Editorial: Fibrosis and inflammation in tissue pathophysiology

In adult mammals, tissue damage activates a wound healing response with acute inflammation followed by either complete repair (for low-grade damage or in highly regenerative tissues, such as the liver) or replacement fibrosis (for extensive damage or in poorly regenerative tissues, such as the myocardium). Persistent damage and repeated insults sustain continuous activation of repair pathways leading to chronic inflammation, progressive tissue fibrosis and sclerosis. Despite the evolutionary advantage conferred by scarring as a rapid repair mechanism, chronic fibrosis leads to tissue adverse remodeling and impaired function. Persistent low-level inflammation and fibrosis are observed in many pathological conditions (e.g. hypertension, obesity, diabetes, genetic diseases), and lead to further complications including atherosclerosis and ischemic events, organ failure, autoimmune diseases, cancer, aging, and reduced resilience to infectious diseases. Pathological fibrosis plays a major role in a wide range of diseases, accounting for an increasingly large fraction of mortality cases worldwide. While recent advances have unveiled many environmental and genetic causes of fibrotic disorders, a better understanding of both ubiquitous and tissue-specific regulatory pathways and cellular dynamics could help to design new targeted therapies, and to identify the etiology of idiopathic diseases. Within this Research Topic, we invite submission of articles (reviews, original research, or methodology articles) on the pathophysiological role of fibrosis and inflammation in different tissues. Areas to be covered include, but are not limited to: - genetic and environmental causes of persistent low-level inflammation and fibrosis (e.g. autoimmunity, hypertension, obesity, diabetes, genetic diseases, latent infections); - comorbidities including systemic sclerosis, neurological disorders, organ failure (heart, skeletal muscle, kidney, liver, lungs), cancer, and reduced resilience to infectious diseases; - in vivo (animal models) and in vitro (organoids, tissue culture) modelling of fibrotic diseases for the discovery of novel therapeutic targets and potential tissue-specific treatments; - vascular responses to inflammation and inflammation of vascular tissues; - system biology approaches to identify molecular and cellular networks leading to chronic inflammation and fibrosis

A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts.

The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer

The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with >80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Insights into the high-energy γ-ray emission of Markarian 501 from extensive multifrequency observations in the Fermi era

We report on the γ-ray activity of the blazar Mrk 501 during the first 480 days of Fermi operation. We find that the average Large Area Telescope (LAT) γ-ray spectrum of Mrk 501 can be well described by a single power-law function with a photon index of 1.78 ± 0.03. While we observe relatively mild flux variations with the Fermi-LAT (within less than a factor of two), we detect remarkable spectral variability where the hardest observed spectral index within the LAT energy range is 1.52 ± 0.14, and the softest one is 2.51 ± 0.20. These unexpected spectral changes do not correlate with the measured flux variations above 0.3 GeV. In this paper, we also present the first results from the 4.5 month long multifrequency campaign (2009 March 15-August 1) on Mrk 501, which included the Very Long Baseline Array (VLBA), Swift, RXTE, MAGIC, and VERITAS, the F-GAMMA, GASP-WEBT, and other collaborations and instruments which provided excellent temporal and energy coverage of the source throughout the entire campaign. The extensive radio to TeV data set from this campaign provides us with the most detailed spectral energy distribution yet collected for this source during its relatively low activity. The average spectral energy distribution of Mrk 501 is well described by the standard one-zone synchrotron self-Compton (SSC) model. In the framework of this model, we find that the dominant emission region is characterized by a size ≲0.1 pc (comparable within a factor of few to the size of the partially resolved VLBA core at 15-43 GHz), and that the total jet power (≃1044 erg s-1) constitutes only a small fraction (∼10-3) of the Eddington luminosity. The energy distribution of the freshly accelerated radiating electrons required to fit the time-averaged data has a broken power-law form in the energy range 0.3 GeV-10 TeV, with spectral indices 2.2 and 2.7 below and above the break energy of 20 GeV. We argue that such a form is consistent with a scenario in which the bulk of the energy dissipation within the dominant emission zone of Mrk 501 is due to relativistic, proton-mediated shocks. We find that the ultrarelativistic electrons and mildly relativistic protons within the blazar zone, if comparable in number, are in approximate energy equipartition, with their energy dominating the jet magnetic field energy by about two orders of magnitude. © 2011. The American Astronomical Society

VIDEOJUEGOS EN LA ENSEÑANZA DE LENGUAS EXTRANJERAS: ACTIVIDADES Y RECURSOS PARA EL APRENDIZAJE

La evolución educativa derivada de los avances tecnológicos durante las dos primeras décadas del siglo XXI parece ser un hecho incuestionable. En pocos años, tanto los profesores como los estudiantes han pasado de utilizar material didáctico en formato papel a utilizar recursos digitalizados, ya sea en sus ordenadores personales, tabletas, teléfonos móviles u otros dispositivos electrónicos. Esta evolución no solo ha cambiado la manera de educar y enseñar, sino que también ha modificado la vida cotidiana de las personas, en especial la de los más jóvenes. En este sentido, ni la manera de aprender, estudiar o jugar son las mismas que las que conocieron aquellos que se educaron en el pasado milenio. Si los jóvenes actuales reciben una educación digital, estos también realizan acciones y se divierten con herramientas en formato electrónico en contextos fuera del aula de aprendizaje. Es por ello que los videojuegos se han convertido gradualmente en una forma de entretenimiento universal para los niños, jóvenes y también adultos del presente. La fusión entre videojuegos y educación era algo inevitable que iba a llegar antes o después; el propósito de esta combinación es, sin duda, una manera de promover la motivación de los alumnos en jugar a un determinado videojuego que a su vez les está enseñando unos contenidos específicos y que promueve que el alumno tenga una actitud positiva hacia el aprendizaje. A través de una revisión bibliográfica, este artículo presenta y describe los principales tipos de actividades y recursos que se utilizan en el diseño de videojuegos serios para promover la enseñanza y el aprendizaje de lenguas extranjeras

Gene-environment interaction impacts on heart development and embryo survival

Congenital heart disease (CHD) is the most common type of birth defect. In recent years, research has focussed on identifying the genetic causes of CHD. However, only a minority of CHD cases can be attributed to single gene mutations. In addition, studies have identified different environmental stressors that promote CHD, but the additive effect of genetic susceptibility and environmental factors is poorly understood. In this context, we have investigated the effects of short-term gestational hypoxia on mouse embryos genetically predisposed to heart defects. Exposure of mouse embryos heterozygous for Tbx1 or Fgfr1/Fgfr2 to hypoxia in utero increased the incidence and severity of heart defects while Nkx2-5+/− embryos died within 2 days of hypoxic exposure. We identified the molecular consequences of the interaction between Nkx2-5 and short-term gestational hypoxia, which suggest that reduced Nkx2-5 expression and a prolonged hypoxia-inducible factor 1α response together precipitate embryo death. Our study provides insight into the causes of embryo loss and variable penetrance of monogenic CHD, and raises the possibility that cases of foetal death and CHD in humans could be caused by similar gene-environment interactions

Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation

In vertebrate hearts, the ventricular trabecular myocardium develops as a sponge-like network of cardiomyocytes that is critical for contraction and conduction, ventricular septation, papillary muscle formation and wall thickening through the process of compaction1. Defective trabeculation leads to embryonic lethality2\u20134 or non-compaction cardiomyopathy (NCC)5. There are divergent views on when and how trabeculation is initiated in different species. In zebrafish, trabecular cardiomyocytes extrude from compact myocardium6, whereas in chicks, chamber wall thickening occurs before overt trabeculation7. In mice, the onset of trabeculation has not been described, but is proposed to begin at embryonic day 9.0, when cardiomyocytes form radially oriented ribs2. Endocardium\u2013myocardium communication is essential for trabeculation, and numerous signalling pathways have been identified, including Notch2,8 and Neuregulin (NRG)4. Late disruption of the Notch pathway causes NCC5. Whereas it has been shown that mutations in the extracellular matrix (ECM) genes Has2 and Vcan prevent the formation of trabeculae in mice9,10 and the matrix metalloprotease ADAMTS1 promotes trabecular termination3, the pathways involved in ECM dynamics and the molecular regulation of trabeculation during its early phases remain unexplored. Here we present a model of trabeculation in mice that integrates dynamic endocardial and myocardial cell behaviours and ECM remodelling, and reveal new epistatic relationships between the involved signalling pathways. NOTCH1 signalling promotes ECM degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas NRG1 promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through NRG1 control of Veg fa, but act antagonistically to establish trabecular architecture. These insights enabled the prediction of persistent ECM and cardiomyocyte growth in a mouse NCC model, providing new insights into the pathophysiology of congenital heart disease