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Neurovascular communication in the brain
FRANKFURT. Function and homeostasis of the brain relies on communication between the complex network of cells, which compose this organ. Consequently, development of the different groups of cells in the brain needs to be coordinated in time and space. The group of Amparo Acker-Palmer (Buchmann Institute of Molecular Life Sciences and the Institute of Cell Biology and Neuroscience, Goethe University) reported in a Research Article in the last issue of the journal Science a novel function of blood vessels in orchestrating the proper development of neuronal cellular networks in the brain.
It is known that vascularization of the brain is necessary to provide neurons and glial cells with oxygen and nutrients important for the metabolic support of neuronal networks. “For several years, we knew that the vascular and nervous systems used very similar vocabulary to develop and function and therefore we postulated that such a common vocabulary could be used to ensure that both systems co-developed in synchroneity and communicated with each other for proper brain function,” explained Acker-Palmer.
To study the communication of the blood vessels and neuronal cells the Acker-Palmer group focused on different aspects of neurovascular development. First, they used the vascularization of the mouse retina as a well-established method to investigate molecules important for vascular growth. Using this method, they discovered that a molecule, Reelin, that had been previously shown to influence neuronal migration was also able to independently influence the growth of vessels using a very similar signaling mechanism by activating the ApoER2 receptor and the Dab1 protein expressed in endothelial cells.
A very important structure in the brain is the cerebral cortex, which plays a key role in all basic functions such as memory, attention, perception, language and consciousness. Neuronal cells in the cerebral cortex are organized in layers and this organization is established during embryonic development. “We decided to eliminate exclusively the Reelin signaling cascade from the endothelial cells and see how this influenced the arrangement of neurons and glial cells in the cerebral cortex,” said Acker-Palmer. Using this system, the scientists revealed the astonishing finding that endothelial cells instruct neurons as to their correct positioning in the cerebral cortex. Mechanistically, they could show that endothelial cells secrete laminins that are deposited in the extracellular matrix surrounding the vessels to anchor properly the glial cell fibers that are necessary for proper neuronal migration and for the proper development of the cerebral cortex.
In the mature brain, glial cells also wrap around the blood capillaries and prevent harmful substances from the blood stream from entering the brain. This is known as the “blood brain barrier” and it is an essential structure that develops in the brain to keep homeostasis. Importantly, Acker-Palmer and her team also showed that the same signaling cascades used by endothelial cells in the cerebral cortex to orchestrate neuronal migration are used to establish communication at the blood brain barrier. “Several neuropsychiatric and neurodegenerative disorders have been associated with abnormal neurovascular communication. Therefore, understanding the signaling pathways and mechanisms involved in such communication is fundamental to finding new approaches for treating dementia and mental illness.”
Publication: Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system, DOI: 10.1126/science.aao2861, (Segarra et al., Science 361, eaao2861 (2018).
Image for download: www.uni-frankfurt.de/73456362
Caption: Blood vessels in red in close communication with proliferating neuronal cells in the mouse cortex at embryonic day 10 (Photo: Cecilia Llao-Cid).
Information: Prof. Amparo Acker-Palmer, Institute of Cellular Biology and Neuroscience, Buchmann Institute of Molecular Life Sciences, Campus Riedberg, Tel.: (069) 798-42563, Acker-Palmer@bio.uni-frankfurt.de.
A social-psychological study shows that the communication situation is more important than social class
FRANKFURT. Are people with more money and education dominating and less warm? A social-psychological study at Goethe University scrutinizes stereotypes.
How is our behavior influenced by our social class? Sociology has long concerned itself with this question. Whether individuals grow up in a working-class environment or in an academic household, they take on behaviors that are typical for their class – so goes the hypothesis. The Frankfurt social-psychologist Dr. Anna Lisa Aydin has found new evidence to support this hypothesis. Her study, which she carried out jointly with researchers from Zurich, Hagen, Idaho and Tel Aviv, and which has been published in the scientific journal Social Psychological and Personality Science also shows, however, that people don’t just rigidly exhibit class-specific behavior, but respond flexibly to counterparts from other social classes.
A large portion of the research on the influence of social class stems from the ideas of the sociologist Pierre Bourdieu. He describes how the environment in which we grow up inscribes itself deeply into our identity. Social-psychological authors argue that people from lower social classes have access to fewer resources and can only influence their environment to a limited degree. They therefore rely more on mutual assistance, making solidarity an important value. People identify with this value and behave cooperatively as a result. People from upper social classes, on the other hand, have access to more resources, can choose from among several alternatives, and are less dependent on mutual assistance. This results in individualistic conceptions of the self where shaping the environment according to one’s own preferences is paramount. These different modes of behavior therefore constitute adaptions to corresponding social environments.
This theory was supported in part by the current study. Overall, more than 2,000 people in Germany were surveyed. For respondents who considered themselves to be members of a lower class, warm and cooperative interaction with other people in their social class was more important than for those who considered themselves members of a higher social class. In addition, those who earned more and were better educated set more value on demonstrating competence and being assertive in their interactions with others than those in the group with lower earnings and less education.
The authors feared that these differences in behavior could lead to a further increase in social inequality in Germany. Individuals who exhibit assertiveness have better chances for social advancement. However, the observed differences in behavior were relatively small. The influence of the social class of the individual’s counterpart had a significantly greater impact. How do people behave when interacting with someone from a lower or higher social group? The majority of those surveyed described social difference in Germany as unjustified or not very justified. As a result, they found it important to behave warmly and cooperatively toward people with less money and education. Conversely, they set value on appearing competent and assertive toward people with more money and education.
These findings are particularly relevant in view of the fact that social inequality is increasing in Germany and other parts of the world, although most people perceive this as unjustified. While research based on sociological theories can explain how this inequality can be exacerbated by conditioning within different social classes, the current study offers an optimistic perspective: in communication situations between people of different classes where class differences are perceived as illegitimate, solidarity with the poor and assertiveness toward the rich are exhibited.
ERC starting grants for projects on stress responses in mitochondria and Jewish translations
FRANKFURT. Once again, researchers at Goethe University were successful in the competition for the prestigious starting grants from the European Research Council (ERC): Dr Christian Münch from the Institute of Biochemistry II at the Faculty of Medicine, and Dr Iris Idelson-Shein from the Seminar for Jewish Studies and the Martin-Buber Chair for Jewish Thought and Philosophy, each received an “ERC Starting Grant.” In this program, the ERC supports excellent researchers in the first five years of their independent careers with a total of 1.5 million euro.
Dr Christian Münch is a biochemist and studies mitochondria, which produce energy for cells. There are up to 2,000 of these tiny power plants in each cell of the body. They are subject to strict quality controls in order to ensure faultless functioning. Christian Münch is particularly interested in a mechanism that is turned on upon misfolding of mitochondrial proteins – known as the “unfolded protein response.” The molecular details of this stress response are poorly understood to date, especially in humans; particularly in regards to its effects on mitochondria themselves and on other areas of cells or neighbouring cells. What signals are prompted by the stress responses and how these are regulated are equally unknown. Christian Münch wants to investigate these open questions.
This project, now supported by the European Research Council, is also highly relevant from a bio-medical perspective. “In numerous diseases, including major diseases like cancer or neurodegeneration, the functioning of the mitochondria is disrupted. In some cases, misfolded mitochondrial proteins are directly responsible for the clinical picture,” explains Christian Münch. Of particular interest to the young researcher is the question of how already-stressed cells communicate with their environment. “I’m convinced there are overarching systems that coordinate the various quality control mechanisms and warn neighbouring cells of imminent danger.” With the ERC project, he hopes to make pioneering discoveries in this area.
Christian Münch has headed an Emmy-Noether research group at the Institute of Biochemistry II at the Faculty of Medicine of the Goethe University since December 2016. Before that he was a postdoctoral fellow at Harvard University in Boston (USA). He obtained his PhD at the University of Cambridge in England in 2011.
Formative translations in Jewish garb
The project of the historian Dr Iris Idelson-Shein deals with Jewish texts that came about as translations from other languages from the sixteenth century to the early nineteenth century. These translations played a crucial role in shaping the culture, literature and history of European Jews in the early modern period. Most Jews in this period were unable to read texts in non-Jewish languages, so that their access to European cultural developments depended almost completely on these kinds of translations.
While translations have been met with great interest by historians of European history in recent decades, they have been largely neglected by historians of early modern Jewry. “So far, no attempt has been made to investigate the totality of Jewish translations in the early modern period,” states Iris Idelson-Shein, ”so that their scope, geographic distribution, development, and sources are largely unknown.”
This scholarly lacuna stems, in part, from the daunting nature of this wildly versatile literature, which drew on sources in different languages, from different genres, spaces and periods. In addition, Jewish authors often presented their translations as original work in order to cloak them in Jewish garb. To approach this rich and deceptive body of texts requires a great familiarity with various literary systems (Jewish and non-Jewish), the command of several languages, and a combination of historical, literary, cultural and other research methods. Idelson-Shein will therefore recruit a multi-lingual and interdisciplinary group of young researchers. The goal is to identify the non-Jewish body of texts that were formative in creating modern Judaism.
Iris Idelson-Shein studied history and philosophy at Tel Aviv University and received her doctorate there in 2011. She is now a research associate at the Martin-Buber Chair for Jewish Thought and Philosophy, and visiting lecturer at the Seminar for Jewish Studies at Goethe University.
Hereditary angioedema is a chronic disorder that can sometimes be life-threatening. Now, a new drug therapy has been successfully tested in an international study headed by the University Hospital Frankfurt.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent painful swellings of the skin and mucous membranes. Without treatment, patients’ quality of life is noticeably compromised: Angioedema may not only be disfiguring; in the gastrointestinal tract it may lead to severe abdominal colic ad in the upper airways it can even be fatal if left untreated. The frequency of angioedema attacks is unpredictable and varies from patient to patient; swellings may occur up to several times a week. The disorder affects about one to two in a hundred thousand people.
A new drug has been developed to help prevent attacks of hereditary angioedema and at the same offer the patients a convenient administration. It has now been investigated in an international study performed at over 26 university facilities in Europe, Canada and Australia. The results were clear: the drug is highly effective with regard to attack prevention and improvement in quality of life while offering a convenient oral administration. Dr. Emel Aygören-Pürsün, specialist in internal medicine at the Division of Oncology, Hematology and Hemostaseology at the Department for Children and Adolescents of the University Hospital Frankfurt, served as the principle investigator of the study. “Hereditary angioedema is a condition that may be associated with lifelong impairment. With this fundamentally new development, we may reduce HAE- attacks and consistently improve our patients’ quality of life,” explains Dr. Emel Aygören-Pürsün. The HAE competence centre at University Hospital Frankfurt is one of the leading institutions nationwide for patient care and the clinical development of therapies for hereditary angioedema. Professor Thomas Klingebiel, Director of the Department for Children and Adolescents, underlines the significance of the results: “Pioneering patient care and cutting-edge clinical research – these are what University Hospital Frankfurt stand for.” The results of the study have now been published in the renowned New England Journal of Medicine.
Genetic disorder leads to uncontrolled swellings
For most cases of hereditary angioedema, the underlying cause is a congenital deficiency or dysfunction of what is known as C1-inhibitor. As a result of C1-inhibitor deficiency, plasma levels of bradykinin increase, a peptide which locally increases the permeability of the smallest blood vessels.
The central role of bradykinin in the development of angioedema attacks is well established for hereditary angioedema. Attacks of angioedema in patients with hereditary angioedema are related to the action of bradykinin, whose generation is closely linked to another plasma protein, called kallikrein. If kallikrein is active, then bradyinin generation is the result. The inhibition of kallikrein should therefore be a suitable measure for prophylaxis of angioedema attacks.
Therapeutic breakthrough in the form of capsules
So far, the prevention of angioedema attacks in hereditary angioedema was bound to medication that required injections. Although drugs were also available as tablets, these proved either ineffective or were not licensed in many countries. In addition, some of them led to severe side effects and could not be administered to children or during pregnancy.
The new drug BCX7353 tested in the study is a synthetic small molecule that acts as a specific kallikrein inhibitor and is administered as capsules. The aim of the development was to achieve an effective prophylaxis with the distinct advantages of an oral administration yet without the side effects of the oral preparations used previously.
During the study, 77 patients were randomized to groups of four different dose levels or placebo. They took the respective dose once daily for 28 days. The patients noted in their diaries the frequency, localization and severity of the attacks; quality of life was recorded at the beginning and the end of the study using a validated questionnaire. Changes in the frequency of the attacks were investigated, as were the side effects from the treatment and the impact on patients’ quality of life.
The results were positive: With a daily dose of 125 mg and higher, a significant reduction of angioedema attacks was demonstrated. Patients who took 125 mg of BCX7353 per day even experienced a reduction in the frequency of their attacks of almost 75 percent compared to placebo; over 40 percent of patients in that dose group remained completely free of attacks during the study. Also the increase in quality of life was most evident for the 125 mg dose; in addition, not only the number of peripheral attacks was reduced in this group but also those in the gastrointestinal tract. Moreover, the side effects of this dose ranged mild.
Overall, the study was able to clearly corroborate the efficacy of BCX7353 and at the same time provide information about the ideal dosage and tolerability of the new drug. Further studies will now be necessary to verify the efficacy and safety with its long-term administration.
Publication: Aygören-Pürsün, E., et al, Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema, New England Journal of Medicine 2018;379:352-62. DOI: 10.1056/NEJMoa1716995.
Further information: Dr. Emel Aygören-Pürsün MD, Internal Medicine and Hemostaseology, Division of Oncology, Hematology and Hemostaseology, Department for Children and Adolescents, University Hospital Frankfurt, Tel. +49 (0)69- 63 01 63 12 / 63 01 63 44, firstname.lastname@example.org
Range of applications for silicones on the increase thanks to modular, combinable building blocks
FRANKFURT. Silicones are synthetic materials used in a broad range of applications. Thanks to the stability of the silicon-oxygen bond, they are resistant to chemicals and environmental influences and also harmless from a physiological point of view. As a result, silicones contribute to making everyday life easier in almost all areas. In the Journal of the American Chemical Society, chemists at Goethe University Frankfurt have now described a new way to produce long-awaited silicon building blocks in a simple and efficient way.
The broad spectrum of applications for silicones ranges from medical implants and cosmetics to hydraulic oils and sealants to corrosion protection – an important topic in view of global corrosion damage to the tune of about US$ 3.3 trillion per year. To optimize silicon-based synthetic materials for specific applications, made-to-measure chlorosilane building blocks are required in order to produce and crosslink the long-chain polymers. This influences, for example, the material’s viscosity and flow properties. Completely new challenges are emerging in the area of 3D printing, with the aid of which products such as individualized running shoes can be manufactured.
Since 1940, the Müller-Rochow Direct Process has formed the backbone of the silicone industry. In this process, elementary silicon is converted with methyl chloride into methylchlorosilanes at high temperatures and pressures in the presence of a copper catalyst. The working group led by Professor Matthias Wagner at the Institute of Inorganic and Analytical Chemistry of Goethe University Frankfurt has now developed a complementary process that has several advantages over the Direct Process: It uses hexachlorodisilane and chlorinated hydrocarbons as starting materials. “Hexachlorodisilane is already mass-produced for the semiconductor industry and the perchlorethylene (PER) we use particularly frequently is a non-flammable liquid which is so inexpensive that it’s used worldwide as a solvent for dry cleaning,” says Matthias Wagner. In addition, the process runs at room temperature and under normal pressure. To activate it, just a small concentration of chloride ions is needed in place of a catalyst.
“Our process produces highly functionalized organochlorosilanes that are ideal crosslinkers. In addition, their special structure offers excellent possibilities to adjust the mechanical flexibility of the silicon chains as desired,” explains co-inventor Isabelle Georg, whose doctoral dissertation is being sponsored by the Evonik Foundation. Julian Teichmann was also involved in the project. He confirms that above all the close collaboration between Goethe University and Evonik had a tremendous influence on his training: “Regular discussion of our results with Evonik’s industrial chemists opened my eyes from the beginning to economic constraints and ecological requirements. It was fascinating to follow the path from our discoveries in the lab via the patenting procedures to realization on a technical scale in practice.”
The chemists in Frankfurt believe that their monomers’ special potential lies in the fact that they contain not only silicon-chlorine bonds but also carbon-carbon multiple bonds. The purpose of the former is to construct the inorganic silicon-oxygen chains; the latter can be linked to form organic polymers. This unique combination permits new routes to inorganic-organic hybrid materials.
Publication: I. Georg et al: Exhaustively Trichlorosilylated C1 and C2 Building Blocks: Beyond the Müller-Rochow Direct Process, in: J. Am. Chem. Soc. 2018, DOI: 10.1021/jacs.8b05950
Further information: Professor Matthias Wagner, Institute of Inorganic and Analytical Chemistry, Riedberg Campus, Tel.: ++49(0)69-798-29156, Matthias.Wagner@chemie.uni-frankfurt.de