207 research outputs found

    Multiparametric Immunoimaging Maps Inflammatory Signatures in Murine Myocardial Infarction Models.

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    In the past 2 decades, research on atherosclerotic cardiovascular disease has uncovered inflammation to be a key driver of the pathophysiological process. A pressing need therefore exists to quantitatively and longitudinally probe inflammation, in preclinical models and in cardiovascular disease patients, ideally using non-invasive methods and at multiple levels. Here, we developed and employed in vivo multiparametric imaging approaches to investigate the immune response following myocardial infarction. The myocardial infarction models encompassed either transient or permanent left anterior descending coronary artery occlusion in C57BL/6 and Apoe-/-mice. We performed nanotracer-based fluorine magnetic resonance imaging and positron emission tomography (PET) imaging using a CD11b-specific nanobody and a C-C motif chemokine receptor 2-binding probe. We found that immune cell influx in the infarct was more pronounced in the permanent occlusion model. Further, using 18F-fluorothymidine and 18F-fluorodeoxyglucose PET, we detected increased hematopoietic activity after myocardial infarction, with no difference between the models. Finally, we observed persistent systemic inflammation and exacerbated atherosclerosis in Apoe-/- mice, regardless of which infarction model was used. Taken together, we showed the strengths and capabilities of multiparametric imaging in detecting inflammatory activity in cardiovascular disease, which augments the development of clinical readouts.This work was supported by National Institute of Health grants R01HL143814 (to Dr Fayad), P01HL131478 (Drs Fayad and Mulder), P41EB025815 (Drs Liu and Gropler ), R35HL145212 (Dr Liu), and R35HL139598 (Dr Nahrendorf) and award K22CA226040 (Dr Rashidian). This work was also supported by an Innovation Research Fund Basic Research Award from the Dana-Farber Cancer Institute (Dr Rashidian). Dr Maier was supported by Deutsche Forschungsgemeinschaft grants (MA 7059/1 and MA 7059/3-1) and is part of SFB1425 funded by the Deutsche Forschungsgemeinschaft (project no. 422681845). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S

    3D Human iPSC Blood Vessel Organoids as a Source of Flow-Adaptive Vascular Cells for Creating a Human-Relevant 3D-Scaffold Based Macrovessel Model

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    3D-scaffold based in vitro human tissue models accelerate disease studies and screening of pharmaceutics while improving the clinical translation of findings. Here is reported the use of human induced pluripotent stem cell (hiPSC)-derived vascular organoid cells as a new cell source for the creation of an electrospun polycaprolactone-bisurea (PCL-BU) 3D-scaffold-based, perfused human macrovessel model. A separation protocol is developed to obtain monocultures of organoid-derived endothelial cells (ODECs) and mural cells (ODMCs) from hiPSC vascular organoids. Shear stress responses of ODECs versus HUVECs and barrier function (by trans endothelial electrical resistance) are measured. PCL-BU scaffolds are seeded with ODECs and ODMCs, and tissue organization and flow adaptation are evaluated in a perfused bioreactor system. ODECs and ODMCs harvested from vascular organoids can be cryopreserved and expanded without loss of cell purity and proliferative capacity. ODECs are shear stress responsive and establish a functional barrier that self-restores after the thrombin challenge. Static bioreactor culture of ODECs/ODMCs seeded scaffolds results in a biomimetic vascular bi-layer hierarchy, which is preserved under laminar flow similar to scaffolds seeded with primary vascular cells. HiPSC-derived vascular organoids can be used as a source of functional, flow-adaptive vascular cells for the creation of 3D-scaffold based human macrovascular models

    WP3 Country reports - Canada

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    This report looks at multilevel governance dynamics and at the integration policies targeting migrants developed by six small and medium-sized towns and rural areas in Canada between 2016 and 2021. Primarily based on interviews conducted in each of the selected municipalities, it provides an overview of 1) national, regional, and local integration policies targeting migrants in Canada; 2) policymaking relations among the key actors involved in these policy processes in the six localities and key features of policy networks within which these actors interact; 3) how these actors perceive and define integration. The report finds that the political orientation of the federal and provincial governments in Canada greatly influenced the dynamics of multilevel governance of immigrant integration in the selected Canadian localities, whereas municipalities, which could voluntarily elect to play a role in integration, were not obligated to do so as part of their formal political mandate. In Ontario and B.C., selected municipalities had conducted multiple initiatives intended to assist newcomers. These initiatives were unintegrated into municipal integration strategies and were done in an ad hoc manner in response to specific appeals from the local communities. In Quebec, selected municipalities towns had existing integration policies and infrastructure, including municipally or regionally-sponsored integration dialogues that were intended to coordinate social service delivery for newcomers. Immigration was characterized by all interviewees as the primary solution to labour shortages and population decline in the selected localities. Yet, factors like housing availability, affordability, housing size, and transportation were key issues of concern for immigrant integration. Familiarity between actors and active community mobilization facilitated immigrant integration despite the lack of ethnic diversity and the limited resources of integration particularly in smaller localities.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101004714

    Muscle weakness is associated with non-contractile muscle tissue of the vastus medialis muscle in knee osteoarthritis

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    Background: Quadriceps weakness is assumed to be associated with compositional properties of the vastus medialis muscle in patients with knee osteoarthritis (OA). Methods: The aim was to determine the association of non-contractile muscle tissue in the vastus medialis muscle, measured with routine MRI, with muscle extensor strength in patients with knee OA. Sagittal T1-weighted 3T MRI of 94 patients with knee OA, routinely acquired in clinical practice were used for analysis. Using the MRI’s, the amount of non-contractile muscle tissue in the vastus medialis muscle was measured, expressed as a percentage of (non)-contractile tissue, dichotomized into a low and a high non-contractile percentage group. Muscle strength was assessed by isokinetic measurement of knee extensors and by conduction of the Get-Up and Go (GUG) test. In regression analyses, associations of percentage of non-contractile muscle tissue with muscle strength and GUG time were determined and controlled for sex, age, BMI and radiographic severity. Results: A high percentage of non-contractile muscle tissue (> 11.2%) was associated with lower muscle strength (B = -0.25, P = 0.006) and with longer GUG time (B = 1.09, P = 0.021). These associations were specifically confounded by sex and BMI, because these two variables decreased the regression coefficient (B) with > 10%. Conclusions: A high percentage of non-contractile muscle tissue in the vastus medialis muscle measured by clinical T1-weighted 3T MRI is associated with muscle weakness. The association is confounded by sex and BMI. Non-contractile muscle tissue seems to be an important compositional property of the vastus medialis muscle underlying quadriceps weakness

    Small molecule-mediated rapid maturation of human induced pluripotent stem cell-derived cardiomyocytes

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    Background: Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) do not display all hallmarks of mature primary cardiomyocytes, especially the ability to use fatty acids (FA) as an energy source, containing high mitochondrial mass, presenting binucleation and increased DNA content per nuclei (polyploidism), and synchronized electrical conduction. This immaturity represents a bottleneck to their application in (1) disease modelling—as most cardiac (genetic) diseases have a middle-age onset—and (2) clinically relevant models, where integration and functional coupling are key. So far, several methods have been reported to enhance iPSC-CM maturation; however, these protocols are laborious, costly, and not easily scalable. Therefore, we developed a simple, low-cost, and rapid protocol to promote cardiomyocyte maturation using two small molecule activators of the peroxisome proliferator-activated receptor ÎČ/ÎŽ and gamma coactivator 1-alpha (PPAR/PGC-1α) pathway: asiatic acid (AA) and GW501516 (GW). Methods and Results: Monolayers of iPSC-CMs were incubated with AA or GW every other day for ten days resulting in increased expression of FA metabolism-related genes and markers for mitochondrial activity. AA-treated iPSC-CMs responsiveness to the mitochondrial respiratory chain inhibitors increased and exhibited higher flexibility in substrate utilization. Additionally, structural maturity improved after treatment as demonstrated by an increase in mRNA expression of sarcomeric-related genes and higher nuclear polyploidy in AA-treated samples. Furthermore, treatment led to increased ion channel gene expression and protein levels. Conclusions: Collectively, we developed a fast, easy, and economical method to induce iPSC-CMs maturation via PPAR/PGC-1α activation. Treatment with AA or GW led to increased metabolic, structural, functional, and electrophysiological maturation, evaluated using a multiparametric quality assessment

    NEXT GENERATION BIOENGINEERED HUMAN MYOCARDIUM

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    Cardiac patches consisting of induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) show beneficial effects when placed on the infarcted heart and the first human clinical trials have been approved. However, current patches do not replicate myocardial tissue, lacking 3D organization, mechanical properties, cellular maturity, and relevant thickness, and thereby fail to provide real contractile support to the failing heart. Previously, we have shown that melt electrowritten (MEW) hexagonal fiber scaffolds can be used to generate contractile cardiac patches that mimic native mechanical properties, thereby inducing iPSC‐CM maturation and tissue organization.[1] Although a huge step forward, these constructs do not yet fully replicate myocardial cellular and ECM composition and organization, and myocardial 3D fiber alignment. To tackle these hurdles, we have investigated the incorporation of additional cardiac cell types like iPSC‐derived cardiac fibroblasts (cFBs) and endothelial cells (ECs), the use of various myocardial and EC‐optimized bioinks for extrusion‐based bioprinting to allow for strategic cell‐type arrangement, and introducing 3D myocardial fiber‐angle orientation by stacking hexagonal MEW scaffolds. We found that the addition of cFBs, the optimization of hydrogel/ECM composition and stiffness (Collagen‐GelMA), and increasing thickness (1cm) and fiber organization by strategically stacking hexagonal meshes, led to the formation of a thick synchronously contracting myocardial tissue‐like construct. Our constructs showed a multi‐layered 3D fiber organization, with cells aligning with the hexagonal microarchitectures and an increase in maturation. Taken together, we have developed a next‐generation bioengineered myocardium with a more native‐like muscle structure and the potential to provide real functional support to the injured heart

    Rehabilitation and outcomes after complicated vs uncomplicated mild TBI: results from the CENTER-TBI study

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    International audienceBackground: Despite existing guidelines for managing mild traumatic brain injury (mTBI), evidence-based treatments are still scarce and large-scale studies on the provision and impact of specific rehabilitation services are needed. This study aimed to describe the provision of rehabilitation to patients after complicated and uncomplicated mTBI and investigate factors associated with functional outcome, symptom burden, and TBI-specific health-related quality of life (HRQOL) up to six months after injury. Methods: Patients (n = 1379) with mTBI from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study who reported whether they received rehabilitation services during the first six months post-injury and who participated in outcome assessments were included. Functional outcome was measured with the Glasgow Outcome Scale – Extended (GOSE), symptom burden with the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and HRQOL with the Quality of Life after Brain Injury – Overall Scale (QOLIBRI-OS). We examined whether transition of care (TOC) pathways, receiving rehabilitation services, sociodemographic (incl. geographic), premorbid, and injury-related factors were associated with outcomes using regression models. For easy comparison, we estimated ordinal regression models for all outcomes where the scores were classified based on quantiles. Results: Overall, 43% of patients with complicated and 20% with uncomplicated mTBI reported receiving rehabilitation services, primarily in physical and cognitive domains. Patients with complicated mTBI had lower functional level, higher symptom burden, and lower HRQOL compared to uncomplicated mTBI. Rehabilitation services at three or six months and a higher number of TOC were associated with unfavorable outcomes in all models, in addition to pre-morbid psychiatric problems. Being male and having more than 13 years of education was associated with more favorable outcomes. Sustaining major trauma was associated with unfavorable GOSE outcome, whereas living in Southern and Eastern European regions was associated with lower HRQOL. Conclusions: Patients with complicated mTBI reported more unfavorable outcomes and received rehabilitation services more frequently. Receiving rehabilitation services and higher number of care transitions were indicators of injury severity and associated with unfavorable outcomes. The findings should be interpreted carefully and validated in future studies as we applied a novel analytic approach. Trial registration: ClinicalTrials.gov NCT02210221

    NEXT GENERATION BIOENGINEERED HUMAN MYOCARDIUM

    No full text
    Cardiac patches consisting of induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) show beneficial effects when placed on the infarcted heart and the first human clinical trials have been approved. However, current patches do not replicate myocardial tissue, lacking 3D organization, mechanical properties, cellular maturity, and relevant thickness, and thereby fail to provide real contractile support to the failing heart. Previously, we have shown that melt electrowritten (MEW) hexagonal fiber scaffolds can be used to generate contractile cardiac patches that mimic native mechanical properties, thereby inducing iPSC‐CM maturation and tissue organization.[1] Although a huge step forward, these constructs do not yet fully replicate myocardial cellular and ECM composition and organization, and myocardial 3D fiber alignment. To tackle these hurdles, we have investigated the incorporation of additional cardiac cell types like iPSC‐derived cardiac fibroblasts (cFBs) and endothelial cells (ECs), the use of various myocardial and EC‐optimized bioinks for extrusion‐based bioprinting to allow for strategic cell‐type arrangement, and introducing 3D myocardial fiber‐angle orientation by stacking hexagonal MEW scaffolds. We found that the addition of cFBs, the optimization of hydrogel/ECM composition and stiffness (Collagen‐GelMA), and increasing thickness (1cm) and fiber organization by strategically stacking hexagonal meshes, led to the formation of a thick synchronously contracting myocardial tissue‐like construct. Our constructs showed a multi‐layered 3D fiber organization, with cells aligning with the hexagonal microarchitectures and an increase in maturation. Taken together, we have developed a next‐generation bioengineered myocardium with a more native‐like muscle structure and the potential to provide real functional support to the injured heart

    WP4 Country Reports - Canada

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    This report looks at migrants’ access to housing, employment, and other relevant resources in six different small and medium-sized towns and rural areas in Canada between 2016 and 2021. Primarily based on interviews conducted in each of the six selected municipalities, secondary data analysis and a policy literature review, it provides an overview of the concrete barriers that migrants face in relation to housing and employment; the local actors who are involved in, and/or seen as responsible for, facilitating their access; any concrete local measures or practices that help or hinder this access; and the specific target groups of these measures, initiatives or practices. The report finds that the concrete barriers facing migrant access to housing are affordability, availability, and size. These factors were particularly acute in Ontario and B.C. where a housing crisis has driven up the average cost of a home and decreased availability. During the study period, Canada possessed low unemployment rates, however, one of the concrete barriers regarding economic integration was foreign credential recognition and language acquisition (English or French). The local actors who were involved included immigrant settlement service organizations, provincial employment ministries, faith organizations or groups of individuals (involved in private sponsorship), provincial/regional chambers of commerce and community service organizations. The measures and practices included employment matching and preparation services, language training programs, job banks, mentoring programs, paid internships, targeted migrant hiring initiatives by municipal and community-service organizations, skills upgrading programs and municipal integration policies. The specific target groups of these measures included immigrants (both economic and resettled refugees) as well as residents.This proejct has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 101004714

    Proteomic analysis of chicken bone marrow-derived dendritic cells in response to an inactivated IBV + NDV poultry vaccine

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    Inactivated poultry vaccines are subject to routine potency testing for batch release, requiring large numbers of animals. The replacement of in vivo tests for cell-based alternatives can be facilitated by the identification of biomarkers for vaccine-induced immune responses. In this study, chicken bone marrow-derived dendritic cells were stimulated with an inactivated vaccine for infectious bronchitis virus and Newcastle disease virus, as well as inactivated infectious bronchitis virus only, and lipopolysaccharides as positive control, or left unstimulated for comparison with the stimulated samples. Next, the cells were lysed and subjected to proteomic analysis. Stimulation with the vaccine resulted in 66 differentially expressed proteins associated with mRNA translation, immune responses, lipid metabolism and the proteasome. For the eight most significantly upregulated proteins, mRNA expression levels were assessed. Markers that showed increased expression at both mRNA and protein levels included PLIN2 and PSMB1. Stimulation with infectious bronchitis virus only resulted in 25 differentially expressed proteins, which were mostly proteins containing Src homology 2 domains. Stimulation with lipopolysaccharides resulted in 118 differentially expressed proteins associated with dendritic cell maturation and antimicrobial activity. This study provides leads to a better understanding of the activation of dendritic cells by an inactivated poultry vaccine, and identified PLIN2 and PSMB1 as potential biomarkers for cell-based potency testing
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