Medicine and Health Sciences Commons^™

Transcriptomic Atlas And Interaction Networks Of Brain Cells In Mouse Cns Demyelination And Remyelination, Jinchao Hou, Yingyue Zhou, Zhangying Cai, Marina Terekhova, Amanda Swain, Prabhakar S Andhey, Rafaela M Guimaraes, Alina Ulezko Antonova, Tian Qiu, Sanja Sviben, Gregory Strout, James A J Fitzpatrick, Yun Chen, Susan Gilfillan, Do-Hyun Kim, Steven J Van Dyken, Maxim N Artyomov, Marco Colonna

2020-Current year OA Pubs

Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFB

Valoctocogene Roxaparvovec Gene Transfer In Participants With Hiv, Margaret V Ragni, Elaine Majerus, Sylvia Fong, Bridget Yates, Stephen Scheeler, Lisa Razon, Hua Yu, Divya B Reddy, Tara M Robinson

2020-Current year OA Pubs

No abstract provided.

Molnupiravir And Risk Of Post-Acute Sequelae Of Covid-19: Cohort Study, Yan Xie, Taeyoung Choi, Ziyad Al-Aly

2020-Current year OA Pubs

OBJECTIVE: To examine whether treatment with the antiviral agent molnupiravir during the first five days of SARS-CoV-2 infection is associated with reduced risk of post-acute adverse health outcomes.

DESIGN: Cohort study.

SETTING: US Department of Veterans Affairs.

PARTICIPANTS: 229 286 participants who tested positive for SARS-CoV-2 between 5 January 2022 and 15 January 2023, had at least one risk factor for progression to severe covid-19, and survived the first 30 days after testing positive were enrolled. 11 472 participants received a prescription for molnupiravir within five days of the positive test result and 217 814 received no covid-19 antiviral or …

Mrgpra3-Expressing Pruriceptors Drive Pruritogen-Induced Alloknesis Through Mechanosensitive Piezo2 Channel, Ping Lu, Yonghui Zhao, Zili Xie, Huan Zhou, Xinzhong Dong, Gregory F Wu, Brian S Kim, Jing Feng, Hongzhen Hu

2020-Current year OA Pubs

Although touch and itch are coded by distinct neuronal populations, light touch also provokes itch in the presence of exogenous pruritogens, resulting in a phenomenon called alloknesis. However, the cellular and molecular mechanisms underlying the initiation of pruritogen-induced mechanical itch sensitization are poorly understood. Here, we show that intradermal injections of histamine or chloroquine (CQ) provoke alloknesis through activation of TRPV1- and MrgprA3-expressing prurioceptors, and functional ablation of these neurons reverses pruritogen-induced alloknesis. Moreover, genetic ablation of mechanosensitive Piezo2 channel function from MrgprA3-expressing prurioceptors also dampens pruritogen-induced alloknesis. Mechanistically, histamine and CQ sensitize Piezo2 channel function, at least in part, …

Activation Of The Plasmodium Egress Effector Subtilisin-Like Protease 1 Is Mediated By Plasmepsin X Destruction Of The Prodomain, Sumit Mukherjee, Armiyaw S. Nasamu, Kelly C. Rubiano, Daniel E. Goldberg

2020-Current year OA Pubs

Following each round of replication, daughter merozoites of the malaria parasite Plasmodium falciparum escape (egress) from the infected host red blood cell (RBC) by rupturing the parasitophorous vacuole membrane (PVM) and the RBC membrane (RBCM). A proteolytic cascade orchestrated by a parasite serine protease, subtilisin-like protease 1 (SUB1), regulates the membrane breakdown. SUB1 activation involves primary autoprocessing of the 82-kDa zymogen to a 54-kDa (p54) intermediate that remains bound to its inhibitory propiece (p31) postcleavage. A second processing step converts p54 to the terminal 47-kDa (p47) form of SUB1. Although the aspartic protease plasmepsin X (PM X) has been implicated …

Microfluidic Device Facilitates In Vitro Modeling Of Human Neonatal Necrotizing Enterocolitis-On-A-Chip, Wyatt E. Lanik, Cliff J. Luke, Lila S. Nolan, Qingqing Gong, Lauren C. Frazer, Jamie M. Rimer, Sarah E. Gale, Raymond Luc, Shay S. Bidani, Carrie A. Sibbald, Angela N. Lewis, Belgacem Mihi, Pranjal Agrawal, Martin Goree, Marlie Maestas, Elise Hu, David F. Peters, Misty Good

2020-Current year OA Pubs

Necrotizing enterocolitis (NEC) is a deadly gastrointestinal disease of premature infants that is associated with an exaggerated inflammatory response, dysbiosis of the gut microbiome, decreased epithelial cell proliferation, and gut barrier disruption. We describe an in vitro model of the human neonatal small intestinal epithelium (Neonatal-Intestine-on-a-Chip) that mimics key features of intestinal physiology. This model utilizes intestinal enteroids grown from surgically harvested intestinal tissue from premature infants and cocultured with human intestinal microvascular endothelial cells within a microfluidic device. We used our Neonatal-Intestine-on-a-Chip to recapitulate NEC pathophysiology by adding infant-derived microbiota. This model, named NEC-on-a-Chip, simulates the predominant features of …

Advances In Mass Spectrometry On Membrane Proteins, Hsin-Chieh Yang, Weikai Li, Jie Sun, Michael L Gross

2020-Current year OA Pubs

Understanding the higher-order structure of membrane proteins (MPs), which are vital for numerous biological processes, is crucial for comprehending their function. Although several biophysical approaches have been used to study the structure of MPs, limitations exist owing to the proteins' dynamic nature and heterogeneity. Mass spectrometry (MS) is emerging as a powerful tool for investigating membrane protein structure and dynamics. Studying MPs using MS, however, must meet several challenges including the lack of stability and solubility of MPs, the complexity of the protein-membrane system, and the difficulty of digestion and detection. To meet these challenges, recent advances in MS have …

Direct Selection Of Dna-Encoded Libraries For Biased Agonists Of Gpcrs On Live Cells, Bo Cai, Amal El Daibani, Yuntian Bai, Tao Che, Casey J Krusemark

2020-Current year OA Pubs

G protein-coupled receptors (GPCRs) are the largest superfamily of human membrane target proteins for approved drugs. GPCR ligands can have a complex array of pharmacological activities. Among these activities, biased agonists have potential to serve as both chemical probes to understand specific aspects of receptor signaling and therapeutic leads with more specific, desired activity. Challenges exist, however, in the development of new biased activators due, in part, to the low throughput of traditional screening approaches. DNA-encoded chemical libraries (DELs) dramatically improve the throughput of drug discovery by allowing a collective selection, rather than discrete screening, of large compound libraries. The …

Modifiable Risk Factors In Women At High Risk Of Breast Cancer: A Systematic Review, Sarah Y Cohen, Carolyn R Stoll, Akila Anandarajah, Michelle Doering, Graham A Colditz

2020-Current year OA Pubs

BACKGROUND: Modifiable risk factors (alcohol, smoking, obesity, hormone use, and physical activity) affect a woman's breast cancer (BC) risk. Whether these factors affect BC risk in women with inherited risk (family history, BRCA1/2 mutations, or familial cancer syndrome) remains unclear.

METHODS: This review included studies on modifiable risk factors for BC in women with inherited risk. Pre-determined eligibility criteria were used and relevant data were extracted.

RESULTS: The literature search resulted in 93 eligible studies. For women with family history, most studies indicated that modifiable risk factors had no association with BC and some indicated decreased (physical activity) or increased …

Serologic Responses To Covid-19 Vaccination In Children With History Of Multisystem Inflammatory Syndrome (Mis-C), Maria A Perez, Carol M Kao, David A Hunstad, Et Al.

2020-Current year OA Pubs

Understanding the serological responses to COVID-19 vaccination in children with history of MIS-C could inform vaccination recommendations. We prospectively enrolled seven children hospitalized with MIS-C and measured SARS-CoV-2 binding IgG antibodies to spike protein variants longitudinally pre- and post-Pfizer-BioNTech BNT162b2 primary series COVID-19 vaccination. We found that SARS-CoV-2 variant cross-reactive IgG antibodies variably waned following acute MIS-C, but were significantly boosted with vaccination and maintained for up to 3 months. We then compared post-vaccination binding, pseudovirus neutralizing, and functional antibody-dependent cell-mediated cytotoxicity (ADCC) titers to the reference strain (Wuhan-hu-1) and Omicron variant (B.1.1.529) among previously healthy children (n = 16) …

Coronavirus Accessory Protein Orf3 Biology And Its Contribution To Viral Behavior And Pathogenesis, Fusheng Si, Shuai Song, Ruisong Yu, Zhen Li, Wenqiang Wei, Chao Wu

2020-Current year OA Pubs

Coronavirus porcine epidemic diarrhea virus (PEDV) is classified in the genus

Plasma Proteomics Of Sars-Cov-2 Infection And Severity Reveals Impact On Alzheimer's And Coronary Disease Pathways, Lihua Wang, Daniel Western, Jigyasha Timsina, Charlie Repaci, Joanne Norton, Pat Kohlfeld, John Budde, Omar H Butt, Alan R Templeton, Jane O'Halloran, Rachel Presti, Charles W Goss, Philip A Mudd, Beau M Ances, Yun Ju Sung, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

Identification of proteins dysregulated by COVID-19 infection is critically important for better understanding of its pathophysiology, building prognostic models, and identifying new targets. Plasma proteomic profiling of 4,301 proteins was performed in two independent datasets and tested for the association for three COVID-19 outcomes (infection, ventilation, and death). We identified 1,449 proteins consistently associated in both datasets with any of these three outcomes. We subsequently created highly accurate models that distinctively predict infection, ventilation, and death. These proteins were enriched in specific biological processes including cytokine signaling, Alzheimer's disease, and coronary artery disease. Mendelian randomization and gene network analyses identified …

Loss Of Fgf9 In Mice Leads To Pancreatic Hypoplasia And Asplenia, Sophie Patzek, Zhe Liu, Sean De La O, Sean Chang, Lauren E Byrnes, Xiuqin Zhang, David M Ornitz, Julie B Sneddon

2020-Current year OA Pubs

Pancreatic development requires spatially and temporally controlled expression of growth factors derived from mesenchyme. Here, we report that in mice the secreted factor Fgf9 is expressed principally by mesenchyme and then mesothelium during early development, then subsequently by both mesothelium and rare epithelial cells by E12.5 and onwards. Global knockout of the

Single-Nucleus Rna-Sequencing Of Autosomal Dominant Alzheimer Disease And Risk Variant Carriers, Logan Brase, Shih-Feng You, Ricardo D'Oliveira Albanus, Brenna C Novotny, Carolina Soriano-Tarraga, Taitea Dykstra, Maria Victoria Fernandez, John P Budde, Kristy Bergmann, John C Morris, Randall J Bateman, Richard J Perrin, Eric Mcdade, Chengjie Xiong, Jonathan Kipnis, Celeste M Karch, Oscar Harari, Et Al.

2020-Current year OA Pubs

Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, the cell-specific effect of variants in these genes is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from the parietal cortex of AD autosomal dominant (APP and PSEN1) and risk-modifying variant (APOE, TREM2 and MS4A) carriers. Within individual cell types, we capture genes commonly dysregulated across variant groups. However, specific transcriptional states are more prevalent within variant carriers. TREM2 oligodendrocytes show a dysregulated autophagy-lysosomal pathway, MS4A microglia have dysregulated complement cascade genes, and …

Refining Expert Recommendations For Implementing Change (Eric) Strategy Surveys Using Cognitive Interviews With Frontline Providers, Vera Yakovchenko, Matthew J Chinman, Carolyn Lamorte, Byron J Powell, Thomas J Waltz, Monica Merante, Sandra Gibson, Brittney Neely, Timothy R Morgan, Shari S Rogal

2020-Current year OA Pubs

BACKGROUND: The Expert Recommendations for Implementing Change (ERIC) compilation includes 73 defined implementation strategies clustered into nine content areas. This taxonomy has been used to track implementation strategies over time using surveys. This study aimed to improve the ERIC survey using cognitive interviews with non-implementation scientist clinicians.

METHODS: Starting in 2015, we developed and fielded annual ERIC surveys to evaluate liver care in the Veterans Health Administration (VA). We invited providers who had completed at least three surveys to participate in cognitive interviews (October 2020 to October 2021). Before the interviews, participants reviewed the complete 73-item ERIC survey and marked …

Cerebral Oximetry Monitoring In Extremely Preterm Infants, Mathias L Hansen, Zachary Vesoulis, Et Al.

2020-Current year OA Pubs

BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking.

METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis.

RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative …

Mutational Analysis Of Anesthetic Binding Sites And Their Effects On Gabaa Receptor Activation And Modulation By Positive Allosteric Modulators Of The Α7 Nicotinic Receptor, Spencer R Pierce, Allison L Germann, Sophia Q Xu, Saumith L Menon, Marcelo O Ortells, Hugo R Arias, Gustav Akk

2020-Current year OA Pubs

The positive allosteric modulators (PAMs) of the α7 nicotinic receptor

Head-To-Head Comparison Of 10 Plasma Phospho-Tau Assays In Prodromal Alzheimer's Disease, Shorena Janelidze, Nicolas R Barthélemy, Yingxin He, Randall J Bateman, Et Al.

2020-Current year OA Pubs

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aβ-status (i.e. abnormal CSF Aβ42/40) at baseline; and 45 of these Aβ-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline …

Mapping Genomic Regulation Of Kidney Disease And Traits Through High-Resolution And Interpretable Eqtls, Seong Kyu Han, Parker C Wilson, Benjamin D Humphreys, Et Al.

2020-Current year OA Pubs

Expression quantitative trait locus (eQTL) studies illuminate genomic variants that regulate specific genes and contribute to fine-mapped loci discovered via genome-wide association studies (GWAS). Efforts to maximize their accuracy are ongoing. Using 240 glomerular (GLOM) and 311 tubulointerstitial (TUBE) micro-dissected samples from human kidney biopsies, we discovered 5371 GLOM and 9787 TUBE genes with at least one variant significantly associated with expression (eGene) by incorporating kidney single-nucleus open chromatin data and transcription start site distance as an "integrative prior" for Bayesian statistical fine-mapping. The use of an integrative prior resulted in higher resolution eQTLs illustrated by (1) smaller numbers of …

A Somato-Cognitive Action Network Alternates With Effector Regions In Motor Cortex, Evan M Gordon, Roselyne J Chauvin, Andrew N Van, Aishwarya Rajesh, Ashley Nielsen, Dillan J Newbold, Nicole A Seider, Samuel R Krimmel, Kristen M Scheidter, Julia Monk, Ryland L Miller, Athanasia Metoki, David F Montez, Annie Zheng, Tomoyuki Nishino, Michael J Myers, Sydney Kaplan, Carolina Badke D'Andrea, Deanna M Barch, Christopher D Smyser, Cynthia E Rogers, Kelly N Botteron, John R Pruett, Jon T Willie, Peter Brunner, Joshua S Shimony, Benjamin P Kay, Scott Marek, Scott A Norris, Chad M Sylvester, Jarod L Roland, Steven E Petersen, Marcus E Raichle, Timothy O Laumann, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations

Reversing Dysdynamism To Interrupt Mitochondrial Degeneration In Amyotrophic Lateral Sclerosis, Gerald W Dorn Ii

2020-Current year OA Pubs

Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic evidence supporting a meaningful pathophysiological role for the constellation of abnormal mitochondrial fusion, fission and transport, collectively designated mitochondrial dysdynamism, in ALS. Following this is a discussion on preclinical studies in ALS mice that seemingly validate the idea that normalizing mitochondrial dynamism can delay ALS by interrupting a vicious cycle of mitochondrial degeneration, leading to neuronal die-back …

Are Cross-Sectional Safety Climate Survey Results In Operating Room Staff Associated With The Surgical Site Infection Rates In Swiss Hospitals?, Yvonne Pfeiffer, Andrew Atkinson, Judith Maag, Michael A. Lane, David Schwappach, Jonas Marschall

2020-Current year OA Pubs

OBJECTIVES: The aim of this study was to investigate the association between surgical site infections (SSIs), a major source of patient harm, and safety and teamwork climate. Prior research has been unclear regarding this relationship.

DESIGN: Based on the Swiss national SSI surveillance and a survey study assessing (a) safety climate and (b) teamwork climate, associations were analysed for three kinds of surgical procedures.

SETTING AND PARTICIPANTS: SSI surveillance data from 20 434 surgeries for hip and knee arthroplasty from 41 hospitals, 8321 for colorectal procedures from 28 hospitals and 4346 caesarean sections from 11 hospitals and survey responses from …

Exogenous Exposures Shape Genetic Predisposition To Lipids, Alzheimer's, And Coronary Heart Disease In The Mlxipl Gene Locus, Yury Loika, Elena Loiko, Fan Feng, Eric Stallard, Anatoliy I Yashin, Konstantin Arbeev, Allison L Kuipers, Mary F Feitosa, Michael A Province, Alexander M Kulminski

2020-Current year OA Pubs

Associations of single nucleotide polymorphisms (SNPs) of the

Dendritic Cells And Cryptosporidium: From Recognition To Restriction, Iti Saraav, L David Sibley

2020-Current year OA Pubs

Host immune responses are required for the efficient control of cryptosporidiosis. Immunity against

Structure Of Anhydrotetracycline-Bound Tet(X6) Reveals The Mechanism For Inhibition Of Type 1 Tetracycline Destructases, Hirdesh Kumar, Emily E Williford, Kevin S Blake, Brett Virgin-Downey, Gautam Dantas, Timothy A Wencewicz, Niraj H Tolia

2020-Current year OA Pubs

Inactivation of tetracycline antibiotics by tetracycline destructases (TDases) remains a clinical and agricultural threat. TDases can be classified as type 1 Tet(X)-like TDases and type 2 soil-derived TDases. Type 1 TDases are widely identified in clinical pathogens. A combination therapy of tetracycline and a TDase inhibitor is much needed to rescue the clinical efficacy of tetracyclines. Anhydrotetracycline is a pan-TDase inhibitor that inhibits both type 1 and type 2 TDases. Here, we present structural, biochemical, and phenotypic evidence that anhydrotetracycline binds in a substrate-like orientation and competitively inhibits the type 1 TDase Tet(X6) to rescue tetracycline antibiotic activity as a …

Motixafortide And G-Csf To Mobilize Hematopoietic Stem Cells For Autologous Transplantation In Multiple Myeloma: A Randomized Phase 3 Trial, Zachary D Crees, Michael P Rettig, Reyka G Jayasinghe, Keith Stockerl-Goldstein, Feng Gao, Mark A Schroeder, Ravi Vij, John F Dipersio, Et Al.

2020-Current year OA Pubs

Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34

Spike-Phase Coupling Patterns Reveal Laminar Identity In Primate Cortex, Zachary W Davis, Nicholas M Dotson, Tom P Franken, Lyle Muller, John H Reynolds

2020-Current year OA Pubs

The cortical column is one of the fundamental computational circuits in the brain. In order to understand the role neurons in different layers of this circuit play in cortical function it is necessary to identify the boundaries that separate the laminar compartments. While histological approaches can reveal ground truth they are not a practical means of identifying cortical layers in vivo. The gold standard for identifying laminar compartments in electrophysiological recordings is current-source density (CSD) analysis. However, laminar CSD analysis requires averaging across reliably evoked responses that target the input layer in cortex, which may be difficult to generate in …

Feasibility Pilot Trial For The Trajectories Of Recovery After Intravenous Propofol Versus Inhaled Volatile Anesthesia (Thrive) Pragmatic Randomised Controlled Trial, Bethany R Tellor Pennington, Douglas A. Colquhoun, Mark D. Neuman, Mary C. Politi, Allison M. Janda, Cathie Spino, Steven Thelen-Perry, Zhenke Wu, Sathish S. Kumar, Stephen H. Gregory, Michael S. Avidan, Sachin Kheterpal, Thrive Research Group

2020-Current year OA Pubs

INTRODUCTION: Millions of patients receive general anaesthesia for surgery annually. Crucial gaps in evidence exist regarding which technique, propofol total intravenous anaesthesia (TIVA) or inhaled volatile anaesthesia (INVA), yields superior patient experience, safety and outcomes. The aim of this pilot study is to assess the feasibility of conducting a large comparative effectiveness trial assessing patient experiences and outcomes after receiving propofol TIVA or INVA.

METHODS AND ANALYSIS: This protocol was cocreated by a diverse team, including patient partners with personal experience of TIVA or INVA. The design is a 300-patient, two-centre, randomised, feasibility pilot trial. Patients 18 years of age …

Symptom Management Care Pathway Adaptation Process And Specific Adaptation Decisions, Emily Vettese, Allison A King, Lisa M Klesges, Et Al.

2020-Current year OA Pubs

BACKGROUND: There is substantial heterogeneity in symptom management provided to pediatric patients with cancer. The primary objective was to describe the adaptation process and specific adaptation decisions related to symptom management care pathways based on clinical practice guidelines. The secondary objective evaluated if institutional factors were associated with adaptation decisions.

METHODS: Fourteen previously developed symptom management care pathway templates were reviewed by an institutional adaptation team composed of two clinicians at each of 10 institutions. They worked through each statement for all care pathway templates sequentially. The institutional adaptation team made the decision to adopt, adapt or reject each statement, …

Simultaneous Inhibition Of Thrombosis And Inflammation Is Beneficial In Treating Acute Myocardial Infarction, Ian Vargas, Ryan P Grabau, Junjie Chen, Carla Weinheimer, Attila Kovacs, William Dominguez-Viqueira, Adam Mitchell, Samuel A Wickline, Hua Pan

2020-Current year OA Pubs

Myocardial ischemia reperfusion injury (IRI) in acute coronary syndromes is a condition in which ischemic/hypoxic injury to cells subtended by the occluded vessel continues despite successful resolution of the thrombotic obstruction. For decades, most efforts to attenuate IRI have focused on interdicting singular molecular targets or pathways, but none have successfully transitioned to clinical use. In this work, we investigate a nanoparticle-based therapeutic strategy for profound but local thrombin inhibition that may simultaneously mitigate both thrombosis and inflammatory signaling pathways to limit myocardial IRI. Perfluorocarbon nanoparticles (PFC NP) were covalently coupled with an irreversible thrombin inhibitor, PPACK (Phe[D]-Pro-Arg-Chloromethylketone), and delivered …