Fighting Cancer from a Chair (Medicine)

Platinum complex inhibits metastasis through conformational modulation of heparan sulfate.

Cisplatin has been used to treat cancer since the 1970s. Since then, many other platinum-containing cytostatic drugs have been developed, such as triplatinNC, a highly charged complex that contains three ligand-bridged platinum atoms. Unlike cisplatin, this drug also directly inhibits metastasis. The reason for this seems to be modulation of the geometry of a sugar component of heparan sulfate, an important component of the extracellular matrix, reports a research team in the journal Angewandte Chemie.

Heparan sulfate, a glycosaminoglycan, is a chain of ring-shaped sugar molecules. It is involved in many regulatory processes, as well as in the growth and metastasis of tumors. In order for a tumor to grow and form metastases, the extracellular matrix must be broken up in certain locations to allow cells to migrate. The splitting of heparan sulfate by the enzyme heparanase and the release of certain growth factors that bind to heparan sulfate play an important role in this process.

In order to shed light on the interaction of heparan sulfate with triplatinNC, a team led by Anil K. Gorle, Susan J. Berners-Price, and Nicholas P. Farrell at Griffith University (Brisbane, Australia), and Virginia Commonwealth University and Massey Cancer Center (Richmond, Virginia, USA), used fondaparinux (FPX), a molecule made of five sugar units, as a model for heparan sulfate. A combination of computer calculations and experimental data showed that triplatinNC changes the geometry of a specific sugar component of heparan sulfate (a sulfated iduronic acid). The six-membered ring of the iduronic acid can adopt two different spatial conformations: a chair form or a twist-boat form. In free FPX, the chair and twist-boat forms are in a 35:65 ratio. In the presence of triplatinNC, this shifts to 75:25. In the now preferred chair form, there is a pocket into which the platinum drug fits very well, allowing it to bind strongly. In actual heparan sulfate, the result of the strong bonding by triplatinNC is to effectively block it from being split by heparanase.

A tumor cell line in a synthetic extracellular matrix served as a model for triple-negative breast cancer, which is an aggressive form of cancer that is especially hard to treat. Treatment with heparinase initiated significant cell migration in the model. Prior treatment with triplatinNC significantly reduced cell migration—an effect not seen with cisplatin. The team was also able to confirm the anti-metastatic activity of triplatinNC in tests with mice.

TriplatinNC thus demonstrates dual activity. In addition to a cytotoxic effect caused by its action on DNA, it has an anti-metastatic effect caused by interference with the functionality of heparan sulfate. This opens new possibilities for the design of anti-metastatic platinum complexes.

Featured image: © Wiley-VCH/ ‘Angewandte Chemie’ https://doi.org/10.1002/anie.202013749

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Reference: Gorle, A.K., Haselhorst, T., Katner, S.J., Everest‐Dass, A.V., Hampton, J.D., Peterson, E.J., Koblinski, J.E., Katsuta, E., Takabe, K., von Itzstein, M., Berners‐Price, S.J. and Farrell, N.P. (2021), Conformational Modulation of Iduronic Acid‐Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs. Angew. Chem. Int. Ed.. https://doi.org/10.1002/anie.202013749 https://onlinelibrary.wiley.com/doi/10.1002/anie.202013749

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Provided by Wiley Online Library

Protein Anchors as a Newly Discovered Key Molecule in Cancer Spread and Epilepsy (Medicine)

Certain anchor proteins inhibit a key metabolic driver that plays an important role in cancer and developmental brain disorders. Scientists from the German Cancer Research Center (DKFZ) and the University of Innsbruck, together with a Europe-wide research network, discovered this molecular mechanism, which could open up new opportunities for personalized therapies for cancer and neuronal diseases. They published their results in the journal Cell.

The signaling protein MTOR (Mechanistic Target of Rapamycin) is a sensor for nutrients such as amino acids and sugars. When sufficient nutrients are available, MTOR boosts metabolism and ensures that sufficient energy and cellular building blocks are available. Since MTOR is a central switch for metabolism, errors in its activation lead to serious diseases. Cancers and developmental disorders of the nervous system leading to behavioral disorders and epilepsy can be the result if MTOR is malfunctioning.

Therefore, the cell controls MTOR activity very precisely with the help of so-called suppressors. These are molecules that inhibit a protein and help to regulate its activity. The-TSC complex is such a suppressor for MTOR. It is named after the disease that causes its absence – tuberous sclerosis (TSC). The TSC complex is located together with MTOR at small structures in the cell, the so-called lysosomes, where it keeps MTOR in check. If the TSC complex – for example due to changes in one of its components – no longer remains at the lysosome, this can lead to excessive MTOR activity with severe health consequences.

Protein with an anchor function

The teams led by Christiane Opitz at DKFZ and Kathrin Thedieck at the University of Innsbruck therefore investigated how the TSC complex binds to lysosomes. They discovered that the G3BP proteins (Ras GTPase-activating protein-binding protein) are located together with the TSC complex on lysosomes. “There, the G3BP proteins form an anchor that ensures that the TSC complex can bind to the lysosomes,” explains Mirja Tamara Prentzell of DKFZ, first author of the publication. This anchor function plays a crucial role in breast cancer cells. If the amount of G3BP proteins is reduced in cell cultures, this not only leads to increased MTOR activity, but also increases cell migration.

Drugs that inhibit MTOR prevent this spread, the researchers were able to show in cell cultures. In breast cancer patients, low levels of G3BP correlate with a poorer prognosis. “Markers like the G3BP proteins could be helpful to personalize therapies based on inhibition of MTOR,” explains Kathrin Thedieck, professor of biochemistry at the University of Innsbruck. The good thing is that drugs that inhibit MTOR are already approved as cancer drugs and could be tested specifically in further studies.

G3BP proteins also inhibit MTOR in the brain. In zebrafish, an important animal model, the researchers observed disturbances in brain development when G3BP is absent. This leads to neuronal hyperactivity similar to epilepsy in humans. These neuronal discharges could be suppressed by drugs that inhibit MTOR. “We therefore hope that patients with rare hereditary neurological diseases in which dysfunctions of the G3BP proteins play a role could benefit from drugs against MTOR,” says Christiane Opitz of DKFZ. In the future, the scientists plan to investigate this together with their Europe-wide research network.

The authors of the current study received funding from the German Research Foundation and the European Union as part of the MESI-STRAT breast cancer consortium (www.mesi-strat.eu), the German Tuberous Sclerosis Foundation and the Dutch TSC Fund foundation, among others.

Featured image: The figure shows the association (white dots) of the anchor protein G3BP1 with the TSC complex in breast cancer cells. Left: G3BP1 present; right, G3BP1 absent. Cell nuclei stained in blue. © Marti Cadena Sandoval/UIBK Innsbruck

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Reference: Prentzell MT, Rehbein U, Cadena Sandoval M, De Meulemeester A, Baumeister R, Brohée L, Berdel B, Bockwoldt M, Carroll B, Chowdhury SR, von Deimling A, Demetriades C, Figlia G, Genomics England Research Consortium, Eca Guimaraes de Araujo M, Heberle AM, Heiland I, Holzwarth B, Huber LA, Jaworski J, Kedra M, Kern K, Kopach A, Korolchuk VI, van ‘t Land-Kuper I, Macias M, Nellist M, Palm W, Pusch S, Ramos Pittol JM, Reil M, Reintjes A, Reuter F, Sampson JR, Scheldeman C, Siekierska A, Stefan E, Teleman AA, Thomas LE, Torres-Quesada O, Trump S, West HD, de Witte P, Woltering S, Yordanov T, Zmorzynska J, Opitz CA#, Thedieck K, “G3BP1 tethers the TSC complex to lysosomes and suppresses mTORC1 in the absence of stress granules”, bioRxiv, 2021. doi: https://doi.org/10.1101/2020.04.16.044081

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Provided by DKFZ

How a Protein Variant Could Explain Resistance to Sleeping Sickness Drug? (Medicine)

A specific variant of the surface protein VSG of African trypanosomes, the causative agents of sleeping sickness, is associated with resistance to the important drug Suramin. Scientists at the German Cancer Research Center have now been able to find a possible explanation for the formation of resistance based on the crystal structure of this protein variant.

Sleeping sickness is widespread in large parts of tropical Africa. The pathogens, African trypanosomes, transmitted by the tsetse fly attack the central nervous system and cause severe neurological disorders. Without treatment, the infection can lead to death.

For more than a hundred years, the drug Suramin, developed in Germany, has been used successfully against early stages of sleeping sickness. To date, there are only a handful of effective substances against the tropical disease, which is why the drug is on the WHO list of Essential Medicines. However, until now it was unclear how the drug actually reaches the inside of the pathogen and how it unfolds its efficacy there.

Scientists have now been able to generate trypanosome strains in the laboratory that exhibit a high level of resistance to Suramin. It turns out that the resistant strains all carried a particular variant of the so-called variable surface glycoprotein, called VSGsur. “This observation suggests that VSGsur is involved in the formation of Suramin resistance – however, we had no idea how this might work,” says Erec Stebbins, a structural biologist at the German Cancer Research Center.

Using high-resolution studies of the protein’s crystal structure, Stebbins was able to show that the VSGsur associated with resistance have a fundamentally different protein structure in a specific region than all other VSGs. This structural deviation allows the drug Suramin to bind to the VSGsur.

When the scientists genetically modified the deviant region of VSGsur, the trypanosomes again became sensitive to Suramin and the drug could no longer bind the VSG.

“We don’t yet understand exactly how Suramin binding to VSGsur relates to resistance,” Stebbins explains. “It’s possible that VSGsur intercepts the drug, so that not enough Suramin reaches the inside of the pathogen. In any case, the results will help us better understand Suramin’s action, which remains mysterious even after 100 years.

Until now, scientists had attributed a single function to the VSGs: they were considered to be a highly effective protective coat for the trypanosomes against the host’s immune system: the unicellular trypanosomes are covered by a dense layer of identical VSGs, against which the infected person’s antibodies are directed. This largely eliminates the parasites – until some of the pathogens switch to a different VSG gene – they have hundreds of them available. As a result, the surface proteins on the protozoa are completely exchanged and the trypanosomes masked in this way are no longer recognized by the antibodies. They multiply furiously, and the infection that the immune system had initially kept in check flares up again violently.

“The binding of Suramin shows us that the VSGs can have other, receptor-like functions beyond immune protection, which we now want to elucidate,” Stebbins says.

Featured image: African trypanosomes, the causative agent of sleeping sickness, in a blood smear © Wikimedia Commons, Alan R Walker

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Reference: Johan Zeelen, Monique van Straaten, Joseph Verdi, Alexander Hempelmann, Hamidreza Hashemi, Kathryn Perez, Philip D. Jeffrey, Silvan Hälg, Natalie Wiedemar, Pascal Mäser, F. Nina Papavasiliou and C. Erec Stebbins, “Structure of trypanosome coat protein VSGsur and function in suramin resistance”, Nature Microbiology 2021, DOI: https://doi.org/10.1038/s41564

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Provided by DKFZ

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About DKFZ

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ’s Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.

Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children’s Tumour Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

Immune Cells are Behind the Depression Experienced in Inflammation (Neuroscience)

Special immune cells found in the brain, microglia, play a key role in the processes that make you feel uneasy and depressed in correlation with inflammation. The findings from a new study on mice suggest that microglial cells contribute to the negative mood experienced during several neurological diseases.

David Engblom’s research group at Linköping University has spent many years looking at why inflammation in the body, such as a common cold or influenza, causes us to feel poorly and despondent, and why we feel like retiring into our shell. The activity of the immune system influences nerve cells in some way. However, normal cells of the immune system are not able to get into the brain: it is sensitive and must be protected. Instead, the brain has its own special immune cells: microglial cells.

Previous research has shown that microglial cells are activated in several neurological diseases, such as Alzheimer’s disease, Parkinson’s disease and stroke. People who are affected by these conditions also often fall into a negative mood. Other previous research has suggested that inflammatory processes also play a role in the development of depression. This led the researchers behind the new study, which has been published in the scientific journal Immunity, to examine more closely whether microglial cells are involved in regulating mood during inflammation.

Professor David Engblom © Per Groth

“The study showed that animals feel sick and uneasy when we activate the microglial cells. We demonstrate that two signal molecules, interleukin-6 and prostaglandin E2, are particularly important in these processes. It’s not surprising that these signal substances are central, but we were a bit surprised that it is the microglial cells that release these molecules”, says David Engblom, professor in the Department of Biomedical and Clinical Sciences (BKV) and Center for Social and Affective Neuroscience (CSAN) at Linköping University.

During inflammation, many processes are initiated in several cell types. One of the challenges in determining the role played by a specific cell type in the body, therefore, is to isolate its effects. In this study, the scientists used a technique known as chemogenetics, which enabled them to switch on the activity specifically in microglial cells in mice. The researchers activated the microglial cells when the mice were being kept in a certain type of surroundings. The mice subsequently avoided this type of surroundings, which the researchers interpret as showing that the animals disliked the experience. The mice also became less interested in a sweet solution, which they normally find very tempting.

In order to investigate whether the microglial cells are an important link between the immune system and mood, the researchers investigated what happened when microglial cells are inhibited. When the microglial cells were not available for activation, the mice did not feel poorly, even when they had inflammation. This reinforces the idea that these cells are necessary for the process.

“Our results show that the activation of microglial cells is sufficient to create aversion and negative mood in mice. It’s natural to suggest that similar processes take place in several human diseases. It’s not unlikely that activated microglia contribute to the discomfort and depressed mood in people with inflammatory and neurological diseases”, says David Engblom.

If further research demonstrates that the biological mechanism described in the study functions in the same way in humans, it may be possible in the long run to reduce symptoms of depression by inhibiting this mechanism.

The study has been financed with support from, among others, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Brain Foundation, Stiftelsen för Parkinsonforskning i Linköping, the Lars Hierta Memorial Foundation, and Region Östergötland.

Featured image: Professor David Engblom arranges the experimental setup used for studying the behaviour of mice. © Per Groth

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Reference: “Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons”, Anna M. Klawonn, Michael Fritz, Silvia Castany, Marco Pignatelli, Carla Canal, Fredrik Similä, Hugo A. Tejeda, Julia Levinsson, Maarit Jaarola, Johan Jakobsson, Juan Hidalgo, Markus Heilig, Antonello Bonci and David Engblom, Immunity, published online on 20 January 2021, doi: 10.1016/j.immuni.2020.12.016

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Provided by Linköping University

Researchers Develop Promising Way to Find New Cancer Drugs (Medicine)

The enzymes in human cells known as histone deacetylases, or HDACs, are targets for a handful of anticancer drugs because of their ability to affect gene expression. Now, researchers from the University of Copenhagen have developed a new method to investigate how these enzymes work on a molecular level. This new method can also help identify more precise possible anti-cancer drug candidates at a very high pace.

All the cells in the human body share the same genes. But how our genes are expressed determines whether a cell becomes a brain cell or a liver cell. In addition, changes in gene expression often play a significant role in development of diseases.

One mechanism that contributes to the changes in gene expression is the interaction between the proteins called histones and enzymes known as HDACs. These enzymes help the cell divide and develop, which is the reason why they serve as targets for anti-cancer medicine: When you inhibit the enzymes, the cancer cells will stop dividing and growing further.

Despite being targets for clinically approved medicines, researchers do not know all the details of how they work in the cell. Now, researchers from the University of Copenhagen have developed a method that will help change that.

“We have shown details of how these enzymes interact with proteins around our DNA, and our method provides a new means for identifying possible anti-cancer drugs very quickly. In the study, we show that the method works: We synthesized a peptide that affected just the right parts of living human cells, using the same target as anti-cancer medicine uses today,” says Carlos Moreno-Yruela, postdoc at the Department of Drug Design and Pharmacology.

Unmodified peptide had effect

HDACs are a group of eleven different enzymes, which means that targeting them all at once with a non-selective medicine will result in affecting many essential processes in the body. This may also explain some of the side effects in the clinically approved HDAC-inhibiting anti-cancer medicine.

“Our detailed insight into the enzymes’ interactions gained with the new method provide hope for the development of more specific HDAC inhibitors with potential as drug candidates. This could bode well for the development of more sophisticated compounds for cancer therapy with fewer side effects,” says Professor Christian Adam Olsen.

Postdoc Carlos Moreno Yruela adding HDAC solution to microarray slides (photo: Joana Daradoumis)

In the study, the researchers used the new method for identifying peptides, which they resynthesized in larger amounts and subjected to human cells. The results were exactly what they hoped: The expected HDACs were also inhibited in living cells.

“We were surprised to see such a prominent effect of an unoptimized peptide in cells. Normally, one would need to introduce a variety of modifications to optimize its properties. But this, almost fully natural, peptide had a really potent effect, which emphasizes the potential of our findings,” says Christian Adam Olsen.

The researchers now hope to use the method for identifying promising drug candidates which could go on to pre-clinical testing.

Read the entire study: “Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases”

The study was funded by the University of Copenhagen, Carlsberg Foundation, the Lundbeck Foundation and the European Research Council.

Featured image: Microarray slides that the researchers use to investigate enzyme interactions (photo: Carlos Moreno Yruela)

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Reference: Moreno-Yruela, C., Bæk, M., Vrsanova, AE. et al. Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases. Nat Commun 12, 62 (2021). https://doi.org/10.1038/s41467-020-20250-9

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Provided by University of Copenhagen

First Observation of the Early Link Between Proteins Linked to Alzheimer’s Disease and Their Impact on Brain Function (Psychiatry)

These results will help researchers to identify at an early stage the people most at risk of developing the disease, well before the first cognitive symptoms appear.

Study conducted by researchers from the CRC In vivo Imaging (GIGA/Faculty of Medicine, Sciences and Psychology) at ULiège demonstrates, for the first time in humans, how the first deposits of tau proteins in the brainstem are associated with neurophysiological processes specific to the early stages of Alzheimer’s disease development. A study published in the scientific journal JCI Insight.

During the pre-clinical stages of Alzheimer’s disease, i.e. when subtle changes are taking place in the brain but no cognitive symptoms can be observed, the cortex presents a state of transient hyperexcitability. To date, several studies conducted in animals have shown that tau and beta-amyloid proteins – central to the development of Alzheimer’s disease – were associated with increased cortical excitability and dysfunction of brain networks. However, the relationship between the accumulation of Alzheimer’s disease-related proteins and cortical hyperexcitability during the earliest stages of the disease remains poorly understood in humans, in particular due to technological limitations in the precise quantification of early protein deposition.

A study, conducted by researchers from the Cyclotron Research Centre (CRC In vivo Imaging / GIGA) of ULiège studied whether the first deposits of tau and beta-amyloid proteins in the brains of healthy individuals aged between 50 and 70 years old could be linked to a higher level of cortical excitability. To do this, we combined different neuroimaging methodologies (magnetic resonance imaging, positron emission tomography) in order to characterise the quantity of tau and beta-amyloid proteins in their first agglomeration regions,” explains Gilles Vandewalle, FNRS Research Associate and head of the laboratory. That is to say, respectively, in the brainstem and in a series of upper cortical areas. “In addition, the researchers also measured the excitability of the participants’ cortex in a non-invasive manner, using transcranial magnetic stimulation techniques in conjunction with the acquisition of electroencephalographic recordings.

State-of-the-art automatic brainstem segmentation methods were used to extract tau burden in its first aggregation site, that is, in the brainstem monoaminergic grey matter (bmGM). Beta-amyloid (Aβ) burden was extracted in the earliest cortical aggregation regions, i.e. in the bilateral medial superior frontal, inferior temporal, and fusiform areas. © Liege University

The results of this study show that an increased amount of tau protein in the brainstem – its primary site of agglomeration – is specifically associated with a higher level of cortical excitability, while the researchers did not observe a significant relationship for the amount of beta-amyloid protein in the upper cortical areas. These results constitute a first in vivo observation in humans of the early link between proteins linked to Alzheimer’s disease and their impact on brain function,” says Maxime Van Egroo, scientific collaborator at the CRC In Vivo Imaging and first author of the scientific article. Furthermore, they suggest that measuring the hyperexcitability of the cortex could be a useful marker to provide information on the progress of certain cerebral pathological processes linked to Alzheimer’s disease, and thus contribute to the early identification of people most at risk of developing the disease, well before the first cognitive symptoms appear. »

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Scientific reference

Van Egroo M. & Al., Early brainstem [18F]THK5351 uptake is linked to cortical hyperexcitability in healthy aging, JCI Insight, January 2021.

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Provided by Leige University

A New Mechanism Protects Against Cancer Cell Migration and Neuron Hyperexcitability (Medicine)

G3BP proteins inhibit the metabolic driver MTOR – a signaling protein that plays a central role in tumor diseases and developmental disorders of the brain. This is reported in this week´s issue of the renowned journal Cell. The study was led by scientists from the University of Innsbruck and the German Cancer Research Center (DKFZ) in collaboration with the Medical University of Innsbruck and a Europe-wide research network.

The signaling protein MTOR (Mechanistic Target of Rapamycin) is a sensor for nutrients such as amino acids and sugars. When sufficient nutrients are available, MTOR boosts metabolism and ensures that sufficient energy and building blocks are available for the growth and function of all cells in the human body. “Because MTOR is such a central switch for metabolism, errors in its activation lead to serious diseases. These include cancers associated with excessive metabolic activity, cell growth and proliferation. Dysregulated MTOR also causes malformations of the nervous system, disturbing stimulus processing and eliciting behavioral disorders and epilepsy.” explains Kathrin Thedieck, Professor of Biochemistry at the University of Innsbruck.

To prevent errors in MTOR-based signal processing, the cell controls its activity very precisely. This is achieved through so-called suppressors, molecules that inhibit a protein and help to regulate its activity. The TSC complex is such a suppressor for MTOR. It is named after the disease that is caused by its absence – tuberous sclerosis complex (TSC) disease. Together with MTOR, the TSC complex localizes to small cellular structures, the lysosomes, where it keeps MTOR in check. If the TSC complex – for example due to changes (mutations) in one of its components – no longer remains at the lysosome, this can lead to excessive MTOR activity with severe consequences for human health.

A molecular TSC anchor at lysosomes

The teams led by Kathrin Thedieck at the University of Innsbruck and Christiane Opitz at DKFZ therefore investigated how the TSC complex binds to lysosomes. They discovered that the G3BP (Ras GTPase-activating protein-binding protein) proteins localize to lysosomes, together with the TSC complex. There, the G3BP proteins form an anchor that ensures that the TSC complex can bind to the lysosomes. This anchor function plays a crucial role in breast cancer. If the amount of G3BP decreases, not only MTOR activity but also cell motility is increased in cancer cell cultures. MTOR inhibitors suppress this hypermotility. In breast cancer patients, low G3BP correlates with a worse prognosis. “G3BP proteins could therefore be valuable markers to personalize therapies and improve the efficacy of drugs that inhibit MTOR.” says Christiane Opitz.

G3BP proteins also inhibit MTOR in the brain. In zebrafish, an important animal model for pharmaceutical research, the scientists observed disturbances in brain development when G3BP was missing. Loss of G3BP also resulted in neuronal hyperactivity and ensuing behavioral abnormalities reminiscent of epilepsy in humans. Compounds that target MTOR suppressed the neuronal hyperactivity. “We therefore anticipate that patients with neurological disorders and G3BP malfunction could benefit from MTOR inhibitors and we look forward to further exploring this together with our scientific network,” says Kathrin Thedieck. Also Lukas A. Huber, Director of Cell Biology at the Medical University of Innsbruck, is pleased with the joint success: “Through this successful collaboration a strong research focus on MTOR and lysosomes is emerging at the two Innsbruck universities, and I am excited to embark on our next projects.” states Lukas A. Huber.

The study was published in Cell. The authors received funding from the German Tuberous Sclerosis Foundation, the Dutch TSC Fonds, the Austrian Science Fund, the German Research Foundation and the European Union, among others, as part of the MESI-STRAT breast cancer consortium (http://www.mesi-strat.eu).

Featured image: The comic illustration shows G3BP (G) tethering the TSC complex to a lysosome, thereby preventing the MTOR (aka Thor) signaling protein from becoming active © Christoph Luchs

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Reference: Mirja Tamara Prentzell, Ulrike Rehbein et al., “G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling”, Cell, 2021. https://doi.org/10.1016/j.cell.2020.12.024

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Provided by University of Innsbruck

New Galaxy Sheds Light on How Stars Form (Astronomy)

Detailed observations of molecular gas in a tidal dwarf galaxy have important implications for our understanding of how stars are formed.

A lot is known about galaxies. We know, for instance, that the stars within them are shaped from a blend of old star dust and molecules suspended in gas. What remains a mystery, however, is the process that leads to these simple elements being pulled together to form a new star.

But now an international team of scientists, including astrophysicists from the University of Bath and the National Astronomical Observatory (OAN) in Madrid, Spain have taken a significant step towards understanding how a galaxy’s gaseous content becomes organised into a new generation of stars.

Their findings have important implications for our understanding of how stars formed during the early days of the universe, when galaxy collisions were frequent and dramatic, and star and galaxy formation occurred more actively than it does now.

For this study, the researchers used the Chile-based Atacama Large Millimeter Array (ALMA) – a network of radio telescopes combined to form one, mega telescope – to observe a type of galaxy called a tidal dwarf galaxy (TDG). TDGs emerge from the debris of two older galaxies colliding with great force. They are actively star-forming systems and pristine environments for scientists trying to piece together the early days of other galaxies, including our own – the Milky Way (thought to be 13.6-billion years old).

“The little galaxy we’ve been studying was born in a violent, gas-rich galactic collision and offers us a unique laboratory to study the physics of star formation in extreme environments,” said co-author Professor Carole Mundell, head of Astrophysics at the University of Bath.

From their observations, the researchers learnt that a TDG’s molecular clouds are similar to those found in the Milky Way, both in terms of size and content. This suggests there is a universal star-formation process at play throughout the universe.

Unexpectedly, however, the TDG in the study (labelled TDG J1023+1952) also displayed a profusion of dispersed gas. In the Milky Way, clouds of gas are by far the most prominent star-forming factories.

“The fact that molecular gas appears in both cloud form and as diffuse gas was a surprise,” said Professor Mundell.

Dr Miguel Querejeta from the OAN in Spain and lead author of the study added: “ALMA’s observations were made with great precision so we can say with confidence that the contribution of diffuse gas is much higher in the tidal dwarf galaxy we studied than typically found in normal galaxies.”

He added: “This most likely means most of the molecular gas in this tidal dwarf galaxy is not involved in forming stars, which questions popular assumptions about star formation.”

Because of the vast distance that separates Earth from TDG J1023+1952 (around 50 million light years), individual clouds of molecular gas appear as tiny regions in the sky when viewed through the naked eye. However, ALMA has the power to distinguish the smallest details.

“We have managed to identify clouds with an apparent size as small as observing a coin placed several kilometres away from us,” said Professor Mundell, adding: “It’s remarkable that we can now study stars and the gas clouds from which they are formed in a violent extragalactic collision with the same detail that we can study those forming in the calm environment of our own Milky Way.”

The paper ALMA Resolves Giant Molecular Clouds in a Tidal Dwarf Galaxy appears in the latest issue of Astronomy & Astrophysics. This research was a collaborative effort of scientists from across the world working remotely. Their expertise covers the physics of stars, dust and gas, and the science of galaxy evolution.

Featured image: A tidal dwarf galaxy (blue) and a spiral galaxy (greyscale). The Milky Way is an example of a spiral galaxy. (Created from images taken by the Hubble Space Telescope and ALMA.)

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Reference: M. Querejeta, F. Lelli, E. Schinnerer et al., “ALMA resolves giant molecular clouds in a tidal dwarf galaxy”, A&A 645, A97 (2021). https://www.aanda.org/articles/aa/full_html/2021/01/aa38955-20/aa38955-20.html

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Provided by University of Bath

Optimal Information About the Invisible (Physics)

How do you measure objects that you can’t see under normal circumstances? Utrecht University and TU Wien (Vienna) open up new possibilities with special light waves.

Laser beams can be used to precisely measure an object’s position or velocity. Normally, however, a clear, unobstructed view of this object is required – and this prerequisite is not always satisfied. In biomedicine, for example, structures are examined, which are embedded in an irregular, complicated environment. There, the laser beam is deflected, scattered and refracted, often making it impossible to obtain useful data from the measurement.

However, Utrecht University (Netherlands) and TU Wien (Vienna, Austria) have now been able to show that meaningful results can be obtained even in such complicated environments. Indeed, there is a way to specifically modify the laser beam so that it delivers exactly the desired information in the complex, disordered environment – and not just approximately, but in a physically optimal way: Nature does not allow for more precision with coherent laser light. The new technology can be used in very different fields of application, even with different types of waves, and has now been presented in the scientific journal “Nature Physics”.

The vacuum and the bathroom window

“You always want to achieve the best possible measurement accuracy – that’s a central element of all natural sciences,” says Stefan Rotter from TU Wien. “Let’s think, for example, of the huge LIGO facility, which is being used to detect gravitational waves: There, you send laser beams onto a mirror, and changes in the distance between the laser and the mirror are measured with extreme precision.” This only works so well because the laser beam is sent through an ultra-high vacuum. Any disturbance, no matter how small, is to be avoided.

Instead of using a straight, ordinary laser beam to estimate the position of a hidden object inside a disordered environment (see top panels), the optimal procedure works by imprinting a pattern on the incoming laser beam that yields the maximum information output on the object and allows one to estimate its position precisely (see bottom panels). © Tu Wein

But what can you do when you are dealing with disturbances that cannot be removed? “Let’s imagine a panel of glass that is not perfectly transparent, but rough and unpolished like a bathroom window” says Allard Mosk from Utrecht University. “Light can pass through, but not in a straight line. The light waves are altered and scattered, so we can’t accurately see an object on the other side of the window with the naked eye.” The situation is quite similar when you want to examine tiny objects inside biological tissue: the disordered environment disturbs the light beam. The simple, regular straight laser beam then becomes a complicated wave pattern that is deflected in all directions.

The optimal wave

However, if you know exactly what the disturbing environment is doing to the light beam, you can reverse the situation: Then it is possible to create a complicated wave pattern instead of the simple, straight laser beam, which gets transformed into exactly the desired shape due to the disturbances and hits right where it can deliver the best result. “To achieve this, you don’t even need to know exactly what the disturbances are,” Dorian Bouchet, the first author of the study explains. “It’s enough to first send a set of trial waves through the system to study how they are changed by the system.”

The scientists involved in this work jointly developed a mathematical procedure that can then be used to calculate the optimal wave from this test data: “You can show that for various measurements there are certain waves that deliver a maximum of information as, e.g., on the spatial coordinates at which a certain object is located.”

Take for example an object that is hidden behind a turbid pane of glass: there is an optimal light wave that can be used to obtain the maximum amount of information about whether the object has moved a little to the right or a little to the left. This wave looks complicated and disordered, but is then modified by the turbid pane in such a way that it arrives at the object in exactly the desired way and returns the greatest possible amount of information to the experimental measuring apparatus.

Laser experiments in Utrecht

The fact that the method actually works was confirmed experimentally at Utrecht University: Laser beams were directed through a disordered medium in the form of a turbid plate. The scattering behaviour of the medium was thereby characterised, then the optimal waves were calculated in order to analyse an object beyond the plate – and this succeeded, with a precision in the nano-meter range.

Then the team carried out further measurements to test the limits of their novel method: The number of photons in the laser beam was significantly reduced to see whether one then still gets a meaningful result. In this way, they were able to show that the method not only works, but is even optimal in a physical sense: “We see that the precision of our method is only limited by the so-called quantum noise,” explains Allard Mosk. “This noise results from the fact that light consists of photons – nothing can be done about that. But within the limits of what quantum physics allows us to do for a coherent laser beam, we can actually calculate the optimal waves to measure different things. Not only the position, but also the movement or the direction of rotation of objects.”

These results were obtained in the context of a program for nanometer-scale imaging of semiconductor structures, in which universities collaborate with industry. Indeed, possible areas of application for this new technology include microbiology but also the production of computer chips, where extremely precise measurements are indispensable.

Featured image: When light gets deflected by a disordered structure it becomes difficult to estimate where the target is located. In this new study a procedure is presented that allows one to reach the optimal estimation precision in such challenging scenarios. © Tu Wein

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Reference:

D. Bouchet, S. Rotter, A.P. Mosk; Maximum information states for coherent scattering measurements, Nature Physics (2021). https://www.nature.com/articles/s41567-020-01137-4

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