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01 september 2023, Contains fulltext : 296660.pdf (Publisher’s version ) (Open Access), Despite comprehensive research efforts over the last decades, the pathomechanisms of age-related macular degeneration (AMD) remain far from being understood. Large-scale genome wide association studies (GWAS) were able to provide a defined set of genetic aberrations which contribute to disease risk, with the strongest contributors mapping to distinct regions on chromosome 1 and 10. While the chromosome 1 locus comprises factors of the complement system with well-known functions, the role of the 10q26-locus in AMD-pathophysiology remains enigmatic. 10q26 harbors a cluster of three functional genes, namely PLEKHA1, ARMS2 and HTRA1, with most of the AMD-associated genetic variants mapping to the latter two genes. High linkage disequilibrium between ARMS2 and HTRA1 has kept association studies from reliably defining the risk-causing gene for long and only very recently the genetic risk region has been narrowed to ARMS2, suggesting that this is the true AMD gene at this locus. However, genetic associations alone do not suffice to prove causality and one or more of the 14 SNPs on this haplotype may be involved in long-range control of gene expression, leaving HTRA1 and PLEKHA1 still suspects in the pathogenic pathway. Both, ARMS2 and HTRA1 have been linked to extracellular matrix homeostasis, yet their exact molecular function as well as their role in AMD pathogenesis remains to be uncovered. The transcriptional regulation of the 10q26 locus adds an additional level of complexity, given, that gene-regulatory as well as epigenetic alterations may influence expression levels from 10q26 in diseased individuals. Here, we provide a comprehensive overview on the 10q26 locus and its three gene products on various levels of biological complexity and discuss current and future research strategies to shed light on one of the remaining enigmatic spots in the AMD landscape.

This contribution discusses the potentials and challenges of using digitised newspapers as a source in relation to other newspaper collections, digitised or not. The author argues that digitisation makes the pitfall of media-centrism even more visible and calls for an even more careful contextualisation of media sources. Instead of focusing too narrowly on a sample of seemingly “representative” digitised newspapers, digitisation may in fact invite us to multiply the types of sources and perspectives we include in our research. Dealing with such diverse sources, both digitized and non-digitized, requires that we highlight how we think about, construct, and analyse our corpus. Ultimately, digitisation can lead to a more exploratory and iterative research approach and thus an understanding of the research corpus as an evolving, interconnected, and reflexive collection of diverse sources.

Ten years after the financial crisis, a key question is whether the various changes in central bank policy that have been introduced since will turn out to be temporary, or whether these changes are here to stay. To shed light on this question, we have conducted surveys among central bank governors and academic economists covering four themes: central bank mandates, central bank policy tools, central bank communication, and the relationship between central banks and government. Several central banks have seen their mandates expanded after the global financial crisis. This tendency is also reflected in the survey results, which show that a majority of respondents (62% of central bankers and 54% of academics) have reconsidered the mandate of their central bank, in countries affected by the crisis and in non-crisis countries alike. Moving away from the predominant pre-crisis view that central banks should mainly be concerned with price stability, many respondents in our surveys mention that financial stability considerations should also be part of the central bank mandate.

This paper studies consumers’ inflation expectations using micro-level data from the University of Michigan’s Surveys of Consumers. It shows that beyond the well-established socioeconomic factors such as income, age, or gender, inflation expectations are also related to respondents’ financial situation, their purchasing attitudes, and their expectations about the macroeconomy. Respondents with current or expected financial difficulties and those with pessimistic attitudes about major purchases, income developments, or unemployment have a stronger upward bias than other households. However, their bias shrinks by more than that of the average household in response to increasing media reporting about inflation.

Item does not contain fulltext, The mechanistic details of the pathogenesis of Chlamydia, an obligate intracellular pathogen of global importance, have eluded scientists due to the scarcity of traditional molecular genetic tools to investigate this organism. Here we report a chemical biology strategy that has uncovered the first essential protease for this organism. Identification and application of a unique CtHtrA inhibitor (JO146) to cultures of Chlamydia resulted in a complete loss of viable elementary body formation. JO146 treatment during the replicative phase of development resulted in a loss of Chlamydia cell morphology, diminishing inclusion size, and ultimate loss of inclusions from the host cells. This completely prevented the formation of viable Chlamydia elementary bodies. In addition to its effect on the human Chlamydia trachomatis strain, JO146 inhibited the viability of the mouse strain, Chlamydia muridarum, both in vitro and in vivo. Thus, we report a chemical biology approach to establish an essential role for Chlamydia CtHtrA. The function of CtHtrA for Chlamydia appears to be essential for maintenance of cell morphology during replicative the phase and these findings provide proof of concept that proteases can be targeted for antimicrobial therapy for intracellular pathogens.

Spore formation in Bacillus subtilis relies on a regulated intramembrane proteolysis (RIP) pathway that synchronizes mother-cell and forespore development. To address the molecular basis of this SpoIV transmembrane signaling, we carried out a structure-function analysis of the activating protease CtpB. Crystal structures reflecting distinct functional states show that CtpB constitutes a ring-like protein scaffold penetrated by two narrow tunnels. Access to the proteolytic sites sequestered within these tunnels is controlled by PDZ domains that rearrange upon substrate binding. Accordingly, CtpB resembles a minimal version of a self-compartmentalizing protease regulated by a unique allosteric mechanism. Moreover, biochemical analysis of the PDZ-gated channel combined with sporulation assays reveal that activation of the SpoIV RIP pathway is induced by the concerted activity of CtpB and a second signaling protease, SpoIVB. This proteolytic mechanism is of broad relevance for cell-cell communication, illustrating how distinct signaling pathways can be integrated into a single RIP module. © 2013 Elsevier Inc.

The mechanistic details of the pathogenesis of Chlamydia, an obligate intracellular pathogen of global importance, have eluded scientists due to the scarcity of traditional molecular genetic tools to investigate this organism. Here we report a chemical biology strategy that has uncovered the first essential protease for this organism. Identification and application of a unique CtHtrA inhibitor (JO146) to cultures of Chlamydia resulted in a complete loss of viable elementary body formation. JO146 treatment during the replicative phase of development resulted in a loss of Chlamydia cell morphology, diminishing inclusion size, and ultimate loss of inclusions from the host cells. This completely prevented the formation of viable Chlamydia elementary bodies. In addition to its effect on the human Chlamydia trachomatis strain, JO146 inhibited the viability of the mouse strain, Chlamydia muridarum, both in vitro and in vivo. Thus, we report a chemical biology approach to establish an essential role for ChlamydiaCtHtrA. The function of CtHtrA for Chlamydia appears to be essential for maintenance of cell morphology during replicative the phase and these findings provide proof of concept that proteases can be targeted for antimicrobial therapy for intracellular pathogens. © 2013 John Wiley & Sons Ltd.

Item does not contain fulltext, The paper presents a semi-automatic approach to creating sentiment dictionaries in many languages. We first produced high-level gold-standard sentiment dictionaries for two languages and then translated them automatically into third languages. Those words that can be found in both target language word lists are likely to be useful because their word senses are likely to be similar to that of the two source languages. These dictionaries can be further corrected, extended and improved. In this paper, we present results that verify our triangulation hypothesis, by evaluating triangulated lists and comparing them to non-triangulated machine-translated word lists

In the study presented, the application of FISH (Fluorescence in situ hybridisation) using different types of polynucleotide probes (classic and synthetic polynucleotide probes targeting rRNA and RINGFISH polynucleotide probes targeting DNA) and the related polynucleotide probe based enrichment technique were tested for their suitability for detection and enrichment of clinically relevant bacteria from real clinical samples. In this context, numerous developments and further evaluations of protocols had to be designed and tested: the determination of the specificity of the polynucleotide probes used, the development of protocols for an adequate permeabilisation of the cell envelopes of Gram-positive bacteria, and the development of a highly time reduced hybridisation protocol. The new developed or modified protocols and the application of the polynucleotide probe enrichment technique were primarily tested and evaluated using classic rRNA targeted polynucleotide probes on pure culture bacteria and clinical samples, which had been spiked with different target organisms. The successful application in this area enabled the further application of the protocols and the transfer of the technique to real clinical samples without artificial spiking, and allowed the successful enrichment of target bacteria from the respective real clinical samples. After integration of the protocols for Gram-positive bacteria and the evaluation of the particular hybridisation parameters regarding the RINGFISH (recognition of individual genes) polynucleotide probes designed (targeting different antibiotic resistance genes of Gram-positive and Gram-negative bacteria), the first time detection and enrichment of target cells from real clinical samples using this type of polynucleotide probes was possible. The last type of polynucleotide probes developed, synthetic polymers of specific oligonucleotide probes, could also be used successfully for detection and enrichment of bacteria from real clinic, Im Rahmen dieser Arbeit wurden die Anwendung von FISH (Fluorescence in situ hybridisation) unter Verwendung verschiedener Arten von Polynukleotidsonden (klassischen und synthetischen Polynukleotidsonden mit den Zielmolekülen rRNA und RINGFISH Polynukleotidsonden mit Antibiotika-Resistenzgenen als Zielmolekül) im Zusammenhang mit der Polynukleotidsonden-gestützten Anreicherungstechnik auf ihre Eignung zur Detektion und Anreicherung klinisch relevanter Bakterien aus realem, klinischen Probenmaterial untersucht. Im Zuge der Anpassung der Polynukleotidsondentechnik an die untersuchten Bakterienspezies, insbesondere an Gram-positive Bakterien und reales, klinisches Probenmaterial, mussten eine Reihe von neuen Protokollen als auch Adaptionen bereits existierender Protokolle entwickelt und evaluiert werden: die Bestimmung der Spezifität der verwendeten Sonden, die Entwicklung von Protokollen zur angemessenen Permeabilisierung der Zellhülle Gram-positiver Bakterien, sowie die Entwicklung eines zeitreduzierten Hybridisierungsprotokolls. Die neu entstandenen Protokolle als auch die Anwendbarkeit und der Transfer der Technik wurden beginnend mit klassischen rRNA zielgerichteten Polynukleotidsonden an Reinkulturen von Bakterien und künstlich mit Zielbakterien versetztem klinischem Probenmaterial evaluiert. Die erfolgreiche Anwendung in diesem Bereich erlaubte die Ausweitung und Übertragung der Technik auf reales klinisches Probematerial, das nicht künstlich mit Zielbakterien versetzt war. Auch die entwickelten RINGFISH (recognition of individual genes) Polynukleotidsonden, zielgerichtet auf verschiedene Antibiotika-Resistenzgene Gram-positiver und Gram-negativer Bakterien, konnten nach Integration der Protokolle für Gram-positive Bakterien sowie Evaluierung der speziellen Hybridisierungsbedingungen zum ersten Mal zur Detektion und Anreicherung von Zielbakterien aus realem, klinischen Probenmaterial verwendet werden. Synthetische Polynukleotidsonden, zielgerichtet auf rRNA und b

In the study presented, the application of FISH (Fluorescence in situ hybridisation) using different types of polynucleotide probes (classic and synthetic polynucleotide probes targeting rRNA and RINGFISH polynucleotide probes targeting DNA) and the related polynucleotide probe based enrichment technique were tested for their suitability for detection and enrichment of clinically relevant bacteria from real clinical samples. In this context, numerous developments and further evaluations of protocols had to be designed and tested: the determination of the specificity of the polynucleotide probes used, the development of protocols for an adequate permeabilisation of the cell envelopes of Gram-positive bacteria, and the development of a highly time reduced hybridisation protocol. The new developed or modified protocols and the application of the polynucleotide probe enrichment technique were primarily tested and evaluated using classic rRNA targeted polynucleotide probes on pure culture bacteria and clinical samples, which had been spiked with different target organisms. The successful application in this area enabled the further application of the protocols and the transfer of the technique to real clinical samples without artificial spiking, and allowed the successful enrichment of target bacteria from the respective real clinical samples. After integration of the protocols for Gram-positive bacteria and the evaluation of the particular hybridisation parameters regarding the RINGFISH (recognition of individual genes) polynucleotide probes designed (targeting different antibiotic resistance genes of Gram-positive and Gram-negative bacteria), the first time detection and enrichment of target cells from real clinical samples using this type of polynucleotide probes was possible. The last type of polynucleotide probes developed, synthetic polymers of specific oligonucleotide probes, could also be used successfully for detection and enrichment of bacteria from real clinic, Im Rahmen dieser Arbeit wurden die Anwendung von FISH (Fluorescence in situ hybridisation) unter Verwendung verschiedener Arten von Polynukleotidsonden (klassischen und synthetischen Polynukleotidsonden mit den Zielmolekülen rRNA und RINGFISH Polynukleotidsonden mit Antibiotika-Resistenzgenen als Zielmolekül) im Zusammenhang mit der Polynukleotidsonden-gestützten Anreicherungstechnik auf ihre Eignung zur Detektion und Anreicherung klinisch relevanter Bakterien aus realem, klinischen Probenmaterial untersucht. Im Zuge der Anpassung der Polynukleotidsondentechnik an die untersuchten Bakterienspezies, insbesondere an Gram-positive Bakterien und reales, klinisches Probenmaterial, mussten eine Reihe von neuen Protokollen als auch Adaptionen bereits existierender Protokolle entwickelt und evaluiert werden: die Bestimmung der Spezifität der verwendeten Sonden, die Entwicklung von Protokollen zur angemessenen Permeabilisierung der Zellhülle Gram-positiver Bakterien, sowie die Entwicklung eines zeitreduzierten Hybridisierungsprotokolls. Die neu entstandenen Protokolle als auch die Anwendbarkeit und der Transfer der Technik wurden beginnend mit klassischen rRNA zielgerichteten Polynukleotidsonden an Reinkulturen von Bakterien und künstlich mit Zielbakterien versetztem klinischem Probenmaterial evaluiert. Die erfolgreiche Anwendung in diesem Bereich erlaubte die Ausweitung und Übertragung der Technik auf reales klinisches Probematerial, das nicht künstlich mit Zielbakterien versetzt war. Auch die entwickelten RINGFISH (recognition of individual genes) Polynukleotidsonden, zielgerichtet auf verschiedene Antibiotika-Resistenzgene Gram-positiver und Gram-negativer Bakterien, konnten nach Integration der Protokolle für Gram-positive Bakterien sowie Evaluierung der speziellen Hybridisierungsbedingungen zum ersten Mal zur Detektion und Anreicherung von Zielbakterien aus realem, klinischen Probenmaterial verwendet werden. Synthetische Polynukleotidsonden, zielgerichtet auf rRNA und b