1,857 results on '"Collins, Sean P"'
Search Results
2. The utility of urine sodium–guided diuresis during acute decompensated heart failure
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Siddiqi, Hasan K., Cox, Zachary L., Stevenson, Lynne W., Damman, Kevin, ter Maaten, Jozine M., Bales, Brian, Han, Jin H., Ivey-Miranda, Juan B., Lindenfeld, JoAnn, Miller, Karen F., Ooi, Henry, Rao, Veena S., Schlendorf, Kelly, Storrow, Alan B., Walsh, Ryan, Wrenn, Jesse, Testani, Jeffrey M., and Collins, Sean P.
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- 2024
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3. Neutrophil-like cells derived from the HL-60 cell-line as a genetically-tractable model for neutrophil degranulation.
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Bhakta, Suhani, Lundgren, Stefan, Sesti, Bethany, Flores, Barbara, Akdogan, Emel, Mercer, Frances, and Collins, Sean
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Humans ,Neutrophils ,HL-60 Cells ,Phagocytosis ,Cell Differentiation ,Granulocyte Precursor Cells ,Cell Degranulation - Abstract
Research on neutrophil biology has been limited by the short life span and limited genetic manipulability of these cells, driving the need for representative and efficient model cell lines. The promyelocytic cell line HL-60 and its subline PLB-985 can be differentiated into neutrophil-like cells (NLCs) and have been used to study neutrophil functions including chemotaxis, phagocytosis, endocytosis, and degranulation. Compared to neutrophils derived from hematopoietic stem cells, NLCs serve as a cost-effective neutrophil model. NLCs derived from both HL-60 and PLB-985 cells have been shown to perform degranulation, an important neutrophil function. However, no study has directly compared the two lines as models for degranulation including their release of different types of mobilizable organelles. Furthermore, Nutridoma, a commercially available supplement, has recently been shown to improve the chemotaxis, phagocytosis, and oxidative burst abilities of NLCs derived from promyelocytic cells, however it is unknown whether this reagent also improves the degranulation ability of NLCs. Here, we show that NLCs derived from both HL-60 and PLB-985 cells are capable of degranulating, with each showing markers for the release of multiple types of secretory organelles, including primary granules. We also show that differentiating HL-60 cells using Nutridoma does not enhance their degranulation activity over NLCs differentiated using Dimethyl Sulfoxide (DMSO) plus Granulocyte-colony stimulating factor (G-CSF). Finally, we show that promyelocytic cells can be genetically engineered and differentiated using these methods, to yield NLCs with a defect in degranulation. Our results indicate that both cell lines serve as effective models for investigating the mechanisms of neutrophil degranulation, which can advance our understanding of the roles of neutrophils in inflammation and immunity.
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- 2024
4. Efficient Hydrogen Evolution from Dimethylamine Borane, Ammonia Borane and Sodium Borohydride Catalyzed by Ruthenium and Platinum Nanoparticles Stabilized by an Amine Modified Polymer Immobilized Ionic Liquid: a Comparative Study
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Alharbi, Adhwa A., Wills, Corinne, Dixon, Casey, Arca, Elisabetta, Chamberlain, Thomas W., Griffiths, Anthony, Collins, Sean M., Wu, Kejun, Yan, Han, Bourne, Richard A., Knight, Julian G., and Doherty, Simon
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- 2024
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5. Microscopic crystallographic analysis of dislocations in molecular crystals
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Pham, Sang T., Koniuch, Natalia, Wynne, Emily, Brown, Andy, and Collins, Sean M.
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Condensed Matter - Materials Science ,Condensed Matter - Mesoscale and Nanoscale Physics - Abstract
Organic molecular crystals encompass a vast range of materials from pharmaceuticals to organic optoelectronics and proteins to waxes in biological and industrial settings. Crystal defects from grain boundaries to dislocations are known to play key roles in mechanisms of growth and also in the functional properties of molecular crystals. In contrast to the precise analysis of individual defects in metals, ceramics, and inorganic semiconductors enabled by electron microscopy, significantly greater ambiguity remains in the experimental determination of individual dislocation character and slip systems in molecular materials. In large part, nanoscale dislocation analysis in molecular crystals has been hindered by the severely constrained electron exposures required to avoid irreversibly degrading these crystals. Here, we present a low-dose, single-exposure approach enabling nanometre-resolved analysis of individual extended dislocations in molecular crystals. We demonstrate the approach for a range of crystal types to reveal dislocation character and operative slip systems unambiguously., Comment: Manuscript (14 pages, 4 figures) and Supplementary Material (32 pages, 19 figures) in a single PDF file
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- 2023
6. Interfacial alloying between lead halide perovskite crystals and hybrid glasses.
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Li, Xuemei, Huang, Wengang, Krajnc, Andraž, Yang, Yuwei, Shukla, Atul, Lee, Jaeho, Ghasemi, Mehri, Martens, Isaac, Chan, Bun, Appadoo, Dominique, Chen, Peng, Wen, Xiaoming, Steele, Julian, Hackbarth, Haira, Sun, Qiang, Mali, Gregor, Lin, Rijia, Bedford, Nicholas, Chen, Vicki, Cheetham, Anthony, Tizei, Luiz, Collins, Sean, Wang, Lianzhou, and Hou, Jingwei
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The stellar optoelectronic properties of metal halide perovskites provide enormous promise for next-generation optical devices with excellent conversion efficiencies and lower manufacturing costs. However, there is a long-standing ambiguity as to whether the perovskite surface/interface (e.g. structure, charge transfer or source of off-target recombination) or bulk properties are the more determining factor in device performance. Here we fabricate an array of CsPbI3 crystal and hybrid glass composites by sintering and globally visualise the property-performance landscape. Our findings reveal that the interface is the primary determinant of the crystal phases, optoelectronic quality, and stability of CsPbI3. In particular, the presence of a diffusion alloying layer is discovered to be critical for passivating surface traps, and beneficially altering the energy landscape of crystal phases. However, high-temperature sintering results in the promotion of a non-stoichiometric perovskite and excess traps at the interface, despite the short-range structure of halide is retained within the alloying layer. By shedding light on functional hetero-interfaces, our research offers the key factors for engineering high-performance perovskite devices.
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- 2023
7. Signaling dynamics distinguish high- and low-priority neutrophil chemoattractant receptors
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Lundgren, Stefan M, Rocha-Gregg, Briana L, Akdoğan, Emel, Mysore, Maya N, Hayes, Samantha, and Collins, Sean R
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Biochemistry and Cell Biology ,Biological Sciences ,Infectious Diseases ,Emerging Infectious Diseases ,Prevention ,Vaccine Related ,Biodefense ,1.1 Normal biological development and functioning ,Underpinning research ,Inflammatory and immune system ,Humans ,Neutrophils ,Leukotriene B4 ,Chemotactic Factors ,Interleukin-8 ,Signal Transduction ,Biochemistry and cell biology - Abstract
Human neutrophils respond to multiple chemoattractants to guide their migration from the vasculature to sites of infection and injury, where they clear pathogens and amplify inflammation. To properly focus their responses during this complex navigation, neutrophils prioritize pathogen- and injury-derived signals over long-range inflammatory signals, such as the leukotriene LTB4, secreted by host cells. Different chemoattractants can also drive qualitatively different modes of migration even though their receptors couple to the same Gαi family of G proteins. Here, we used live-cell imaging to demonstrate that the responses differed in their signaling dynamics. Low-priority chemoattractants caused transient responses, whereas responses to high-priority chemoattractants were sustained. We observed this difference in both primary neutrophils and differentiated HL-60 cells, for downstream signaling mediated by Ca2+, a major regulator of secretion, and Cdc42, a primary regulator of polarity and cell steering. The rapid attenuation of Cdc42 activation in response to LTB4 depended on the phosphorylation sites Thr308 and Ser310 in the carboxyl-terminal tail of its receptor LTB4R in a manner independent of endocytosis. Mutation of these residues to alanine impaired chemoattractant prioritization, although it did not affect chemoattractant-dependent differences in migration persistence. Our results indicate that distinct temporal regulation of shared signaling pathways distinguishes between receptors and contributes to chemoattractant prioritization.
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- 2023
8. Whole-genome screens reveal regulators of differentiation state and context-dependent migration in human neutrophils.
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Belliveau, Nathan, Footer, Matthew, Akdoǧan, Emel, van Loon, Aaron, Collins, Sean, and Theriot, Julie
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Humans ,Neutrophils ,Cell Differentiation ,Leukocytes ,Cell Movement ,Actin Cytoskeleton - Abstract
Neutrophils are the most abundant leukocyte in humans and provide a critical early line of defense as part of our innate immune system. We perform a comprehensive, genome-wide assessment of the molecular factors critical to proliferation, differentiation, and cell migration in a neutrophil-like cell line. Through the development of multiple migration screen strategies, we specifically probe directed (chemotaxis), undirected (chemokinesis), and 3D amoeboid cell migration in these fast-moving cells. We identify a role for mTORC1 signaling in cell differentiation, which influences neutrophil abundance, survival, and migratory behavior. Across our individual migration screens, we identify genes involved in adhesion-dependent and adhesion-independent cell migration, protein trafficking, and regulation of the actomyosin cytoskeleton. This genome-wide screening strategy, therefore, provides an invaluable approach to the study of neutrophils and provides a resource that will inform future studies of cell migration in these and other rapidly migrating cells.
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- 2023
9. A complex of Wnt/planar cell polarity signaling components Vangl1 and Fzd7 drives glioblastoma multiforme malignant properties
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Dreyer, Courtney A, VanderVorst, Kacey, Natwick, Dean, Bell, George, Sood, Prachi, Hernandez, Maria, Angelastro, James M, Collins, Sean R, and Carraway, Kermit L
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Brain Cancer ,Cancer ,Neurosciences ,Rare Diseases ,Brain Disorders ,2.1 Biological and endogenous factors ,Humans ,Mice ,Animals ,Glioblastoma ,Cell Polarity ,Actins ,Wnt Signaling Pathway ,Cell Proliferation ,Cell Line ,Tumor ,Noncanonical Wnt signaling ,Planar cell polarity ,Motility ,Proliferation ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Targeting common oncogenic drivers of glioblastoma multiforme (GBM) in patients has remained largely ineffective, raising the possibility that alternative pathways may contribute to tumor aggressiveness. Here we demonstrate that Vangl1 and Fzd7, components of the non-canonical Wnt planar cell polarity (Wnt/PCP) signaling pathway, promote GBM malignancy by driving cellular proliferation, migration, and invasiveness, and engage Rho GTPases to promote cytoskeletal rearrangements and actin dynamics in migrating GBM cells. Mechanistically, we uncover the existence of a novel Vangl1/Fzd7 complex at the leading edge of migrating GBM cells and propose that this complex is critical for the recruitment of downstream effectors to promote tumor progression. Moreover, we observe that depletion of FZD7 results in a striking suppression of tumor growth and latency and extends overall survival in an intracranial mouse xenograft model. Our observations support a novel mechanism by which Wnt/PCP components Vangl1 and Fzd7 form a complex at the leading edge of migratory GBM cells to engage downstream effectors that promote actin cytoskeletal rearrangements dynamics. Our findings suggest that interference with Wnt/PCP pathway function may offer a novel therapeutic strategy for patients diagnosed with GBM.
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- 2023
10. Hydroxychloroquine for pre-exposure prophylaxis of COVID-19 in health care workers: a randomized, multicenter, placebo-controlled trial Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine (HERO-HCQ)
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Naggie, Susanna, Milstone, Aaron, Castro, Mario, Collins, Sean P, Lakshmi, Seetha, Anderson, Deverick J, Cahuayme-Zuniga, Lizbeth, Turner, Kisha Batey, Cohen, Lauren W, Currier, Judith, Fraulo, Elizabeth, Friedland, Anne, Garg, Jyotsna, George, Anoop, Mulder, Hillary, Olson, Rachel E, O'Brien, Emily C, Rothman, Russell L, Shenkman, Elizabeth, Shostak, Jack, Woods, Christopher W, Anstrom, Kevin J, Hernandez, Adrian F, and Program, HERO Research
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Biomedical and Clinical Sciences ,Clinical Sciences ,Prevention ,Emerging Infectious Diseases ,Lung ,Infectious Diseases ,Clinical Research ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Infection ,Good Health and Well Being ,Humans ,COVID-19 ,SARS-CoV-2 ,Hydroxychloroquine ,Pre-Exposure Prophylaxis ,COVID-19 Drug Treatment ,Health Personnel ,Treatment Outcome ,Health care workers ,Trial design ,HERO Research Program ,Microbiology ,Medical Microbiology ,Public Health and Health Services ,Clinical sciences ,Epidemiology ,Public health - Abstract
ObjectivesTo determine whether hydroxychloroquine (HCQ) is safe and effective at preventing COVID-19 infections among health care workers (HCWs).MethodsIn a 1: 1 randomized, placebo-controlled, double-blind, parallel-group, superiority trial at 34 US clinical centers, 1360 HCWs at risk for COVID-19 infection were enrolled between April and November 2020. Participants were randomized to HCQ or matched placebo. The HCQ dosing included a loading dose of HCQ 600 mg twice on day 1, followed by 400 mg daily for 29 days. The primary outcome was a composite of confirmed or suspected COVID-19 clinical infection by day 30, defined as new-onset fever, cough, or dyspnea and either a positive SARS-CoV-2 polymerase chain reaction test (confirmed) or a lack of confirmatory testing due to local restrictions (suspected).ResultsStudy enrollment closed before full accrual due to recruitment challenges. The primary end point occurred in 41 (6.0%) participants receiving HCQ and 53 (7.8%) participants receiving placebo. No difference in the proportion of participants experiencing clinical infection (estimated difference of -1.8%, 95% confidence interval -4.6-0.9%, P = 0.20) was identified nor any significant safety issues.ConclusionOral HCQ taken as prescribed appeared safe among HCWs. No significant clinical benefits were observed. The study was not powered to detect a small but potentially important reduction in infection.Trial registrationNCT04334148.
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- 2023
11. Medication Discussions With Patients With Cardiovascular Disease in the Emergency Department: An Opportunity for Emergency Nurses to Engage Patients to Support Medication Reconciliation.
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Stolldorf, Deonni, Jones, Abby, Miller, Karen, Paz, Hadassah, Danesh, Valerie, Collins, Sean, Dietrich, Mary, Storrow, Alan, and Mumma, Bryn
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Cardiovascular ,Emergency department ,Medication ,Medication reconciliation ,Patient involvement ,Adult ,Humans ,Middle Aged ,Medication Reconciliation ,Cross-Sectional Studies ,Cardiovascular Diseases ,Emergency Service ,Hospital ,Health Literacy - Abstract
INTRODUCTION: This study aimed to investigate the level of patient involvement in medication reconciliation processes and factors associated with that involvement in patients with cardiovascular disease presenting to the emergency department. METHODS: An observational and cross-sectional design was used. Patients with cardiovascular disease presenting to the adult emergency department of an academic medical center completed a structured survey inclusive of patient demographics and measures related to the study concepts. Data abstracted from the electronic health record included the patients medical history and emergency department visit data. Our multivariable model adjusted for age, gender, education, difficulty paying bills, health status, numeracy, health literacy, and medication knowledge and evaluated patient involvement in medication discussions as an outcome. RESULTS: Participants (N = 93) median age was 59 years (interquartile range 51-67), 80.6% were white, 96.8% were not Hispanic, and 49.5% were married or living with a partner. Approximately 41% reported being employed and 36.9% reported an annual household income of
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- 2023
12. Leading edge competition promotes context-dependent responses to receptor inputs to resolve directional dilemmas in neutrophil migration
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Hadjitheodorou, Amalia, Bell, George RR, Ellett, Felix, Irimia, Daniel, Tibshirani, Robert, Collins, Sean R, and Theriot, Julie A
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Biochemistry and Cell Biology ,Biological Sciences ,1.1 Normal biological development and functioning ,Underpinning research ,Neutrophils ,Cell Movement ,Carrier Proteins ,Cdc42 ,cytoskeleton ,microfluidics ,motility ,neutrophils ,optogenetics ,polarity ,statistical learning ,Biochemistry and cell biology - Abstract
Maintaining persistent migration in complex environments is critical for neutrophils to reach infection sites. Neutrophils avoid getting trapped, even when obstacles split their front into multiple leading edges. How they re-establish polarity to move productively while incorporating receptor inputs under such conditions remains unclear. Here, we challenge chemotaxing HL60 neutrophil-like cells with symmetric bifurcating microfluidic channels to probe cell-intrinsic processes during the resolution of competing fronts. Using supervised statistical learning, we demonstrate that cells commit to one leading edge late in the process, rather than amplifying structural asymmetries or early fluctuations. Using optogenetic tools, we show that receptor inputs only bias the decision similarly late, once mechanical stretching begins to weaken each front. Finally, a retracting edge commits to retraction, with ROCK limiting sensitivity to receptor inputs until the retraction completes. Collectively, our results suggest that cell edges locally adopt highly stable protrusion/retraction programs that are modulated by mechanical feedback.
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- 2023
13. Vangl-dependent Wnt/planar cell polarity signaling mediates collective breast carcinoma motility and distant metastasis
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VanderVorst, Kacey, Dreyer, Courtney A, Hatakeyama, Jason, Bell, George RR, Learn, Julie A, Berg, Anastasia L, Hernandez, Maria, Lee, Hyun, Collins, Sean R, and Carraway, Kermit L
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Breast Cancer ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Mice ,Wnt Signaling Pathway ,Cell Polarity ,Neoplasms ,Cell Movement ,Collective cell migration ,Planar cell polarity ,Non-canonical Wnt ,Metastasis ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundIn light of the growing appreciation for the role of collective cell motility in metastasis, a deeper understanding of the underlying signaling pathways will be critical to translating these observations to the treatment of advanced cancers. Here, we examine the contribution of Wnt/planar cell polarity (Wnt/PCP), one of the non-canonical Wnt signaling pathways and defined by the involvement of the tetraspanin-like proteins Vangl1 and Vangl2, to breast tumor cell motility, collective cell invasiveness and mammary tumor metastasis.MethodsVangl1 and Vangl2 knockdown and overexpression and Wnt5a stimulation were employed to manipulate Wnt/PCP signaling in a battery of breast cancer cell lines representing all breast cancer subtypes, and in tumor organoids from MMTV-PyMT mice. Cell migration was assessed by scratch and organoid invasion assays, Vangl protein subcellular localization was assessed by confocal fluorescence microscopy, and RhoA activation was assessed in real time by fluorescence imaging with an advanced FRET biosensor. The impact of Wnt/PCP suppression on mammary tumor growth and metastasis was assessed by determining the effect of conditional Vangl2 knockout on the MMTV-NDL mouse mammary tumor model.ResultsWe observed that Vangl2 knockdown suppresses the motility of all breast cancer cell lines examined, and overexpression drives the invasiveness of collectively migrating MMTV-PyMT organoids. Vangl2-dependent RhoA activity is localized in real time to a subpopulation of motile leader cells displaying a hyper-protrusive leading edge, Vangl protein is localized to leader cell protrusions within leader cells, and actin cytoskeletal regulator RhoA is preferentially activated in the leader cells of a migrating collective. Mammary gland-specific knockout of Vangl2 results in a striking decrease in lung metastases in MMTV-NDL mice, but does not impact primary tumor growth characteristics.ConclusionsWe conclude that Vangl-dependent Wnt/PCP signaling promotes breast cancer collective cell migration independent of breast tumor subtype and facilitates distant metastasis in a genetically engineered mouse model of breast cancer. Our observations are consistent with a model whereby Vangl proteins localized at the leading edge of leader cells in a migrating collective act through RhoA to mediate the cytoskeletal rearrangements required for pro-migratory protrusion formation.
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- 2023
14. Flagella-driven motility is a target of human Paneth cell defensin activity
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Akahoshi, Douglas T, Natwick, Dean E, Yuan, Weirong, Lu, Wuyuan, Collins, Sean R, and Bevins, Charles L
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Microbiology ,Biochemistry and Cell Biology ,Biological Sciences ,Infectious Diseases ,Prevention ,Emerging Infectious Diseases ,Biotechnology ,Digestive Diseases ,Animals ,Humans ,Paneth Cells ,Flagellin ,Anti-Infective Agents ,Bacteria ,Flagella ,Mammals ,Immunology ,Medical Microbiology ,Virology ,Medical microbiology - Abstract
In the mammalian intestine, flagellar motility can provide microbes competitive advantage, but also threatens the spatial segregation established by the host at the epithelial surface. Unlike microbicidal defensins, previous studies indicated that the protective activities of human α-defensin 6 (HD6), a peptide secreted by Paneth cells of the small intestine, resides in its remarkable ability to bind microbial surface proteins and self-assemble into protective fibers and nets. Given its ability to bind flagellin, we proposed that HD6 might be an effective inhibitor of bacterial motility. Here, we utilized advanced automated live cell fluorescence imaging to assess the effects of HD6 on actively swimming Salmonella enterica in real time. We found that HD6 was able to effectively restrict flagellar motility of individual bacteria. Flagellin-specific antibody, a classic inhibitor of flagellar motility that utilizes a mechanism of agglutination, lost its activity at low bacterial densities, whereas HD6 activity was not diminished. A single amino acid variant of HD6 that was able to bind flagellin, but not self-assemble, lost ability to inhibit flagellar motility. Together, these results suggest a specialized role of HD6 self-assembly into polymers in targeting and restricting flagellar motility.
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- 2023
15. Modeling Subcellular Protein Recruitment Dynamics for Synthetic Biology
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Badu-Nkansah, Kwabena A, Sernas, Diana, Natwick, Dean E, and Collins, Sean R
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Biochemistry and Cell Biology ,Biological Sciences ,Cell Membrane ,Diffusion ,Optogenetics ,Signal Transduction ,Synthetic Biology ,Compartmentalization ,Localization ,Mathematical modeling ,Plasma membrane ,Protein dynamics ,Protein recruitment ,Signal transduction ,iLID ,Other Chemical Sciences ,Developmental Biology ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
Compartmentalized protein recruitment is a fundamental feature of signal transduction. Accordingly, the cell cortex is a primary site of signaling supported by the recruitment of protein regulators to the plasma membrane. Recent emergence of optogenetic strategies designed to control localized protein recruitment has offered valuable toolsets for investigating spatiotemporal dynamics of associated signaling mechanisms. However, determining proper recruitment parameters is important for optimizing synthetic control. In this chapter, we describe a stepwise process for building linear differential equation models that characterize the kinetics and spatial distribution of optogenetic protein recruitment to the plasma membrane. Specifically, we outline how to construct (1) ordinary differential equations that capture the kinetics, efficiency, and magnitude of recruitment and (2) partial differential equations that model spatial recruitment dynamics and diffusion. Additionally, we explore how these models can be used to evaluate the overall system performance and determine how component parameters can be tuned to optimize synthetic recruitment.
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- 2023
16. Outcomes of the National Heart, Lung, and Blood Institute K12 program in emergency care research: 7‐year follow‐up
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Morris, Cynthia D, Cook, Jennifer NB, Lin, Amber, Scott, Jane D, Kuppermann, Nathan, Callaway, Clifton W, Yealy, Donald M, Lowe, Robert A, Richardson, Lynne D, Kimmel, Stephen, Holmes, James F, Collins, Sean, Becker, Lance B, Storrow, Alan B, Newgard, Harrison J, Baren, Jill, and Newgard, Craig D
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Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Research ,Awards and Prizes ,Biomedical Research ,Cohort Studies ,Emergency Medical Services ,Female ,Follow-Up Studies ,Humans ,Male ,National Heart ,Lung ,and Blood Institute (U.S.) ,National Institutes of Health (U.S.) ,United States ,Public Health and Health Services ,Emergency & Critical Care Medicine ,Clinical sciences - Abstract
BackgroundLong-term follow-up for clinician-scientist training programs is sparse. We describe the outcomes of clinician-scientist scholars in the National Heart Lung and Blood Institute (NHLBI) K12 program in emergency care research up to 8.7 years after matriculation in the program.MethodsThis was a cohort study of faculty clinician-scientist scholars enrolled in a NHLBI K12 research training program at 6 sites across the US, with median follow-up 7.7 years (range 5.7-8.7 years) from the date of matriculation. Scholars completed electronic surveys in 2017 and 2019, with the 2019 survey collecting information for their current work setting, percent time for research, and grant funding from all sources. We used NIH RePorter and online resources to verify federal grants through March 2021. The primary outcome was a funded career development award (CDA) or research project grant (RPG) where the scholar was principal investigator. We included funding from all federal sources and national foundations.ResultsThere were 43 scholars, including 16 (37%) women. Over the follow-up period, 32 (74%) received an individual CDA or RPG, with a median of 36 months (range 9-83 months) after entering the program. Of the 43 scholars, 23 (54%) received a CDA and 22 (51%) received an RPG, 7 (16%) of which were R01s. Of the 23 scholars who received a CDA, 13 (56%) subsequently had an RPG funded. Time to CDA or RPG did not differ by sex (women vs. men log-rank test p = 0.27) or specialty training (emergency medicine versus other specialties, p = 0.59).ConclusionsAfter 7 years of follow-up for this NHLBI K12 emergency care research training program, three quarters of clinician-scientist scholars had obtained CDA or RPG funding, with no notable differences by sex or clinical training.
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- 2022
17. Unveiling the interaction mechanisms of electron and X-ray radiation with halide perovskite semiconductors using scanning nano-probe diffraction
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Orri, Jordi Ferrer, Doherty, Tiarnan A. S., Johnstone, Duncan, Collins, Sean M., Simons, Hugh, Midgley, Paul A., Ducati, Caterina, and Stranks, Samuel D.
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Condensed Matter - Materials Science ,Physics - Applied Physics - Abstract
The interaction of high-energy electrons and X-ray photons with soft semiconductors such as halide perovskites is essential for the characterisation and understanding of these optoelectronic materials. Using nano-probe diffraction techniques, which can investigate physical properties on the nanoscale, we perform studies of the interaction of electron and X-ray radiation with state-of-the-art (FA$_{0.79}$MA$_{0.16}$Cs$_{0.05}$)Pb(I$_{0.83}$Br$_{0.17}$)$_3$ hybrid halide perovskite films (FA, formamidinium; MA, methylammonium). We track the changes in the local crystal structure as a function of fluence using scanning electron diffraction and synchrotron nano X-ray diffraction techniques. We identify perovskite grains from which additional reflections, corresponding to PbBr$_2$, appear as a crystalline degradation phase after fluences of ~200 e$^-${\AA}$^{-2}$. These changes are concomitant with the formation of small PbI$_2$ crystallites at the adjacent high-angle grain boundaries, with the formation of pinholes, and with a phase transition from tetragonal to cubic. A similar degradation pathway is caused by photon irradiation in nano-X-ray diffraction, suggesting common underlying mechanisms. Our approach explores the radiation limits of these materials and provides a description of the degradation pathways on the nanoscale. Addressing high-angle grain boundaries will be critical for the further improvement of halide polycrystalline film stability, especially for applications vulnerable to high-energy radiation such as space photovoltaics., Comment: 25 pages, 5 figures
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- 2022
18. Implementation of a transition of care pathway for low-risk patients presenting to the emergency department with venous thromboembolism
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Baird, Alexandra Moran, Aday, Aaron W., Sullivan, Alexander E., Street, Tiffany, Barrett, Tyler W., Collins, Sean P., Stubblefield, William B., DNP, Megan M. Shifrin, and Beckman, Joshua A.
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- 2024
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19. Derivation and external validation of a portable method to identify patients with pulmonary embolism from radiology reports: The READ-PE algorithm
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Christensen, Matthew A., Stubblefield, William B., Wang, Grace, Altheimer, Alyssa, Ouadah, Sarah J., Birrenkott, Drew A., Peters, Gregory A., Prucnal, Christiana, Harshbarger, Savanah, Chang, Kyle, Storrow, Alan B., Ward, Michael J., Collins, Sean P., Kabrhel, Christopher, and Wrenn, Jesse O.
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- 2024
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20. Contemporary Decongestion Strategies in Patients Hospitalized for Heart Failure: A National Community-Based Cohort Study
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Zheng, Jimmy, Ambrosy, Andrew P., Bhatt, Ankeet S., Collins, Sean P., Flint, Kelsey M., Fonarow, Gregg C., Fudim, Marat, Greene, Stephen J., Lala, Anuradha, Testani, Jeffrey M., Varshney, Anubodh S., Wi, Ryan S.K., and Sandhu, Alexander T.
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- 2024
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21. Host cells subdivide nutrient niches into discrete biogeographical microhabitats for gut microbes
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Liou, Megan J, Miller, Brittany M, Litvak, Yael, Nguyen, Henry, Natwick, Dean E, Savage, Hannah P, Rixon, Jordan A, Mahan, Scott P, Hiyoshi, Hirotaka, Rogers, Andrew WL, Velazquez, Eric M, Butler, Brian P, Collins, Sean R, McSorley, Stephen J, Harshey, Rasika M, Byndloss, Mariana X, Simon, Scott I, and Bäumler, Andreas J
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Microbiology ,Medical Microbiology ,Biomedical and Clinical Sciences ,Biological Sciences ,Biodefense ,Digestive Diseases ,Microbiome ,Foodborne Illness ,Infectious Diseases ,Emerging Infectious Diseases ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Infection ,Escherichia coli ,Gastrointestinal Microbiome ,Humans ,Nitrates ,Nutrients ,Salmonella typhimurium ,Enterobacterales ,Salmonella ,biogeography ,chemotaxis ,gut microbiota ,nitrate ,nutrient niches ,Immunology ,Biochemistry and cell biology ,Medical microbiology - Abstract
Changes in the microbiota composition are associated with many human diseases, but factors that govern strain abundance remain poorly defined. We show that a commensal Escherichia coli strain and a pathogenic Salmonella enterica serovar Typhimurium isolate both utilize nitrate for intestinal growth, but each accesses this resource in a distinct biogeographical niche. Commensal E. coli utilizes epithelial-derived nitrate, whereas nitrate in the niche occupied by S. Typhimurium is derived from phagocytic infiltrates. Surprisingly, avirulent S. Typhimurium was shown to be unable to utilize epithelial-derived nitrate because its chemotaxis receptors McpB and McpC exclude the pathogen from the niche occupied by E. coli. In contrast, E. coli invades the niche constructed by S. Typhimurium virulence factors and confers colonization resistance by competing for nitrate. Thus, nutrient niches are not defined solely by critical resources, but they can be further subdivided biogeographically within the host into distinct microhabitats, thereby generating new niche opportunities for distinct bacterial species.
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- 2022
22. Efficacy and Safety of Dapagliflozin in Patients With Acute Heart Failure
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Cox, Zachary L., Collins, Sean P., Hernandez, Gabriel A., McRae, A. Thomas, III, Davidson, Beth T., Adams, Kirkwood, Aaron, Mark, Cunningham, Luke, Jenkins, Cathy A., Lindsell, Christopher J., Harrell, Frank E., Jr., Kampe, Christina, Miller, Karen F., Stubblefield, William B., and Lindenfeld, JoAnn
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- 2024
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23. On the use of solid 133Ba sources as surrogate for liquid 131I in SPECT/CT calibration: a European multi-centre evaluation
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Tran-Gia, Johannes, Denis-Bacelar, Ana M., Ferreira, Kelley M., Robinson, Andrew P., Bobin, Christophe, Bonney, Lara M., Calvert, Nicholas, Collins, Sean M., Fenwick, Andrew J., Finocchiaro, Domenico, Fioroni, Federica, Giannopoulou, Katerina, Grassi, Elisa, Heetun, Warda, Jewitt, Stephanie J., Kotzasarlidou, Maria, Ljungberg, Michael, Lourenço, Valérie, McGowan, Daniel R., Mewburn-Crook, Jamie, Sabot, Benoit, Scuffham, James, Sjögreen Gleisner, Katarina, Solc, Jaroslav, Thiam, Cheick, Tipping, Jill, Wevrett, Jill, and Lassmann, Michael
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- 2023
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24. Mapping nanocrystalline disorder within an amorphous metal–organic framework
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Sapnik, Adam F., Sun, Chao, Laulainen, Joonatan E. M., Johnstone, Duncan N., Brydson, Rik, Johnson, Timothy, Midgley, Paul A., Bennett, Thomas D., and Collins, Sean M.
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- 2023
- Full Text
- View/download PDF
25. WASP integrates substrate topology and cell polarity to guide neutrophil migration
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Brunetti, Rachel M, Kockelkoren, Gabriele, Raghavan, Preethi, Bell, George RR, Britain, Derek, Puri, Natasha, Collins, Sean R, Leonetti, Manuel D, Stamou, Dimitrios, and Weiner, Orion D
- Subjects
Actin Cytoskeleton ,Cell Movement ,Cell Polarity ,HEK293 Cells ,HL-60 Cells ,Humans ,Neutrophils ,Substrate Specificity ,Wiskott-Aldrich Syndrome Protein ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
To control their movement, cells need to coordinate actin assembly with the geometric features of their substrate. Here, we uncover a role for the actin regulator WASP in the 3D migration of neutrophils. We show that WASP responds to substrate topology by enriching to sites of inward, substrate-induced membrane deformation. Superresolution imaging reveals that WASP preferentially enriches to the necks of these substrate-induced invaginations, a distribution that could support substrate pinching. WASP facilitates recruitment of the Arp2/3 complex to these sites, stimulating local actin assembly that couples substrate features with the cytoskeleton. Surprisingly, WASP only enriches to membrane deformations in the front half of the cell, within a permissive zone set by WASP's front-biased regulator Cdc42. While WASP KO cells exhibit relatively normal migration on flat substrates, they are defective at topology-directed migration. Our data suggest that WASP integrates substrate topology with cell polarity by selectively polymerizing actin around substrate-induced membrane deformations in the front half of the cell.
- Published
- 2022
26. Empagliflozin in Heart Failure: Regional Nephron Sodium Handling Effects
- Author
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Rao, Veena S., Ivey-Miranda, Juan B., Cox, Zachary L., Moreno-Villagomez, Julieta, Maulion, Christopher, Bellumkonda, Lavanya, Chang, John, Field, M. Paul, Wiederin, Daniel R., Butler, Javed, Collins, Sean P., Turner, Jeffrey M., Wilson, F. Perry, Inzucchi, Silvio E., Wilcox, Christopher S., Ellison, David H., and Testani, Jeffrey M.
- Published
- 2024
- Full Text
- View/download PDF
27. Long‐term mortality after tuberculosis treatment among persons living with HIV in Haiti
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Joseph, Yvetot, Yao, Zhiwen, Dua, Akanksha, Severe, Patrice, Collins, Sean E, Bang, Heejung, Jean‐Juste, Marc Antoine, Ocheretina, Oksana, Apollon, Alexandra, McNairy, Margaret L, Dupnik, Kathryn, Cremieux, Etienne, Byrne, Anthony, Pape, Jean W, and Koenig, Serena P
- Subjects
HIV/AIDS ,Tuberculosis ,Rare Diseases ,Infectious Diseases ,Prevention ,Clinical Research ,Infection ,Good Health and Well Being ,Cohort Studies ,HIV Infections ,Haiti ,Humans ,Prospective Studies ,HIV ,AIDS ,tuberculosis ,long-term mortality ,opportunistic infections ,Clinical Sciences ,Public Health and Health Services ,Other Medical and Health Sciences - Abstract
IntroductionLong-term mortality among TB survivors appears to be higher than control populations without TB in many settings. However, data are limited among persons with HIV (PWH). We assessed the association between cured TB and long-term mortality among persons with PWH in Haiti.MethodsA prospective cohort of PWH from the CIPRA HT-001 trial was followed from study enrolment (August 2005 to July 2008) to study closure (December 2018) to compare mortality between participants with and without TB. The index date for the survival analysis was defined as 240 days after TB diagnosis or randomization date. Time to death was described using Kaplan-Meier curves, and log-rank tests were used to compare time to death between the TB and no-TB cohorts. The association between TB and long-term mortality was estimated with multivariable Cox models.ResultsOf the 816 participants in the CIPRA HT-001 trial, 77 were excluded for a history of TB prior to study enrolment and 31 were excluded due to death or attrition prior to the index date, leaving 574 in the no-TB and 134 in the TB cohort. Twenty-four (17.9%) participants in the TB and 48 (8.4%) in the no-TB cohort died during follow-up. Five and 10-year mortality rates were 14.2% and 17.9% respectively, in the TB cohort, and 6.1% and 8.4% in the no-TB cohort. In Kaplan-Meier analysis, participants in the TB cohort had a significantly shorter time to death (log-rank p
- Published
- 2021
28. Scanning electron diffraction tomography of strain
- Author
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Tovey, Robert, Johnstone, Duncan N., Collins, Sean M., Lionheart, William R. B., Midgley, Paul A., Benning, Martin, and Schönlieb, Carola-Bibiane
- Subjects
Mathematics - Numerical Analysis ,Condensed Matter - Materials Science - Abstract
Strain engineering is used to obtain desirable materials properties in a range of modern technologies. Direct nanoscale measurement of the three-dimensional strain tensor field within these materials has however been limited by a lack of suitable experimental techniques and data analysis tools. Scanning electron diffraction has emerged as a powerful tool for obtaining two-dimensional maps of strain components perpendicular to the incident electron beam direction. Extension of this method to recover the full three-dimensional strain tensor field has been restricted though by the absence of a formal framework for tensor tomography using such data. Here, we show that it is possible to reconstruct the full non-symmetric strain tensor field as the solution to an ill-posed tensor tomography inverse problem. We then demonstrate the properties of this tomography problem both analytically and computationally, highlighting why incorporating precession to perform scanning precession electron diffraction may be important. We establish a general framework for non-symmetric tensor tomography and demonstrate computationally its applicability for achieving strain tomography with scanning precession electron diffraction data.
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- 2020
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29. Optimized iLID Membrane Anchors for Local Optogenetic Protein Recruitment
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Natwick, Dean E and Collins, Sean R
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Biochemistry and Cell Biology ,Biological Sciences ,Bioengineering ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Cell Membrane ,Cell Surface Extensions ,Gene Expression ,HEK293 Cells ,Humans ,Intracellular Space ,Kinetics ,Light ,Membrane Fusion Proteins ,Models ,Theoretical ,Optogenetics ,Plasmids ,Protein Domains ,Protein Multimerization ,Protein Transport ,Signal Transduction ,optogenetics ,mathematical modeling ,Medicinal and Biomolecular Chemistry ,Biomedical Engineering ,Biochemistry and cell biology ,Bioinformatics and computational biology - Abstract
Optogenetic protein dimerization systems are powerful tools to investigate the biochemical networks that cells use to make decisions and coordinate their activities. These tools, including the improved Light-Inducible Dimer (iLID) system, offer the ability to selectively recruit components to subcellular locations, such as micron-scale regions of the plasma membrane. In this way, the role of individual proteins within signaling networks can be examined with high spatiotemporal resolution. Currently, consistent recruitment is limited by heterogeneous optogenetic component expression, and spatial precision is diminished by protein diffusion, especially over long time scales. Here, we address these challenges within the iLID system with alternative membrane anchoring domains and fusion configurations. Using live cell imaging and mathematical modeling, we demonstrate that the anchoring strategy affects both component expression and diffusion, which in turn impact recruitment strength, kinetics, and spatial dynamics. Compared to the commonly used C-terminal iLID fusion, fusion proteins with large N-terminal anchors show stronger local recruitment, slower diffusion of recruited components, efficient recruitment over wider gene expression ranges, and improved spatial control over signaling outputs. We also define guidelines for component expression regimes for optimal recruitment for both cell-wide and subcellular recruitment strategies. Our findings highlight key sources of imprecision within light-inducible dimer systems and provide tools that allow greater control of subcellular protein localization across diverse cell biological applications.
- Published
- 2021
30. Optogenetic control of receptors reveals distinct roles for actin- and Cdc42-dependent negative signals in chemotactic signal processing
- Author
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Bell, George, Rincón, Esther, Akdoğan, Emel, and Collins, Sean
- Abstract
During chemotaxis, neutrophils use cell surface G-Protein Coupled Receptors (GPCRs) to detect chemoattractant gradients 1–4 . The downstream signaling system is wired with multiple feedback loops that amplify weak inputs and promote spatial separation of cell front and rear activities 1, 5–8 . Positive feedback could promote rapid signal spreading 9 , yet information from the receptors is transmitted with high spatial fidelity, enabling detection of small differences in chemoattractant concentration across the cell 1 . How the signal transduction network achieves signal amplification while preserving spatial information remains unclear. The GTPase Cdc42 is a cell-front polarity coordinator that is predictive of cell turning, suggesting an important role in spatial processing 10 . To directly measure information flow from receptors to Cdc42, we paired zebrafish parapinopsina, an optogenetic GPCR that allows reversible ON/OFF receptor control with a spectrally compatible red/far red Cdc42 FRET biosensor. Using this new toolkit, we show that positive and negative signals downstream of G-proteins shape a rapid, dose-dependent Cdc42 response. Furthermore, F-actin and Cdc42 itself provide two distinct negative signals that limit the duration and spatial spread of Cdc42 activation, maintaining output signals local to the originating receptors.
- Published
- 2021
31. Multimorbidity in patients with acute heart failure across world regions and country income levels (REPORT-HF): a prospective, multicentre, global cohort study
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Gerhardt, Teresa, Gerhardt, Louisa M S, Ouwerkerk, Wouter, Roth, Gregory A, Dickstein, Kenneth, Collins, Sean P, Cleland, John G F, Dahlstrom, Ulf, Tay, Wan Ting, Ertl, Georg, Hassanein, Mahmoud, Perrone, Sergio V, Ghadanfar, Mathieu, Schweizer, Anja, Obergfell, Achim, Filippatos, Gerasimos, Lam, Carolyn S P, Tromp, Jasper, and Angermann, Christiane E
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- 2023
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- View/download PDF
32. Randomized controlled trial of urinE chemiStry guided aCute heArt faiLure treATmEnt (ESCALATE): Rationale and design
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Cox, Zachary L., Siddiqi, Hasan K., Stevenson, Lynne W., Bales, Brian, Han, Jin H., Hart, Kimberly, Imhoff, Brant, Ivey-Miranda, Juan B., Jenkins, Cathy A., Lindenfeld, JoAnn, Shotwell, Matthew S., Miller, Karen F., Ooi, Henry, Rao, Veena S., Schlendorf, Kelly, Self, Wesley H., Siew, Edward D., Storrow, Alan, Walsh, Ryan, Wrenn, Jesse O., Testani, Jeffrey M., and Collins, Sean P.
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- 2023
- Full Text
- View/download PDF
33. SUMO is a pervasive regulator of meiosis.
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Bhagwat, Nikhil R, Owens, Shannon N, Ito, Masaru, Boinapalli, Jay V, Poa, Philip, Ditzel, Alexander, Kopparapu, Srujan, Mahalawat, Meghan, Davies, Owen Richard, Collins, Sean R, Johnson, Jeffrey R, Krogan, Nevan J, and Hunter, Neil
- Subjects
S. cerevisiae ,SUMO ,Ubiquitin ,cell biology ,crossing over ,developmental biology ,homologous recombination ,meiosis ,proteomics ,Biochemistry and Cell Biology - Abstract
Protein modification by SUMO helps orchestrate the elaborate events of meiosis to faithfully produce haploid gametes. To date, only a handful of meiotic SUMO targets have been identified. Here, we delineate a multidimensional SUMO-modified meiotic proteome in budding yeast, identifying 2747 conjugation sites in 775 targets, and defining their relative levels and dynamics. Modified sites cluster in disordered regions and only a minority match consensus motifs. Target identities and modification dynamics imply that SUMOylation regulates all levels of chromosome organization and each step of meiotic prophase I. Execution-point analysis confirms these inferences, revealing functions for SUMO in S-phase, the initiation of recombination, chromosome synapsis and crossing over. K15-linked SUMO chains become prominent as chromosomes synapse and recombine, consistent with roles in these processes. SUMO also modifies ubiquitin, forming hybrid oligomers with potential to modulate ubiquitin signaling. We conclude that SUMO plays diverse and unanticipated roles in regulating meiotic chromosome metabolism.
- Published
- 2021
34. Dose–response with stereotactic body radiotherapy for prostate cancer: A multi-institutional analysis of prostate-specific antigen kinetics and biochemical control
- Author
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Levin-Epstein, Rebecca G, Jiang, Naomi Y, Wang, Xiaoyan, Upadhyaya, Shrinivasa K, Collins, Sean P, Suy, Simeng, Aghdam, Nima, Mantz, Constantine, Katz, Alan J, Miszczyk, Leszek, Napieralska, Aleksandra, Namysl-Kaletka, Agnieszka, Prionas, Nicholas, Bagshaw, Hilary, Buyyounouski, Mark K, Cao, Minsong, Agazaryan, Nzhde, Dang, Audrey, Yuan, Ye, Kupelian, Patrick A, Zaorsky, Nicholas G, Spratt, Daniel E, Mohamad, Osama, Feng, Felix Y, Mahal, Brandon A, Boutros, Paul C, Kishan, Arun U, Juarez, Jesus, Shabsovich, David, Jiang, Tommy, Kahlon, Sartajdeep, Patel, Ankur, Patel, Jay, Nickols, Nicholas G, Steinberg, Michael L, Fuller, Donald B, and Kishan, Amar U
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Clinical Research ,Cancer ,Radiation Oncology ,Aging ,Urologic Diseases ,Prostate Cancer ,6.5 Radiotherapy and other non-invasive therapies ,Humans ,Kinetics ,Male ,Prospective Studies ,Prostate-Specific Antigen ,Prostatic Neoplasms ,Radiosurgery ,Prostate cancer ,Stereotactic body radiation therapy ,SBRT ,Dose-escalation ,Dose-response ,Biochemical control ,Dose–response ,Other Physical Sciences ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis ,Medical and biological physics - Abstract
Background and purposeThe optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens.Materials and methodsIn 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35 Gy/5 fractions [35/5, n = 265, 13.4%], 36.25 Gy/5 fractions [36.25/5, n = 711, 37.3%], 40 Gy/5 fractions [40/5, n = 684, 35.8%], and 38 Gy/4 fractions [38/4, n = 257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA ≤0.2 and ≤0.5 ng/mL, and BCR-free survival (BCRFS).ResultsMedian follow-up was 72.3 months. Median nPSA was 0.01 ng/mL for 38/4, and 0.17-0.20 ng/mL for 5-fraction regimens (p
- Published
- 2021
35. WASP integrates substrate topology and cell polarity to guide neutrophil migration
- Author
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Brunetti, Rachel M, Kockelkoren, Gabriele, Raghavan, Preethi, Bell, George RR, Britain, Derek, Puri, Natasha, Collins, Sean R, Leonetti, Manuel D, Stamou, Dimitrios, and Weiner, Orion D
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,1.1 Normal biological development and functioning ,Generic health relevance ,Inflammatory and immune system - Abstract
To control their shape and movement, cells leverage nucleation promoting factors (NPFs) to regulate when and where they polymerize actin. Here we investigate the role of the immune-specific NPF WASP during neutrophil migration. Endogenously-tagged WASP localizes to substrate-induced plasma membrane deformations. Super-resolution imaging of live cells reveals that WASP preferentially enriches to the necks of these substrate-induced membrane invaginations, a distribution that could support substrate pinching. Unlike other curvature-sensitive proteins, WASP only enriches to membrane deformations at the cell front, where it controls Arp2/3 complex recruitment and actin polymerization. Despite relatively normal migration on flat substrates, WASP depletion causes defects in topology sensing and directed migration on textured substrates. WASP therefore both responds to and reinforces cell polarity during migration. Surprisingly, front-biased WASP puncta continue to form in the absence of Cdc42. We propose that WASP integrates substrate topology with cell polarity for 3D guidance by selectively polymerizing actin around substrate-induced membrane deformations at the leading edge. A misregulation of WASP-mediated contact guidance could provide insight into the immune disorder Wiskott-Aldrich syndrome.
- Published
- 2021
36. Optogenetic control of receptors reveals distinct roles for actin- and Cdc42-dependent negative signals in chemotactic signal processing
- Author
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Bell, George RR, Rincón, Esther, Akdoğan, Emel, and Collins, Sean R
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Neurosciences ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance - Abstract
During chemotaxis, neutrophils use cell surface G-Protein Coupled Receptors (GPCRs) to detect chemoattractant gradients 1–4 . The downstream signaling system is wired with multiple feedback loops that amplify weak inputs and promote spatial separation of cell front and rear activities 1, 5–8 . Positive feedback could promote rapid signal spreading 9 , yet information from the receptors is transmitted with high spatial fidelity, enabling detection of small differences in chemoattractant concentration across the cell 1 . How the signal transduction network achieves signal amplification while preserving spatial information remains unclear. The GTPase Cdc42 is a cell-front polarity coordinator that is predictive of cell turning, suggesting an important role in spatial processing 10 . To directly measure information flow from receptors to Cdc42, we paired zebrafish parapinopsina, an optogenetic GPCR that allows reversible ON/OFF receptor control with a spectrally compatible red/far red Cdc42 FRET biosensor. Using this new toolkit, we show that positive and negative signals downstream of G-proteins shape a rapid, dose-dependent Cdc42 response. Furthermore, F-actin and Cdc42 itself provide two distinct negative signals that limit the duration and spatial spread of Cdc42 activation, maintaining output signals local to the originating receptors.
- Published
- 2021
37. Directional reorientation of migrating neutrophils is limited by suppression of receptor input signaling at the cell rear through myosin II activity
- Author
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Hadjitheodorou, Amalia, Bell, George RR, Ellett, Felix, Shastry, Shashank, Irimia, Daniel, Collins, Sean R, and Theriot, Julie A
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Neurosciences ,Underpinning research ,1.1 Normal biological development and functioning ,Cell Movement ,Cell Polarity ,Chemotaxis ,HL-60 Cells ,Humans ,Myosin Light Chains ,Myosin Type II ,Neutrophils ,Phosphorylation ,cdc42 GTP-Binding Protein ,rhoA GTP-Binding Protein - Abstract
To migrate efficiently to target locations, cells must integrate receptor inputs while maintaining polarity: a distinct front that leads and a rear that follows. Here we investigate what is necessary to overwrite pre-existing front-rear polarity in neutrophil-like HL60 cells migrating inside straight microfluidic channels. Using subcellular optogenetic receptor activation, we show that receptor inputs can reorient weakly polarized cells, but the rear of strongly polarized cells is refractory to new inputs. Transient stimulation reveals a multi-step repolarization process, confirming that cell rear sensitivity to receptor input is the primary determinant of large-scale directional reversal. We demonstrate that the RhoA/ROCK/myosin II pathway limits the ability of receptor inputs to signal to Cdc42 and reorient migrating neutrophils. We discover that by tuning the phosphorylation of myosin regulatory light chain we can modulate the activity and localization of myosin II and thus the amenability of the cell rear to 'listen' to receptor inputs and respond to directional reprogramming.
- Published
- 2021
38. Examining the Timeliness of ST-elevation Myocardial Infarction Transfers
- Author
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Ward, Michael J., Vogus, Timothy J., Munoz, Daniel, Collins, Sean P., Moser, Kelly, Jenkins, Cathy A., Liu, Dandan, and Kripalani, Sunil
- Subjects
Emergency medicine ,emergency medical services ,inter-facility transfers ,process ,quality improvement ,ST-elevation myocardial infarction ,care coordination - Abstract
Introduction: Despite large-scale quality improvement initiatives, substantial proportions of patients with ST-elevation myocardial infarction (STEMI) transferred to percutaneous coronary intervention centers do not receive percutaneous coronary intervention within the recommended 120 minutes. We sought to examine the contributory role of emergency medical services (EMS) activation relative to percutaneous coronary intervention center activation in the timeliness of care for patients transferred with STEMI.Methods: We conducted a retrospective analysis of interfacility transfers from emergency departments (ED) to a single percutaneous coronary intervention center between 2011–2014. We included emergency department (ED) patients transferred to the percutaneous coronary intervention center and excluded scene transfers and those given fibrinolytics. We calculated descriptive statistics and used multivariable linear regression to model the association of variables with ED time intervals (arrival to electrocardiogram [ECG], ECG-to-EMS activation, and ECG-to-STEMI alert) adjusting for patient age, gender, mode of arrival, weekday hour presentation, facility transfers in the past year, and transferring facility distance.Results: We identified 159 patients who met inclusion criteria. Subjects were a mean of 59 years old (standard deviation 13), 22% female, and 93% White; 59% arrived by private vehicle, and 24% presented after weekday hours. EDs transferred a median of 9 STEMIs (interquartile range [IQR] 3, 15) in the past year and a median of 65 miles (IQR 35, 90) from the percutaneous coronary intervention center. Median ED length of stay was 65 minutes (IQR 51, 85). Among component intervals, arrival to ECG was 6%, ECG-to-EMS activation 32%, and ECG-to-STEMI alert was 49% of overall ED length of stay. Only 18% of transfers had EMS activation earlier than STEMI alert. ECG-to-EMS activation was shorter in EDs achieving length of stay ≤60 minutes compared to those >60 minutes (12 vs 31 minutes, P
- Published
- 2021
39. Global Variations According to Sex in Patients Hospitalized for Heart Failure in the REPORT-HF Registry
- Author
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Tromp, Jasper, Ezekowitz, Justin A., Ouwerkerk, Wouter, Chandramouli, Chanchal, Yiu, Kai Hang, Angermann, Christiane E., Dahlstrom, Ulf, Ertl, Georg, Hassanein, Mahmoud, Perrone, Sergio V., Ghadanfar, Mathieu, Schweizer, Anja, Obergfell, Achim, Dickstein, Kenneth, Collins, Sean P., Filippatos, Gerasimos, Cleland, John G.F., and Lam, Carolyn S.P.
- Published
- 2023
- Full Text
- View/download PDF
40. Ultrafast long-range energy transport via light-matter coupling in organic semiconductor films
- Author
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Pandya, Raj, Chen, Richard Y. S., Gu, Qifei, Sung, Jooyoung, Schnedermann, Christoph, Ojambati, Oluwafemi S., Chikkaraddy, Rohit, Gorman, Jeffrey, Jacucci, Gianni, Onelli, Olimpia D., Willhammar, Tom, Johnstone, Duncan N., Collins, Sean M., Midgley, Paul A., Auras, Florian, Baikie, Tomi, Jayaprakash, Rahul, Mathevet, Fabrice, Soucek, Richard, Du, Matthew, Vignolini, Silvia, Lidzey, David G, Baumberg, Jeremy J., Friend, Richard H., Barisien, Thierry, Legrand, Laurent, Chin, Alex W., Musser, Andrew J., Yuen-Zhou, Joel, Saikin, Semion K., Kukura, Philipp, and Rao, Akshay
- Subjects
Physics - Applied Physics ,Physics - Chemical Physics ,Quantum Physics - Abstract
The formation of exciton-polaritons allows the transport of energy over hundreds of nanometres at velocities up to 10^6 m s^-1 in organic semiconductors films in the absence of external cavity structures.
- Published
- 2019
41. Prostate bed and organ-at-risk deformation: Prospective volumetric and dosimetric data from a phase II trial of stereotactic body radiotherapy after radical prostatectomy.
- Author
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Yoon, Stephanie, Cao, Minsong, Aghdam, Nima, Shabsovich, David, Kahlon, Sartajdeep, Ballas, Leslie, Collins, Sean, Steinberg, Michael, and Kishan, Amar
- Subjects
Post-prostatectomy ,Prostate cancer ,Stereotactic body radiotherapy ,Cone-Beam Computed Tomography ,Humans ,Male ,Prospective Studies ,Prostatectomy ,Prostatic Neoplasms ,Radiosurgery ,Radiotherapy Dosage ,Radiotherapy Planning ,Computer-Assisted ,Radiotherapy ,Intensity-Modulated ,Rectum - Abstract
PURPOSE: Stereotactic body radiotherapy (SBRT) in the post-prostatectomy setting is investigational. A major concern is the deformable prostate bed clinical target volume (CTV) and the closely juxtaposed organs-at-risk (OARs). We report a volumetric and dosimetric analysis of kilovoltage cone-beam CT (CBCT) data from the first 18 patients enrolled on a phase II trial of post-prostatectomy SBRT. With instructions on bladder filling and rectal preparation, we hypothesized acceptable CTV coverage while minimal overdosing to OARs could be achieved. METHODS: All patients received 5 fractions of 6-6.8 Gy to the prostate bed. CBCT were taken prior to and halfway through each fraction. CTV and OARs were contoured for each CBCT. Changes in inter- and intra-fraction volume and dose were calculated. Relative changes in CTV V95%, bladder V32.5 Gy, and rectal V32.5 Gy and V27.5 Gy were evaluated. RESULTS: Interfraction CTV volume remained stable, with median change +5.69% (IQR -1.73% to +9.84%). CTV V95% exhibited median change -0.74% (IQR -9.15% to -0.07%). Volumetric and dosimetric changes were minor from interfraction rotation and intrafraction motion. CTV V95% was ≥93% in 13 of 18 (72%) patients; in the remaining five, median change was -14.09% (IQR -16.64% to -13.56%). Interfraction CTV volume change was significantly larger among patients with CTV V95%
- Published
- 2020
42. Delineation of the SUMO-Modified Proteome Reveals Regulatory Functions Throughout Meiosis
- Author
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Bhagwat, Nikhil, Owens, Shannon, Ito, Masaru, Boinapalli, Jay, Poa, Philip, Ditzel, Alexander, Kopparapu, Srujan, Mahalawat, Meghan, Davies, Owen, Collins, Sean, Johnson, Jeffrey, Krogan, Nevan, and Hunter, Neil
- Subjects
Biotechnology ,Genetics ,1.1 Normal biological development and functioning - Abstract
Protein modification by SUMO helps orchestrate the elaborate events of meiosis to faithfully produce haploid gametes. To date, only a handful of meiotic SUMO targets have been identified. Here we delineate a multidimensional SUMO-modified meiotic proteome in budding yeast, identifying 2747 conjugation sites in 775 targets, and defining their relative levels and dynamics. Modified sites cluster in disordered regions and only a minority match consensus motifs. Target identities and modification dynamics imply that SUMOylation regulates all levels of chromosome organization and each step of homologous recombination. Execution-point analysis confirms these inferences, revealing functions for SUMO in S-phase, the initiation of recombination, chromosome synapsis and crossing over. K15-linked SUMO chains become prominent as chromosomes synapse and recombine, consistent with roles in these processes. SUMO also modifies ubiquitin, forming hybrid oligomers with potential to modulate ubiquitin signaling. We conclude that SUMO plays diverse and unanticipated roles in regulating meiotic chromosome metabolism.
- Published
- 2019
43. What are the Data for Current Prognostic Tools Used to Determine the Risk of Short-Term Adverse Events in Patients with Acute Heart Failure?
- Author
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Long, Brit, Keim, Samuel M., Gottlieb, Michael, and Collins, Sean P.
- Published
- 2023
- Full Text
- View/download PDF
44. MP14-07 PREFERENCES FOR ANDROGEN DEPRIVATION THERAPIES BY PRIOR HORMONAL TREATMENT EXPOSURE IN PATIENTS WITH PROSTATE CANCER: A DISCRETE CHOICE EXPERIMENT
- Author
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Collins, Sean P., primary, Thorley, Jared, additional, Hong, Agnes, additional, Gatoulis, Sergio C., additional, Flanders, Scott C., additional, Maculaitis, Martine C., additional, Hauber, Brett, additional, and Chakoian, Marty, additional
- Published
- 2024
- Full Text
- View/download PDF
45. Impact of neoadjuvant relugolix on patient-reported sexual function and bother
- Author
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Hsueh, Jessica Y., primary, Gallagher, Lindsey, additional, Koh, Min Ji, additional, Eden, Shaine, additional, Shah, Sarthak, additional, Wells, Markus, additional, Danner, Malika, additional, Zwart, Alan, additional, Ayoob, Marilyn, additional, Kumar, Deepak, additional, Leger, Paul, additional, Dawson, Nancy A., additional, Suy, Simeng, additional, Rubin, Rachel, additional, and Collins, Sean P., additional
- Published
- 2024
- Full Text
- View/download PDF
46. Directional Sinogram Inpainting for Limited Angle Tomography
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Tovey, Robert, Benning, Martin, Brune, Christoph, Lagerwerf, Marinus J., Collins, Sean M., Leary, Rowan K., Midgley, Paul A., and Schoenlieb, Carola-Bibiane
- Subjects
Mathematics - Optimization and Control - Abstract
In this paper we propose a new joint model for the reconstruction of tomography data under limited angle sampling regimes. In many applications of Tomography, e.g. Electron Microscopy and Mammography, physical limitations on acquisition lead to regions of data which cannot be sampled. Depending on the severity of the restriction, reconstructions can contain severe, characteristic, artefacts. Our model aims to address these artefacts by inpainting the missing data simultaneously with the reconstruction. Numerically, this problem naturally evolves to require the minimisation of a non-convex and non-smooth functional so we review recent work in this topic and extend results to fit an alternating (block) descent framework. We illustrate the effectiveness of this approach with numerical experiments on two synthetic datasets and one Electron Microscopy dataset., Comment: Revised manuscript accepted for publication in Inverse Problems
- Published
- 2018
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47. Current Emergency Department Disposition of Patients With Acute Heart Failure: An Opportunity for Improvement
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Sax, DANA R., MARK, DUSTIN G., RANA, JAMAL S., REED, MARY E., LINDENFELD, JOANN, STEVENSON, LYNNE W., STORROW, ALAN B., BUTLER, JAVED, PANG, PETER S., and COLLINS, SEAN P.
- Published
- 2022
- Full Text
- View/download PDF
48. Oxygen-Free Days as an Outcome Measure in Clinical Trials of Therapies for COVID-19 and Other Causes of New-Onset Hypoxemia
- Author
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Moskowitz, Ari, Shotwell, Matthew S., Gibbs, Kevin W., Harkins, Michelle, Rosenberg, Yves, Troendle, James, Merck, Lisa H., Files, D. Clark, de Wit, Marjolein, Hudock, Kristin, Thompson, B. Taylor, Gong, Michelle N., Ginde, Adit A., Douin, David J., Brown, Samuel M., Rubin, Eileen, Joly, Meghan Morrison, Wang, Li, Lindsell, Christopher J., Bernard, Gordon R., Semler, Matthew W., Collins, Sean P., and Self, Wesley H.
- Published
- 2022
- Full Text
- View/download PDF
49. MicroRNA-214 targets PTK6 to inhibit tumorigenic potential and increase drug sensitivity of prostate cancer cells.
- Author
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Cagle, Patrice, Niture, Suryakant, Srivastava, Anvesha, Ramalinga, Malathi, Aqeel, Rasha, Rios-Colon, Leslimar, Chimeh, Uchechukwu, Suy, Simeng, Collins, Sean P, Dahiya, Rajvir, and Kumar, Deepak
- Abstract
Prostate cancer is the most commonly diagnosed cancer in men with African American men disproportionally suffering from the burden of this disease. Biomarkers that could discriminate indolent from aggressive and drug resistance disease are lacking. MicroRNAs are small non-coding RNAs that affect numerous physiological and pathological processes, including cancer development and have been suggested as biomarkers and therapeutic targets. In the present study, we investigated the role of miR-214 on prostate cancer cell survival/migration/invasion, cell cycle regulation, and apoptosis. miR-214 was differentially expressed between Caucasian and African American prostate cancer cells. Importantly, miR-214 overexpression in prostate cancer cells induced apoptosis, inhibiting cell proliferation and colony forming ability. miR-214 expression in prostate cancer cells also inhibited cell migration and 3D spheroid invasion. Mechanistically, miR-214 inhibited prostate cancer cell proliferation by targeting protein tyrosine kinase 6 (PTK6). Restoration of PTK6 expression attenuated the inhibitory effect of miR-214 on cell proliferation. Moreover, simultaneous inhibition of PTK6 by ibrutinib and miR-214 significantly reduced cell proliferation/survival. Our data indicates that miR-214 could act as a tumor suppressor in prostate cancer and could potentially be utilized as a biomarker and therapeutic target.
- Published
- 2019
50. Efficient Front-Rear Coupling in Neutrophil Chemotaxis by Dynamic Myosin II Localization.
- Author
-
Chan, Caleb, Hadjitheodorou, Amalia, Lam, Pui-Ying, Lou, Sunny, Yang, Hee, Jorgensen, Julianne, Ellett, Felix, Irimia, Daniel, Davidson, Michael, Fischer, Robert, Huttenlocher, Anna, Meyer, Tobias, Ferrell, James, Theriot, Julie, Tsai, Tony, and Collins, Sean
- Subjects
actin network retrograde flow ,actin-myosin interaction ,cell mechanics ,cell migration ,cytoskeleton dynamics ,myosin light chain phosphorylation ,neutrophil chemotaxis ,Actin Cytoskeleton ,Actins ,Animals ,Animals ,Genetically Modified ,Cell Line ,Cell Movement ,Cell Polarity ,Cell Surface Extensions ,Chemotaxis ,Cytoskeletal Proteins ,Cytoskeleton ,Female ,Humans ,Myosin Type II ,Myosins ,Neutrophils ,Zebrafish ,Zebrafish Proteins - Abstract
Efficient chemotaxis requires rapid coordination between different parts of the cell in response to changing directional cues. Here, we investigate the mechanism of front-rear coordination in chemotactic neutrophils. We find that changes in the protrusion rate at the cell front are instantaneously coupled to changes in retraction at the cell rear, while myosin II accumulation at the rear exhibits a reproducible 9-15-s lag. In turning cells, myosin II exhibits dynamic side-to-side relocalization at the cell rear in response to turning of the leading edge and facilitates efficient turning by rapidly re-orienting the rear. These manifestations of front-rear coupling can be explained by a simple quantitative model incorporating reversible actin-myosin interactions with a rearward-flowing actin network. Finally, the system can be tuned by the degree of myosin regulatory light chain (MRLC) phosphorylation, which appears to be set in an optimal range to balance persistence of movement and turning ability.
- Published
- 2019
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