Biology subjects

Jones, C. E.

Publications and source records attributed to Jones, C. E..

8 recordsLinked to original sources

bioRxiv2025

A computational model to study hemodynamics during atrial fibrillation

Atrial fibrillation (AF) is associated with reduced cardiac output, which is correlated with increased symptomatic burden and declined quality of life. Predicting hemodynamic effects of AF remains challenging due to the complex interplay of multiple contributing mechanisms. Computational modeling offers a valuable tool for simulating hemodynamics. However, existing models are lacking the capabilities to both replicate beat-to-beat hemodynamic variations during AF while being well suited for fitting to clinical data. In this study, we present a computational model comprising: 1) an electrical subsystem that generates uncoordinated atrial and irregular ventricular activation times characteristic of AF, and 2) a mechanical subsystem that simulates hemodynamics using a reduced order model. The model was fitted to replicate individual hemodynamic measurements from 17 patients in the SMURF study during both normal sinus rhythm (NSR) and AF. The fitted model matched a large majority (75%) of blood pressure and intracardiac pressure measurements in both NSR and AF with absolute simulation errors well below 10 mmHg. Furthermore, a large majority of left atrial and left ventricular ejection fraction measurements during NSR were matched with absolute simulation errors well below 10%. The model consistently underestimated right ventricular diastolic pressure during NSR while overestimating right ventricular systolic and mean left atrial pressures during AF. The presented approach of modeling atrial activity in AF as uncoordinated atrial contractions, rather than no atrial contraction, achieved lower overall absolute simulation errors when fitting to individual patients. This computationally efficient model provides a platform for future investigations of patient-specific hemodynamics during AF.

bioengineering↗

bioRxiv2025

HIV-1 Vpr alters cellular transcription by targeting the PAF1 complex

Innate immunity represents the first line of defence against viral infections, and successful pathogens like HIV-1 have evolved mechanisms to bypass these barriers. The PAF1 complex (PAF1c) has emerged as a key regulator of antiviral innate immune responses, inhibiting the replication of various viruses, including HIV-1. While its role in transcription regulation is well documented, little is known about how PAF1c inhibits HIV-1 and how HIV-1 circumvents this antiviral activity. Here we demonstrate that Vpr induces the rapid and transient downmodulation of PAF1c shortly after infection, a process that correlates with significant transcriptomic changes within the host cell. Transcriptomic profiling reveals that PAF1 knockdown mirrors many of the gene expression changes induced by HIV-1 infection, indicating that Vpr antagonism of PAF1c is a means by which HIV-1 may modulate host gene expression to favour replication. Further, we show that the loss of PAF1c leads to the suppression of interferon-stimulated genes (ISGs) and several known HIV-1 restriction factors. Overall, the evidence supports the emerging role of PAF1 as a regulator of a broad antiviral transcriptional program, but also suggests a specific anti-HIV activity that is countered by HIV-1 Vpr.

microbiology↗

bioRxiv2024

Synergistic Biophysics and Machine Learning Modeling to Rapidly Predict Cardiac Growth Probability

AO_SCPLOWBSTRACTC_SCPLOWComputational models that can predict growth and remodeling of the heart could have important clinical applications. However, the time it takes to calibrate and run current models while considering data uncertainty and variability makes them impractical for routine clinical use. This study aims to address this need by creating a computational framework to efficiently predict cardiac growth probability. We utilized a biophysics model to rapidly simulate cardiac growth following mitral valve regurgitation (MVR). Here we developed a two-tiered Bayesian History Matching approach augmented with Gaussian process emulators for efficient calibration of model parameters to align with growth outcomes within a 95% confidence interval. We first generated a synthetic data set to assess the accuracy of our framework, and the effect of changes in data uncertainty on growth predictions. We then calibrated our model to match baseline and chronic canine MVR data and used an independent data set to successfully validate the ability of our calibrated model to accurately predict cardiac growth probability. The combined biophysics and machine learning modeling framework we proposed in this study can be easily translated to predict patient-specific cardiac growth.

bioengineering↗

bioRxiv2024

Transcriptome analysis of Drosophila suzukii reveals molecular mechanisms conferring pyrethroid and spinosad resistance

Drosophila suzukii lay eggs in soft-skinned, ripening fruits, making this insect a serious threat to berry production. Since its 2008 introduction into North America, growers have used insecticides, such as pyrethroids and spinosads, as the primary approach for D. suzukii management, resulting in detections of insecticide resistance in this pest. This study sought to identify the molecular mechanisms conferring insecticide resistance in these populations. We sequenced the transcriptomes of two pyrethroid- and two spinosad-resistant isofemale lines. In both pyrethroid-resistant lines and one spinosad-resistant line, we identified overexpression of metabolic genes that are implicated in resistance in other insect pests. In the other spinosad-resistant line, we observed an overexpression of cuticular genes that have been linked to resistance. Our findings enabled the development of molecular diagnostics that we used to confirm persistence of insecticide resistance in California, U.S.A. To validate these findings, we leveraged D. melanogaster mutants with reduced expression of metabolic or cuticular genes that were found to be upregulated in resistant D. suzukii to demonstrate that these genes are involved in promoting resistance. This study is the first to characterize the molecular mechanisms of insecticide resistance in D. suzukii and provides insights into how current management practices can be optimized.

genomics↗

bioRxiv2023

CO-EXPRESSION OF DISTINCT COILED COILS CAN LEAD TO THEIR ENTANGLEMENT

L1 (LINE1) non-LTR retrotransposons are ubiquitous genomic parasites and the dominant transposable element in humans having generated about 40% of their genomic DNA during their [~]100 million years (Myr) of activity in primates. L1 replicates in early embryos, causing genetic diversity and defects, but can be active in some somatic stem cells, tumors and during aging. L1 encodes two proteins essential for retrotransposition: ORF2, a replicase, and ORF1, a coiled coil mediated homo trimer, which functions as a nucleic acid chaperone. Both proteins contain highly conserved domains and preferentially bind their encoding transcript to form an L1 ribonucleoprotein (RNP), which mediates retrotransposition. However, the coiled coil has undergone episodes of substantial amino acid replacement to the extent that a given L1 family can concurrently express multiple ORF1s that differ in the sequence of their coiled coils. Here we show that such distinct ORF1p sequences can become entangled forming heterotrimers when co-expressed from separate vectors.

molecular biology↗

bioRxiv2021

Differential ampicillin/ceftriaxone susceptibility among diverse Enterococcus faecalis from infective endocarditis

Enterococcus faecalis is a leading cause of infective endocarditis (IE), especially among older patients with comorbidities. Here we investigated the genomic diversity and antimicrobial susceptibility of 33 contemporary E. faecalis isolates from definite or probable IE cases at the University of Pittsburgh Medical Center (UPMC) between 2018 and 2020. Isolates belonging to two multi-locus sequence types (STs), ST6 and ST179, were isolated from nearly 40% of IE patients. Both of these dominant STs carried known beta-lactam resistance-associated mutations affecting the low-affinity penicillin-binding protein 4 (PBP4). We assessed the ability of ampicillin and ceftriaxone (AC) both alone and in combination to inhibit genetically diverse E. faecalis IE isolates in checkerboard synergy assays and an in vitro one-compartment pharmacokinetic-pharmacodynamic (PK-PD) model of AC treatment. ST6 isolates as well as an isolate with a mutation in the PP2C-type protein phosphatase IreP had higher ceftriaxone MICs compared to other isolates, and showed diminished in vitro synergy of AC. Additionally, both ST6 and ST179 isolates exhibited regrowth after 48 hours of humanized exposures to AC. Overall, we found evidence for diminished in vitro AC activity among E. faecalis IE isolates with PBP4 and IreP mutations. This study highlights the need to evaluate alternate antibiotic combinations in clinical practice against diverse contemporary E. faecalis IE isolates.

microbiology↗

bioRxiv2020

Monitoring S. pombe genome stress by visualizing end-binding protein Ku

Studies of genome stability have exploited visualization of fluorescently tagged proteins in live cells to characterize DNA damage, checkpoint, and repair responses. In this report, we describe a new tool for fission yeast, a tagged version of the end-binding protein Pku70 which is part of the KU protein complex. We compare Pku70 localization to other markers upon treatment to various genotoxins, and identify a unique pattern of distribution. Pku70 provides a new tool to define and characterize DNA lesions and the repair response.

molecular biology↗

bioRxiv2018

HIV-1 Vpr accessory protein interacts with REAF and mitigates its associated anti-viral activity.

The Human Immunodeficiency Virus type 1 (HIV-1) accessory protein Vpr enhances viral replication in both macrophages and in cycling T cells to a lesser extent. Virion packaged Vpr is released in target cells shortly after entry, suggesting its requirement in the early phase of infection. Previously, we described REAF (RNA-associated Early-stage Antiviral Factor, RPRD2), a constitutively expressed protein that potently restricts HIV replication at or during reverse transcription. Here, we show that a virus without intact vpr is more highly restricted by REAF and, using delivery by VLPs, that Vpr alone is sufficient for REAF degradation in primary macrophages. REAF is more highly expressed in macrophages than in cycling T cells and we detect, by co-immunoprecipitation assay, an interaction between Vpr protein and endogenous REAF. Vpr acts very quickly during the early phase of replication and induces the degradation of REAF within 30 minutes of viral entry. Using Vpr F34I and Q65R viral mutants, we show that nuclear localisation and interaction with cullin4A-DBB1 (DCAF1) E3 ubiquitin ligase is required for REAF degradation by Vpr. In response to infection, cells upregulate REAF levels. This response is curtailed in the presence of Vpr. These findings support the hypothesis that Vpr induces the degradation of a factor, REAF, which impedes HIV infection in macrophages.\n\nImportanceFor at least 30 years, it has been known that HIV-1 Vpr, a protein carried in the virion, is important for efficient infection of primary macrophages. Vpr is also a determinant of the pathogenic effects of HIV-1 in vivo. A number of cellular proteins that interact with Vpr have been identified. So far, it has not been possible to associate these proteins with altered viral replication in macrophages, or to explain why Vpr is carried in the virus particle. Here we show that Vpr mitigates the antiviral effects of REAF, a protein highly expressed in primary macrophages and one which inhibits virus replication early during reverse transcription. REAF is degraded by Vpr within 30 minutes of virus entry, in a manner dependent on the nuclear localization of Vpr and its interaction with the cells protein degradation machinery.

microbiology↗