Scholarly Works, Biomedical Engineering and Mechanics

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  • A scoping review on examination approaches for identifying tactile deficits at the upper extremity in individuals with stroke
    Paul, Arco P.; Nayak, Karan; Sydnor, Lindsey C.; Kalantaryardebily, Nahid; Parcetich, Kevin M.; Miner, Daniel G.; Wafford, Q. E.; Sullivan, Jane E.; Gurari, Netta (2024-06-08)
    Purpose: Accurate perception of tactile stimuli is essential for performing and learning activities of daily living. Through this scoping review, we sought to summarize existing examination approaches for identifying tactile deficits at the upper extremity in individuals with stroke. The goal was to identify current limitations and future research needs for designing more comprehensive examination tools. Methods: A scoping review was conducted in accordance with the Joanna Briggs Institute methodological framework and the PRISMA for Scoping Reviews (PRISMA-ScR) guidelines. A database search for tactile examination approaches at the upper extremity of individuals with stroke was conducted using Medline (Ovid), The Cochrane Library (Wiley), CINAHL Plus with Full Text (Ebsco), Scopus (Elsevier), PsycInfo (Ebsco), and Proquest Dissertations and Theses Global. Original research and review articles that involved adults (18 years or older) with stroke, and performed tactile examinations at the upper extremity were eligible for inclusion. Data items extracted from the selected articles included: if the examination was behavioral in nature and involved neuroimaging, the extent to which the arm participated during the examination, the number of possible outcomes of the examination, the type(s) of tactile stimulation equipment used, the location(s) along the arm examined, the peripheral nerves targeted for examination, and if any comparison was made with the non-paretic arm or with the arms of individuals who are neurotypical. Results: Twenty-two articles met the inclusion criteria and were accepted in this review. Most examination approaches were behavioral in nature and involved self-reporting of whether a tactile stimulus was felt while the arm remained passive (i.e., no volitional muscle activity). Typically, the number of possible outcomes with these behavioral approaches were limited (2-3), whereas the neuroimaging approaches had many more possible outcomes (> 15). Tactile examinations were conducted mostly at the distal locations along the arm (finger or hand) without targeting any specific peripheral nerve. Although a majority of articles compared paretic and non-paretic arms, most did not compare outcomes to a control group of individuals who are neurotypical. Discussion: Our findings noted that most upper extremity tactile examinations are behavioral approaches, which are subjective in nature, lack adequate resolution, and are insufficient to identify the underlying neural mechanisms of tactile deficits. Also, most examinations are administered at distal locations of the upper extremity when the examinee’s arm is relaxed (passive). Further research is needed to develop better tactile examination tools that combine behavioral responses and neurophysiological outcomes, and allow volitional tactile exploration. Approaches that include testing of multiple body locations/nerves along the upper extremity, provide higher resolution of outcomes, and consider normative comparisons with individuals who are neurotypical may provide a more comprehensive understanding of the tactile deficits occurring following a stroke.
  • The probability of chromatin to be at the nuclear lamina has no systematic effect on its transcription level in fruit flies
    Afanasyev, Alexander Y.; Kim, Yoonjin; Tolokh, Igor S.; Sharakhov, Igor V.; Onufriev, Alexey V. (2024-05-06)
    Background: Multiple studies have demonstrated a negative correlation between gene expression and positioning of genes at the nuclear envelope (NE) lined by nuclear lamina, but the exact relationship remains unclear, especially in light of the highly stochastic, transient nature of the gene association with the NE. Results: In this paper, we ask whether there is a causal, systematic, genome-wide relationship between the expression levels of the groups of genes in topologically associating domains (TADs) of Drosophila nuclei and the probabilities of TADs to be found at the NE. To investigate the nature of this possible relationship, we combine a coarse-grained dynamic model of the entire Drosophila nucleus with genome-wide gene expression data; we analyze the TAD averaged transcription levels of genes against the probabilities of individual TADs to be in contact with the NE in the control and lamins-depleted nuclei. Our findings demonstrate that, within the statistical error margin, the stochastic positioning of Drosophila melanogaster TADs at the NE does not, by itself, systematically affect the mean level of gene expression in these TADs, while the expected negative correlation is confirmed. The correlation is weak and disappears completely for TADs not containing lamina-associated domains (LADs) or TADs containing LADs, considered separately. Verifiable hypotheses regarding the underlying mechanism for the presence of the correlation without causality are discussed. These include the possibility that the epigenetic marks and affinity to the NE of a TAD are determined by various non-mutually exclusive mechanisms and remain relatively stable during interphase. Conclusions: At the level of TADs, the probability of chromatin being in contact with the nuclear envelope has no systematic, causal effect on the transcription level in Drosophila. The conclusion is reached by combining model-derived time-evolution of TAD locations within the nucleus with their experimental gene expression levels.
  • Applying Proteomics and Computational Approaches to Identify Novel Targets in Blast-Associated Post-Traumatic Epilepsy
    Browning, Jack L.; Wilson, Kelsey A.; Shandra, Oleksii; Wei, Xiaoran; Mahmutovic, Dzenis; Maharathi, Biswajit; Robel, Stefanie; VandeVord, Pamela J.; Olsen, Michelle L. (MDPI, 2024-03-01)
    Traumatic brain injury (TBI) can lead to post-traumatic epilepsy (PTE). Blast TBI (bTBI) found in Veterans presents with several complications, including cognitive and behavioral disturbances and PTE; however, the underlying mechanisms that drive the long-term sequelae are not well understood. Using an unbiased proteomics approach in a mouse model of repeated bTBI (rbTBI), this study addresses this gap in the knowledge. After rbTBI, mice were monitored using continuous, uninterrupted video-EEG for up to four months. Following this period, we collected cortex and hippocampus tissues from three groups of mice: those with post-traumatic epilepsy (PTE+), those without epilepsy (PTE), and the control group (sham). Hundreds of differentially expressed proteins were identified in the cortex and hippocampus of PTE+ and PTE relative to sham. Focusing on protein pathways unique to PTE+, pathways related to mitochondrial function, post-translational modifications, and transport were disrupted. Computational metabolic modeling using dysregulated protein expression predicted mitochondrial proton pump dysregulation, suggesting electron transport chain dysregulation in the epileptic tissue relative to PTE. Finally, data mining enabled the identification of several novel and previously validated TBI and epilepsy biomarkers in our data set, many of which were found to already be targeted by drugs in various phases of clinical testing. These findings highlight novel proteins and protein pathways that may drive the chronic PTE sequelae following rbTBI.
  • Scaling analysis of taenidia in beetle tracheae
    Staples, Anne; Wilmsen, Sara; Zaslavsky, Sasha; Hopkins, Devyn; Khan, Saadbin; Socha, John (2024-01-04)
  • Comparison of the Biomechanics of the Mouse Astrocytic Lamina Cribrosa Between Glaucoma and Optic Nerve Crush Models
    Korneva, Arina; Kimball, Elizabeth C.; Johnson, Thomas V.; Quillen, Sarah E.; Pease, Mary E.; Quigley, Harry A.; Nguyen, Thao D. (Association for Research in Vision and Ophthalmology (ARVO), 2023-12-13)
    PURPOSE. The strain response of the mouse astrocytic lamina (AL) to an ex vivo mechanical test was compared between two protocols: eyes that underwent sustained intraocular pressure (IOP) increase and eyes after optic nerve crush. METHODS. Chronic IOP elevation was induced by microbead injection or the optic nerve was crushed in mice with widespread green fluorescence. After 3 days or 6 weeks, eyes were inflation tested by a published method of two-photon fluorescence to image the AL. Digital volume correlation was used to calculate strains. Optic nerve axon damage was also evaluated. RESULTS. In the central AL but not the peripheral AL, four strains were greater in eyes at the 3-day glaucoma time point than control (P from 0.029 to 0.049, n = 8 eyes per group). Also, at this time point, five strains were greater in the central AL compared to the peripheral AL (P from 0.041 to 0.00003). At the 6-week glaucoma time point, the strains averaged across the specimen, in the central AL, and the peripheral AL were indistinguishable from the respective controls. Strains were not significantly different between controls and eyes 3 days or 6 weeks after crush (n = 8 and 16). CONCLUSIONS. We found alterations in the ex vivo mechanical behavior in eyes from mice with experimental glaucoma but not in those with crushed optic nerves. The results of this study demonstrate that significant axon injury does not directly affect mechanical behavior of the astrocytic lamina.
  • Effects of Covid-19 Pandemic and Response on Student Performance in Large Foundational Mechanics Courses
    Lord, James; Thompson, M. K. (ASEE Conferences, 2023-06-25)
    In Spring 2020, institutions were forced to make rapid changes to their teaching, attendance, assessment, and academic relief policies. Our institution moved all classes and assessment online, removed most attendance policies, extended the drop deadline, and allowed students to alter their grading system from A-F to credit/no-credit. Most classes and assessments continued to be online in Fall 2020 and Spring 2021, before returning to typical pre-pandemic scheduling in Fall 2021. These accommodations were necessary to respond to public health advice, student and faculty illness, and ongoing uncertainty at the time. However, there are growing concerns about the effect that the pandemic and associated policies had on student learning and preparation for follow-on courses. We analyze student grade data and withdrawal rate for three large multi-section foundational mechanics courses between Fall 2015 - Fall 2022: Statics (91 sections), Mechanics of Deformable Bodies ('Deformables') (79 sections), and Dynamics (73 sections). Specifically, we look at Grade Point Average (GPA) and the proportion of students receiving either D grades, F grades, or withdrawing from each course (collectively known as the DFW rate). We separate our data into 4 time periods and compare results across these periods: Fall 2015 - Fall 2019 ('pre-pandemic'), Spring 2020 ('early-pandemic'), Fall 2020 - Spring 2021 ('mid-pandemic'), and Fall 2021 - Fall 2022 ('post-pandemic'). We find a significant increase in GPA and decrease in DFW rate in the Spring 2020 semester when classes were moved online and institutional polices were very lenient around grading and drop policies. Since Fall 2021 (when both course modality and institutional policies largely reverted) GPA and DFW rates in Statics have been virtually identical to pre-pandemic rates. However, we see significant decreases in GPA and significant increases in DFW rate in both Deformables and Dynamics. Statics is a prerequisite for both of these courses. This general trend was observed for almost all faculty members who taught classes across this time period, although the size of the effect varied. One section of Deformables has been offered asynchronously online since Fall 2015. This class also saw the same trends in GPA and DFW rate across the study period. We do not explicitly explore the reasons for these changes in this paper, but our experience in these classes suggests that students who took Statics mid-pandemic are not as well prepared for follow-on courses as students were pre-pandemic. The changes in GPA and DFW rate are a concern that is likely to extend to higher level courses. We intend to continue to track student progress through these courses and report on longer-term trends. Larger studies are warranted to help explain these trends.
  • Animal locomotion: Wing-like femoral lobes help orchid mantid nymphs glide
    Socha, John J.; Khandelwal, Pranav C. (Elsevier, 2024-02)
    The femoral lobes of the orchid mantis give this fierce predator a flower-like appearance, but they also assist in gliding, showing that form can match function in more ways than one.
  • A Year at the Forefront of Gliding Locomotion
    Khandelwal, Pranav C.; Zakaria, Mohamed A.; Socha, John J. (Company of Biologists, 2023-08-15)
    This review highlights the largely understudied behavior of gliding locomotion, which is exhibited by a diverse range of animals spanning vertebrates and invertebrates, in air and in water. The insights in the literature gained from January 2022 to December 2022 continue to challenge the previously held notion of gliding as a relatively simple form of locomotion. Using advances in field/lab data collection and computation, the highlighted studies cover gliding in animals including seabirds, flying lizards, flying snakes, geckos, dragonflies, damselflies, and dolphins. Altogether, these studies present gliding as a sophisticated behavior resulting from the interdependent aspects of morphology, sensing, environment, and likely selective pressures. This review uses these insights as inspiration to encourage researchers to revisit gliding locomotion, both in the animal's natural habitat and in the laboratory, and to investigate questions spanning gliding biomechanics, ecology, sensing, and the evolution of animal flight.
  • A biologically accurate model of directional hearing in the parasitoid fly Ormia ochracea
    Mikel-Stites, Max R.; Salcedo, Mary K.; Socha, John J.; Marek, Paul E.; Staples, Anne E. (Cold Spring Harbor Laboratory, 2021-09-17)
    Although most binaural organisms localize sound sources using neurological structures to amplify the sounds they hear, some animals use mechanically coupled hearing organs instead. One of these animals, the parasitoid fly Ormia ochracea, has astoundingly accurate sound localization abilities and can locate objects in the azimuthal plane with a precision of 2°, equal to that of humans. This is accomplished despite an intertympanal distance of only 0.5 mm, which is less than 1/100th of the wavelength of the sound emitted by the crickets that it parasitizes. In 1995, Miles et al. developed a model of hearing mechanics in O. ochracea, which works well for incoming sound angles of less than ±30°, but suffers from reduced accuracy (up to 60% error) at higher angles. Even with this limitation, it has served as the basis for multiple bio-inspired microphone designs for decades. Here, we present critical improvements to the classic O. ochracea hearing model based on information from 3D reconstructions of O. ochracea’s tympana. The 3D images reveal that the tympanal organ has curved lateral faces in addition to the flat front-facing prosternal membranes represented in the Miles model. To mimic these faces, we incorporated spatially-varying spring and damper coefficients that respond asymmetrically to incident sound waves, making a new quasi-two-dimensional (q2D) model. The q2D model has high accuracy (average errors of less than 10%) for the entire range of incoming sound angles. This improved biomechanical hearing model can inform the development of new technologies and may help to play a key role in developing improved hearing aids. Significance Statement: The ability to identify the location of sound sources is critical to organismal survival and for technologies that minimize unwanted background noise, such as directional microphones for hearing aids. Because of its exceptional auditory system, the parasitoid fly Ormia ochracea has served as an important model for binaural hearing and a source of bioinspiration for building tiny directional microphones with outsized sound localization abilities. Here, we performed 3D imaging of the fly’s tympanal organs and used the morphological information to improve the current model for hearing in O. ochracea. This model greatly expands the range of biological accuracy from ±30° to all incoming sound angles, providing a new avenue for studies of binaural hearing and further inspiration for fly-inspired technologies.
  • 3D X-ray analysis of the subterranean burrowing depth and pupal chamber size of Laricobius (Coleoptera: Derodontidae), a specialist predator of Adelges tsugae (Hemiptera: Adelgidae)
    Hillen, Ashleigh P.; Foley, Jeremiah R.; Salcedo, Mary K.; Socha, John J.; Salom, Scott M. (Oxford University Press, 2023-05-01)
    The non-native hemlock woolly adelgid (HWA), Adelges tsugae Annand (Hemiptera: Adelgidae), has caused a significant decline of eastern hemlock, Tsuga canadensis L. (Pinales: Pinaceae), and Carolina hemlock, Tsuga caroliniana Engelmann (Pinales: Pinaceae), in eastern North America. Biological control of HWA has focused on the use of 2 Laricobius spp. (Coleoptera: Derodontidae), natural predators of HWA, which require arboreal and subterranean life phases to complete their development. In its subterranean phase, Laricobius spp. are subject to abiotic factors including soil compaction or soil-applied insecticides used to protect hemlock from HWA. This study used 3D X-ray microcomputed tomography (micro-CT) to identify the depth at which Laricobius spp. burrows during its subterranean lifecycle, characterize pupal chamber volume, and determine whether soil compaction had a significant effect on these variables. The mean burrowing depth in the soil of individuals was 27.0 mm ± 14.8 (SD) and 11.4 mm ± 11.8 (SD) at compaction levels of 0.36 and 0.54 g/ cm3, respectively. The mean pupal chamber volume was 11.15 mm3 ± 2.8 (SD) and 7.65 mm3 ± 3.5 (SD) in soil compacted at 0.36 and 0.54 g/cm3, respectively. These data show that soil compaction influences burrowing depth and pupal chamber size for Laricobius spp.This information will help us better identify the effect of soil-applied insecticide residues on estivating Laricobius spp. and soil-applied insecticide residues in the field. Additionally, these results demonstrate the utility of 3D micro-CT in assessing subterranean insect activity in future studies.
  • Pregnancy-induced remodeling of the murine reproductive tract: a longitudinal in vivo magnetic resonance imaging study
    Suarez, Aileen C.; Gimenez, Clara J.; Russell, Serena R.; Wang, Maosen; Munson, Jennifer M.; Myers, Kristin M.; Miller, Kristin S.; Abramowitch, Steven D.; De Vita, Rafaella (Springer, 2024-01-05)
    Mammalian pregnancy requires gradual yet extreme remodeling of the reproductive organs to support the growth of the embryos and their birth. After delivery, the reproductive organs return to their non-pregnant state. As pregnancy has traditionally been understudied, there are many unknowns pertaining to the mechanisms behind this remarkable remodeling and repair process which, when not successful, can lead to pregnancy-related complications such as maternal trauma, pre-term birth, and pelvic floor disorders. This study presents the first longitudinal imaging data that focuses on revealing anatomical alterations of the vagina, cervix, and uterine horns during pregnancy and postpartum using the mouse model. By utilizing advanced magnetic resonance imaging (MRI) technology, T1-weighted and T2-weighted images of the reproductive organs of three mice in their in vivo environment were collected at five time points: non-pregnant, mid-pregnant (gestation day: 9–10), late pregnant (gestation day: 16–17), postpartum (24–72 h after delivery) and three weeks postpartum. Measurements of the vagina, cervix, and uterine horns were taken by analyzing MRI segmentations of these organs. The cross-sectional diameter, length, and volume of the vagina increased in late pregnancy and then returned to non-pregnant values three weeks after delivery. The cross-sectional diameter of the cervix decreased at mid-pregnancy before increasing in late pregnancy. The volume of the cervix peaked at late pregnancy before shortening by 24–72 h postpartum. As expected, the uterus increased in cross-sectional diameter, length, and volume during pregnancy. The uterine horns decreased in size postpartum, ultimately returning to their average non-pregnant size three weeks postpartum. The newly developed methods for acquiring longitudinal in vivo MRI scans of the murine reproductive system can be extended to future studies that evaluate functional and morphological alterations of this system due to pathologies, interventions, and treatments.
  • The Impact of Line-of-Sight and Connected Vehicle Technology on Mitigating and Preventing Crash and Near-Crash Events
    Herbers, Eileen; Doerzaph, Zachary; Stowe, Loren (MDPI, 2024-01-12)
    Line-of-sight (LOS) sensors developed in newer vehicles have the potential to help avoid crash and near-crash scenarios with advanced driving-assistance systems; furthermore, connected vehicle technologies (CVT) also have a promising role in advancing vehicle safety. This study used crash and near-crash events from the Second Strategic Highway Research Program Naturalistic Driving Study (SHRP2 NDS) to reconstruct crash events so that the applicable benefit of sensors in LOS systems and CVT can be compared. The benefits of CVT over LOS systems include additional reaction time before a predicted crash, as well as a lower deceleration value needed to prevent a crash. This work acts as a baseline effort to determine the potential safety benefits of CVT-enabled systems over LOS sensors alone.
  • Head Impact Exposure in Youth and Collegiate American Football
    Choi, Grace B.; Smith, Eric P.; Duma, Stefan M.; Rowson, Steven; Campolettano, Eamon; Kelley, Mireille E.; Jones, Derek A.; Stitzel, Joel D.; Urban, Jillian E.; Genemaras, Amaris; Beckwith, Jonathan G.; Greenwald, Richard M.; Maerlender, Arthur; Crisco, Joseph J. (Springer, 2022-05-04)
    The relationship between head impact and subsequent brain injury for American football players is not well-defined, especially for youth. The objective of this study is to quantify and assess Head Impact Exposure (HIE) metrics among youth and collegiate football players. This multi-season study enrolled 639 unique athletes (354 collegiate; 285 youth, ages 9–14), recording 476,209 head impacts (367,337 collegiate; 108,872 youth) over 971 sessions (480 collegiate; 491 youth). Youth players experienced 43 and 65% fewer impacts per competition and practice, respectively, and lower impact magnitudes compared to collegiate players (95th percentile peak linear acceleration (PLA, g) competition: 45.6 vs 61.9; 95th percentile PLA practice: 42.6 vs 58.8; 95th percentile peak rotational acceleration (PRA, rad·s−2) competition: 2262 vs 4422; 95th percentile PRA practice: 2081 vs 4052; 95th percentile HITsp competition: 25.4 vs 32.8; 95th percentile HITsp practice: 23.9 vs 30.2). Impacts during competition were more frequent and of greater magnitude than during practice at both levels. Quantified comparisons of head impact frequency and magnitude between youth and collegiate athletes reveal HIE differences as a function of age, and expanded insight better informs the development of age-appropriate guidelines for helmet design, prevention measures, standardized testing, brain injury diagnosis, and recovery management.
  • Ultrasonic Bubble Cleaner as a Sustainable Solution
    Howell, Justin; Ham, Emerson; Jung, Sunghwan (MDPI, 2023-10-28)
    We aim to develop a floor-cleaning design by exploiting oscillating bubbles combined with ambient pressure waves to clean various surfaces. Previous studies of this method in lab settings have proven its efficacy, but practical applications, especially concerning real-world conditions like dirt surfaces, remain largely unprobed. Our findings indicate that, excluding a configuration with a heavy mass bottom transducer, all tested configurations achieved approximately 60–70% cleaning performance. A slight improvement in cleaning performance was observed with the introduction of microbubbles, although it was within the error margin. Particularly noteworthy is the substantial reduction in water consumption in configurations with a water pocket, decreasing from 280 mL to a mere 3 mL, marking a significant step toward more environmentally sustainable cleaning practices, such as reduced water usage. This research provides implications for real-world cleaning applications, promising an eco-friendly and efficient cleaning alternative that reduces water usage and handles a variety of materials without causing damage.
  • Efferocytosis is restricted by axon guidance molecule EphA4 via ERK/Stat6/MERTK signaling following brain injury
    Soliman, Eman; Leonard, John; Basso, Erwin K. G.; Gershenson, Ilana; Ju, Jing; Mills, Jatia; de Jager, Caroline; Kaloss, Alexandra M.; Elhassanny, Mohamed; Pereira, Daniela; Chen, Michael; Wang, Xia; Theus, Michelle H. (2023-11-09)
    Background Efferocytosis is a process that removes apoptotic cells and cellular debris. Clearance of these cells alleviates neuroinflammation, prevents the release of inflammatory molecules, and promotes the production of anti-inflammatory cytokines to help maintain tissue homeostasis. The underlying mechanisms by which this occurs in the brain after injury remain ill-defined. Methods We used GFP bone marrow chimeric knockout (KO) mice to demonstrate that the axon guidance molecule EphA4 receptor tyrosine kinase is involved in suppressing MERTK in the brain to restrict efferocytosis of resident microglia and peripheral-derived monocyte/macrophages. Results Single-cell RNAseq identified MERTK expression, the primary receptor involved in efferocytosis, on monocytes, microglia, and a subset of astrocytes in the damaged cortex following brain injury. Loss of EphA4 on infiltrating GFP-expressing immune cells improved functional outcome concomitant with enhanced efferocytosis and overall protein expression of p-MERTK, p-ERK, and p-Stat6. The percentage of GFP+ monocyte/macrophages and resident microglia engulfing NeuN+ or TUNEL+ cells was significantly higher in KO chimeric mice. Importantly, mRNA expression of Mertk and its cognate ligand Gas6 was significantly elevated in these mice compared to the wild-type. Analysis of cell-specific expression showed that p-ERK and p-Stat6 co-localized with MERTK-expressing GFP + cells in the peri-lesional area of the cortex following brain injury. Using an in vitro efferocytosis assay, co-culturing pHrodo-labeled apoptotic Jurkat cells and bone marrow (BM)-derived macrophages, we demonstrate that efferocytosis efficiency and mRNA expression of Mertk and Gas6 was enhanced in the absence of EphA4. Selective inhibitors of ERK and Stat6 attenuated this effect, confirming that EphA4 suppresses monocyte/macrophage efferocytosis via inhibition of the ERK/Stat6 pathway. Conclusions Our findings implicate the ERK/Stat6/MERTK axis as a novel regulator of apoptotic debris clearance in brain injury that is restricted by peripheral myeloid-derived EphA4 to prevent the resolution of inflammation.
  • Megakaryocyte-induced contraction of plasma clots: Cellular mechanisms and structural mechanobiology
    Kim, Oleg V.; Litvinov, Rustem I.; Gagne, Alyssa L.; French, Deborah L.; Brass, Lawrence F.; Weisel, John W. (American Society of Hematology, 2023)
    Non-muscle cell contractility is an essential feature underlying diverse cellular processes such as motility, morphogenesis, division and genome replication, intracellular transport, and secretion. Blood clot contraction is a well-studied process driven by contracting platelets. Megakaryocytes, which are the precursors to platelets, can be found in the bone marrow and in the lungs. Although they express many of the same proteins and structures found in platelets, little is known about their ability to engage with extracellular proteins such as fibrin and contract. Here we have measured the ability of megakaryocytes to compress plasma clots. Megakaryocytes derived from human induced pluripotent stem cells (iMKs) were suspended in human platelet-free blood plasma and stimulated with thrombin. Using real-time macroscale optical tracking, confocal microscopy, and biomechanical measurements, we found that activated iMKs caused macroscopic volumetric clot shrinkage, as well as densification and stiffening of the fibrin network via fibrin-attached plasma membrane protrusions undergoing extension-retraction cycles that cause shortening and bending of fibrin fibers. Contraction induced by iMKs involved two kinetic phases with distinct rates and durations. It was suppressed by inhibitors of non-muscle myosin IIA, actin polymerization, and integrin αIIbβ3-fibrin interactions, indicating that the molecular mechanisms of iMK contractility were similar or identical to those in activated platelets. Our findings provide new insights into megakaryocyte biomechanics and suggest that iMKs can be used as a model system to study platelet contractility. Physiologically, the ability of MKs to contract plasma clots may play a role in the mechanical remodeling of intravascular blood clots and thrombi.
  • Combined computational modeling and experimental study of the biomechanical mechanisms of platelet-driven contraction of fibrin clots
    Michael, Christian; Pancaldi, Francesco; Britton, Samuel; Kim, Oleg V.; Peshkova, Alina D.; Vo, Khoi; Xu, Zhiliang; Litvinov, Rustem I.; Weisel, John W.; Alber, Mark (Nature Portfolio, 2023-08-24)
    While blood clot formation has been relatively well studied, little is known about the mechanisms underlying the subsequent structural and mechanical clot remodeling called contraction or retraction. Impairment of the clot contraction process is associated with both life-threatening bleeding and thrombotic conditions, such as ischemic stroke, venous thromboembolism, and others. Recently, blood clot contraction was observed to be hindered in patients with COVID-19. A three-dimensional multiscale computational model is developed and used to quantify biomechanical mechanisms of the kinetics of clot contraction driven by platelet-fibrin pulling interactions. These results provide important biological insights into contraction of platelet filopodia, the mechanically active thin protrusions of the plasma membrane, described previously as performing mostly a sensory function. The biomechanical mechanisms and modeling approach described can potentially apply to studying other systems in which cells are embedded in a filamentous network and exert forces on the extracellular matrix modulated by the substrate stiffness.
  • Ablative and Immunostimulatory Effects of Histotripsy Ablation in a Murine Osteosarcoma Model
    Hay, Alayna N.; Imran, Khan Mohammad; Hendricks-Wenger, Alissa; Gannon, Jessica M.; Sereno, Jacqueline; Simon, Alex; Lopez, Victor A.; Coutermarsh-Ott, Sheryl; Vlaisavljevich, Eli; Allen, Irving C.; Tuohy, Joanne L. (MDPI, 2023-10-09)
    Background: Osteosarcoma (OS) is the most frequently occurring malignant bone tumor in humans, primarily affecting children and adolescents. Significant advancements in treatment options for OS have not occurred in the last several decades, and the prognosis remains grim with only a 70% rate of 5-year survival. The objective of this study was to investigate the focused ultrasound technique of histotripsy as a novel, noninvasive treatment option for OS. Methods: We utilized a heterotopic OS murine model to establish the feasibility of ablating OS tumors with histotripsy in a preclinical setting. We investigated the local immune response within the tumor microenvironment (TME) via immune cell phenotyping and gene expression analysis. Findings: We established the feasibility of ablating heterotopic OS tumors with ablation characterized microscopically by loss of cellular architecture in targeted regions of tumors. We observed greater populations of macrophages and dendritic cells within treated tumors and the upregulation of immune activating genes 72 h after histotripsy ablation. Interpretation: This study was the first to investigate histotripsy ablation for OS in a preclinical murine model, with results suggesting local immunomodulation within the TME. Our results support the continued investigation of histotripsy as a novel noninvasive treatment option for OS patients to improve clinical outcomes and patient prognosis.
  • Profiling renal dysfunction using Raman chemometric urinalysis, with special reference to COVID19, lupus nephritis, and diabetic nephropathy
    Robertson, John L.; Issa, Amr Sayed; Gomez, Mariana; Sullivan, Kathleen; Senger, Ryan S. (Knowledge Enterprise Journals, 2023-09-30)
    Background: Many systemic and urinary tract diseases alter renal structure and function, including changing the composition of urine. While routine urinalysis (physical properties, sediment evaluation, urine chemistry analytes) is useful in screening, it has limitations on separating disease processes, structural changes, and functional abnormalities. Likewise, while many individual ‘biomarkers’ have been used to screen for disease, they have not met with widespread clinical adoption. The recent COVID19 Pandemic and the recognition of post-acute sequelae SARS-CoV-2 infection (PASC) have highlighted the need for rapid, scalable, economical, and accurate screening tools for managing disease. Aims: Validate a Raman spectroscopy-based screening technology for urine analysis that could be used for recognition and quantification of systemic and renal effects of acute and PASC COVID19 disease. Methods: One hundred ten (110) urine specimens were obtained from consented adults diagnosed with COVID19 disease by RT-PCR and/or proximate (household) contact With RT-PCR-confirmed COVID19 disease. Samples were analyzed using Raman chemometric urinalysis, a technology that detects hundreds of discrete chemicals in urine and applies computational comparison-machine learning to detect COVID19-associated molecular patterns (‘fingerprints’). Results: When compared with the urine multimolecular ‘fingerprints’ of healthy individuals and patients with known systemic diseases (diabetes mellitus, lupus) that alter renal structure and function, patients with acute and PASC COVID19 had unique ‘fingerprints’ indicative of alterations in renal function (i.e. – infection altered urine composition). Differences in disease severity (mild to severe) were reflected by different ‘fingerprints’ in urine. Roughly 20% of hospitalized patients developed a degree of renal dysfunction (decrements in eGFR) that were correlated with distinct changes in urine fingerprints. Conclusion: Raman chemometric urinalysis may be a useful tool in management of patients with COVID19 disease, particularly in detecting patients with evolving renal dysfunction for whom there should be attention to medication use and renal health restoration/preservation.