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| Open AccessMucosal prime-boost immunization with live murine pneumonia virus-vectored SARS-CoV-2 vaccine is protective in macaques
Immunization via the respiratory route is predicted to increase the effectiveness of SARS-CoV-2 vaccines. Here, Kaiser et al. describe a murine pneumonia virus vectored vaccine expressing spike protein, and show that intranasal immunization of male rhesus macaques provides good mucosal and systemic immunogenicity and efficacy.
- Jaclyn A. Kaiser
- , Christine E. Nelson
- & Cyril Le Nouën
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Article
| Open AccessConsistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs
Xenotransplantation is an imminent clinical reality but concerns remain around the logistics of procurement and the experimental immunosuppression regimens required to achieve long-term xenograft survival. Here the authors show more than 6 month survival of genetically modified porcine kidneys in baboons after regulatory compliant organ procurements, clinically relevant organ preservation times and FDA-approved immunosuppressive reagents.
- Daniel Eisenson
- , Yu Hisadome
- & Kazuhiko Yamada
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| Open AccessVISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response
VISTA is a pH-dependent inhibitory checkpoint for T-cells that is abundant on myeloid lineage cells and antagonists of VISTA may successfully reinvigorate anti-tumour immunity. Here, the authors show that the antibody SNS-101, which is currently being investigated in humans in a clinical trial, is characterized by pH-sensitivity that endows it with favorable pharmacokinetic and safety profiles, and enhanced therapeutic effect when combined with PD-1 checkpoint inhibitors.
- Thomas Thisted
- , F. Donelson Smith
- & Edward H. van der Horst
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| Open AccessEnzymatic conversion of human blood group A kidneys to universal blood group O
ABO blood group compatibility restrictions limit the availability of organs for patients awaiting transplantation. Here, the authors show the rapid enzymatic removal of blood group A antigens from the vasculature of human kidneys using normothermic and hypothermic machine perfusion technologies to make universal blood group O organs for transplantation.
- Serena MacMillan
- , Sarah A. Hosgood
- & Michael L. Nicholson
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Article
| Open AccessNAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice
Circulating monocytes contribute to the transition to pain chronicity but the molecular events that cause their deployment are still unclear. Using a mouse model of hyperalgesic priming, here the authors show that blood monocytes contribute to the emergence of chronic pain via a mechanism that requires a transient disruption of NAAA-regulated lipid signaling.
- Yannick Fotio
- , Alex Mabou Tagne
- & Daniele Piomelli
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Article
| Open AccessPrior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection
Flavivirus infection or vaccination can induce cross-reactive immune responses. Here, the authors show how previous immunization with the tick-borne encephalitis virus vaccine affects the immune response to the yellow fever vaccine, suggesting that the yellow fever vaccine virus conceals epitopes shared with other flaviviruses in flavivirus-naive but not flavivirus-pre-exposed individuals.
- Antonio Santos-Peral
- , Fabian Luppa
- & Simon Rothenfusser
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| Open AccessBiomimetic computer-to-brain communication enhancing naturalistic touch sensations via peripheral nerve stimulation
Loss of communication between the brain and the body severely impacts the sensorimotor abilities of disabled individuals. Here, the authors design and test a neuroscience-driven framework for advancing bionic devices that leverages biomimetic stimulation to induce physiologically plausible information flow in animals and enhances patient performance with neuroprostheses.
- Giacomo Valle
- , Natalija Katic Secerovic
- & Stanisa Raspopovic
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Article
| Open AccessSmith-specific regulatory T cells halt the progression of lupus nephritis
Antigen specific regulatory T cells (Treg) play key roles in the peripheral tolerance to suppress autoreactive immune cells and represent potential avenue for therapeutic intervention. Here the authors identify Smith specific Treg and engineer Treg based cell therapy showing suppression of inflammation in a murine model of lupus nephritis.
- Peter J. Eggenhuizen
- , Rachel M. Y. Cheong
- & Joshua D. Ooi
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Article
| Open AccessAn intranasal live-attenuated SARS-CoV-2 vaccine limits virus transmission
In this study, the authors evaluated the protective capacity of a mucosal, live-attenuated SARS-CoV-2 vaccine and show that it induces systemic and mucosal humoral immunity, protects from clinical disease symptoms, and prevents virus transmission in hamsters more efficiently than an intramuscular mRNA vaccine.
- Julia M. Adler
- , Ricardo Martin Vidal
- & Jakob Trimpert
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| Open AccessIdentification of 5-HT2A receptor signaling pathways associated with psychedelic potential
Serotonin 5-HT2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT2A-selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT2A-Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.
- Jason Wallach
- , Andrew B. Cao
- & John D. McCorvy
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Article
| Open AccessRepurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms
Three drugs initially developed for other conditions, 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat and varespladib, have shown promise in preventing the lethality of snakebite envenoming. Here, Hall et al., show that a combination of these drugs can combat the local dermonecrotic effects caused by diverse cytotoxic venoms.
- Steven R. Hall
- , Sean A. Rasmussen
- & Nicholas R. Casewell
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Article
| Open AccessA generative adversarial network model alternative to animal studies for clinical pathology assessment
Generative AI has the potential to transform the way chemical and drug safety research is conducted. Here the authors show AnimalGAN, a model developed using Generative Adversarial Networks, which simulates virtual animal experiments to generate multidimensional rat clinical pathology measurements.
- Xi Chen
- , Ruth Roberts
- & Weida Tong
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| Open AccessAerosol delivery of SARS-CoV-2 human monoclonal antibodies in macaques limits viral replication and lung pathology
Here the authors deliver aerosolized human monoclonal antibodies to SARS-CoV-2-infected rhesus macaques and show that the treatment significantly reduces viral RNA and infectious virus in the respiratory tracts, limits lung pathology, and decreases inflammatory cytokines.
- Daniel N. Streblow
- , Alec J. Hirsch
- & Nancy L. Haigwood
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| Open AccessProduction of leishmanin skin test antigen from Leishmania donovani for future reintroduction in the field
As leishmaniasis control programs and new vaccines are advancing, it is necessary to re-introduce the leishmanin skin test to monitor transmission and immunity. This study describes the generation and validation of a new leishmanin skin test antigen for future re-introduction into endemic countries.
- Ranadhir Dey
- , Jalal Alshaweesh
- & Greg Matlashewski
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Article
| Open AccessFertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model
Successful engraftment of human hematopoietic stem cells during gene therapy requires myeloablative conditioning of the recipient, at the expense of toxicity. Authors show here that a single-dose of anti-CD117 antibody-drug conjugate achieves similar engraftment results as traditional multi-dose busulfan conditioning but preserves fertility in a non-human primate model.
- Naoya Uchida
- , Ulana Stasula
- & John F. Tisdale
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| Open AccessIn vivo noninvasive systemic myography of acute systemic vasoactivity in female pregnant mice
The assessment of selective therapeutics targeted to treat altered vasoactivity, a major characteristic of cardiovascular and oncological diseases, is still challenging due to unknown whole-body selectivity. Here the authors demonstrate that photoacoustic tomography has the potential to capture significant acute vasodilation of major arteries and vasculature selectivity.
- Kristie Huda
- , Dylan J. Lawrence
- & Carolyn L. Bayer
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Article
| Open AccessDecoding the endometrial niche of Asherman’s Syndrome at single-cell resolution
Asherman’s Syndrome is characterized by intrauterine scarring and infertility. Here, the authors decode the Asherman’s Syndrome endometrial cell niche by single-cell RNA sequencing and in vitro analyses of patient-derived endometrial organoids.
- Xavier Santamaria
- , Beatriz Roson
- & Carlos Simon
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| Open AccessSimultaneous magnetic resonance imaging of pH, perfusion and renal filtration using hyperpolarized 13C-labelled Z-OMPD
pH alterations are a hallmark of many pathologies including cancer and kidney disease. Here the authors describe [1,5- 13 C2]Z-OMPD as a probe for hyperpolarized 13C-MRI with good pH sensitivity and hyperpolarization properties which combined with tailored MRI protocols allow sub-minute imaging of pH, renal perfusion and filtration simultaneously.
- Martin Grashei
- , Pascal Wodtke
- & Franz Schilling
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| Open AccessClearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1
Muscle stem cells drive muscle regeneration and are affected in myotonic dystrophy type 1. Here, the authors demonstrate that some muscle stem cells show signs of senescence in myotonic dystrophy type 1 and administer senolytics to eliminate these defective cells and restore myogenesis.
- Talita C. Conte
- , Gilberto Duran-Bishop
- & Nicolas A. Dumont
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Article
| Open AccessAutomatically annotated motion tracking identifies a distinct social behavioral profile following chronic social defeat stress
Accurate phenotyping is key to deciphering behavior. Here, authors show the utility of the software package DeepOF in supervised and unsupervised identification of distinct individual and social behavioral patterns following chronic social stress.
- Joeri Bordes
- , Lucas Miranda
- & Mathias V. Schmidt
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| Open AccessAbrupt perturbation and delayed recovery of the vaginal ecosystem following childbirth
Childbirth prompts a vaginal inflammatory response and loss of Lactobacillus dominance. This disturbance, the authors show, reverberates deep into the first postpartum year, with evidence of recovery in only 49% of women by year’s end.
- Elizabeth K. Costello
- , Daniel B. DiGiulio
- & David A. Relman
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| Open AccessUltrasound-responsive low-dose doxorubicin liposomes trigger mitochondrial DNA release and activate cGAS-STING-mediated antitumour immunity
Chemotherapy-induced cytosolic DNA has been shown to activate the cGAS-STING pathway. Here, the authors demonstrate that the efficacy of low-dose doxorubicin to elicit a STING-mediated anti-tumour immune response can be enhanced by liposomal-loading with indocyanine green, resulting in ultrasound-activatable enhanced nuclear doxorubicin localisation and release of mitochondrial DNA.
- Chaoyu Wang
- , Ruoshi Zhang
- & Rui Kuai
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Article
| Open AccessPregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions
The increase in detoxification gene expression is a common transcriptome marker for longevity interventions. Here, the authors show that nomilin extends lifespan and healthspan in animals through activation of PXR regulated detoxification functions.
- Shengjie Fan
- , Yingxuan Yan
- & Cheng Huang
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Article
| Open AccessDynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with few effective treatment options available. Here, the authors use dynamic BH3 profiling to measure drug-induced mitochondrial priming and identify AZD8055 and navitoclax as a pro-apoptotic drug combination in ex vivo and preclinical MPM models.
- Danielle S. Potter
- , Ruochen Du
- & Anthony Letai
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Article
| Open AccessImmunogenicity and protective efficacy of SARS-CoV-2 mRNA vaccine encoding secreted non-stabilized spike in female mice
In this study, the authors provide pre-clinical evaluation of immunogenicity of the “ChulaCov19” mRNA vaccine encoding the ectodomain of the SARS-CoV-2 S protein. The vaccine induced potent immune response when applied as homologous prime/boost immunization or as heterologous booster and protected mice from disease.
- Eakachai Prompetchara
- , Chutitorn Ketloy
- & Kiat Ruxrungtham
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Article
| Open AccessHybrid photoacoustic and fast super-resolution ultrasound imaging
Dual photoacoustic and fast super-resolution ultrasound imaging technique bridges the physiological and structural details in vivo. The authors demonstrated that this interleaved technology allows revealing the transient changes of blood flow and blood oxygenation over time.
- Shensheng Zhao
- , Jonathan Hartanto
- & Yun-Sheng Chen
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| Open AccessThe IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer
Glypican-1 (GPC1) expression is elevated in pancreatic cancer and has been exploited as a therapeutic target. Here the authors report the development of VHH nanobody-based CAR-T cells targeting GPC1, showing anti-tumor activity in pancreatic cancer preclinical models.
- Nan Li
- , Alex Quan
- & Mitchell Ho
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Article
| Open AccessP2X3 receptor antagonism attenuates the progression of heart failure
Despite medications, heart failure worsens with time with many patients dying within five years of diagnosis. Here the authors show that blocking purinergic receptors in the carotid body stops heart failure progression, improves its function, reduces sleep apneas and systemic inflammation in male rats.
- Renata M. Lataro
- , Davi J. A. Moraes
- & Julian F. R. Paton
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Article
| Open AccessIntegrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria
Severe sepsis has a high mortality rate. Here, the authors provide genomic, transcriptomic, proteomic and metabolomic data across four sepsis-causing pathogens and identify a signature of global increase in fatty acid and lipid biosynthesis as well as cholesterol acquisition.
- Andre Mu
- , William P. Klare
- & Mark J. Walker
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Article
| Open AccessBeta variant COVID-19 protein booster vaccine elicits durable cross-neutralization against SARS-CoV-2 variants in non-human primates
Waning protective efficacy of mRNA-based booster vaccinations has been observed against newly emerging SARS-CoV-2 variants of concern. In this work, Pavot et al. formulate a monovalent Beta vaccine and demonstrate durable cross-neutralising antibody responses in non-human primates, against a spectrum of variants.
- Vincent Pavot
- , Catherine Berry
- & Valerie Lecouturier
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Article
| Open AccessSmall-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model
Idiopathic pulmonary fibrosis is a disease caused by persistent micro-injuries to the lung ultimately resulting in death. Here, the authors describe the use of a small molecule OGG1 inhibitor, TH5487, as a potent and potentially clinically relevant treatment for IPF.
- L. Tanner
- , A. B. Single
- & A. Egesten
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| Open AccessSafeguarding genome integrity during gene-editing therapy in a mouse model of age-related macular degeneration
Undesired chromosomal translocations, vector integrations, and large deletions remain a problem for therapeutic gene editing in vivo. Here, the authors compare the CRISPR-Cas9TX variant with CRISPR-Cas9 and show elimination of chromosomal translocations and reduction of AVV integration when targeting Vegfa for the treatment of age-related macular degeneration in a mouse model.
- Jianhang Yin
- , Kailun Fang
- & Jiazhi Hu
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Article
| Open AccessPharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation
Here, authors show that Smad3 acetylation via HDAC6 inhibition reverses Duchenne muscular dystrophy-like symptoms in the mdx mouse model, suggesting a potential therapeutic target for the disorder.
- Alexis Osseni
- , Aymeric Ravel-Chapuis
- & Laurent Schaeffer
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Article
| Open AccessHBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids
Complex neuropathologies, like macular degeneration, are common but incompletely understood. Here the authors report a complex human retina pathology organoid model induced by HBEGF-TNF, causing PIEZO1-mediated photoreceptor degeneration by cell extrusion.
- Manuela Völkner
- , Felix Wagner
- & Mike O. Karl
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Article
| Open AccessInhibition of interleukin-1β reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm
Inflammatory cytokines are elevated in patients with myeloproliferative neoplasms (MPN). Here the authors show that the JAK2-V617F mutation is associated with increased expression of IL-1 in MPN patients and that loss of IL-1β in JAK2-V617F mutant hematopoietic cells reduces MPN symptoms and myelofibrosis in a mouse model.
- Shivam Rai
- , Elodie Grockowiak
- & Radek C. Skoda
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Article
| Open AccessO-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis
Hyperammonemia occurs in liver diseases affecting ureagenesis, and is life-threatening. Here, the authors show that liver UDP-GlcNAc is increased during hyperammonemia, leading to O-GlcNAcylation of the rate-limiting ureagenesis enzyme CPS1, that enhanced ureagenesis and ammonia detoxification. They also showed that pharmacological increase of protein O-GlcNAcylation reduces hyperammonemia in mouse models of liver disease.
- Leandro R. Soria
- , Georgios Makris
- & Nicola Brunetti-Pierri
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Article
| Open AccessAntiviral efficacy of favipiravir against Zika and SARS-CoV-2 viruses in non-human primates
Repurposed antiviral drugs present as a valuable resource in the defence during outbreaks, with rigorous evaluation in large animal models keys for translation to clinical implementation. Here, the authors explore the antiviral activity of favipiravir against Zika virus and SARS-CoV-2 in cynomolgus macaques, in order to support future clinical investigations into this RNA polymerase inhibitor.
- Romain Marlin
- , Delphine Desjardins
- & Roger Le Grand
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Article
| Open AccessTemporally restricted activation of IFNβ signaling underlies response to immune checkpoint therapy in mice
Immune checkpoint blockade (ICB) is partially successful as a cancer therapy. Here using mouse models, the authors transcriptionally monitor responding and non-responding tumours showing that responding tumours were associated with transient IFN-β signalling which could promote the anti-tumour response.
- Rachael M. Zemek
- , Wee Loong Chin
- & W. Joost Lesterhuis
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Article
| Open AccessThe RalGAPα1–RalA signal module protects cardiac function through regulating calcium homeostasis
Here the authors show that a RalGAPα1-RalA signal nexus regulates calcium homeostasis in cardiomyocytes via the calcium pump SERCA2a, which plays a protective role to maintain cardiac function under pressure overload conditions.
- Sangsang Zhu
- , Chao Quan
- & Shuai Chen
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Article
| Open AccessIn situ 3D bioprinting with bioconcrete bioink
Bioinks used in current in-situ bioprinting have limitations when applied to complex operational environments. Here, the authors report on the creation of a microgel reinforced GelMA bioink which can be simply prepared and used in different biomedical settings. The application is demonstrated in a cranial defect model.
- Mingjun Xie
- , Yang Shi
- & Yong He
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Article
| Open AccessProtective effect of platinum nano-antioxidant and nitric oxide against hepatic ischemia-reperfusion injury
Pharmacological interventions against hepatic ischemia-reperfusion injury remain limited. Here, the authors provide a nanotherapeutics-based solution combining reactive oxygen species scavenging and nitric oxide modulation.
- Jing Mu
- , Chunxiao Li
- & Xiaoyuan Chen
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Article
| Open AccessAI-enabled, implantable, multichannel wireless telemetry for photodynamic therapy
The efficacy of photodynamic therapy is highly dependent on light delivery to activate a photosensitizer. Here the authors report AI-enabled, implantable, multichannel wireless telemetry for photodynamic therapy to enable uniform delivery of multi-wavelength light to tumors.
- Woo Seok Kim
- , M. Ibrahim Khot
- & Sung Il Park
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Article
| Open AccessIn vivo imaging of invasive aspergillosis with 18F-fluorodeoxysorbitol positron emission tomography
Current diagnostic methods for invasive aspergillosis are time-consuming and poorly sensitive. Here, the authors show that positron emission tomography with 2-deoxy-2-18F-fluorosorbitol can visualize Aspergillus fumigatus infection of the lungs, brain and muscles in mouse models, and can distinguish pulmonary aspergillosis from other diseases such as Staphylococcus aureus infection and lung cancer.
- Dong-Yeon Kim
- , Ayoung Pyo
- & Jung-Joon Min
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Article
| Open AccessProtein-based SARS-CoV-2 spike vaccine booster increases cross-neutralization against SARS-CoV-2 variants of concern in non-human primates
Emerging SARS-CoV-2 variants of concern (VOCs) raise questions on vaccine effectiveness. Here, the authors show that an adjuvanted protein-based SARS-CoV-2 spike vaccine booster increases cross-neutralization of VOC, including omicron, in non-human primates.
- Vincent Pavot
- , Catherine Berry
- & Valerie Lecouturier
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Article
| Open AccessEndothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm formation
Pannexin-1 ion channels on endothelial cells regulate vascular inflammation and remodeling to mediate aortic aneurysm formation. Pharmacological blockade of Pannexin-1 channels may offer translational therapeutic mitigation of aneurysmal pathology.
- Amanda C. Filiberto
- , Michael D. Spinosa
- & Ashish K. Sharma
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Article
| Open AccessTargeting ferroptosis protects against experimental (multi)organ dysfunction and death
Catalytic iron is associated with intensive care unit mortality and is known to cause free radical-mediated cellular toxicity. Here the authors show that a soluble ferrostatin-analogue (a ferroptosis inhibitor) protects mice from injury and death in experimental iron overload induced and genetic models of organ dysfunction, but not sepsis-induced multiorgan dysfunction.
- Samya Van Coillie
- , Emily Van San
- & Tom Vanden Berghe
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Article
| Open AccessCompressive stress-mediated p38 activation required for ERα + phenotype in breast cancer
Reliable luminal estrogen receptor (ERα+) breast cancer models are limited. Here, the authors use patient derived breast epithelial and breast cancer explant cultures grown in several extracellular matrix scaffolds and show that ERα expression is regulated by matrix stiffness via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation.
- Pauliina M. Munne
- , Lahja Martikainen
- & Juha Klefström
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Article
| Open AccessProtective mucosal immunity against SARS-CoV-2 after heterologous systemic prime-mucosal boost immunization
While current COVID-19 vaccines provide certain protection, more effective vaccination strategies are still desirable. Here the authors show, using mouse vaccination models, that priming with a systemic mRNA and boosting with an intranasal adenoviral vector vaccine induces comprehensive T cell and mucosal immunity.
- Dennis Lapuente
- , Jana Fuchs
- & Matthias Tenbusch
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Article
| Open AccessResolvin-D2 targets myogenic cells and improves muscle regeneration in Duchenne muscular dystrophy
Glucocorticoids delay muscle wasting in Duchenne Muscular Dystrophy by reducing inflammation; but also have harmful side effects. Here, the authors show that Resolvin-D2 is more effective than glucocorticoids in mitigating muscular dystrophy in mouse models, due to its ability to dampen inflammation and target myogenic cells to improve muscle regeneration.
- Junio Dort
- , Zakaria Orfi
- & Nicolas A. Dumont