predict relationships between PTPRJ-regulated signaling pathways and cell phenotypes. The model effectively separated contributions to variance arising from the PTPRJ expression background and growth factor context. In testing model predictions, we demonstrated that PTPRJ suppressed MET-induced cell cell proliferation via regulation of a HER3/AKT signaling axis that stabilized PTPRJ expression through an unanticipated feedback mechanism. We also found that PTPRJ regulated HSC3 cell migration via JNK signaling that was preferentially activated by MET. Our results identify new regulatory nodes through which PTPRJ influences cancer cell phenotypes and demonstrates that these processes preferentially occur in the context of distinct RTK activation states.

systems biology↗

bioRxiv2025

PTPRJ-Targeting Peptide Agonist Induces Broad Cellular Signaling Perturbations and DNA Damage in Lung Cancer Cells

Receptor protein tyrosine phosphatases (RPTPs) are key regulators of cell signaling. However, their study and therapeutic targeting have been limited by the lack of known natural ligands or selective agonists, as well as an incomplete understanding of their structure-function relationships. Nonetheless, receptor homodimerization has been shown to suppress RPTP catalytic activity by restricting substrate access, offering a promising strategy for examining and modulating their function. Our previous work on PTPRJ, a member of the RPTP family, showed that its transmembrane domain regulates homodimerization, thereby controlling access to receptor tyrosine kinase (RTK) substrates and their phosphorylation levels. We also developed peptides that disrupt this dimerization, thereby inhibiting RTK phosphorylation and reducing cancer cell migration. These peptides were then engineered for selective, pH-sensitive insertion into the acidic tumor microenvironment to enhance efficacy while limiting off-target effects. Yet how broadly PTPRJ activation reshapes the phosphotyrosine landscape and whether those changes yield coherent cellular phenotypes remains unclear. In this study, we employed tyrosine phosphoproteomics, immunoblotting, immunofluorescence, and functional assays to assess the global impact of our lead peptide candidate, Hybrid 7, in A549 lung cancer cells that endogenously express PTPRJ. We find that Hybrid 7 decreases EGFR phosphorylation and selectively reduces phosphorylation across additional RTKs and motility adaptors, producing strong inhibition of EGF-driven migration and reduced proliferation. Hybrid 7 also elevates reactive oxygen species and DNA damage, and enforces CDK1-dependent G2/M arrest, indicating a primarily cytostatic, checkpoint-mediated response. These findings highlight the potential of RPTP-targeting peptides as valuable tools for dissecting RPTP function and as possible therapeutic agents capable of modulating key oncogenic pathways and inhibiting cancer progression.

biochemistry↗

bioRxiv2023

Isolation may select for earlier and higher peak viral load but shorter duration in SARS-CoV-2 evolution

During the COVID-19 pandemic, human behavior change as a result of nonpharmaceutical interventions such as isolation may have induced directional selection for viral evolution. By combining previously published empirical clinical data analysis and multi-level mathematical modeling, we found that the SARS-CoV-2 variants selected for as the virus evolved from the pre-Alpha to the Delta variant had earlier and higher infectious periods but a shorter duration of infection. Selection for increased transmissibility shapes the viral load dynamics, and the isolation measure is likely to be a driver of these evolutionary transitions. In addition, we showed that a decreased incubation period and an increased proportion of asymptomatic infection were also positively selected for as SARS-CoV-2 mutated to the extent that people did not isolate. We demonstrated that the Omicron variants evolved in these ways to adapt to human behavior. The quantitative information and predictions we present here can guide future responses in the potential arms race between pandemic interventions and viral evolution.

evolutionary biology↗

bioRxiv2022

A histone methylation-MAPK signaling axis drives durable epithelial-mesenchymal transition in hypoxic pancreas cancer

Here, we show that hypoxia drives especially long-lasting epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) primarily through a positive-feedback histone methylation-MAPK signaling axis. We find that transformed cells preferentially undergo EMT in hypoxic tumor regions in multiple model systems and that hypoxia drives a cell-autonomous EMT in PDAC cells which, unlike EMT in response to growth factors, can last for weeks. We further demonstrate that hypoxia reduces histone demethylase KDM2A activity, suppresses PP2 family phosphatase expression, and activates MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors play only a supporting role. This mechanism can be antagonized in vivo by combinations of MAPK inhibitors that may be effective in multi-drug therapies designed to target EMT.

cancer biology↗

bioRxiv2018

Comparative Biochemical and Structural Analysis of Novel Cellulose Binding Proteins (Tapirins) from Extremely Thermophilic Caldicellulosiruptor Species

Genomes of extremely thermophilic Caldicellulosiruptor species encode novel cellulose binding proteins, t[a]pirins, located proximate to the type IV pilus locus. Previously, the C-terminal domain of a t[a]pirin (Calkro_0844) from Caldicellulosiruptor kronotskyensis was shown to be structurally unique and have a cellulose binding affinity akin to family 3 carbohydrate binding modules (CBM3). Here, full-length and C-terminal versions of t[a]pirins from Caldicellulosiruptor bescii (Athe_1870), Caldicellulosiruptor hydrothermalis (Calhy_0908), Caldicellulosiruptor kristjanssonii (Calkr_0826), and Caldicellulosiruptor naganoensis (NA10_0869) were produced recombinantly in Escherichia coli and compared to Calkro_0844. All five t[a]pirins bound to microcrystalline cellulose, switchgrass, poplar, filter paper, but not to xylan. Densitometry analysis of bound protein fractions visualized by SDS-PAGE revealed that Calhy_0908 and Calkr_0826 (from weakly cellulolytic species) associated with the cellulose substrates to a greater extent than Athe_1870, Calkro_0844 and NA10_0869 (from strongly cellulolytic species), perhaps to associate closely with biomass to capture glucans released from lignocellulose by cellulases produced in Caldicellulosiruptor communities. Three-dimensional structures of the C-terminal binding regions of Calhy_0908 and Calkr_0826 were closely related to Calkro_0844, despite the fact that their amino acid sequence identities compared to Calkro_0844 were only 16% and 36%, respectively. Unlike the parent strain, C. bescii mutants lacking the t[a]pirin genes did not bind to cellulose following short-term incubation, reinforcing the significance of these proteins in cell association with plant biomass. Given the scarcity of carbohydrates in neutral terrestrial hot springs, t[a]pirins likely help cells scavenge carbohydrates from lignocellulose to support growth and survival of Caldicellulosiruptor species.\n\nImportanceMechanisms by which microorganisms attach to and degrade lignocellulose are important to understand if effective approaches for conversion of plant biomass into fuels and chemicals are to be developed. Caldicellulosiruptor species grow on carbohydrates from lignocellulose at elevated temperatures and have biotechnological significance for that reason. Novel cellulose binding proteins, called t[a]pirins, are involved in the way Caldicellulosiruptor species interact with microcrystalline cellulose and here additional information about the diversity of these proteins across the genus is provided, including three dimensional structural comparisons.

microbiology↗