Universität Konstanz

Why 3,000 bars are needed to take a comprehensive look at a protein: Researchers present a new high-pressure spectroscopy method to unravel the properties of proteins' native structures. A pressure of 3,000 bar is applied to the cold shock protein B of Bacillus subtilis in a small tube in the NMR spectroscopy laboratory at the University of Konstanz. This is roughly three times the water pressure at the deepest point of the ocean. The pressure is so intense that the highly dynamic protein shows structural features that would not be sufficiently visible under normal pressure. But why do scientists apply such high pressure, which does not occur anywhere else on our planet under natural conditions? The answer is: To study processes and properties that are too volatile to be observed under normal conditions. "This high pressure allows us to make states visible that actually do exist at 1 bar, but which we can only observe directly at 3,000 bar," explains Frederic Berner, University of Konstanz. Literally "under high pressure," the doctoral researcher investigates the properties of a protein determined by its structure, and how changes in the structure in turn influence its properties. In the research group Physical Chemistry and Nuclear Magnetic Resonance at the University of Konstanz, led by Michael Kovermann, he recently implemented a new method for analyzing the structural properties of proteins at 3,000 bar with as little influence as possible from surrounding effects. The two researchers now present their new methodological approach in the journal Angewandte Chemie International Edition. Proteins: How structure influences their properties Proteins are the basic building blocks of life. They consist of amino acid chains whose three-dimensional structure can take on a wide variety of formations. They "fold" in the same way as a long paper ribbon can be folded into different shapes. The functional properties of a protein depend largely on its folding, so that the same protein can have very different effects in the cell, depending on the form in which it is folded. "What is important for proteins is their structure, which in turn is linked to functionalities. If you want to identify biochemical mechanisms, you need information about their structure," says Berner. Scientists aim to capture the properties of the protein structure in its "pure" form -- as unclouded as possible by influences from its environment. For two reasons, however, that is not so easy: Firstly, there are almost always interactions with the solvent surrounding the protein and with neighbouring sections of its molecular chain. Secondly, proteins are highly dynamic, their folding is always in motion. For example, there are proteins that constantly fold apart and go back like scissors. In the fraction of the second it opens, a chemical reaction takes place. This happens far too quickly for researchers to be able to examine it directly. Under high pressure And this is where the pressure of 3,000 bar comes in: The molecule is pressed into a certain state -- its structure is manipulated: The scissors remain open. Using magnetic resonance spectroscopy, the researchers can now study specific structural properties of the protein that are not directly visible under normal pressure. Previous analysis methods often have accepted the environmental effects and try to factor them out afterwards. Kovermann's and Berner's new high-pressure method, in contrast, can suppress or "correct" the environmental effects from the outset ("intrinsically") and thus allows a view of the protein that is affected as little as possible. It makes particular sense to use and compare the new method in combination with existing methods, as this way the various influencing factors become visible in detail. The high-pressure process invented at the University of Konstanz has brought about very good results even in the early phase of its application. Frederic Berner and Michael Kovermann explain that further experiments and computer simulations will now take place to further test and potentially refine the process.

Research reveals strong social relationships make hyenas more likely to team up against lions, even when there's no obvious benefit. After more than 35 years of surveillance, Michigan State University researchers are exposing some of the secret workings of mobs. To be clear, these mobs are made up of spotted hyenas. Publishing in the journal Proceedings of the Royal Society B, the MSU team revealed that relationships and social interactions between hyenas can influence when two or more animals decide to work together to attack lions. This type of cooperative behavior is called mobbing. "Social relationships can overcome barriers to mobbing and let hyenas achieve cooperation," said Tracy Montgomery, a lead author of the new report. Montgomery started the project while earning her doctorate in the lab of Kay Holekamp at MSU and was supported by the Dr. Marvin Hensley Endowed Scholarship Fund in Zoology. "If hyenas greet each other, they're more likely to mob," said Montgomery, who is now a postdoctoral researcher at the Max Planck Institute of Animal Behavior and the University of Konstanz in Germany. "If they have strong social bonds, they're more likely to mob." Spotted hyenas are social creatures with complex social structures that are similar to baboons and other primates. Researchers study animals like these to explore how cooperative behaviors -- like teaming up against a common foe -- have evolved not just in wildlife, but in humans as well. "It's fascinating because this seems like something humans would do," said Kenna Lehmann, another lead author who also worked on the project while earning her doctorate as part of Holekamp's team. She's now an assistant professor at MSU. "The relationships they build over time make a difference," Lehmann said. "It's not just, 'I'll give you a zebra leg if you help.'" "One of the coolest things about this paper is the finding that hyenas are sensitive to social relationships across a range of temporal scales," added Holekamp, a University Distinguished Professor of integrative biology in MSU's College of Natural Science. "They base their decisions about whether or not to cooperate in mobbing lions on both immediate-term friendly behaviors and long-term, friendship-like relationships." 'So weird and fascinating' Holekamp has been studying hyenas in Kenya for 35 years, but that wasn't her original plan. "I went to Kenya in 1988 thinking I'd do a dissertation-length project -- three or four years -- with hyenas, then I'd move on to study dolphins or monkeys or some other animals," said Holekamp, who is also a core faculty member in MSU's Ecology, Evolution and Behavior, or EEB, program. "But the hyenas proved to be so weird and fascinating that they have kept my rapt attention." Take, as a weird and fascinating example, the fact that female spotted hyenas have what are known as pseudo-penises. Understanding why female genitalia is so similar to male genitalia is one of the big, looming biological questions about hyenas, Holekamp said. Although that question doesn't factor directly into this study, it does underscore why Holekamp finds hyenas so interesting. "Spotted hyenas appear to violate many of the basic rules of mammalian biology," Holekamp said. "By studying them, we can potentially determine what the rules really are." As doctoral students working with Holekamp, both Montgomery and Lehmann became interested in what hyenas' rules of engagement were when it comes to mobbing lions. "We wanted to understand why they would risk themselves in this way -- because it is risky -- and what they got out of it," Montgomery said. When researchers are able to determine what caused the death of a hyena, it's a lion more than 25% of the time. Lions and hyenas have overlapping territories, though. So, Lehmann and Montgomery first examined mobbing through the lens of its obvious benefits, such as fighting off lions for food. In a 2017 report published in Current Zoology, the team showed that, although mobbing occurred most frequently near freshly killed food, hyenas also formed mobs when there was no obvious benefit. "There were times we'd be watching them thinking, 'Why are you doing that? That is such a bad idea,'" Lehmann said. 30 years in the making In their new study, the researchers dug deeper into mobbing behavior to look at other motivations. In doing so, they also discovered that mobbing was more frequent when the risk of injury or death to hyenas was lower, even in the absence of a benefit. For example, male lions are larger than females and more dangerous to hyenas. Hyenas were more likely to mob when there weren't any male lions around. Conversely, in spotted hyenas, females are larger than males and females were more likely to join mobs. But it was the social components of mobbing that stood out most to researchers, and it's a discovery made possible by observing several generations of hyenas in the same habitat over 35 years. During that time, the team always had several collaborators present at its research camp in the Maasai Mara National Reserve. "There's no way we would have been able to do this study without it being part of a 35-year project," Lehmann said. One of the big reasons is that researchers don't see mobs every day -- far from it. The team observed about 1,000 mobbing interactions between hyenas and lions over the past three decades. Rarer still are the interactions where researchers could record all the information they needed. "These interactions are extremely fast paced, there are often many hyenas and lions present and most are moving around fairly quickly," Holekamp said. "This makes accurately recording what happens in adequate detail to include in our analyses very challenging." Of those roughly 1,000 interactions, 325 had robust enough data for Montgomery and Lehmann to analyze and make their discoveries. The two credited the hard work of students, research assistants and other collaborators over the past 30 years, who helped standardize and organize observations from the field into usable data sets. And Holekamp's team is still working to find what other secrets those data sets hold. "Finding these results was really exciting, but I feel like the fun part of science is you answer a question and you immediately have 50 more," Montgomery said. "There are so many more things that we need to do with this data." This project was supported by the National Science Foundation, the National Institutes of Health and by the Human Frontier Science Program. You can learn more about the Mara Hyena project on the team's blog and help support their next 30 years of research by donating.

ZUG, Switzerland, Nov. 15, 2023 (GLOBE NEWSWIRE) -- Pharvaris (Nasdaq: PHVS), a clinical-stage company developing novel, oral bradykinin B2 receptor antagonists to treat and prevent hereditary angioedema (HAE) attacks, today announced the appointment of Stefan Abele, Ph.D., as Chief Technical Operations Officer. In this role, he will be responsible for all chemistry, manufacturing, and controls (CMC) activities, supply chain, and program management as Pharvaris progresses into late-stage clinical development. Dr. Abele joins Pharvaris with more than 20 years of experience in process development, end-to-end Active Pharmaceutical Ingredients (API) supply chain, cross-functional CMC activities, GMP manufacturing, global vendor management, and people leadership. “Stefan joins Pharvaris at a transformative time as we prepare to transition into a late-stage clinical company and prepare for commercialization in the coming years,” said Berndt Modig, Chief Executive Officer of Pharvaris. “His experience building sustainable and scalable production strategies for clinical-stage candidates and commercial-grade medicines as well as setting up agile expert teams will be instrumental in the execution of our Phase 3 studies and diligent preparations for commercialization. We welcome Stefan and the insights he will bring to our executive team.” Dr. Abele added, “Deucrictibant could significantly improve the current standard of care for those living with HAE and Pharvaris is poised to make a meaningful impact on the entire HAE community. To our knowledge, deucrictibant is the only orally bioavailable B2 receptor antagonist in development for the treatment of HAE; I am excited to have the opportunity to join the Pharvaris team and contribute my expertise in the development of this novel therapeutic.” Previously, Dr. Abele served as the Senior Vice President, Chemical Development and Commercial Manufacturing at Idorsia Pharmaceuticals, where he and his team were responsible for the API development and manufacturing of QUVIVIQ (daridorexant), PIVLAZ (clazosentan), and aprocitentan. Prior to Idorsia, Dr. Abele worked at Actelion Pharmaceuticals where he established and grew the fully integrated Chemistry Process R&D department. Earlier, he held positions of growing responsibility at Carbogen-Amcis, including as Head of Production and as a manager of teams in R&D and GMP manufacturing of APIs for global pharma companies. Dr. Abele holds a Diploma in Chemistry from the University of Konstanz and a Ph.D. in Synthetic Organic Chemistry from the ETH Zurich. About PharvarisBuilding on its deep-seated roots in HAE, Pharvaris is a clinical-stage company developing novel, oral bradykinin B2 receptor antagonists to treat and prevent HAE attacks. By directly pursuing this clinically proven therapeutic target with novel small molecules, the Pharvaris team aspires to offer people with all sub-types of HAE efficacious, safe, and easy-to-administer alternatives to treat attacks, both on-demand and prophylactically. The company brings together the best talent in the industry with deep expertise in rare diseases and HAE. For more information, visit https://pharvaris.com/. 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