The Human Monocyte-A Circulating Sensor of Infection and a Potent and Rapid Inducer of Inflammation

Monocytes were previously thought to be the precursors of all tissue macrophages but have recently been found to represent a unique population of cells, distinct from the majority of tissue macrophages. Monocytes and intestinal macrophages seem now to be the only monocyte/macrophage populations that originate primarily from adult bone marrow. To obtain a better view of the biological function of monocytes and how they differ from tissue macrophages, we have performed a quantitative analysis of its transcriptome in vivo and after in vitro stimulation with E. coli LPS. The monocytes rapidly responded to LPS by producing extremely high amounts of mRNA for the classical inflammatory cytokines, IL-1 alpha, IL-1 beta, IL-6 and TNF-alpha, but almost undetectable amounts of other cytokines. IL-6 was upregulated 58,000 times, from almost undetectable levels at baseline to become one of the major transcripts already after a few hours of cultivation. The cells also showed very strong upregulation of a number of chemokines, primarily IL-8, Ccl2, Ccl3, Ccl3L3, Ccl20, Cxcl2, Cxcl3 and Cxcl4. IL-8 became the most highly expressed transcript in the monocytes already after four hours of in vitro culture in the presence of LPS. A high baseline level of MHC class II chains and marked upregulation of super oxide dismutase (SOD2), complement factor B, complement factor C3 and coagulation factor 3 (F3; tissue factor) at four hours of in vitro culture were also observed. This indicates a rapid protective response to high production of oxygen radicals, to increase complement activation and possibly also be an inducer of local coagulation. Overall, these findings give strong support for monocytes acting primarily as potent mobile sensors of infection and rapid activators of a strong inflammatory response

User-centered Development of a Clinical Decision Support System

Scientific progress is offering increasingly better ways to tailor a patient’s treatment to the patient’s needs, i.e., better support for optimal clinical decision-making can be offered. Choosing the appropriate treatment for a patient depends on numerous factors, including pathology results, tumor stage, genetic, and molecular characteristics. Bayesian networks are a type of probabilistic artificial intelligence, which in principle would be suitable to support complex clinical decision-making. However, most clinicians do not have experience with these networks. This paper describes an approach of developing a clinical decision support system based on Bayesian networks, that does not require insight knowledge about the underlying computational model for its use. It is developed as a therapy-oriented approach with a focus on usability and explainability. The approach features the computation and presentation of individualized treatment recommendations, comparison of treatments and patient cases, as well as explanations and visualizations providing additional information on the current patient case

Marginal zone B cells : From housekeeping function to autoimmunity?

Marginal zone (MZ) B cells comprise a subset of innate-like B cells found predominantly in the spleen, but also in lymph nodes and blood. Their principal functions are participation in quick responses to blood-borne pathogens and secretion of natural antibodies. The latter is important for housekeeping functions such as clearance of apoptotic cell debris. MZ B cells have B cell receptors with low poly-/self-reactivity, but they are not pathogenic at steady state. However, if simultaneously stimulated with self-antigen and pathogen- and/or damageassociated molecular patterns (PAMPs/DAMPs), MZ B cells may participate in the initial steps towards breakage of immunological tolerance. This review summarizes what is known about the role of MZ B cells in autoimmunity, both in mouse models and human disease. We cover factors important for shaping the MZ B cell compartment, how the functional properties of MZ B cells may contribute to breaking tolerance, and how MZ B cells are being regulated

Nodal marginal zone B cells in mice : a novel subset with dormant self-reactivity

Marginal zone (MZ) B cells, representing a distinct subset of innate-like B cells, mount rapid T-independent responses to blood-borne antigens. They express low-affinity polyreactive antigen receptors that recognize both foreign and self-structures. The spleen is considered the exclusive site for murine MZ B cells. However, we have here identified B cells with a MZ B-cell phenotype in the subcapsular sinuses of mouse lymph nodes. The nodal MZ (nMZ) B cells display high levels of IgM, costimulators and TLRs, and are represented by naive and memory cells. The frequency of nMZ B cells is about 1-6% of nodal B cells depending on mouse strain, with higher numbers in older mice and a trend of increased numbers in females. There is a significant expansion of nMZ B cells following immunization with an autoantigen, but not after likewise immunization with a control protein or with the adjuvant alone. The nMZ B cells secrete autoantibodies upon activation and can efficiently present autoantigen to cognate T cells in vitro, inducing T-cell proliferation. The existence of self-reactive MZ B cells in lymph nodes may be a source of autoantigen-presenting cells that in an unfortunate environment may activate T cells leading to autoimmunity

The Human Monocyte-A Circulating Sensor of Infection and a Potent and Rapid Inducer of Inflammation

Monocytes were previously thought to be the precursors of all tissue macrophages but have recently been found to represent a unique population of cells, distinct from the majority of tissue macrophages. Monocytes and intestinal macrophages seem now to be the only monocyte/macrophage populations that originate primarily from adult bone marrow. To obtain a better view of the biological function of monocytes and how they differ from tissue macrophages, we have performed a quantitative analysis of its transcriptome in vivo and after in vitro stimulation with E. coli LPS. The monocytes rapidly responded to LPS by producing extremely high amounts of mRNA for the classical inflammatory cytokines, IL-1 alpha, IL-1 beta, IL-6 and TNF-alpha, but almost undetectable amounts of other cytokines. IL-6 was upregulated 58,000 times, from almost undetectable levels at baseline to become one of the major transcripts already after a few hours of cultivation. The cells also showed very strong upregulation of a number of chemokines, primarily IL-8, Ccl2, Ccl3, Ccl3L3, Ccl20, Cxcl2, Cxcl3 and Cxcl4. IL-8 became the most highly expressed transcript in the monocytes already after four hours of in vitro culture in the presence of LPS. A high baseline level of MHC class II chains and marked upregulation of super oxide dismutase (SOD2), complement factor B, complement factor C3 and coagulation factor 3 (F3; tissue factor) at four hours of in vitro culture were also observed. This indicates a rapid protective response to high production of oxygen radicals, to increase complement activation and possibly also be an inducer of local coagulation. Overall, these findings give strong support for monocytes acting primarily as potent mobile sensors of infection and rapid activators of a strong inflammatory response

Quantitative In-Depth Transcriptome Analysis Implicates Peritoneal Macrophages as Important Players in the Complement and Coagulation Systems

To obtain a more detailed picture of macrophage (M phi) biology, in the current study, we analyzed the transcriptome of mouse peritoneal M phi s by RNA-seq and PCR-based transcriptomics. The results show that peritoneal M phi s, based on mRNA content, under non-inflammatory conditions produce large amounts of a number of antimicrobial proteins such as lysozyme and several complement components. They were also found to be potent producers of several chemokines, including platelet factor 4 (PF4), Ccl6, Ccl9, Cxcl13, and Ccl24, and to express high levels of both TGF-beta 1 and TGF-beta 2. The liver is considered to be the main producer of most complement and coagulation components. However, we can now show that M phi s are also important sources of such compounds including C1qA, C1qB, C1qC, properdin, C4a, factor H, ficolin, and coagulation factor FV. In addition, FX, FVII, and complement factor B were expressed by the M phi s, altogether indicating that M phi s are important local players in both the complement and coagulation systems. For comparison, we analyzed human peripheral blood monocytes. We show that the human monocytes shared many characteristics with the mouse peritoneal M phi s but that there were also many major differences. Similar to the mouse peritoneal M phi s, the most highly expressed transcript in the monocytes was lysozyme, and high levels of both properdin and ficolin were observed. However, with regard to connective tissue components, such as fibronectin, lubricin, syndecan 3, and extracellular matrix protein 1, which were highly expressed by the peritoneal M phi s, the monocytes almost totally lacked transcripts. In contrast, monocytes expressed high levels of MHC Class II, whereas the peritoneal M phi s showed very low levels of these antigen-presenting molecules. Altogether, the present study provides a novel view of the phenotype of the major M phi subpopulation in the mouse peritoneum and the large peritoneal M phi s and places the transcriptome profile of the peritoneal M phi s in a broader context, including a comparison of the peritoneal M phi transcriptome with that of human peripheral blood monocytes and the liver

Is there a Tornado in Alex's Blood Flow? A Case Study for Narrative Medical Visualization

Narrative visualization advantageously combines storytelling with new media formats and techniques, like interactivity, to create improved learning experiences. In medicine, it has the potential to improve patient understanding of diagnostic procedures and treatment options, promote confidence, reduce anxiety, and support informed decision-making. However, limited scientific research has been conducted regarding the use of narrative visualization in medicine. To explore the value of narrative visualization in this domain, we introduce a data-driven story to inform a broad audience about the usage of measured blood flow data to diagnose and treat cardiovascular diseases. The focus of the story is on blood flow vortices in the aorta, with which imaging technique they are examined, and why they can be dangerous. In an interdisciplinary team, we define the main contents of the story and the resulting design questions. We sketch the iterative design process and implement the story based on two genres. In a between-subject study, we evaluate the suitability and understandability of the story and the influence of different navigation concepts on user experience. Finally, we discuss reusable concepts for further narrative medical visualization projects.publishedVersio

Introduction and evaluation of the Open Energy Ontology (OEO)

See attached fil

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer

Introducing the Open Energy Ontology: Enhancing data interpretation and interfacing in energy systems analysis

Heterogeneous data, different definitions and incompatible models are a huge problem in many domains, with no exception for the field of energy systems analysis. Hence, it is hard to re-use results, compare model results or couple models at all. Ontologies provide a precisely defined vocabulary to build a common and shared conceptualisation of the energy domain. Here, we present the Open Energy Ontology (OEO) developed for the domain of energy systems analysis. Using the OEO provides several benefits for the community. First, it enables consistent annotation of large amounts of data from various research projects. One example is the Open Energy Platform (OEP). Adding such annotations makes data semantically searchable, exchangeable, re-usable and interoperable. Second, computational model coupling becomes much easier. The advantages of using an ontology such as the OEO are demonstrated with three use cases: data representation, data annotation and interface homogenisation. We also describe how the ontology can be used for linked open data (LOD)