Press releases – August 2020

 

Aug 26 2020
15:30

International research group identifies three forms of disease progression for “acute decompensated liver cirrhosis” 

  When liver cirrhosis is deadly 

FRANKFURT. When the body can no longer compensate the gradual failure of the liver caused by liver cirrhosis, there is a high risk of acute decompensated liver cirrhosis. In some patients this develops quickly into an often deadly acute-on-chronic liver failure, in which other organs such as the kidneys or brain fail. A study by an international team of researchers headed by Professor Jonel Trebicka from the Frankfurt University Hospital and funded by the foundation EF Clif, has discovered which patients are particularly at risk. With their findings, the scientists have laid the foundation for the development of preventive therapy to prevent acute-on-chronic liver failure. 

The liver has many functions: it stores nutrients and vitamins, produces dextrose, coagulation factors and hormones, and breaks down toxins, drugs and alcohol. Chronic alcohol abuse, viruses or other diseases can damage the liver and lead to chronic liver disease. Without treatment, chronic liver disease leads to liver cirrhosis in the final stages, in which liver tissue turns into connective tissue, making the liver increasingly unable to carry out its functions. The result: the blood’s clotting ability is impaired, toxic metabolic products are fortified, the liver is not adequately supplied with blood and blood pressure rises in the portal veins that supply the liver.

The body tries to compensate for the reduced liver function. For example, new veins develop as alternative circulation from the oesophagus, stomach and intestines which expand into varicose veins. When the disease progresses to the point that this kind of compensation is no longer possible – physicians speak of acute decompensated liver cirrhosis – the situation becomes life-threatening: tissue fluid (ascites) collects in the abdominal cavity, leading to bacterial infections and internal bleeding, for example in the oesophagus. Difficulty concentrating, mood swings and sleepiness are signs of a poisoning of the brain (hepatic encephalopathy) that can result in a hepatic coma.

A European clinical study headed by Professor Jonel Trebicka, and carried out under the umbrella of the European Foundation for the Study of Chronic Liver Failure, has for the first time identified three clinical course variations in patients admitted to the hospital with acute decompensated cirrhosis.

1.    The first clinical course is characterised by high blood inflammation values, indicating inflammatory reactions throughout the body. Within three months after admission to the hospital, a number of body organs fail: the acute decompensation becomes “acute-on-chronic liver failure” (ACLF). The physicians therefore call this variation Pre-ACLF. More than half of patients die from it; only a third survive after a year.

2.    Patients with the second clinical course do not develop ACLF and have moderate inflammation values. They suffer, however, from significant hypertension in the portal vein. Approximately 20 percent die within the following three months, another 15 percent over the course of the following year. The physicians named this variation “instable decompensated liver cirrhosis”.

3.    The patients with the third clinical course exhibit neither high inflammation values nor frequent complications. They do not develop ACLF in the first three months. Within a year, however, one in ten dies. The physicians call this variation “stable decompensated liver cirrhosis.“

Lead investigator Professor Jonel Trebicka, gastroenterologist and hepatologist at Medical Clinic I of  University Hospital Frankfurt explains: “We are now working intensively on the development of new diagnostic options, especially for the group of pre-ACLF patients, in order to identify this group before admission to the hospital so that preventive measures can be implemented early on. The development of preventive therapies for the often deadly ACLF is one of our most important research goals in this context.”

Study co-author Professor Stefan Zeuzem, Dean of the Faculty of Medicine and Director of Medical Clinic I at Frankfurt University Hospital explains: “Liver diseases are one of the main focal points of Medical Clinic I and we offer numerous specialised outpatient departments for patients with acute and chronic liver diseases. So on the one hand we were able to observe patients for the study. On the other hand, the research findings on improving ACLF prevention and therapies will rapidly benefit all of our patients.”

The research findings are part of a European-wide study called PREDICT. The study observes the clinical course of acute decompensated liver cirrhosis in order to find early indications for the development of acute-on-chronic liver failures (ACLF). The study was funded by the European Foundation for the Study of Chronic Liver Failure. 136 scientists from 47 centres and institutions in 14 European countries are participating in PREDICT.

Publication: Jonel Trebicka, Javier Fernandez, Maria Papp, Paolo Caraceni, Wim Laleman, Carmine Gambino, et al.: The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. Journal of Hepatology, https://doi.org/10.1016/j.jhep.2020.06.013

Further information:
University Hospital Frankfurt, Goethe University Frankfurt
Medical Clinic I
Professor Jonel Trebicka
Section Translational Hepatology,
Medical Clinic I (Director: Professor Stefan Zeuzem)
Goethe University/University Hospital Frankfurt
Tel. +49 69 6301 80789 (Jennifer Biondo, secretarial office)
Jonel.Trebicka@kgu.de.

 

Aug 24 2020
14:15

Wastewater provides indication of the degree of infection in population 

SARS-CoV-2 viruses in wastewater: monitoring COVID-19 and estimating potential transmission risk

FRANKFURT/AACHEN. Since the beginning of the pandemic, research groups have been working on methods to detect SARS-CoV-2 viruses in wastewater to be used to monitor the degree of COVID-19 transmission among the population. The idea is simple: since infected people shed SARS-CoV-2 viruses in their faeces, wastewater samples could give an indication of the infection numbers among all the residents connected to a wastewater treatment plant. Given sufficient sensitivity, these analyses could function as an early-warning system for authorities, allowing early detection of local case increases within the catchment area of a treatment plant. 

A consortium of Frankfurt virologists, ecotoxicologists and evolution researchers, and water researchers from Aachen have now shown for the first time in Germany that SARS-CoV-2 genetic material can be detected in treatment plants using modern molecular methods. Analyses revealed 3 to 20 gene equivalents per millilitre of raw wastewater in all nine treatment plants tested during the first pandemic wave in April 2020. This concentration level was also measured in studies in the Netherlands and the USA.

The researchers were astonished that older retention samples from the years 2017 and 2018, before the outbreak of the pandemic, also delivered signals. Extensive method validation revealed that the gene primer erroneously registered not only SARS-CoV-2, but other non-disease causing coronaviruses in wastewater as well. The current method, developed specifically for SARS-CoV-2 in wastewater, has been confirmed through gene sequencing.

The method can be now employed for what is called wastewater-based epidemiology: the measured viral load of a treatment plant allows conclusions on the number of COVID-19 infected individuals in the catchment area. In the largest treatment plant, 1,037 acute cases were estimated in the catchment area for a viral load of 6 trillion (6 x 1012) gene equivalencies pro day; in smaller treatment plants with viral loads lower by two orders of magnitude, 36 cases were estimated.

The sensitivity is sufficient as an early warning system to indicate whether the action value of 50 incidents per 100,000 residents has been exceeded. Earlier hopes that the precision would be sufficient to determine the estimated number infected people not reported through laboratory diagnosis have not yet been fulfilled. However, the scientists believe that further improvements in the methods are possible.

In vitro cell tests have shown that the SARS-CoV-2 fragments verified in the wastewater are non-infectious. However, due to the high loads and low retention capacity of conventional treatment plants, the behaviour of SARS-CoV-2 in the water cycle should be investigated more deeply. The authors of the study are working on making their knowledge available for an application of the method soon, with the goal of achieving a close cooperation between health ministries, environmental ministries, treatment plant operators and professional associations.

The research team was formed on the initiative of the non-profit Research Institute for Water and Waste Management at RWTH Aachen (FiW), the Institute of Environmental Engineering at RWTH Aachen (ISA), the Institute for Medical Virology at University Hospital Frankfurt (KGU) and Department for Evolution Ecology and Environmental Toxicology at the Institute of Ecology, Evolution and Diversity at Goethe University Frankfurt, and is supported by six water boards in North Rhine-Westphalia, the LOEWE Centre for Translational Biodiversity Genomics (TBG) and the University of Saskatoon in Canada.

Publication: Sandra Westhaus, Frank-Andreas Weber, Sabrina Schiwy, Volker Linnemann, Markus Brinkmann, Marek Widera, Carola Greve, Axel Janke, Henner Hollert, Thomas Wintgens, Sandra Ciesek. Detection of SARS-CoV-2 in raw and treated wastewater in Germany – suitability for COVID-19 surveillance and potential transmission risks. Science of the Total Environment. https://doi.org/10.1016/j.scitotenv.2020.141750, https://www.sciencedirect.com/science/article/pii/S0048969720352797

Further information

University Hospital Frankfurt
Institute for Medical Virology
Prof. Dr. Sandra Ciesek through
University Hospital Frankfurt Press Office
Tel. +49 69 6301 86442
kommunikation@kgu.de

Goethe University Frankfurt
Institute of Ecology, Evolution and Diversity
Dept. Evolution Ecology and Environmental Toxicology
and LOEWE Centre for Translational Biodiversity Genomics (TBG)
Prof. Dr. rer. nat. Henner Hollert
hollert@bio.uni-frankfurt.de

Research Institute for Water and Waste Management at RWTH Aachen (FiW)
Dr. sc. Frank-Andreas Weber
weber@fiw.rwth-aachen.de

RWTH Aachen University
Institute of Environmental Engineering (ISA)
Univ.-Prof. Dr.-Ing. habil. Thomas Wintgens
wintgens@isa.rwth-aachen.de

 

CARE (Corona Accelerated R&D in Europe), supported by Europe’s Innovative Medicines Initiative (IMI), is the largest undertaking of its kind dedicated to discovering and developing urgently needed treatment options for COVID-19. The initiative is committed to a long-term understanding of the disease and development of therapies for COVID-19 and future coronavirus threats in addition to urgent efforts to repurpose existing therapies as potential immediate response. The CARE consortium will accelerate COVID-19 R&D by bringing together the leading expertise and projects of 37 teams from academic and non-profit research institutions and pharmaceutical companies into a comprehensive drug discovery engine.

Complete news release here.

 

Aug 10 2020
13:35

Innovative method opens up new perspectives for reconstructing climatic conditions of past eras

Exact climate data from the past

FRANKFURT. Corals and cave carbonates are important archives of past climate. This is because the composition of these carbonate deposits can reveal the temperatures that prevailed at the Earth’s surface at the time they formed. An international team of geoscientists led by Goethe University Frankfurt, Germany, has now developed a new method that makes it possible to identify whether the composition of these deposits was exclusively controlled by temperature, or if the formation process itself exerted an additional control. The new method allows scientists to determine past Earth surface temperatures more reliably and to study the processes involved in calcareous skeleton formation of modern and extinct species. (Nature Communications, DOI 10.1038/s41467-020-17501-0)

Corals precipitate their calcareous skeletons (calcium carbonate) from seawater. Over thousands of years, vast coral reefs form due to the deposition of this calcium carbonate. During precipitation, corals prefer carbonate groups containing specific variants of oxygen (chemical symbol: O). For example, the lower the water temperature, the higher the abundance of a heavy oxygen variant, known as isotope 18O, within the precipitated carbonate. Unfortunately, the 18O abundance of the seawater also influences the abundance of 18O in the calcium carbonate – and the contribution of 18O from seawater cannot be resolved when determining temperatures based on carbonate 18O abundances alone.

A great step forward was the discovery that the isotopic composition of the precipitated carbonate allows temperature determinations independent of the composition of the water if the abundance of a specific, very rare carbonate group is measured. This carbonate group contains two heavy isotopes, a heavy carbon isotope (13C) and a heavy oxygen isotope (18O) which are referred to as “clumped isotopes”. Clumped isotopes are more abundant at lower temperatures.

However, even with this method there was still a problem: The mineralization process itself can affect the incorporation of heavy isotopes in the calcium carbonate (kinetic effects). If unidentified, the bias introduced by such kinetic effects leads to inaccurate temperature determinations. This particularly applies for climatic archives like corals and cave carbonates.

An international research group led by Professor Jens Fiebig at the Department of Geosciences at Goethe University Frankfurt has now found a solution to this problem. They have developed a highly sensitive method by which – in addition to the carbonate group containing 13C and 18O – the abundance of another, even rarer carbonate group can be determined with very high precision. This group also contains two heavy isotopes, namely two heavy oxygen isotopes (18O).

If the theoretical abundances of these two rare carbonate groups are plotted against each other in a graph, the influence of the temperature is represented by a straight line. If, for a given sample, the measured abundances of the two heavy carbonate groups produce a point away from the straight line, this deviation is due to the influence of the mineralization process.

David Bajnai, Fiebig’s former PhD student, applied this method to various climatic archives. Among others, he examined various coral species, cave carbonates and the fossil skeleton of a squid-like cephalopod (belemnite).

Today, Dr. Bajnai is a post-doctoral researcher at the University of Cologne. He explains: “We were able to show that – in addition to temperature – the mechanisms of mineralization also greatly affect the composition of many of the carbonates that we examined. In the case of cave carbonates and corals, the observed deviations from the exclusive temperature control confirm model calculations of the respective mineralization processes conducted by Dr. Weifu Guo, our collaborator at the Woods Hole Oceanographic Institution in the USA. The new method, for the first time, makes it possible to quantitatively assess the influence of the mineralization process itself. This way, the exact temperature of carbonate formation can be determined.”

Professor Jens Fiebig is convinced that the new method holds great potential: “We will further validate our new method and identify climatic archives that are particularly suitable for an accurate and highly precise reconstruction of past Earth surface temperatures. We also intend to use our method to study the effect that anthropogenic ocean acidification has on carbonate mineralization, for instance in corals. The new method might even allow us to estimate the pH values of earlier oceans.” If all this succeeds, the reconstruction of environmental conditions that prevailed throughout Earth’s history could be greatly improved, he adds.

Publication: David Bajnai, Weifu Guo, Christoph Spötl, Tyler B. Coplen, Katharina Methner, Niklas

Löffler, Emilija Krsnik, Eberhard Gischler, Maximilian Hansen, Daniela Henkel, Gregory D. Price, Jacek Raddatz, Denis Scholz, Jens Fiebig: Dual clumped isotope thermometry resolves kinetic biases in carbonate formation temperatures, Nature Communications, DOI 10.1038/s41467-020-17501-0, http://www.nature.com/ncomms

Further information:
Professor Jens Fiebig
Department of Geosciences
Goethe University Frankfurt
Tel.: +49 (0) 69 798 40182
Jens.Fiebig@em.uni-frankfurt.de

Dr. David Bajnai
Institute of Geology and Mineralogy
University of Cologne
Tel.: +49 (0)221 470 89829

David.Bajnai@uni-koeln.de
Dr. Weifu Guo
Department of Geology and Geophysics
Woods Hole Oceanographic Institution
Woods Hole, MA
USA
Tel.: +1 508 289 3380
wfguo@whoi.edu

 

Aug 7 2020
14:36

​How microbes in the primordial atmosphere obtained energy without oxygen

Oldest enzyme in cellular respiration isolated

FRANKFURT. Researchers from Goethe University have found what is perhaps the oldest enzyme in cellular respiration. They have now been able to isolate an extremely fragile protein complex called “Rnf" from the heat-loving bacterium Thermotoga maritima. In fact, the genes that encode for the enzyme were already discovered around 10 years ago. However, the researchers from Frankfurt have now succeeded for the first time in isolating the enzyme and thus in proving that it really is formed by bacteria and used for cellular energy production. (Communications Biology, DOI 10.1038/s42003-020-01158 -y)

In the first billion years, there was no oxygen on Earth. Life developed in an anoxic environment. Early bacteria probably obtained their energy by breaking down various substances by means of fermentation. However, there also seems to have been a kind of “oxygen-free respiration". This was suggested by studies on primordial microbes that are still found in anoxic habitats today.

“We already saw ten years ago that there are genes in these microbes that perhaps encode for a primordial respiration enzyme. Since then, we – as well as other groups worldwide – have attempted to prove the existence of this respiratory enzyme and to isolate it. For a long time unsuccessfully because the complex was too fragile and fell apart at each attempt to isolate it from the membrane. We found the fragments, but were unable to piece them together again," explains Professor Volker Müller from the Department of Molecular Microbiology and Bioenergetics at Goethe University.  

Through hard work and perseverance, his doctoral researchers Martin Kuhns and Dragan Trifunovic then achieved a breakthrough in two successive doctoral theses. “In our desperation, we at some point took a heat-loving bacterium, Thermotoga maritima, which grows at temperatures between 60 and 90°C," explains Dragan Trifunovic, who will shortly complete his doctorate. “Thermotoga also contains Rnf genes, and we hoped that the Rnf enzyme in this bacterium would be a bit more stable. Over the years, we then managed to develop a method for isolating the entire Rnf enzyme from the membrane of these bacteria."

As the researchers report in their current paper, the enzyme complex functions a bit like a pumped-storage power plant that pumps water into a lake higher up and produces electricity via a turbine from the water flowing back down again.

Only in the bacterial cell the Rnf enzyme (biochemical name = ferredoxin:NAD-oxidoreductase) transports sodium ions out of the cell's interior via the cell membrane to the outside and in so doing produces an electric field. This electric field is used to drive a cellular “turbine" (ATP synthase): It allows the sodium ions to flow back along the electric field into the cell's interior and in so doing it obtains energy in the form of the cellular energy currency ATP.  

The biochemical proof and the bioenergetic characterization of this primordial Rnf enzyme explains how first forms of life produced the central energy currency ATP. The Rnf enzyme evidently functions so well that it is still contained in many bacteria and some archaea today, in some pathogenic bacteria as well where the role of the Rnf enzyme is still entirely unclear.
“Our studies thus radiate far beyond the organism Thermotoga maritima under investigation and are extremely important for bacterial physiology in general," explains Müller, adding that it is important now to understand exactly how the Rnf enzyme works and what role the individual parts play. “I'm happy to say that we're well on the way here, since we're meanwhile able to produce the Rnf enzyme ourselves using genetic engineering methods," he continues.


Publication: Kuhns, M, Trifunovic, D., Huber, H., Müller, V. (2020). The Rnf complex is a Na+ coupled respiratory enzyme in a fermenting bacterium, Thermotoga maritima. Communications Biology, DOI 10.1038/s42003-020-01158-y https://www.nature.com/commsbio/

A Photo is available here: http://www.uni-frankfurt.de/90861461

Caption: Ph.D. student Dragan Trifunovic with a big bottle and a small test tube containing cultured Thermotoga maritima bacteria (Photo: Uwe Dettmar for Goethe University Frankfurt)


Further Information:
Prof. Volker Müller
Molecular Microbiology and Bioenergetics
Goethe-University Frankfurt
Tel.: (069) 798-29507;
vmueller@bio.uni-frankfurt.de