A new high resolution method allows for the first time precise identification and quantification of interactions of a receptor with two ligands simultaneously.
Signalling processes in organisms are governed by specific extracellular and intracellular interactions and involve hundreds of different functionally highly versatile receptors situated in cell membranes. For scientists wishing to understand signalling processes the situation is made more complex by the receptors not only being unevenly distributed and often able to bind more than one ligand but also by the same type of receptor being able to bind a ligand strongly, weakly or not all. New methods that allow precise quantifications of such complex interactions are urgently required.
A new high resolution method developed by an international team of scientists including Robert Tampé and Ralph Wieneke from Goethe University Frankfurt now allows for the first time precise identification and quantification of interactions of a receptor with two ligands simultaneously. The new method has been published in the latest edition of the journal Nature Communications.
Atomic force microscopy (AFM) is a powerful technique for nanoscale characterization of surfaces. It makes use of a cantilever with an extremely fine tip. Force-distance curve-based atomic force microscopy (FD-based AFM) combines high-resolution imaging and single-molecule force spectroscopy. In studies using biological samples, the AFM tip approaches and retracts from the sample for each pixel. FD-based AFM methods use different coatings of the AFM tip as a toolbox and such methods have made impressive progress in recent years. For the detection of specific binding sites FD-based AFM requires tethering of a ligand to the AFM tip. While contouring protein complexes in a membrane such functionalized AFM tips can then measure the interactions of the tethered ligand to the protein. It had not been possible to image single membrane receptors and simultaneously detect their interactions with more than one ligand, but the new method has overcome this hurdle.
For their proof of principle the scientists used the human protease-activated receptor 1 (PAR1), one of the large family of G-protein-coupled membrane receptors. GPCRs mediate most cellular responses to hormones and neurotransmitters, as well as being responsible for vision, olfaction and taste. GPCRs can coexist in different functional states in the cell membrane and can bind various ligands at different strength or affinity. The GPCR PAR1 is activated by the coagulation protease thrombin which triggers signalling cascades to initiate cellular responses that help orchestrate haemostasis, thrombosis, inflammation and possibly also tissue repair. With the aid of their new FD-based AFM method human PAR1 in proteoliposomes could be imaged while simultaneously detecting extracellular and intracellular interactions of PAR1 with two ligands. The surface chemistry and nanoscopic method developed are applicable to a range of biological systems in vitro and in vivo.
Image for download: www.uni-frankfurt.de/58953180
Contact: Robert Tampé, Institute of Biochemistry, firstname.lastname@example.org
Goethe University Frankfurt, Max von Laue Straße 9, 60438 Frankfurt/Germany
Mining already took place 3500 years ago in the Austrian region of Montafon
FRANKFURT/BARTHOLOMÄBERG. Mining in the Alps dates back much further than previously thought – in the Austrian region of Montafon since the Bronze Age. Thanks to C14 dating, a group of researchers from Goethe University in Frankfurt led by Professor Rüdiger Krause of the Institute of Archaeological Sciences was able to detect in the course of prospecting in the Bartholomäberg region at a height of 1450 metres ancient traces of mining from the middle Bronze Age. The C14 method, also known as the radiocarbon method, makes a relatively precise age classification possible, for example of charcoal, on the basis of decreasing radioactivity in carbonaceous material.
It was in this way that the researchers also discovered that 2500 years later – towards the end of the Early Middle Ages – mining evidently even resumed there, since there are clear traces in the terrain from this period too. That means that this is one of the oldest mining areas provable to date in a mountainous region of Europe. The discovery, which was made possible through funding from the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG)), equates according to Professor Krause to “a small sensation, since the academic world had so far not considered that Bronze Age mining in the Montafon mining area could be possible.” There are only very few places with evidence of Alpine mining in the early and late Middle Ages either. Professor Krause now sees an exciting link, for instance, to the historically documented nine iron-smelting furnaces in Drusengau – the region around Bludenz, Klostertal and Montafon – which are mentioned in the Imperial Register of Chur (Churer Reichsurbar) of the year 843.
Professor Krause and his team, which includes archaeobotanists and a large number of students from Goethe University, have been researching for 15 years in the Montafon region, which lies in the Central Alps in the south of the Austrian federal state of Vorarlberg. The objective is to explore early settlement history and early mining in this unique inner-Alpine “settlement chamber” with Bronze Age and Iron Age settlements and Bronze Age castle buildings with stone walls up to 3 metres thick.
Excavations in the newly discovered mining area are due to commence next summer. An exciting project, as the only other evidence of comparably ancient mining activity is in the Eastern Alps, for example in the famous Mitterberg mining area, where Bronze Age miners dug galleries as far down as 200 metres and developed mining on the most intensive scale in this period in the Alps. “What significance our new site in Montafon had in the context of Bronze Age copper supply in the Alps will be seen when we examine it further”, says Professor Krause.
For archaeological research in Frankfurt, Montafon – with its special colonization history with Bronze Age and Iron Age settlements – is an important priority. After all, it is regarded as a model region for an interdisciplinary approach where archaeobotany, soil science and metal analysis, in particular the analysis of heavy metals in the ground as a relict of ancient mining, are very important sources of information. Work focuses on questions about what could have originally induced people to settle in this Alpine valley landscape. From what point in time onwards was their self-sufficient economy – gathering as well as livestock, arable and pasture farming – supplemented by mining activity? Thanks to the researchers in Frankfurt it is now known that this inner-Alpine valley landscape has been inhabited on a continuous basis since about 2000 B.C. and that Montafon can today look back on 4000 years of settlement history.
The scientific “breakthroughs” in the former mining area are now also visible in book form: On the 9th of November, the first monograph on the archaeology and early history of mining in Montafon will be presented in Bartholomäberg (Montafon): A “colourful” book richly illustrated with photographs and diagrams, which wants to familiarize the reader and observer in short and easily comprehensible words and in a lively way with the oldest history of an Alpine valley landscape using the example of Montafon as well as with the different types of exploration. Martin Vallaster, Mayor of the Municipality of Bartholomäberg, is noticeably impressed: “We are all very proud of this book, which is a product of lasting value for relaying the research results and their wide variety of new findings. Allow yourself when reading this book to be transported into the world of our ancestors and experience our exciting and unique settlement history”.
Book details: Rüdiger Krause, Archäologie im Gebirge. Montafoner Zeitmaschine. Frühe Besiedlungsgeschichte und Bergbau im Montafon, Vorarlberg (Österreich).
With contributions by Lisa Bringemeier, Rudolf Klopfer, Astrid Röpke, Astrid Stobbe, Franziska Würfel. 150 pages, 213 colour and large-format images, 23 x 23 cm, hard cover, € 19,80 Bartholomäberg/Bonn 2015 (ISBN 978-3-7749-3981-0), Distribution: Dr. Rudolf Habelt GmbH, Bonn (Germany), www.habelt.de
Information: Prof. Dr. Rüdiger Krause, Faculty of Linguistics, Culture and Arts, Westend Campus, Tel.: +160-824 7 824, Email: email@example.com
Download photographs: www.uni-frankfurt.de/58833010
Social researchers in Frankfurt present study results – Publication in new issue of "American Journal of Sociology”
FRANKFURT. Family policy influences not only families’ economic behaviour, but also sends out clear normative signals on which people base their individual life plans: The longer a mother takes a break from work after the birth of a child, the more she loses interest in her own career: Professor Markus Gangl and Dr. Andrea Ziefle, sociologists at Goethe University in Frankfurt, are now able to prove this empirically. Their article entitled “The Making of a Good Woman: Extended Parental Leave Entitlements and Mothers’ Work Commitment in Germany” has just appeared in the internationally renowned “American Journal of Sociology” (121 (2)).
It was already becoming evident in international research that short periods of parental leave of up to one or one-and-a half years, such as are common in Scandinavia, lead to better integration of mothers in the employment market. This is clearly contrary to experience in Anglo-Saxon countries, where family is primarily a private issue. The longer parental leave is made possible by legislation, the more the disadvantages of this leave are of consequence. “Research to date considered the reason for this rather to be the behaviour of employers who tend to entrust mothers who have been absent for longer periods less frequently with demanding jobs or important tasks”, says Gangl and continues: “We call this ‘statistical discrimination’.” The two sociologists are, however, now able to show that this is not the only reason for the negative impact of longer parental leave. “The subjective attitude of mothers towards employment decreases considerably over the course of time. That means, through the longer break from work these women increasingly lose interest in working on their own professional perspectives”, says Ziefle.
In order to verify this statement, the two social researchers used the survey data - unique worldwide - of the Socio-Economic Panel. Incidentally, this empirical social research instrument, which was developed over 30 years ago at Goethe University in close cooperation with colleagues in Mannheim, has been used annually since 1984 – it is now in its 30th year - to interview representatively selected persons and households in Germany with regard to their income and living conditions. In their study, the researchers examined closely the answers which women had given regarding their subjective attitude to employment at various points in time: How did women’s attitude change after parental leave in Germany was extended in 1992 from 18 months to three years? Asked about their attitude to work after a longer period of parental leave, the mothers replied that gainful employment was no longer so important to them and that the family ranked first instead.
At that time, incidentally, almost 50 percent of the mothers had not worked prior to the child’s birth. Today it is only one third. “And in the 1990s it was possible to observe even amongst those housewives who were not gainfully employed that entering a profession became less and less an issue the longer the new law applied”, says Gangl and interprets this as an “effect of habituation to the new political environment”. Not only social awareness has slowly but constantly changed since the 1990s, but also the legal framework, such as greater involvement of fathers in parental leave as well as divorce legislation.
What relevance do the results of this retrospective study have for the situation today? “The study shows for the first time: Family policy not only has an influence on families’ economic behaviour. It is also the normative signals which are sent out and evidently subconsciously influence individual life plans”, explains Gangl. The researchers are not stopping at this retrospective analysis: “From another study, which we published last year, we know that mothers have gone back to work sooner as a result of the new family allowance”, says Andrea Ziefle. “We are working now on finding out whether the new family policy of recent years is also reflected in the subjective attitudes of fathers and mothers.”
Publication: Gangl, Markus, and Andrea Ziefle. 2015. The Making of a Good Woman: Extended Parental Leave Entitlements and Mothers’ Work Commitment in Germany. American Journal of Sociology 121 (2).
The C. elegans feeding apparatus is a model for genetic arrhythmia.
FRANKFURT. Researchers at the Goethe University have developed a simple model using the nematode Caenorhabditis elegans that can be used to test substances for treating genetically-mediated cardiac arrhythmias. They used the nematode feeding apparatus for this purpose, a rhythmically active muscle pump that resembles the muscle cells in the mammalian heart. This could be an important step on the road to personalised treatment.
Cardiac arrhythmias often have genetic causes. The same mutation is often detected in patients with the same type of arrhythmia. However, it is not clear from the outset whether other mutations in the same gene have the same effects. The effects of the arrhythmia could also differ depending on the type of mutation. This knowledge could definitely be significant for treatment. This is because a type of medication that works particularly well for a specific mutation could be less beneficial for other mutations. Researchers have long been searching for a simple model that can be used to create certain genetic defects and in which the efficacy of substances can be tested.
The research group, led by Alexander Gottschalk at the Institute of Biochemistry and the Buchmann Institute at the Goethe University, used the nematode Caenorhabditis elegans because it is easy to modify it genetically. The nematode feeding apparatus uses ion channels similar to those in muscle cells of the mammalian heart. Ion channels play an important role in regulating cardiac muscle excitation, and mutations in their genes often lead to arrhythmias.
The researchers used optogenetic techniques, since the feeding apparatus, i.e. the pharynx, does not naturally pump as regularly as required in order to recognise arrhythmias. They introduced photo-activated ion channels into the muscle cells using a genetic approach. In this way, the apparatus can be transformed into a light-activated muscle pump with highly regular action. They then introduced various ion channel mutations, which are responsible for the so-called Timothy syndrome (LQT8) in humans. In practice, the mutated pharynx then demonstrated aberrant pump behaviour.
"We were able to improve or reverse these arrythmic effects using a substance that is already known to be pharmacologically active, and which is administered to patients with Timothy syndrome in a modified form", explains Prof Alexander Gottschalk. The goal is to use the worm to search for new active substances for other types of arrhythmia. These could even potentially be patient-specific if the exact mutation is transferred to the worm. The ease of genetic mutability of the nematode is highly advantageous in this regard when compared to a mouse model, which would be very difficult to generate. In order to facilitate the search for new medications, the researchers also developed a new optical method with which several animals can be analysed in parallel.
Publication: C. Schüler, E. Fischer, L. Shaltiel, W. Steuer Costa, A. Gottschalk. (2015) Arrhythmogenic effects of mutated L-type Ca2+-channels on an optogenetically paced muscular pump in Caenorhabditis elegans. Scientific Reports 5: 14427.
Informationen: Prof. Alexander Gottschalk, Institut für Biochemie, Campus Riedberg, Tel.: (069) 798-42518, firstname.lastname@example.org.
An image is available for download at: www.uni-frankfurt.de/58253225
Image text: The feeding apparatus (pharynx) of an optogentically modified nematode can reliably follow various "commando" frequencies (blue text). The control shows the reaction in a healthy worm. Below, a "sick" worm with a defective calcium channel that pumps irregularly at high frequencies.
Business Ethics Professor Minnameier: Code of ethics not very helpful / Misconduct among bankers is more of a structural than a moral problem
FRANKFURT. Unethical conduct by employees of financial institutions can usually be traced back to improper incentives in the internal corporate structure, according to Gerhard Minnameier, Professor for Business Ethics and Business Education at the Goethe University Frankfurt, interviewed in the latest edition of the Faculty of Economics newsletter. "If one looks at the high-profile fraud cases, then the internal rules were formally contravened, but informally virtually everyone did it like that." At an informal level it may be unclear to the individual which rules actually apply. Since employees are always striving for recognition, their behaviour ultimately depends on what companies recognise:
A hard-earned position in a competitive hierarchy or contributions to the company's success.
In order to change the behaviour of the employees, companies have to create a culture which is based on a collaborative approach for the benefit of the company, according to Minnameier. In addition to selecting suitable employees, the key thing in this regard is to create structures which promote a sense of teamwork and which ensure that individuals do not exploit the cooperative nature of their colleagues. "We are familiar with this problem from game theory or the prisoner's dilemma: if some people behave in a cooperative manner but no mechanisms are in place to protect them, then it can be advantageous for others not to cooperate", Minnameier explains. So an employer who wants to create a collaborative environment also has to ensure that "black sheep" stand out and/or don't have any incentives to corrupt the morals of the rest.
On the other hand, according to Minnameier, establishing a code of ethics which doesn't reflect the factual, actual criteria used to evaluate the actions of the individual is not very productive. At best, such a code of ethics could serve to remind the employees of the moral principles. However, the effect does not tend to last very long and it cannot be repeated endlessly.
The complete interview is available for download at: http://bit.ly/1KkUZWR
Prof. Dr. Gerhard Minnameier, email@example.com, Tel: 069 798 34688