Pathologische Trauer bei affektiver Störung

In der vorliegenden Studie wurde innerhalb eines Jahres das Vorliegen pathologischer Trauer unter stationaeren Patienten mit einer depressiven Episode an der psychiatrischen Klinik der WWU Muenster untersucht. Als Messinstrumente dienten die IES-R, das ICG, der BDI, die MADRS, das STAI, die HAMA, das BSI und der F-SOZU. Alle 103 Patienten wiesen einen Verlust auf, jedoch erfuellte keiner alle drei Kriterien des ICG, und somit nicht die Diagnose einer komplizierten Trauer. Betrachtete man die Erfuellung der ICG-Kriterien in Bezug auf die uebrigen Messinstrumente, fand man fuer den IES-R und den BSI signifikante Unterschiede. Wurde eine Gruppe Kompliziert Trauernder gebildet, die im ICG Werte in den oberen 20 % erreichten, konnten signifikante Korrelationen zu traumatischem Erleben, Depressionsschwere, psychischer Belastung und Angst verzeichnet werden. Geschlecht, Alter, Glaube, Schulabschluss oder soziale Unterstuetzung hatten keinen Einfluss auf die Praesenz einer Komplizierten Trauer

Die Rolle des Flagellums und bakterieller Motilität in der Virulenz von Salmonella

Flagella are sophisticated nanomachines and important virulence factors of many pathogenic bacteria. Besides the ability to swim through liquid environments, the flagellum also contributes to successful infection of the host cell by enhancing cell adhesion and invasion. The flagellum consists out of three main parts: (i) the basal body, (ii) a flexible hook, and (iii) a long helical filament. Due to its purposes in distinct infection phases, flagellar gene expression, assembly, and functionality has to be regulated tightly in response to environmental cues. In this thesis, new motility regulators have been identified and mechanisms of flagella modification have been characterised according to their contribution to motility and pathogenesis of Salmonella. In the first chapter, five genes (rflP, yjcC, STM1267, STM3363, and rfaG) have been shown to influence swimming and/or swarming motility via alterations of flagellar gene expression or assembly. In the second chapter, a recently described transcriptional activator of flagellar gene expression, HilD, was characterised regarding its contribution to bacterial motility. HilD overexpression resulted in non-motile bacteria independently of flagellar assembly. It is likely that metabolic changes through collapse of the proton-motive force led to the described motility defect. Further, HilD was shown to activate expression of numerous fimbrial structures, such as Pef, Saf, or curli fimbriae. In the third chapter, alternate expression of the two antigenically distinct flagellins, FliC and FljB, was investigated regarding its importance for Salmonella physiology. FliC flagellin variants facilitated target-site selection and Spi-1 injectisome-dependent invasion during swimming on epithelial host cell surfaces. FljB-expressing bacteria were outcompeted by FliC-expressing bacteria during eukaryotic cell invasion and colonisation in the gastroenteritis mouse model. The fourth chapter focused on the posttranslational modification of the filament by the methylase FliB. FliB methylated lysine residues of the surface-exposed D2 and D3 domains of both flagellins, FliC and FljB. Moreover, flagellin methylation affected epithelial cell adhesion and invasion in a mannose-dependent manner. Consequently, strains deficient in flagellin methylation were outcompeted during dissemination in the gastroenteritis mouse model.Flagellen sind komplexe Nanomaschinen und wichtige Virulenzfaktoren für viele pathogene Bakterien. Neben gerichteter Fortbewegung in flüssigen Medien trägt das Flagellum durch erhöhte Adhäsion und Invasion von eukaryotischen Zellen maßgeblich zur effektiven Infektion der Wirtszelle bei. Das Flagellum besteht aus drei Hauptkomponenten: (i) dem Basalkörper, (ii) einem flexiblen Haken und (iii) einem langen helikalen Filament. Durch unterschiedliche Aufgaben während des Infektionszyklus ist eine strenge Regulierung der Genexpression, Assemblierung und Funktionalität des Flagellums als Antwort auf veränderte Umweltbedingungen von großer Bedeutung. In dieser Arbeit wurden neue Motilitätsregulatoren und deren Mechanismen der Flagellenmodifikation in Hinsicht auf Motilität und Pathogenität von Salmonella identifiziert und näher charakterisiert. Im ersten Kapitel wurden fünf Gene (rflP, yjcC, STM1267, STM3363 und rfaG) ermittelt, die das Schwimm- und Schwärmverhalten durch Änderung der flagellaren Genexpression oder des Flagellenaufbaus beeinträchtigt haben. Im zweiten Kapitel wurde ein zuvor beschriebener Transkriptionsaktivator der flagellaren Genexpression, HilD, bezüglich dessen Auswirkung auf Motilität charakterisiert. HilD-Induktion führte zu einem Verlust an Motilität unabhängig von der flagellaren Assemblierung. Die Ergebnisse weisen auf einen Mechanismus durch einen veränderten Metabolismus und einer Kollabierung der protonenmotorischen Kraft hin. Weiterhin resultierte die Überexpression von HilD in einer erhöhten Expression verschiedener Fimbrien (Pef, Saf oder Curli Fimbrien). Im dritten Kapitel wurde die Expression unterschiedlicher Flagelline, FliC und FljB, bezüglich der biologischen Relevanz in Salmonella analysiert. FliC-flagellierte Bakterien ermöglichten die Auswahl geeigneter Infektionsstellen und somit auch die Spi-1-abhängige Invasion während des Schwimmens nahe der Wirtszelloberfläche. Desweiteren hatten FliC-exprimierende Bakterien einen Vorteil während der Kolonisierung im Gastroenteritis-Mausmodell. Das vierte Kapitel fokusierte sich auf die posttranslationale Modikation des Filaments durch die Methylase FliB. FliB methylierte Lysinreste der exponierten D2 und D3 Domänen sowohl von FliC als auch von FljB. Die Methylierung des Flagellins trug außerdem zur Mannose-abhängigen Adhäsion und Invasion von Epithelzellen bei. Bakterien ohne methyliertes Flagellin waren demnach stark hinsichtlich der Kolonisierung im Gastroenteritis Mausmodell benachteiligt

Genome-Wide Linkage Analysis of Malaria Infection Intensity and Mild Disease

Although balancing selection with the sickle-cell trait and other red blood cell disorders has emphasized the interaction between malaria and human genetics, no systematic approach has so far been undertaken towards a comprehensive search for human genome variants influencing malaria. By screening 2,551 families in rural Ghana, West Africa, 108 nuclear families were identified who were exposed to hyperendemic malaria transmission and were homozygous wild-type for the established malaria resistance factors of hemoglobin (Hb)S, HbC, alpha(+) thalassemia, and glucose-6-phosphate-dehydrogenase deficiency. Of these families, 392 siblings aged 0.5–11 y were characterized for malaria susceptibility by closely monitoring parasite counts, malaria fever episodes, and anemia over 8 mo. An autosome-wide linkage analysis based on 10,000 single-nucleotide polymorphisms was conducted in 68 selected families including 241 siblings forming 330 sib pairs. Several regions were identified which showed evidence for linkage to the parasitological and clinical phenotypes studied, among them a prominent signal on Chromosome 10p15 obtained with malaria fever episodes (asymptotic z score = 4.37, empirical p-value = 4.0 × 10(−5), locus-specific heritability of 37.7%; 95% confidence interval, 15.7%–59.7%). The identification of genetic variants underlying the linkage signals may reveal as yet unrecognized pathways influencing human resistance to malaria

Spatial proteomics revealed a CX3CL1-dependent crosstalk between the urothelium and relocated macrophages through IL-6 during an acute bacterial infection in the urinary bladder

The urothelium of the urinary bladder represents the first line of defense. However, uropathogenic E. coli (UPEC) damage the urothelium and cause acute bacterial infection. Here, we demonstrate the crosstalk between macrophages and the urothelium stimulating macrophage migration into the urothelium. Using spatial proteomics by MALDI-MSI and LC-MS/MS, a novel algorithm revealed the spatial activation and migration of macrophages. Analysis of the spatial proteome unravelled the coexpression of Myo9b and F4/80 in the infected urothelium, indicating that macrophages have entered the urothelium upon infection. Immunofluorescence microscopy additionally indicated that intraurothelial macrophages phagocytosed UPEC and eliminated neutrophils. Further analysis of the spatial proteome by MALDI-MSI showed strong expression of IL-6 in the urothelium and local inhibition of this molecule reduced macrophage migration into the urothelium and aggravated the infection. After IL-6 inhibition, the expression of matrix metalloproteinases and chemokines, such as CX3CL1 was reduced in the urothelium. Accordingly, macrophage migration into the urothelium was diminished in the absence of CX3CL1 signaling in Cx3cr1gfp/gfp mice. Conclusively, this study describes the crosstalk between the infected urothelium and macrophages through IL-6-induced CX3CL1 expression. Such crosstalk facilitates the relocation of macrophages into the urothelium and reduces bacterial burden in the urinary bladder. © 2020, The Author(s)

The Staphylococcus aureus Protein Sbi Acts as a Complement Inhibitor and Forms a Tripartite Complex with Host Complement Factor H and C3b

The Gram-positive bacterium Staphylococcus aureus, similar to other pathogens, binds human complement regulators Factor H and Factor H related protein 1 (FHR-1) from human serum. Here we identify the secreted protein Sbi (Staphylococcus aureus binder of IgG) as a ligand that interacts with Factor H by a—to our knowledge—new type of interaction. Factor H binds to Sbi in combination with C3b or C3d, and forms tripartite Sbi∶C3∶Factor H complexes. Apparently, the type of C3 influences the stability of the complex; surface plasmon resonance studies revealed a higher stability of C3d complexed to Sbi, as compared to C3b or C3. As part of this tripartite complex, Factor H is functionally active and displays complement regulatory activity. Sbi, by recruiting Factor H and C3b, acts as a potent complement inhibitor, and inhibits alternative pathway-mediated lyses of rabbit erythrocytes by human serum and sera of other species. Thus, Sbi is a multifunctional bacterial protein, which binds host complement components Factor H and C3 as well as IgG and β2-glycoprotein I and interferes with innate immune recognition

Explorative data analysis of MCL reveals gene expression networks implicated in survival and prognosis supported by explorative CGH analysis

<p>Abstract</p> <p>Background</p> <p>Mantle cell lymphoma (MCL) is an incurable B cell lymphoma and accounts for 6% of all non-Hodgkin's lymphomas. On the genetic level, MCL is characterized by the hallmark translocation t(11;14) that is present in most cases with few exceptions. Both gene expression and comparative genomic hybridization (CGH) data vary considerably between patients with implications for their prognosis.</p> <p>Methods</p> <p>We compare patients over and below the median of survival. Exploratory principal component analysis of gene expression data showed that the second principal component correlates well with patient survival. Explorative analysis of CGH data shows the same correlation.</p> <p>Results</p> <p>On chromosome 7 and 9 specific genes and bands are delineated which improve prognosis prediction independent of the previously described proliferation signature. We identify a compact survival predictor of seven genes for MCL patients. After extensive re-annotation using GEPAT, we established protein networks correlating with prognosis. Well known genes (CDC2, CCND1) and further proliferation markers (WEE1, CDC25, aurora kinases, BUB1, PCNA, E2F1) form a tight interaction network, but also non-proliferative genes (SOCS1, TUBA1B CEBPB) are shown to be associated with prognosis. Furthermore we show that aggressive MCL implicates a gene network shift to higher expressed genes in late cell cycle states and refine the set of non-proliferative genes implicated with bad prognosis in MCL.</p> <p>Conclusion</p> <p>The results from explorative data analysis of gene expression and CGH data are complementary to each other. Including further tests such as Wilcoxon rank test we point both to proliferative and non-proliferative gene networks implicated in inferior prognosis of MCL and identify suitable markers both in gene expression and CGH data.</p

Einführung in die Linguistik DaF/DaZ

Horstmann S, Settineri J, Freitag D. Einführung in die Linguistik DaF/DaZ. Grundwissen DaF/DaZ. Paderborn: UTB ; Schöningh; 2020