Leukocyte beta2-integrins; genes and disease

Integrins are heterodimeric transmembrane receptors that mediate cell-cell and cell-extracellular matrix interactions. Beta2-integrins are expressed exclusively in leukocytes and mediate many important functions in the immune system. Beta2-integrin genes are important in the pathologies of several diseases and genetic syndromes. These include Leukocyte Adhesion Deficiency (LAD) and Systemic Lupus Erythematosus (SLE), disorders which lie at opposite ends of the spectrum of immunological diseases. In LAD-I and LAD-III syndromes, beta2-integrin expression or function is reduced or absent. In SLE, genetic variants of the ITGAM gene, which encodes for the alpha M/CD11b chain of the beta2-integrin Mac-1,are associated with SLE development. In this mini review we summarise current knowledge regarding the involvement of beta2-integrins in LAD and SLE. Interestingly, dysfunctional beta2-integrins have been linked to both disorders, shedding light on the diverse roles of these receptors in the immune system

Extracting sensory experiences and cultural ecosystem services from actively crowdsourced descriptions of everyday lived landscapes

Acknowledgements We would like to thank everyone who took part in Window Expeditions, without you this research would not have been possible! We would also like to extend our gratitude to the anonymous reviewers whose helpful comments improved the quality of this paper. Funding University Research Priority Program (URPP) – Language and Space & Swiss National Science Foundation Grant [P500PT_214436]Peer reviewe

Continuous Experimentation for Automotive Software on the Example of a Heavy Commercial Vehicle in Daily Operation

As the automotive industry focuses its attention more and more towards the software functionality of vehicles, techniques to deliver new software value at a fast pace are needed. Continuous Experimentation, a practice coming from the web-based systems world, is one of such techniques. It enables researchers and developers to use real-world data to verify their hypothesis and steer the software evolution based on performances and user preferences, reducing the reliance on simulations and guesswork. Several challenges prevent the verbatim adoption of this practice on automotive cyber-physical systems, e.g., safety concerns and limitations from computational resources; nonetheless, the automotive field is starting to take interest in this technique. This work aims at demonstrating and evaluating a prototypical Continuous Experimentation infrastructure, implemented on a distributed computational system housed in a commercial truck tractor that is used in daily operations by a logistic company on public roads. The system comprises computing units and sensors, and software deployment and data retrieval are only possible remotely via a mobile data connection due to the commercial interests of the logistics company. This study shows that the proposed experimentation process resulted in the development team being able to base software development choices on the real-world data collected during the experimental procedure. Additionally, a set of previously identified design criteria to enable Continuous Experimentation on automotive systems was discussed and their validity confirmed in the light of the presented work.Comment: Paper accepted to the 14th European Conference on Software Architecture (ECSA 2020). 16 pages, 5 figure

A beta 2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation

beta 2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of beta(2)-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the beta 2-integrin (TTT/AAA-beta 2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-beta 2-integrin KI dendritic cells, which leads to a failure of MRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of beta 2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of beta 2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function

beta 2 Integrin Signaling Cascade in Neutrophils : More Than a Single Function

Neutrophils are the most prevalent leukocytes in the human body. They have a pivotal role in the innate immune response against invading bacterial and fungal pathogens, while recent emerging evidence also demonstrates their role in cancer progression and anti-tumor responses. The efficient execution of many neutrophil effector responses requires the presence of beta 2 integrins, in particular CD11a/CD18 or CD11b/CD18 heterodimers. Although extensively studied at the molecular level, the exact signaling cascades downstream of beta 2 integrins still remain to be fully elucidated. In this review, we focus mainly on inside-out and outside-in signaling of these two beta 2 integrin members expressed on neutrophils and describe differences between various neutrophil stimuli with respect to integrin activation, integrin ligand binding, and the pertinent differences between mouse and human studies. Last, we discuss how integrin signaling studies could be used to explore the therapeutic potential of targeting beta 2 integrins and the intracellular signaling cascade in neutrophils in several, among other, inflammatory conditions in which neutrophil activity should be dampened to mitigate disease.Peer reviewe

Between-individual variation in nematode burden among juveniles in a wild host:Variation in nematode burdens of juvenile birds

Parasite infection in young animals can affect host traits related to demographic processes such as survival and reproduction, and is therefore crucial to population viability. However, variation in infection among juvenile hosts is poorly understood. Experimental studies have indicated that effects of parasitism can vary with host sex, hatching order and hatch date, yet it remains unclear whether this is linked to differences in parasite burdens. We quantified gastrointestinal nematode burdens of wild juvenile European shags (Phalacrocorax aristotelis) using two in situ measures (endoscopy of live birds and necropsy of birds that died naturally) and one non-invasive proxy measure (fecal egg counts (FECs)). In situ methods revealed that almost all chicks were infected (98%), that infections established at an early age and that older chicks hosted more worms, but FECs underestimated prevalence. We found no strong evidence that burdens differed with host sex, rank or hatch date. Heavier chicks had higher burdens, demonstrating that the relationship between burdens and their costs is not straightforward. In situ measures of infection are therefore a valuable tool in building our understanding of the role that parasites play in the dynamics of structured natural populations

The early corrosion behaviour of hot dip galvanised steel pre-treated with bis-1,2-(triethoxysilyl)ethane

Abstract The present work aims at correlating the evolution of the analytical composition of bis-1,2-(triethoxysilyl)ethane films formed on hot dip galvanised steel substrate during immersion in NaCl solution with the corrosion performance of the pre-treated substrates. The electrochemical tests were carried out by electrochemical impedance spectroscopy and the analytical characterisation was performed by X-ray photoelectron spectroscopy (XPS), Auger electron spectroscopy (AES) and infrared spectroscopy (FT-IR). The electrochemical results show that the functional silane provides temporary corrosion protection for hot dip galvanised steel during immersion in NaCl-containing solutions. The analytical results show that the chemical composition of the silane film changes during immersion in the aggressive solution. During the first days of immersion these changes improve the corrosion resistance of the pre-treated substrate

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

Promoting adult hippocampal neurogenesis is expected to induce neuroplastic changes that improve mood and alleviate anxiety. However, the underlying mechanisms remain largely unknown and the hypothesis itself is controversial. Here we show that mice lacking Jnk1, or c-Jun N-terminal kinase (JNK) inhibitor-treated mice, display increased neurogenesis in adult hippocampus characterized by enhanced cell proliferation and survival, and increased maturation in the ventral region. Correspondingly, anxiety behaviour is reduced in a battery of tests, except when neurogenesis is prevented by AraC treatment. Using engineered retroviruses, we show that exclusive inhibition of JNK in adult-born granule cells alleviates anxiety and reduces depressive-like behaviour. These data validate the neurogenesis hypothesis of anxiety. Moreover, they establish a causal role for JNK in the hippocampal neurogenic niche and anxiety behaviour, and advocate targeting of JNK as an avenue for novel therapies against affective disorders.Peer reviewe

Biomaterials-enabled cornea regeneration in patients at high risk for rejection of donor tissue transplantation

The severe worldwide shortage of donor organs, and severe pathologies placing patients at high risk for rejecting conventional cornea transplantation, have left many corneal blind patients untreated. Following successful pre-clinical evaluation in mini-pigs, we tested a biomaterials-enabled pro-regeneration strategy to restore corneal integrity in an open-label observational study of six patients. Cell-free corneal implants comprising recombinant human collagen and phosphorylcholine were grafted by anterior lamellar keratoplasty into corneas of unilaterally blind patients diagnosed at high-risk for rejecting donor allografts. They were followed-up for a mean of 24 months. Patients with acute disease (ulceration) were relieved of pain and discomfort within 1-2 weeks post-operation. Patients with scarred or ulcerated corneas from severe infection showed better vision improvement, followed by corneas with burns. Corneas with immune or degenerative conditions transplanted for symptom relief only showed no vision improvement overall. However, grafting promoted nerve regeneration as observed by improved touch sensitivity to normal levels in all patients tested, even for those with little/no sensitivity before treatment. Overall, three out of six patients showed significant vision improvement. Others were sufficiently stabilized to allow follow-on surgery to restore vision. Grafting outcomes in mini-pig corneas were superior to those in human subjects, emphasizing that animal models are only predictive for patients with non-severely pathological corneas; however, for establishing parameters such as stable corneal regeneration and nerve regeneration, our pig model is satisfactory. While further testing is merited, we have nevertheless shown that cell-free implants are potentially safe, efficacious options for treating high-risk patients