Open Access Publications

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Open access publications by faculty, postdocs, and graduate students in the Department of Biomedical Engineering.


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Now showing 1 - 5 of 9
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    Stress deprivation of tendon explants or Tpm3.1 inhibition in tendon cells reduces F-actin to promote a tendinosis-like phenotype
    (Molecular Biology of the Cell, 2022-12-01) Inguito, Kameron L.; Schofield, Mandy M.; Faghri, Arya D.; Bloom, Ellen T.; Heino, Marissa; West, Valerie C.; Ebron, Karl Matthew M.; Elliot, Dawn M.; Parreno, Justin
    Actin is a central mediator between mechanical force and cellular phenotype. In tendons, it is speculated that mechanical stress deprivation regulates gene expression by reducing filamentous (F)-actin. However, the mechanisms regulating tenocyte F-actin remain unclear. Tropomyosins (Tpms) are master regulators of F-actin. There are more than 40 Tpm isoforms, each having the unique capability to stabilize F-actin subpopulations. We investigated F-actin polymerization in stress-deprived tendons and tested the hypothesis that stress fiber–associated Tpm(s) stabilize F-actin to regulate cellular phenotype. Stress deprivation of mouse tail tendon down-regulated tenogenic and up-regulated protease (matrix metalloproteinase-3) mRNA levels. Concomitant with mRNA modulation were increases in G/F-actin, confirming reduced F-actin by tendon stress deprivation. To investigate the molecular regulation of F-actin, we identified that tail, Achilles, and plantaris tendons express three isoforms in common: Tpm1.6, 3.1, and 4.2. Tpm3.1 associates with F-actin in native and primary tenocytes. Tpm3.1 inhibition reduces F-actin, leading to decreases in tenogenic expression, increases in chondrogenic expression, and enhancement of protease expression in mouse and human tenocytes. These expression changes by Tpm3.1 inhibition are consistent with tendinosis progression. A further understanding of F-actin regulation in musculoskeletal cells could lead to new therapeutic interventions to prevent alterations in cellular phenotype during disease progression.
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    Membrane-wrapped nanoparticles for nucleic acid delivery
    (Biomaterials Science, 2022-06-29) Scully, Mackenzie A.; Sterin, Eric H.; Day, Emily S.
    There is an unmet need for carriers that can deliver nucleic acids (NAs) to cancer cells and tumors to perpetuate gene regulation and manage disease progression. Membrane-wrapped nanoparticles (NPs) can be loaded with exogenously designed nucleic acid cargoes, such as plasmid deoxyribonucleic acid (pDNA), messenger ribonucleic acid (mRNA), small interfering RNA (siRNA), microRNA (miRNA), and immunostimulatory CpG oligodeoxynucleotides (CpG ODNs), to mitigate challenges presented by NAs’ undesirable negative charge, hydrophilicity, and relatively large size. By conjugating or encapsulating NAs within membrane-wrapped NPs, various physiological barriers can be overcome so that NAs experience increased blood circulation half-lives and enhanced accumulation in intended sites. This review discusses the status of membrane-wrapped NPs as NA delivery vehicles and their advancement in gene regulation for cancer management in vitro and in vivo. With continued development, membrane-wrapped NPs have great potential as future clinical tools to treat cancer and other diseases with a known genetic basis.
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    Secretion of the disulphide bond generating catalyst QSOX1 from pancreatic tumour cells into the extracellular matrix: Association with extracellular vesicles and matrix proteins
    (Journal of Extracellular Biology, 2022-07-02) Millar-Haskell, Catherine S.; Sperduto, John L.; Slater, John H.; Thorpe, Colin; Gleghorn, Jason P.
    Quiescin sulfhydryl oxidase 1 (QSOX1) is a disulphide bond generating catalyst that is overexpressed in solid tumours. Expression of QSOX1 is linked to cancer cell invasion, tumour grade, and aberrant extracellular matrix (ECM) protein deposition. While the secreted version of QSOX1 is known to be present in various fluids and secretory tissues, its presence in the ECM of cancer is less understood. To characterize secreted QSOX1, we isolated extracellular vesicles (and particles) (EV(P)s) from conditioned media using ultracentrifugation and separated the supernatant using tangential flow filtration. We discovered that most of the secreted QSOX1 resides in the EVP-depleted supernatant and in the soluble protein fraction. Very little QSOX1 could be detected in the EVP fraction. We used immunofluorescence to image subpopulations of EVs and found QSOX1 in Golgi-derived vesicles and medium/large vesicles, but in general, most extracellular QSOX1 was not attributed to these vesicles. Next, we quantified QSOX1 co-localization with the EV marker Alix. For the medium/large EVs, ∼98% contained QSOX1 when fibronectin was used as a coating. However, on collagen coatings, only ∼60% of these vesicles contained QSOX1, suggesting differences in EV cargo based on ECM coated surfaces. About 10% of small EVs co-localized with QSOX1 on every ECM protein surface except for collagen (0.64%). We next investigated adhesion of QSOX1 to ECM proteins in vitro and in situ and found that QSOX1 preferentially adheres to fibronectin, laminins, and Matrigel compared to gelatin and collagen. This mechanism was found to be, in part, mediated by the formation of mixed disulphides between QSOX1 and cysteine-rich ECM proteins. In summary, we found that QSOX1 (1) is in subpopulations of medium/large EVs, (2) seems to interact with small Alix+ EVs, and (3) adheres to cysteine-rich ECM proteins, potentially through the formation of intermediate disulphides. These observations offer significant insight into how enzymes, such as QSOX1, can facilitate matrix remodelling events in solid tumour progression.
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    Relationships between aggression, sensation seeking, brain stiffness, and head impact exposure: Implications for head impact prevention in ice hockey
    (Brain and Behavior, 2022-04-23) DiFabio, Melissa S.; Smith, Daniel R.; Breedlove, Katherine M.; Buckley, Thomas A.; Johnson, Curtis L.
    Objectives: The objectives of this study were to (1) examine the relationship between the number of head impacts sustained in a season of men's collegiate club ice hockey and behavioral traits of aggression and sensation seeking, and (2) explore the neural correlates of these behaviors using neuroimaging. Design: Retrospective cohort study. Methods: Participants (n = 18) completed baseline surveys to quantify self-reported aggression and sensation-seeking tendencies. Aggression related to playing style was quantified through penalty minutes accrued during a season. Participants wore head impact sensors throughout a season to quantify the number of head impacts sustained. Participants (n = 15) also completed baseline anatomical and magnetic elastography neuroimaging scans to measure brain volumetric and viscoelastic properties. Pearson correlation analyses were performed to examine relationships between (1) impacts, aggression, and sensation seeking, and (2) impacts, aggression, and sensation seeking and brain volume, stiffness, and damping ratio, as an exploratory analysis. Results: Number of head impacts sustained was significantly related to the number of penalty minutes accrued, normalized to number of games played (r = .62, p < .01). Our secondary, exploratory analysis revealed that number of impacts, sensation seeking, and aggression were related to stiffness or damping ratio of the thalamus, amygdala, hippocampus, and frontal cortex, but not volume. Conclusions: A more aggressive playing style was related to an increased number of head impacts sustained, which may provide evidence for future studies of head impact prevention. Further, magnetic resonance elastography may aid to monitor behavior or head impact exposure. Researchers should continue to examine this relationship and consider targeting behavioral modification programs of aggression to decrease head impact exposure in ice hockey.
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    Altered brain functional connectivity in the frontoparietal network following an ice hockey season
    (European Journal of Sport Science, 2022-05-08) DiFabio, Melissa S.; Smith, Daniel R.; Breedlove, Katherine M.; Pohlig, Ryan T.; Buckley, Thomas A.; Johnson, Curtis L.
    Sustaining sports-related head impacts has been reported to result in neurological changes that potentially lead to later-life neurological disease. Advanced neuroimaging techniques have been used to detect subtle neurological effects resulting from head impacts, even after a single competitive season. The current study used resting-state functional magnetic resonance imaging to assess changes in functional connectivity of the frontoparietal network, a brain network responsible for executive functioning, in collegiate club ice hockey players over one season. Each player was scanned before and after the season and wore accelerometers to measure head impacts at practices and home games throughout the season. We examined pre- to post-season differences in connectivity within the frontoparietal and default mode networks, as well as the relationship between the total number of head impacts sustained and changes in connectivity. We found a significant interaction between network region of interest and time point (p = .016), in which connectivity between the left and right posterior parietal cortex seed regions increased over the season (p < .01). Number of impacts had a significant effect on frontoparietal network connectivity, such that more impacts were related to greater connectivity differences over the season (p = .042). Overall, functional connectivity increased in ice hockey athletes over a season between regions involved in executive functioning, and sensory integration, in particular. Furthermore, those who sustained more impacts had the greatest changes in connectivity. Consistent with prior findings in resting-state sports-related head impact literature, these findings have been suggested to represent brain injury. Highlights: Functional connectivity of the frontoparietal network significantly increased between the pre- and post-season, which may be a compensatory mechanism driven by neural tissue injury caused by repetitive head impacts. Changes in frontoparietal network connectivity are related to head impact exposure, measured as the number of head impacts sustained in a single season. Functional connectivity of the default mode network did not change over an ice hockey season.
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