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Understanding the progress of viral infections

Researchers use stem cells to develop a simulation model for pathological mechanisms of actionCredit: Marlen Keß It is only 120…

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Researchers use stem cells to develop a simulation model for pathological mechanisms of action

It is only 120 millionths of a millimetre in size but can bring entire countries to a standstill: the Corona virus. Even if it were to disappear one day, viral infections will still be among the most frequent and difficult-to-treat diseases in humans. Even decades of research have only produced a few standardized vaccines and strategies for treatment to combat just a small number of viruses. Nor has there been much research into viral mechanisms of action – which was a reason for Prof. Guiscard Seebohm and his team at the Institute for the Genetics of Heart Diseases of Münster University to focus their attention on precisely this topic. And the team has now succeeded in making a groundbreaking development: it has created a viral expression model which can be used to simulate and analyse a large number of viral infections – including the one with SARS-CoV-2. The results can be read in the current issue of Scientific Reports published by the “Nature” journal.

One virus that is much less well-known than SARS-CoV-2, but which can be transmitted in the same way, is the Coxsackie virus B3 (CVB3). “Its symptoms,” explains Guiscard Seebohm, “are mostly similar to those for flu, as is the recovery time: after two or three weeks, any patients with a CVB3 infection are, as a rule, well again, and don’t have any obvious long-term impairment.” But – not always, says Guiscard Seebohm, who heads the Cellular Electrophysiology and Molecular Biology department. Apart from any acute infections, he explains, a viral infection also contains the risk of a chronic infection, with the consequence of continuous damage to certain internal organs – which can lead to death. This means that months or even years later, an inflammation of the heart muscle, or type 1 diabetes, can occur in some patients who had CVB3 in the past. Histological examinations of patients showed, in some cases, serious damage to the tissue structure. Also: even years after the acute infection occurred, tissue analyses prove the existence of a virus in the genes.

So far there has been an insufficient amount of study devoted to the question of how a CVB3 infection becomes chronic and how exactly an acute infection progresses. In this respect, the Guiscard Seebohm team has succeeded in taking a great step forward. It developed an expression model for CVB3, based on stem cells, in order to get to the bottom of the mechanisms of action in this virus – as a prototype for the effects of viruses in general. In a study, the model was tested for its controllability in heart muscle cells cultured from stem cells. In the process, the team of researchers was able to achieve a stable integration of the genetic information from a non-infectious variant of CVB3 into the genetic material in human stem cells. The latter can be converted into any kind of human tissue in the laboratory, making it possible to precisely investigate viral mechanisms. The CVB3 expression can be specifically activated by means of a chemical signal.

Guiscard Seebohm is delighted at this success, because, as he says, “As a result of this unique human viral expression system based on stem cells, it will now be possible to simulate a large number of diseases in their progression and, for the first time, analyse them with the utmost precision.” In Guiscard Seebohm’s view there is something else that is just as important: the system is completely controllable. The team of researchers managed to steer the CVB3 expression in the expression model time-wise, both in stem cells and in differentiated heart muscle cells. At the same time, the researchers were able to vary the quantity of viral proteins produced as well as their localization. In other words, the extent of the viral infection, the infection pattern and the time progression can all be adapted to whatever topics researchers are working on.

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Source: https://bioengineer.org/understanding-the-progress-of-viral-infections/

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Bioengineer

How do good metals go bad?

New measurements have solved a mystery in solid state physics: How is it that certain metals do not seem to

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New measurements have solved a mystery in solid state physics: How is it that certain metals do not seem to adhere to the valid rules?

We all have a clear picture in mind when we think of metals: We think of solid, unbreakable objects that conduct electricity and exhibit a typical metallic sheen. The behaviour of classical metals, for example their electrical conductivity, can be explained with well-known, well-tested physical theories.

But there are also more exotic metallic compounds that pose riddles: Some alloys are hard and brittle, special metal oxides can be transparent. There are even materials right at the border between metal and insulator: tiny changes in chemical composition turn the metal into an insulator – or vice versa. In such materials, metallic states with extremely poor electrical conductivity occur; these are referred to as “bad metals”. Until now, it seemed that these “bad metals” simply could not be explained with conventional theories. New measurements now show that these metals are not that “bad” after all. Upon closer inspection, their behaviour fits in perfectly with what we already knew about metals.

Small change, big difference

Prof. Andrej Pustogow and his research group at the Institute for Solid State Physics at TU Wien (Vienna) are conducting research on special metallic materials – small crystals that have been specially grown in the laboratory. “These crystals can take on the properties of a metal, but if you vary the composition just a little bit, we are suddenly dealing with an insulator that no longer conducts electricity and is transparent like glass at certain frequencies,” says Pustogow.

Right at this transition, one encounters an unusual phenomenon: the electrical resistance of the metal becomes extremely large – larger, in fact, than should be possible at all according to conventional theories. “Electrical resistance has to do with the electrons being scattered at each other or at the atoms of the material”, explains Andrej Pustogow. According to this view, the greatest possible electrical resistance should occur if the electron is scattered at every single atom on its way through the material – after all, there is nothing between an atom and its neighbour that could throw the electron off its path. But this rule does not seem to apply to so-called “bad metals”: They show a much higher resistance than this model would allow.

It all depends on the frequency

The key to solving this puzzle is that the material properties are frequency-dependent. “If you just measure the electrical resistance by applying a DC voltage, you only get a single number – the resistance at zero frequency,” says Andrej Pustogow. “We, on the other hand, made optical measurements using light waves with different frequencies.”

This showed that the “bad metals” are not so “bad” after all: At low frequencies they hardly conduct any current, but at higher frequencies they behave as one would expect from metals. The research team considers tiny amounts of impurities or defects in the material, that can no longer be adequately shielded by a metal at the boundary to an insulator, as a possible cause. These defects can cause some areas of the crystal to no longer conduct electricity because there the electrons remain localized in a certain place instead of moving through the material. If a DC voltage is applied to the material so that the electrons can move from one side of the crystal to the other, then virtually every electron will eventually hit such an insulating region and current can hardly flow.

At high AC frequency, on the other hand, every electron moves back and forth continuously – it does not cover a long distance in the crystal because it keeps changing direction. This means that in this case many electrons do not even come into contact with one of the insulating regions in the crystal.

Hope for important further steps

“Our results show that optical spectroscopy is a very important tool for answering fundamental questions in solid-state physics,” says Andrej Pustogow. “Many observations for which it was previously believed that exotic, novel models had to be developed could very well be explained by existing theories if they were adequately extended. Our measurement method shows where the additions are necessary.” Already in earlier studies, Prof. Pustogow and his international colleagues gained important insight into the boundary region between metal and insulator using spectroscopic methods, thus establishing a fundament for theory.

The metallic behaviour of materials subject to strong correlations between the electrons is also particularly relevant for so-called “unconventional superconductivity” – a phenomenon that was discovered half a century ago but is still not fully understood.

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Contact

Ass. Prof. Dr. Andrej Pustogow

Institute for Solid State Physics

TU Wien

+43 1 58801 13128

[email protected]

http://www.ifp.tuwien.ac.at/forschung/pustogow-research/home

https://www.tuwien.at/en/tu-wien/news/news-articles/news/wie-werden-gute-metalle-schlecht

Right at this transition, one encounters an unusual phenomenon: the electrical resistance of the metal becomes extremely large – larger, in fact, than should be possible at all according to conventional theories. “Electrical resistance has to do with the electrons being scattered at each other or at the atoms of the material”, explains Andrej Pustogow. According to this view, the greatest possible electrical resistance should occur if the electron is scattered at every single atom on its way through the material – after all, there is nothing between an atom and its neighbour that could throw the electron off its path. But this rule does not seem to apply to so-called “bad metals”: They show a much higher resistance than this model would allow.

Source: https://bioengineer.org/how-do-good-metals-go-bad/

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Solving the puzzle of polymers binding to ice for Cryopreservation

Credit: Credit: University of Warwick Cryoprotectants are used to protect biological material during frozen storage They have to be removed

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  • Cryoprotectants are used to protect biological material during frozen storage
  • They have to be removed when defrosting, and how much to use and how exactly they inhibit ice recrystallisation is poorly understood
  • The polymer poly(vinyl)alcohol (PVA) is arguably the most potent ice recrystallisation inhibitor and researchers from the University of Warwick have unravelled how exactly it works.
  • This newly acquired knowledge base provides novel guidelines to design the next generation of cryoprotectants

When biological material (cells, blood, tissues) is frozen, cryoprotectants are used to prevent the damage associated with the formation of ice during the freezing process. New polymeric cryoprotectants are emerging, alongside the established cryoprotectants, but how exactly they manage to control ice formation and growth is still largely unknown. This is especially true for PVA, a deceptively simple synthetic polymer that interacts with ice by means of mechanisms that have now been revealed at the atomistic level thanks to researchers from the University of Warwick.

Cryoprotectants are crucial when freezing biological material to lessen the cellular damage involved with the formation of ice. Ice re-crystallization, that is the process by which larger ice crystals grow at the expense of smaller ones, is one of the major issues affecting the current cryopreservation protocols and it is still poorly understood. Researchers from the University of Warwick have investigated how a rather popular polymer with the potential to be used in cryopreservation binds to the growing ice crystals.

In the paper, ‘The atomistic details of the ice recrystallisation inhibition activity of PVA’, published in the journal Nature Communications, researchers from the University of Warwick have found that, contrary to the emerging consensus, shorter or longer polymeric chains of poly(vinyl)alcohol (PVA) all bind to ice.

Up to now, the community has been working under the assumption that short polymers do not bind strongly enough to the ice crystals, but in this work Dr. Sosso and co-workers have demonstrated that it is the subtle balance between these binding interactions and the effective volume occupied by the polymers at the interface with ice that determine their effectiveness in hindering ice re-crystallization.

This work brings together experimental measurements of ice recrystallization inhibition and computer simulations. The latter are invaluable tools to gain microscopic insight into processes such as the formation of ice, as they are able to see what is happening in very fast or very small processes which are hard to see via even the most advanced experimental techniques.

This work sheds new light onto the fundamental principles at the heart of ice re-crystallization, pinpointing design principles that can be directly harnessed to design the next generation of cryoprotectants. This achievement is a testament to the strength of what is affectionately known as ‘Team Ice’ at Warwick, an ever-growing collaborative network with the potential to make a huge impact on many aspects of ice formation, from atmospheric science to medicinal chemistry.

Fabienne Bachtiger, a PhD student working in the research group of Dr. Sosso (Department of Chemistry) who has spearheaded this work, explains:
“We have found that even rather short chains of PVA, containing just ten polymeric units, do bind to ice, and that small block co-polymers of PVA bind too. It is important for the experimental community to know this, as they have been working under different assumptions up to now. In fact, this means we can successfully use much smaller polymers than previously thought. This is crucial information to aid the development of new more active cryoprotectants.”

Dr. Gabriele Sosso, from the Department of Chemistry at the University of Warwick, who is leading a substantial computational effort to investigate the formation of ice in biological matter, points out that:
“With this contribution we have added a crucial piece to the puzzle of how exactly polymeric cryoprotectants interact with growing ice crystals. This is part of a larger body of computational and theoretical work that my group is pursuing with the intent to understand how cryoprotectants work at the molecular level, so as to identify designing principles that can be directly probed by our experimental colleagues. Warwick is the perfect place to further our understanding of ice, and this work showcases the impact of the very exciting collaboration between my research group and the Gibson Group.”

Professor Matthew Gibson, from the Department of Chemistry and Warwick Medical School at the University of Warwick adds: “Ice re-crystallization is a real challenge in cryobiology, leading to damage to cells but also in frozen foods or infrastructure. Understanding how even this ‘simple’ polymer works to control ice re-crystallization is a major step forward to discover new cryoprotectants, and ultimately to use them in the real world.”

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15 MARCH 2021

  • This newly acquired knowledge base provides novel guidelines to design the next generation of cryoprotectants
  • Source: https://bioengineer.org/solving-the-puzzle-of-polymers-binding-to-ice-for-cryopreservation/

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    Bioengineer

    Debris of stellar explosion found at unusual location

    eROSITA space telescope finds largest supernova remnant ever discovered with X-raysCredit: eROSITA/MPE (X-ray), CHIPASS / SPASS / N. Hurley-Walker, ICRAR-Curtin

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    eROSITA space telescope finds largest supernova remnant ever discovered with X-rays

    Credit: eROSITA/MPE (X-ray), CHIPASS / SPASS / N. Hurley-Walker, ICRAR-Curtin (Radio)

    In the first all-sky survey by the eROSITA X-ray telescope onboard SRG, astronomers at the Max Planck Institute for Extraterrestrial Physics have identified a previously unknown supernova remnant, dubbed “Hoinga”. The finding was confirmed in archival radio data and marks the first discovery of a joint Australian-eROSITA partnership established to explore our Galaxy using multiple wavelengths, from low-frequency radio waves to energetic X-rays. The Hoinga supernova remnant is very large and located far from the galactic plane – a surprising first finding – implying that the next years might bring many more discoveries.

    Massive stars end their lives in gigantic supernova explosions when the fusion processes in their interiors no longer produce enough energy to counter their gravitational collapse. But even with hundreds of billions of stars in a galaxy, these events are pretty rare. In our Milky Way, astronomers estimate that a supernova should happen on average every 30 to 50 years. While the supernova itself is only observable on a timescale of months, their remnants can be detected for about 100 000 years. These remnants are composed of the material ejected by the exploding star at high velocities and forming shocks when hitting the surrounding interstellar medium.

    About 300 such supernova remnants are known today – much less than the estimated 1200 that should be observable throughout our home Galaxy. So, either astrophysicists have misunderstood the supernova rate or a large majority has been overlooked so far. An international team of astronomers are now using the all-sky scans of the eROSITA X-ray telescope to look for previously unknown supernova remnants. With temperatures of millions of the degrees, the debris of such supernovae emits high-energy radiation, i.e. they should show up in the high-quality X-ray survey data.

    “We were very surprised that the first supernova remnant popped up straight away,” says Werner Becker at the Max Planck Institute for Extraterrestrial Physics. Named after the first author’s hometown’s Roman name, “Hoinga” is the largest supernova remnant ever discovered in X-rays. With a diameter of about 4.4 degrees, it covers an area about 90 times bigger than the size of the full Moon. “Moreover, it lies very far off the galactic plane, which is very unusual,” he adds. Most previous searches for supernova remnants have concentrated on the disk of our galaxy, where star formation activity is highest and stellar remnants therefore should be more numerous, but it seems that many supernova remnants have been overlooked by this search strategy.

    After the astronomers found the object in the eROSITA all-sky data, they turned to other resources to confirm its nature. Hoinga is – although barely – visible also in data taken by the ROSAT X-ray telescope 30 years ago, but nobody noticed it before due to its faintness and its location at high galactic latitude. However, the real confirmation came from radio data, the spectral band where 90% of all known supernova remnants were found so far.

    “We went through archival radio data and it had been sitting there, just waiting to be discovered,” marvels Natasha Walker-Hurley, from the Curtin University node of the International Centre for Radio Astronomy Research in Australia. “The radio emission in 10-year-old surveys clearly confirmed that Hoinga is a supernova remnant, so there may be even more of these out there waiting for keen eyes.”

    The eROSITA X-ray telescope will perform a total of eight all-sky surveys and is about 25 times more sensitive than its predecessor ROSAT. Both observatories were designed, build and are operated by the Max Planck Institute for Extraterrestrial Physics. The astronomers expected to discover new supernova remnants in its X-ray data over the next few years, but they were surprised to identify one so early in the programme. Combined with the fact that the signal is already present in decades-old data, this implies that many supernova remnants might have been overlooked in the past due to low-surface brightness, being in unusual locations or because of other nearby emission from brighter sources. Together with upcoming radio surveys, the eROSITA X-ray survey shows great promise for finding many of the missing supernova remnants, helping to solve this long-standing astrophysical mystery.

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    Original publication

    W. Becker, N. Hurley-Walker, Ch. Weinberger, L. Nicastro, M. G. F. Mayer, A. Merloni, J. Sanders
    Hoinga – A Supernova Remnant Discovered in the SRG/eROSITA All-Sky Survey eRASS1
    Astronomy & Astrophysics, accepted 12 February 2021

    https://www.mpg.de/16527751/0302-ext0-giant-cloud-found-at-unusual-location-151510-x

    Source: https://bioengineer.org/debris-of-stellar-explosion-found-at-unusual-location/

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