During myocardial infarction, sterile inflammation occurs. The danger model is a solid theoretic framework that explains this inflammation as danger associated molecular patterns activate the immune system. The innate immune system can sense danger signals through different pathogen recognition receptors (PRR) such as toll-like receptors, nod-like receptors and receptors for advanced glycation endproducts. Activation of a PRR results in the production of cytokines and the recruitment of leukocytes to the site of injury. Due to tissue damage and necrosis of cardiac cells, danger signals such as extracellular matrix (ECM) breakdown products, mitochondrial DNA, heat shock proteins and high mobility box 1 are released. Matricellular proteins are non-structural proteins expressed in the ECM and are upregulated upon injury. Some members of the matricellular protein family (like tenascin-C, osteopontin, CCN1 and the galectins) have been implicated in the inflammatory and reparative responses following myocardial infarction and may function as danger signals. In a clinical setting, danger signals can function as prognostic and/or diagnostic biomarkers and for drug targeting. In this review we will provide an overview of the established knowledge on the role of danger signals in myocardial infarction and we will discuss areas of interest for future research.

How is public engagement perceived to contribute to open science? This commentary highlights common reflections on this question from interviews with 12 public engagement fellows in Utrecht University’s Open Science Programme in the Netherlands. We identify four reasons why public engagement is an essential enabler of open science. Interaction between academics and society can: (1) better align science with the needs of society; (2) secure a relationship of trust between science and society; (3) increase the quality and impact of science; and (4) support the impact of open access and FAIR data practices (data which meet principles of findability, accessibility, interoperability and reusability). To be successful and sustainable, such public engagement requires support in skills training and a form of institutionalisation in a university-wide system, but, most of all, the fellows express the importance of a formal and informal recognition and rewards system. Our findings suggest that in order to make public engagement an integral part of open science, universities should invest in institutional support, create awareness, and stimulate dialogue among staff members on how to ‘do’ good public engagement.

Open, prospective registration of a study protocol can improve research rigour in a number of ways. Through preregistration, key features of the study’s methodology are recorded and maintained as a permanent record, enabling comparison of the completed study with what was planned. By recording the study hypothesis and planned outcomes a priori, preregistration creates transparency and can reduce the risk of several common biases, such as hypothesising after results are known and outcome switching or selective outcome reporting. Second, preregistration raises awareness of measures to reduce bias, such as randomisation and blinding. Third, preregistration provides a comprehensive listing of planned studies, which can prevent unnecessary duplication and reduce publication bias. Although commonly acknowledged and applied in clinical research since 2000, preregistration of animal studies is not yet the norm. In 2018 we launched the first dedicated, open, online register for animal study protocols: wwwpreclinicaltrialseu. Here, we provide insight in the development of preclinicaltrials.eu (PCT) and evaluate its use during the first 3 years after its launch. Furthermore, we elaborate on ongoing developments such as the rise of comparable registries, increasing support for preregistration in the Netherlands—which led to the funding of PCT by the Dutch government—and pilots of mandatory preregistration by several funding bodies. We show the international coverage of currently registered protocols but with the overall low number of (pre)registered protocols.

Background & Aims: Inflammation plays an important role in the development of esophageal adenocarcinoma and its metaplastic precursor lesion, Barrett’s esophagus. Toll-like receptor (TLR) 2 signalling and lysosomal function have been linked to inflammation-associated carcinogenesis. We examined the expression of TLR2 in the esophagus and the effect of long-term TLR2 activation on morphological changes and expression of factors involved in lysosomal function in a Barrett’s esophagus epithelium cell line. Methods: TLR2 expression in normal squamous esophagus, reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma biopsies was assessed with Q-RT-PCR, in situ hybridization and immunohistochemistry. Barrett’s esophagus epithelium cells (BAR-T) were incubated with acid and bile salts in the presence or absence of the TLR2 agonist Pam3CSK4 for a period up to 4 weeks. Morphological changes were assessed with electron microscopy, while Q-RT-PCR was used to determine the expression of lysosomal enzymes (Cathepsin B and C) and factors involved in endocytosis (LAMP-1 and M6PR) and autophagy (LC3 and Rab7). Results: TLR2 was expressed in normal squamous esophagus, reflux esophagitis, Barrett’s esophagus but was most prominent in esophageal adenocarcinoma. Long-term TLR2 activation in acid and bile salts exposed BAR-T cells resulted in more and larger lysosomes, more mitochondria and increased expression of LAMP-1, M6PR, Cathepsin B and C when compared to BAR-T cells incubated with acid and bile salts but no TLR2 agonist. Factors associated with autophagy (LC3 and Rab7) expression remained largely unchanged. Conclusion: Activation of TLR2 in acid and bile salts exposed Barrett epithelium cells resulted in an increased number of mitochondria and lysosomes and increased expression of lysosomal enzymes and factors involved in endocytosis. Abbreviations: BE: Barrett’s esophagus; DCA: deoxycholic acid; EAC: esophageal adenocarcinoma; GCA: glycocholic acid; IL8: interleukin 8; IHC: immunohistochemistry; ISH: in situ hybridization; LAMP-1: lysosomal-associated membrane protein-1; LC3: microtubule-associated protein 1A/1B-light chain 3; M6PR: mannose-6-phosphate receptor; NF-κB: Nuclear Factor–κB; PPIs: proton pump inhibitors; Q-RT-PCR: Quantitative reverse transcriptase polymerase chain reaction; RE: reflux esophagitis; SQ: normal squamous esophagus; TCDCA: taurochenodeoxycholic acid; TLR: Toll-like receptor; TNFα: tumor necrosis factor α.

Open science in its broadest sense can make better science and provide benefits to researchers. When applied to animal experimentation, it can prevent unnecessary use of animals, because knowledge and experiences about past animal experimentation are shared openly to be consulted and used by other researchers. By extension, open science can accelerate the much anticipated transition towards animal-free innovations or New Approach Methodologies (NAMs). The purpose of this paper is to bring together and further share the preparations and findings of a symposium held at Utrecht University on aspects of open science that researchers doing animal experiments can and should take into account to improve their research and benefit themselves. The paper offers a one-figure guideline for that purpose.

Growth differentiation factor 15 (GDF15) levels are associated with increased mortality and rehospitalisation in heart failure (HF) patients. Whether GDF15 is causally involved in the pathobiology of HF remains largely unknown. Using the transverse aortic constriction (TAC) mouse model, we investigated the role of GDF15 in pressure overload-induced HF. Following TAC, circulating GDF15 levels increased significantly. Compared to wild type (WT) littermates, genetically deficient Gdf15^-/- mice developed more pronounced adverse cardiac remodelling one week after TAC, characterised by increased cardiac volumes and impaired myocardial global deformation. This further aggravated into severe HF in Gdf15^-/- mice over 42 days follow-up. Cardiac remodelling in Gdf15^-/- was accompanied by enhanced perivascular fibrosis and increased co-localization of fibroblast- and endothelial-specific markers in the cardiac endothelium of Gdf15^-/- mice, suggestive of endothelial plasticity and Endothelial-to-Mesenchymal transition (EndMT)-like changes. To further explore potential endothelial mechanisms underlying these observations, we performed complementary in vitro experiments in GDF15 knockdown endothelial cells. GDF15 deficiency impaired barrier function and enhanced Activin A-induced mesenchymal marker expression, consistent with increased endothelial phenotypic modulation. Together, these findings demonstrate that the loss of GDF15 aggravates pressure overload-induced heart failure, hallmarked by perivascular fibrosis and signs of endothelial dysfunction. Our data further support a potential protective role for GDF15 in maintaining endothelial integrity during cardiac stress.