Biology subjects

Page, D.

Publications and source records attributed to Page, D..

4 recordsLinked to original sources

bioRxiv2024

MPAC: a computational framework for inferring cancer pathway activities from multi-omic data

Fully capturing cellular state requires examining genomic, epigenomic, transcriptomic, proteomic, and other assays for a biological sample and comprehensive computational modeling to reason with the complex and sometimes conflicting measurements. Modeling these so-called multi-omic data is especially beneficial in disease analysis, where observations across omic data types may reveal unexpected patient groupings and inform clinical outcomes and treatments. We present Multi-omic Pathway Analysis of Cells (MPAC), a computational framework that interprets multi-omic data through prior knowledge from biological pathways. MPAC leverages network relationships encoded in pathways through a factor graph to infer consensus activity levels for proteins and associated pathway entities from multi-omic data, runs permutation testing to eliminate spurious activity predictions, and groups biological samples by pathway activities to allow identifying and prioritizing proteins with potential clinical relevance, e.g., associated with patient prognosis. Using DNA copy number alteration and RNA-seq data from head and neck squamous cell carcinoma patients from The Cancer Genome Atlas as an example, we demonstrate that MPAC predicts a patient subgroup related to immune responses not identified by analysis with either input omic data type alone. Key proteins identified via this subgroup have pathway activities related to clinical outcome as well as immune cell compositions. Our MPAC R package, available at https://bioconductor.org/packages/MPAC, enables similar multi-omic analyses on new datasets.

bioinformatics↗

bioRxiv2024

Multifocal Ectopic Purkinje Premature Contractions due to neutralization of an SCN5A negative charge: structural insights into the gating pore hypothesis

BackgroundWe identified a novel SCN5A variant, E171Q, in a neonate with very frequent ectopy and reduced ejection fraction which normalized after arrhythmia suppression by flecainide. This clinical picture is consistent with multifocal ectopic Purkinje-related premature contractions (MEPPC). Most previous reports of MEPPC have implicated SCN5A variants such as R222Q that neutralize positive charges in the S4 voltage sensor helix of the channel protein NaV1.5 and generate a gating pore current. Methods and ResultsE171 is a highly conserved negatively-charged residue located in the S2 transmembrane helix of NaV1.5 domain I. E171 is a key component of the Gating Charge Transfer Center, a region thought to be critical for normal movement of the S4 voltage sensor helix. We used heterologous expression, CRISPR-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and molecular dynamics simulations to demonstrate that E171Q generates a gating pore current, which was suppressed by a low concentration of flecainide (IC50 = 0.71{+/-}0.07 {micro}M). R222Q shifts voltage dependence of activation and inactivation in a negative direction but we observed positive shifts with E171Q. E171Q iPSC-CMs demonstrated abnormal spontaneous activity and prolonged action potentials. Molecular dynamics simulations revealed that both R222Q and E171Q proteins generate a water-filled permeation pathway that underlies generation of the gating pore current. ConclusionPreviously identified MEPPC-associated variants that create gating pore currents are located in positively-charged residues in the S4 voltage sensor and generate negative shifts in the voltage dependence of activation and inactivation. We demonstrate that neutralizing a negatively charged S2 helix residue in the Gating Charge Transfer Center generates positive shifts but also create a gating pore pathway. These findings implicate the gating pore pathway as the primary functional and structural determinant of MEPPC and widen the spectrum of variants that are associated with gating pore-related disease in voltage-gated ion channels.

genetics↗

bioRxiv2019

Neuronal differentiation affects tissue mechanics and progenitor arrangement in the vertebrate neuroepithelium

Cell division, movement and differentiation contribute to pattern formation in developing tissues. This is the case in the vertebrate neural tube where neurons differentiate in a characteristic pattern from a highly dynamic proliferating pseudostratified epithelium. To investigate how progenitor proliferation and differentiation affect cell arrangement and growth of the neural tube, we use experimental measurements to develop a mechanical model of the apical surface of the neuroepithelium that incorporates inter-kinetic nuclear movement and spatially varying rates of neuronal differentiation. Simulations predict that tissue growth and the shape of lineage-related clones of cells differ with the rate of differentiation. Growth is isotropic in regions of high differentiation, but dorsoventrally biased in regions of low differentiation. This is consistent with experimental observations. The absence of directional signalling in the simulations indicates that global mechanical constraints are sufficient to explain the observed differences in anisotropy. This provides insight into how the tissue growth rate affects cell dynamics and growth anisotropy and opens up possibilities to study the coupling between mechanics, pattern formation and growth in the neural tube.

developmental biology↗

bioRxiv2018

Relationship between Parathyroid Hormone Levels and Hazards of Fracture, Vascular Events and Death in Stage 3 and 4 Chronic Kidney Disease

Background and ObjectivesChronic kidney disease (CKD) affects [~]20% of older adults and secondary hyperparathyroidism (HPT) is a common condition in these patients. Studies have linked HPT to a greater risk of fractures, vascular events and mortality. However, the optimal parathyroid hormone (PTH) level needed to minimize these events remains uncertain.\n\nDesign, setting, participants and measurementsWe assessed relationships between baseline serum PTH levels and the subsequent 10-year probability of clinical fractures, vascular events and death in stage 3 and 4 CKD patients. We used Marshfield Clinic Health System electronic health records to analyze data from adult CKD patients spanning from 1985 to 2013. We required [≥]2 PTH measurements at baseline and used ICD-9 codes to identify medical conditions, fractures, vascular events and death. In multivariate models, we assessed relationships between serum PTH and the three clinical outcomes, controlling for age, gender, co-morbidities and osteoporosis medication.\n\nResults7594 subjects had a mean age of 68{+/-}13 years and 55% were women. Fractures, vascular events and death occurred in 19%, 60% and 29% of the cohort, respectively. In multivariate models including the whole cohort regardless of PTH assay, the probability of fracture, vascular events and death were minimized at a PTH of 23, 50 and 50 pg/mL. Below these cutpoints, the probability of fractures and death dramatically increased. When confining the analysis to patients measured using a 2nd generation PTH assay (n=5108), the hazards of fracture, vascular events and death were minimized at a PTH of zero, 60 and 58 pg/mL. Any of these clinical outcomes was minimized at a baseline PTH of 58 pg/mL.\n\nConclusionsOur study suggests that parathyroid hormone levels around 60 pg/mL might reduce the risk of fractures, vascular events and death in CKD patients. Additional epidemiologic studies and randomized clinical trials are needed to confirm these findings.

epidemiology↗