Scientists at the Goethe University have discovered that single cells in the innermost layer of blood vessels proliferate after injury and in so doing make a significant contribution to the formation of new vessels.
FRANKFURT. How new blood vessels form in mammals, for example during development or after injury, was so far not known exactly. Scientists at the Goethe University have now been able to shed light on this process. They have shown that single cells in the innermost layer of blood vessels proliferate after injury and in so doing make a significant contribution to the formation of new vessels.
Observation in the living organism – and especially in the heart – of how new blood vessels form is not possible in mammals. That is why only endpoints can ever be seen, i.e. that new veins and arteries have formed and of what type of cells they consist. However, little is known to date about the actual process of new vessel formation, although this knowledge could contribute in future to remedying tissue damage, such as occurs in diabetes or following an ischemia-induced heart attack.
That is the reason why Professor Stefanie Dimmeler and her fellow researchers at the Institute of Cardiovascular Regeneration of Goethe University Frankfurt have studied the fate of single cells in the innermost vascular layer, i.e. the endothelial cells, during development and after tissue damage in what are known as Confetti mice. In these models, the researchers can mark specific cell types and distinguish between them with the help of fluorescent proteins. In the models used, only endothelial cells fluoresced in three different colors. Since the cells continue to fluoresce when they divide, single endothelial cells and their “progeny” can be tracked. In so doing, the scientists sought to answer the question of whether cell division in the formation of new blood vessels, as known from zebrafish, takes place more or less randomly or whether specific cells divide again and again to produce new vessels.
Clonal expansion after a heart attack
In damaged heart tissue following a heart attack, the researchers were able to observe that certain cells had divided repeatedly. They also detected this cell division, which is referred to as clonal expansion, in damaged tissue in skeletal muscles caused by ischemia. To do so, they analyzed the fluorescence in endothelial cells in tissue slices taken from the damaged areas. They found the ratio of clonally expanding cells – between 30 and 50 percent - very surprising. “But perhaps we’re even underestimating the ratio of clonal expansion,” presumes Dimmeler. “Because after all we haven’t conducted a three-dimensional analysis but instead identified the fluorescing cells in two-dimensional tissue slices.” In addition, further experiments showed that the vessels formed through clonal expansion are also supplied with blood and thus able to function.
In new-born models, by contrast, Professor Dimmeler and her team did not observe any clonal expansion in the formation of new vessels in the retina. It would therefore seem that the growth of blood vessels during normal development results from the random multiplication and integration of cells. This result coincides with observations in zebrafish, in which what is known as “cell mixing” also plays an important role in the formation of new blood vessels during development.
The researchers were keen to characterize the dividing cells more precisely and to this purpose they analyzed which genes are transcribed in single examples of the clonally expanding endothelial cells. “Surprisingly, we found a large number of gene products that are typical for the transition from an endothelial to a mesenchymal cell,” says Dimmeler. This transition, or EndMT process, is a contributor in many pathogenic processes, such as scarring or arteriosclerosis. In endothelial cells, the gene products typical for EndMT do not, however, mirror a transition but instead presumably just an intermediate stage that enables the cells to detach themselves from the cell assembly in order to multiply.
Clonal expansion as possible therapy for heart attack patients
Dimmeler and her team now want to find out what happens with the clonally expanded cells in the long term, since at present they are only able to track their fate for about two months. “We want to know what has happened to these cells after a year and whether the new blood vessels are just as good as the old ones in the long term,” says Dimmeler.
Is clonal expansion different in older patients? This is another question she finds fascinating. “It might be that clonal expansion is no longer that efficient in older people, which is why a lot of damaged tissue dies off after a heart attack and forms scar tissue which cannot be reactivated through the formation of new blood vessels,” says Dimmeler. “If we manage to characterize the clonally expanding cells more precisely, we will hopefully find ways to re-stimulate this process.”
Clonal Expansion of Endothelial Cells Contributes to Ischemia-Induced Neovascularization. Manavski, Y., Lucas, T., Glaser, S. F., Dorsheimer, L., Gunther, S., Braun, T., Rieger, M. A., Zeiher, A. M., Boon, R. A. & Dimmeler, S. Circulation research 122, 670-677, (2018).
Further information: Professor Stefanie Dimmeler, Institute of Cardiovascular Regeneration, University Hospital Frankfurt, Tel.: +49(0)69-6301-7440; Email: Dimmeler@em.uni-frankfurt.de
Research group simulates effect of these climate protection goals on global freshwater resources
FRANKFURT. What difference does it make to the Earth’s water resources if we can limit global warming to 1.5°C instead of 2°C? A research group led by Goethe University Frankfurt has simulated these scenarios with global hydrological models. An important result: High flows and thus flood hazards will increase significantly over an average of 21 percent of the global land area if the temperature rises by 2°C. On the other hand, if we manage to limit the rise in global warming to 1.5°C only 11 percent of the global land area would be affected.
According to the Paris Agreement on climate change of December 2015, the increase in global average temperature should be kept well below 2°C compared to pre-industrial levels, if possible even below 1.5°C. To find out what the two scenarios mean specifically in terms of reducing risks for the global freshwater system, the Federal Ministry of Education and Research commissioned a study which has now been published and is intended for inclusion in the forthcoming special report by the Intergovernmental Panel on Climate Change (IPCC) on global warming of 1.5°C.
As the research group led by Professor Petra Döll from the Department of Physical Geography at Goethe University Frankfurt reports in the current issue of “Environmental Research Letters”, it used two global hydrological models for the analysis, which were “fed” with a new type of climate simulations, known as HAPPI simulations. These are more suitable than previous types of simulations for quantifying the risks of the two long-term climate goals. By calculating seven indicators, risks for humans, freshwater organisms and vegetation were characterized.
“If we compare four groups of countries with different per-capita incomes, those countries with a low or lower middle income would profit most from a limitation of global warming to 1.5°C in the sense that the increase in flood risk in those countries would remain far lower than at 2°C,” explains Petra Döll, first author of the study. Countries with a high income would profit most of all from the fact that rivers and land would dry out far less in the dry months of the year.
Professor Döll performed the study in cooperation with the Potsdam Institute for Climate Impact Research and Climate Analytics in Berlin. She is an expert on water and has been investigating the potential impacts of climate change on the Earth’s freshwater systems for twenty years.
A picture can be downloaded under: http://www.uni-frankfurt.de/71631166
Caption: Access to clean water is a major challenge facing many people, such as this boy in the semi-arid Northeast Region of Brazil. Photo: Petra Döll.
Publication: Petra Döll, Tim Trautmann, Dieter Gerten, Hannes Müller Schmied, Sebastian Ostberg, Fahad Saaed und Carl-Friedrich Schleussner: Risks for the global freshwater system at 1.5 ◦C and 2 ◦C global warming, in: Enviromental Research Letters 13 (2018) 044038, https://doi.org/10.1088/1748-9326/aab792
Further information: Professor Petra Döll, Department of Physical Geography, Faculty of Geosciences and Geography, Riedberg Campus, Tel.: +49(0)69-798-40219, firstname.lastname@example.org
Harold James Appointed Visiting Professor of Financial History 2018
FRANKFURT. Harold James, Princeton University, will hold the Visiting Professorship of Financial History at Goethe University Frankfurt’s House of Finance this year. The professorship is endowed by Metzler Bank and Friedrich Flick Förderungsstiftung.
Harold James is Claude and Lore Kelly Professor in European Studies, Professor of History and International Affairs, and Director of the Program in Contemporary European Politics and Society at Princeton University. Furthermore Professor Harold James holds the position of Official Historian at the International Monetary Fund. His research focuses on Economics and Financial History and Modern European History. James was educated at Cambridge University (Ph.D. in 1982) and a Fellow of Peterhouse for eight years before joining Princeton University in 1986. In 2004 he was awarded the Helmut Schmidt Prize for Economic History, and in 2005 the Ludwig Erhard Prize for writing about economics.
James’ publications include a study of the interwar depression in Germany (“The German Slump”, 1986), an analysis of the changing character of national identity in Germany (“A German Identity 1770-1990” 1989), and a study on “International Monetary Cooperation Since Bretton Woods” (1996). He was a co-author of a history of Deutsche Bank (1995) which won the Financial Times Global Business Book Award in 1996, and he wrote the book “The Deutsche Bank and the Nazi Economic War Against the Jews” (2001). Furthermore he published “The End of Globalization: Lessons from the Great Depression” (2001); “Europe Reborn: A History 1914-2000” (2003); “The Roman Predicament: How the Rules of International Order Create the Politics of Empire” (2006), and “Family Capitalism: Wendels, Haniels and Falcks”. His most recent works are “The Globalization Cycle” (2009); “Making the European Monetary Union” (2012), and “The Euro and the Battle of Economic Ideas (with Markus K. Brunnermeier and Jean-Pierre Landau)” (2016).
During his stay in Frankfurt, Harold James will deliver a CFS Presidential Lecture on 28 May. Also, he will give a seminar in the Ph.D. program of the University’s Graduate School GSEFM at the House of Finance on the topic “Thinking About Financial History”. On 8 June 2018, James will give the keynote address in an international research conference on “Lehman – 10 Years After” which he co-organizes together with Bernd Rudolph, LMU.
Professor James is the fourth holder of the Visiting Professorship of Financial History. In the context of this professorship, distinguished international experts in banking and financial history are invited to share their research insights and methods with researchers, students and the interested public in Frankfurt. Cooperation partners are the Research Center SAFE at the House of Finance and the Institut für Bank- und Finanzgeschichte. Previous Visiting Professors were Benjamin Friedman, Harvard University (2015), Caroline Fohlin, Emory University, Atlanta (2016) and Hans-Joachim Voth, University of Zurich (2017). The Visiting Professorship was initially endowed by Metzler Bank and Edmond de Rothschild Group in 2014 on the occasion of Goethe University’s centennial.
Information: Ursula Maßner, House of Finance, Faculty of economics and business administration, Westend Campus, Phone +49 (0)69 798 30091, E-Mail email@example.com
Researchers of Goethe University decode the mechanism of chemotherapy induced female infertility
FRANKFURT. One of the most significant impairments of the quality of life after a chemotherapy is infertility. Researchers of the Goethe University and the University Tor Vergata in Rome have now identified the mechanism of chemotherapy-induced infertility in females.
Many chemotherapeutics act by damaging the DNA. Since cancer cells divide more often than most normal cells, they react more sensitive to DNA damaging agents. One exception are oocytes. To prevent birth defects they initiate a cellular death program if DNA damage is detected. This process, called apoptosis, is triggered in oocytes by the protein p63. Oocytes contain a high concentration of an oocyte-specific isoform of p63 which plays a key role as a quality control factor in causing infertility.
In contrast to men who produce new sperm cells throughout their life women are born with a finite number of oocytes. When this pool is depleted menopause starts. This pool of oocytes can be depleted prematurely by chemotherapy resulting in early menopause. This results not only in infertility but also in hormone-based problems such as osteoporosis.
Scientists in the laboratory of Prof Volker Dötsch at the Institute for Biophysical Chemistry of Goethe University have now deciphered the mechanism leading to premature loss of the oocyte pool caused by treatment with chemotherapy. In non-damaged oocytes p63 exists in an inactive form. DNA damage caused by chemo- or radiotherapy results in the modification of p63 with phosphate groups which triggers a conformational change to the active form. Active p63 starts the cell death program which leads to the elimination of the oocyte. The scientists describe in the online edition of the journal „Nature Structural and Molecular Biology“ the molecular details of this activation mechanism and the enzymes responsible for it.
These results open new opportunities for developing a therapy for preserving oocytes of female cancer patients treated with chemotherapeutics. In experiments with mouse ovaries inhibiting the identified enzymes saved the oocytes from cell death despite treatment with chemotherapeutics.
Publication: Tuppi M., Kehrloesser S., Coutandin D.W. et al. Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63, in: Nature Structural and Molecular Biology. DOI: 10.1038/s41594-018-0035-7
Astrophysicists at Goethe University Frankfurt answer this question by computing images of feeding non-Einsteinian black holes: At present it is hard to tell them apart from standard black holes.
FRANKFURT. One of the most fundamental predictions of Einstein's theory of relativity is the existence of black holes. In spite of the recent detection of gravitational waves from binary black holes by LIGO, direct evidence using electromagnetic waves remains elusive and astronomers are searching for it with radio telescopes. Astrophysicists at Goethe University Frankfurt, and collaborators in the ERC-funded project BlackHoleCam in Bonn and Nijmegen have created and compared self-consistent and realistic images of the shadow of an accreting supermassive black hole - such as the black-hole candidate Sagittarius A* (Sgr A*) in the heart of our galaxy - both in general relativity and in a different theory of gravity. The goal was to test if Einsteinian black holes can be distinguished from those in alternative theories of gravity.
Not all of the light rays (or photons) produced by matter falling into a black hole are trapped by the event horizon, a region of spacetime from which nothing can escape. Some of these photons will reach distant observers, so that when a black hole is observed directly a “shadow” is expected against the background sky. The size and shape of this shadow will depend on the black-hole’s properties but also on the theory of gravity.
Because the largest deviations from Einstein’s theory of relativity are expected very close to the event horizon and since alternative theories of gravity make different predictions on the properties of the shadow, direct observations of Sgr A* represent a very promising approach for testing gravity in the strongest regime. Making such images of the black-hole shadow is the primary goal of the international Event Horizon Telescope Collaboration (EHTC), which combines radio data from telescopes around the world.
Scientists from the BlackHoleCam team in Europe, who are part of the EHTC, have now gone a step further and investigated whether it is possible to distinguish between a "Kerr" black hole from Einstein’s gravity and a "dilaton" black hole, which is a possible solution of an alternative theory of gravity.
The researchers studied the evolution of matter falling into the two very different types of black holes and calculated the radiation emitted to construct the images. Furthermore, real-life physical conditions in the telescopes and interstellar medium were used to create physically realistic images. “To capture the effects of different black holes we used realistic simulations of accretion disks with near-identical initial setups. These expensive numerical simulations used state-of-the-art codes and took several months on the Institute’s supercomputer LOEWE,” says Dr. Yosuke Mizuno, lead author of the study.
Moreover, expected radio images obviously have a limited resolution and image fidelity. When using realistic image resolutions, the scientists found, to their surprise, that even highly non-Einsteinian black holes could disguise themselves as normal black holes.
“Our results show that there are theories of gravity in which black holes can masquerade as Einsteinian, so new techniques of analyzing EHT data may be needed to tell them apart,” remarks Luciano Rezzolla, professor at Goethe University and leader of the Frankfurt team. “While we believe general relativity is correct, as scientists we need to be open-minded. Luckily, future observations and more advanced techniques will eventually settle these doubts,” concludes Rezzolla.
“Indeed, independent information from an orbiting pulsar, which we are actively searching for, will help eliminate these ambiguities,” says Michael Kramer, director at the MPI for Radio Astronomy in Bonn. Heino Falcke (professor at Radboud University), who 20 years ago proposed using radio telescopes to image the shadow of black holes, is optimistic. “There is little doubt that the EHT will eventually obtain strong evidence of a black-hole shadow. These results encourage us to refine our techniques beyond the current state of the art and thus make even sharper images in the future."
Yosuke Mizuno1, Ziri Younsi1, Christian M. Fromm1, , Oliver Porth1, Mariafelicia De Laurentis1, Hector Olivares1, Heino Falcke2, Michael Kramer3 and Luciano Rezzolla1,4 'The current ability to test theories of gravity with black hole shadows, Nature Astronomy, doi: 10.1038/s41550-018-0449-5
1Institute for Theoretical Physics, Goethe University, Frankfurt, Germany
2Radboud University, Nijmegen, The Netherlands
3Max-Planck Institute for Radio Astronomy, Bonn, Germany
4Institute for Advanced Studies, Frankfurt, Germany
Contact phone numbers:
Mizuno: Mobile: +49 159 02104299, Office: +49 69 79847885
Falcke: Mobile: +49 151 23040365, Office: +31 24 3652020
Kramer: Mobile: +49 160 90747348, Office: +49 228 525278
Rezzolla: Mobile: +49 170 3022982, Office: +49 69 79847871
You can download a figure from: www.uni-frankfurt.de/71465647
Credit: Fromm/Younsi/Mizuno/Rezzolla (Frankfurt)
BlackHoleCam is an ERC-funded Synergy Grant that aims to image, measure and understand astrophysical black holes. Its PIs, Falcke, Kramer and Rezzolla, test fundamental predictions of Einstein’s theory of General Relativity. The BlackHoleCam team members are active partners of the international Event Horizon Telescope Collaboration (ETHC). Goethe University is a stakeholder institute and represented on the EHTC's executive board.