Chemokine und Chemokinrezeptor-exprimierende T-Zellen in bronchoalveolärer Lavage bei interstitiellen Lungenerkrankungen im Vergleich zu chronischer Bronchitis und malignen Erkrankungen der Lunge

In der vorliegenden Arbeit wurde bronchoalveolären Lavage Flüssigkeit (BALF) von Patienten mit interstitiellen Lungenerkrankungen (23 Patienten) auf Chemokinkonzentrationen und Chemokinrezeptorexressionsmuster der Lymphozyten analysiert und die Ergebnisse mit Patienten, die an chronischer Bronchitis (6 Patienten) oder malignen Erkrankungen (9 Patienten) der Lunge erkrankt waren verglichen. Mittels ELISA wurden die Chemokinkonzentrationen und mittels Durchflusszytometrie der Anteil an Chemokinrezeptor-exprimierenden T-Zellen in der BALF bestimmt. Hierbei wurden die Chemokinkonzentrationen von MCP 1, TARC, MDC und RANTES und die Häufigkeit CCR2+, CCR5+, CCR4+ und CXCR3+ Zellen innerhalb der CD4+ und CD8+ T-Zellpopulationen gemessen. Es konnte gezeigt werden, dass bei interstitiellen Lungenerkrankungen im Vergleich zu den Kontrollgruppen die MCP-1 Konzentration knapp signifikant (p = 0,055) und die CCR2+CD4+T-Zellen signifikant erhöht waren. Im Zusammenhang mit Daten aus Kinder- und Erwachsenenstudien, in denen in der bronchoalveolären Lavageflüssigkeit erhöhte MCP-1 Werte und vermehrt CCR2+ T-Zellen nachgewiesen wurden, legen diese Ergebnisse eine wichtige Rolle der MCP 1/CCR2-Achse in der Pathogenese der interstitiellen Lungenerkrankungen nahe. Ebenso fanden sich bei interstitiellen Lungenerkrankungen signifikant mehr der TH2-assoziierten CCR4+ T-Zellen; bei dem TH1-assoziierten Rezeptor CXCR3+ ergab sich kein Unterschied. Gemeinsam mit ähnlichen Ergebnissen einiger Studien in Mausmodellen und humanen Studien weisen sie auf eine TH2-Polarisierung der T Zellen bei interstitiellen Lungenerkrankungen hin, welche hierbei einen profibrotischen Effekt haben sollen. Gleichzeitig konnten bei interstitiellen Lungenerkrankungen signifikant mehr CCR5+CD4+ und CCR5+CD8+ Zellen als in den Kontrollgruppen nachgewiesen werden. Da auch bei gesunden Menschen CCR5+ T-Zellen nachgewiesen werden konnten, postulieren wir, dass CCR5+ T-Zellen auch unabhängig von der Polarisierung der T-Zellen ein regulärer Bestandteil des bronchoalveolären Raumes im Rahmen einer normalen Immunreaktion sind. Insgesamt hat diese explorative Analyse aufgezeigt, dass sowohl die MCP 1/CCR2-Achse, als auch TH2-polarisierte T-Zellen ein potentielles Angriffsziel in der Behandlung interstitieller Lungenerkrankungen darstellen könnten. Die Ergebnisse sollten den Anstoß für ausführlichere Untersuchungen mit einem wesentlich größeren Patientenkollektiv geben

<i>Moorella</i> Strains for the Production of Biochemicals from Syngas

In the process of sugar fermentation, a significant portion of lignocellulosic biomass is left unused. An alternative is the gasification into syngas, a carbon-rich gas mixture. Syngas serves as energy and carbon source for acetogenic bacteria, which can then produce biochemicals. In the syngas fermentation process even the recalcitrant lignin portion can be fully converted into higher value compounds. Still the cost-effectiveness of this process requires better understanding of the metabolism and modification of the acetogenic strains. In my PhD project I am laying the basis for production of higher value biochemicals (acetone) from syngas using Moorella strains as cell factories. Moorella has outstanding abilities that make it especially suitable for the syngas fermentation process (thermophily, carbon source utilization). Firstly, the project focuses on understanding the primary metabolism in acetogenic bacteria. The main research aspect is to determine acceptance of, and the exact growth rates on different carbon sources (C1, C6, gaseous substrates) in different Moorella strains. Genome analysis on pathway level is performed to link the genotype to the phenotype. Differential expression analysis between heterotrophic and autotrophic growth (RNA-seq) serves to elucidate the regulatory mechanisms underlying carbon source utilization. In the second part of my project I am developing tools for genetic manipulation of Moorella strains. For example, a pyrF deletion strains, which allows heterologous gene expression was constructed. These tools developed in my project will be applied to engineer bacterial cell factories for production of higher value biochemicals like acetone

Nanoparticular Inhibitors of Flavivirus Proteases from Zika, West Nile and Dengue Virus Are Cell-Permeable Antivirals

Viral proteases have been established as drug targets in several viral diseases including human immunodeficiency virus and hepatitis C virus infections due to the essential role of these enzymes in virus replication. In contrast, no antiviral therapy is available to date against flaviviral infections including those by Zika virus (ZIKV), West Nile virus (WNV), or dengue virus (DENV). Numerous potent inhibitors of flaviviral proteases have been reported; however, a huge gap remains between the in vitro and intracellular activities, possibly due to low cellular uptake of the charged compounds. Here, we present an alternative, nanoparticular approach to antivirals. Conjugation of peptidomimetic inhibitors and cell-penetrating peptides to dextran yielded chemically defined nanoparticles that were potent inhibitors of flaviviral proteases. Peptide-dextran conjugates inhibited viral replication and infection in cells at nontoxic, low micromolar or even nanomolar concentrations. Thus, nanoparticular antivirals might be alternative starting points for the development of broad-spectrum antiflaviviral drugs.C.N. thanks the Australian Research Council for a Discovery Early Career Research Award (DE190100015) and the Freie Universität Berlin for a Rising Star fellowship

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

[Photograph 2012.201.B1316.0175]

Photograph used for a story in the Daily Oklahoman newspaper. Caption: "Ernest Trumble, of the Southeastern State College music faculty, hardly expects to make the best seller list with his new book on "The Evolution of Fauxbourdon," even though it has several characteristics of a "whodunit.

Exploiting the potential of gas fermentation

The use of gas fermentation for production of chemicals and fuels with lower environmental impact is a technology that is gaining increasing attention. Over 38 Gt of CO2 is annually being emitted from industrial processes, thereby contributing significantly to the concentration of greenhouse gases in the atmosphere. Together with the gasification of biomass and different waste streams, these gases have the potential for being utilized for production of chemicals through fermentation processes. Acetogens are among the most studied organisms capable of utilizing waste gases. Although engineering of heterologous production of higher value compounds has been successful for a number of acetogens, the processes are challenging due to the redox balance and the lack of efficient engineering tools. In this review, we address the availability of different gaseous feedstock and gasification processes, and we focus on the advantages of alternative fermentation scenarios, including thermophilic production strains, multi-stage fermentations, mixed cultures, as well as mixotrophy. Such processes have the potential to significantly broaden the product portfolio, increase the product concentrations and yields, while enabling the exploitation of alternative and mixed feedstocks. The reviewed processes also have the potential to address challenges associated with product inhibition and may contribute to reducing the costs of downstream processing. Given the widespread availability of gases, such processes will likely significantly impact the transition towards a more sustainable society