Statistical Inference for Propagation Processes on Complex Networks

Die Methoden der Netzwerktheorie erfreuen sich wachsender Beliebtheit, da sie die Darstellung von komplexen Systemen durch Netzwerke erlauben. Diese werden nur mit einer Menge von Knoten erfasst, die durch Kanten verbunden werden. Derzeit verfügbare Methoden beschränken sich hauptsächlich auf die deskriptive Analyse der Netzwerkstruktur. In der hier vorliegenden Arbeit werden verschiedene Ansätze für die Inferenz über Prozessen in komplexen Netzwerken vorgestellt. Diese Prozesse beeinflussen messbare Größen in Netzwerkknoten und werden durch eine Menge von Zufallszahlen beschrieben. Alle vorgestellten Methoden sind durch praktische Anwendungen motiviert, wie die Übertragung von Lebensmittelinfektionen, die Verbreitung von Zugverspätungen, oder auch die Regulierung von genetischen Effekten. Zunächst wird ein allgemeines dynamisches Metapopulationsmodell für die Verbreitung von Lebensmittelinfektionen vorgestellt, welches die lokalen Infektionsdynamiken mit den netzwerkbasierten Transportwegen von kontaminierten Lebensmitteln zusammenführt. Dieses Modell ermöglicht die effiziente Simulationen verschiedener realistischer Lebensmittelinfektionsepidemien. Zweitens wird ein explorativer Ansatz zur Ursprungsbestimmung von Verbreitungsprozessen entwickelt. Auf Grundlage einer netzwerkbasierten Redefinition der geodätischen Distanz können komplexe Verbreitungsmuster in ein systematisches, kreisrundes Ausbreitungsschema projiziert werden. Dies gilt genau dann, wenn der Ursprungsnetzwerkknoten als Bezugspunkt gewählt wird. Die Methode wird erfolgreich auf den EHEC/HUS Epidemie 2011 in Deutschland angewandt. Die Ergebnisse legen nahe, dass die Methode die aufwändigen Standarduntersuchungen bei Lebensmittelinfektionsepidemien sinnvoll ergänzen kann. Zudem kann dieser explorative Ansatz zur Identifikation von Ursprungsverspätungen in Transportnetzwerken angewandt werden. Die Ergebnisse von umfangreichen Simulationsstudien mit verschiedenstensten Übertragungsmechanismen lassen auf eine allgemeine Anwendbarkeit des Ansatzes bei der Ursprungsbestimmung von Verbreitungsprozessen in vielfältigen Bereichen hoffen. Schließlich wird gezeigt, dass kernelbasierte Methoden eine Alternative für die statistische Analyse von Prozessen in Netzwerken darstellen können. Es wurde ein netzwerkbasierter Kern für den logistischen Kernel Machine Test entwickelt, welcher die nahtlose Integration von biologischem Wissen in die Analyse von Daten aus genomweiten Assoziationsstudien erlaubt. Die Methode wird erfolgreich bei der Analyse genetischer Ursachen für rheumatische Arthritis und Lungenkrebs getestet. Zusammenfassend machen die Ergebnisse der vorgestellten Methoden deutlich, dass die Netzwerk-theoretische Analyse von Verbreitungsprozessen einen wesentlichen Beitrag zur Beantwortung verschiedenster Fragestellungen in unterschiedlichen Anwendungen liefern kann

Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4(+) T cells

Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33(+)S100A9(+) cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17–producing CD4(+) T cells. This chemokine was released by activated IMCs. Elimination of CD4(+) T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4(+) T cells

Rapid Immunomagnetic Negative Enrichment of Neutrophil Granulocytes from Murine Bone Marrow for Functional Studies In Vitro and In Vivo

Polymorphonuclear neutrophils (PMN) mediate early immunity to infection but can also cause host damage if their effector functions are not controlled. Their lack or dysfunction is associated with severe health problems and thus the analysis of PMN physiology is a central issue. One prerequisite for PMN analysis is the availability of purified cells from primary organs. While human PMN are easily isolated from peripheral blood, this approach is less suitable for mice due to limited availability of blood. Instead, bone marrow (BM) is an easily available reservoir of murine PMN, but methods to obtain pure cells from BM are limited. We have developed a novel protocol allowing the isolation of highly pure untouched PMN from murine BM by negative immunomagnetic isolation using a complex antibody cocktail. The protocol is simple and fast (∼1 h), has a high yield (5–10*106 PMN per animal) and provides a purity of cells equivalent to positive selection (>80%). Most importantly, cells obtained by this method are non-activated and remain fully functional in vitro or after adoptive transfer into recipient animals. This method should thus greatly facilitate the study of primary murine PMN in vitro and in vivo

Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes

S100A8 and S100A9 are EF-hand Ca2+ binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target proteins. S100A8 and S100A9 expression levels increased in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases and they are implicated in the numerous disease pathologies. The Ca2+ and Zn2+-binding properties of S100A8/A9 have a pivotal influence on their conformation and oligomerization state, including self-assembly into homo- and heterodimers, tetramers and larger oligomers. Here we review how the unique chemical and conformational properties of individual proteins and their structural plasticity at the quaternary level account for S100A8/A9 functional diversity. Additional functional diversification occurs via non-covalent assembly into oligomeric and fibrillar amyloid complexes discovered in the aging prostate and reproduced in vitro. This process is also regulated by Ca2+and Zn2+-binding and effectively competes with the formation of the native complexes. High intrinsic amyloid-forming capacity of S100A8/A9 proteins may lead to their amyloid depositions in numerous ailments characterized by their elevated expression patterns and have additional pathological significance requiring further thorough investigation

S100A8/A9 Is Not Involved in Host Defense against Murine Urinary Tract Infection

Background: Inflammation is commonly followed by the release of endogenous proteins called danger associated molecular patterns (DAMPs) that are able to warn the host for eminent danger. S100A8/A9 subunits are DAMPs that belong to the S100 family of calcium binding proteins. S100A8/A9 complexes induce an inflammatory response and their expression correlates with disease severity in several inflammatory disorders. S100A8/A9 promote endotoxin-and Escherichia (E.) coli-induced sepsis showing its contribution in systemic infection. The role of S100A8/A9 during a local infection of the urinary tract system caused by E. coli remains unknown. Methodology/Principal Findings: We investigated the contribution of S100A8/A9 in acute urinary tract infection (UTI) by instilling 2 different doses of uropathogenic E. coli transurethrally in wild type (WT) and S100A9 knockout (KO) mice. Subsequently, we determined bacterial outgrowth, neutrophilic infiltrate and inflammatory mediators in bladder and kidney 24 and 48 hours later. UTI resulted in a substantial increase of S100A8/A9 protein in bladder and kidney tissue of WT mice. S100A9 KO mice displayed similar bacterial load in bladder or kidney homogenate compared to WT mice using 2 different doses at 2 different time points. S100A9 deficiency had little effect on the inflammatory responses to E. Coli-induced UTI infection, as assessed by myeloperoxidase activity in bladder and kidneys, histopathologic analysis, and renal and bladder cytokine concentrations. Conclusions: We show that despite high S100A8/A9 expression in bladder and kidney tissue upon UTI, S100A8/A9 does not contribute to an effective host response against E. Coli in the urinary tract syste

Gut mucosal DAMPs in IBD: From mechanisms to therapeutic implications

Endogenous damage-associated molecular patterns (DAMPs) are released during tissue damage and have increasingly recognized roles in the etiology of many human diseases. The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), are immune-mediated conditions where high levels of DAMPs are observed. DAMPs such as calprotectin (S100A8/9) have an established clinical role as a biomarker in IBD. In this review, we use IBD as an archetypal common chronic inflammatory disease to focus on the conceptual and evidential importance of DAMPs in pathogenesis and why DAMPs represent an entirely new class of targets for clinical translation. </p

Joining S100 proteins and migration:for better or for worse, in sickness and in health

The vast diversity of S100 proteins has demonstrated a multitude of biological correlations with cell growth, cell differentiation and cell survival in numerous physiological and pathological conditions in all cells of the body. This review summarises some of the reported regulatory functions of S100 proteins (namely S100A1, S100A2, S100A4, S100A6, S100A7, S100A8/S100A9, S100A10, S100A11, S100A12, S100B and S100P) on cellular migration and invasion, established in both culture and animal model systems and the possible mechanisms that have been proposed to be responsible. These mechanisms involve intracellular events and components of the cytoskeletal organisation (actin/myosin filaments, intermediate filaments and microtubules) as well as extracellular signalling at different cell surface receptors (RAGE and integrins). Finally, we shall attempt to demonstrate how aberrant expression of the S100 proteins may lead to pathological events and human disorders and furthermore provide a rationale to possibly explain why the expression of some of the S100 proteins (mainly S100A4 and S100P) has led to conflicting results on motility, depending on the cells used. © 2013 Springer Basel