Biozentrum

Schönau am Königssee, Germany

Biozentrum

Schönau am Königssee, Germany
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News Article | November 17, 2016
Site: www.sciencedaily.com

We humans walk with our feet. This is true, but not entirely. Walking, as part of locomotion, is a coordinated whole-body movement that involves both the arms and legs. Researchers at the Biozentrum of the University of Basel and the Friedrich Miescher Institute for Biomedical Research have identified different subpopulations of neurons in the spinal cord with long projections. Published in Neuron, the results show that these neurons coordinate movement of arms and legs and ensure a stable body posture during locomotion. The locomotor pattern consists of a highly controlled sequence of muscle contractions, which are controlled by neuronal circuits in the spinal cord and the brain. The research group of Prof. Silvia Arber at the Biozentrum of the University of Basel and the Friedrich Miescher Institute for Biomedical Research now reveal that specific, long projecting neurons, traversing our spinal cord, form an important basis for the coordination of fore- and hindlimbs. These neurons couple local networks over long distances and thereby ensure posture and rhythm of our body during locomotion. Even though humans rose from the quadrupedal position to stand on their feet during evolution, coordination and alternation patterns of the four limbs are still needed in order to move efficiently as in all other quadrupedal species. "We showed that the diametric movement of fore- and hindlimbs is reflected in neuronal circuits of the spinal cord," says Ludwig Ruder, first author of the study. Thus, axons of most excitatory neurons cross the midline of the spinal cord and contact contralateral networks. In contrast, inhibitory neurons project predominantly on the same side of the body. The diagonal and mirrored pattern of the excitatory neuronal connections is very interesting when observing the coordination of arms and legs in a runner as Usain Bolt. "During running, not only do his legs move, but synchronously and diametrically also his arms -- in complete coordination with each other," says Ruder. Long projecting neurons control whole body parameters of locomotion and distribute information of the brain To demonstrate the importance of long projection neurons in the spinal cord for the walking pattern, the researchers selectively eliminated those neurons. "Upon inactivation of spinal long projection neurons that couple local networks, not only is the stability and speed during running impaired, but also the coordinated fore- and hindlimb movements fall apart at higher speeds," says Ruder. Interestingly, local movement patterns within a single limb remain however unaffected. This reinforces the specific role of long projecting neurons in the regulation of whole body movement. In a next step, the research team observed that the neurons with long projections broadcast their signals throughout the spinal cord and receive extensive input from various brain regions. This organization of long projection neurons and their connections places them at an important intersection between integrating information from the brain and distributing it in the spinal cord. Up to now, researchers investigated mainly local spinal networks and their role in movement. In contrast, neurons with long projections have not been studied all that much. "However, the results of our new study show that long projecting neurons in the spinal cord exhibit a very important role for the coordination of the locomotor pattern," explains Silvia Arber. "Henceforth, we plan to investigate how the brain interacts differently with local and long projecting spinal neurons to control them specifically." In the long run, these results can be important to restore functionality after spinal cord injuries.


We humans walk with our feet. This is true, but not entirely. Walking, as part of locomotion, is a coordinated whole-body movement that involves both the arms and legs. Researchers at the Biozentrum of the University of Basel and the Friedrich Miescher Institute for Biomedical Research have identified different subpopulations of neurons in the spinal cord with long projections. Published in Neuron, the results show that these neurons coordinate movement of arms and legs and ensure a stable body posture during locomotion. The locomotor pattern consists of a highly controlled sequence of muscle contractions, which are controlled by neuronal circuits in the spinal cord and the brain. The research group of Prof. Silvia Arber at the Biozentrum of the University of Basel and the Friedrich Miescher Institute for Biomedical Research now reveal that specific, long projecting neurons, traversing our spinal cord, form an important basis for the coordination of fore- and hindlimbs. These neurons couple local networks over long distances and thereby ensure posture and rhythm of our body during locomotion. Even though humans rose from the quadrupedal position to stand on their feet during evolution, coordination and alternation patterns of the four limbs are still needed in order to move efficiently as in all other quadrupedal species. "We showed that the diametric movement of fore- and hindlimbs is reflected in neuronal circuits of the spinal cord", says Ludwig Ruder, first author of the study. Thus, axons of most excitatory neurons cross the midline of the spinal cord and contact contralateral networks. In contrast, inhibitory neurons project predominantly on the same side of the body. The diagonal and mirrored pattern of the excitatory neuronal connections is very interesting when observing the coordination of arms and legs in a runner as Usain Bolt. "During running, not only do his legs move, but synchronously and diametrically also his arms -- in complete coordination with each other", says Ruder. To demonstrate the importance of long projection neurons in the spinal cord for the walking pattern, the researchers selectively eliminated those neurons. "Upon inactivation of spinal long projection neurons that couple local networks, not only is the stability and speed during running impaired, but also the coordinated fore- and hindlimb movements fall apart at higher speeds", says Ruder. Interestingly, local movement patterns within a single limb remain however unaffected. This reinforces the specific role of long projecting neurons in the regulation of whole body movement. ... and distribute information of the brain In a next step, the research team observed that the neurons with long projections broadcast their signals throughout the spinal cord and receive extensive input from various brain regions. This organization of long projection neurons and their connections places them at an important intersection between integrating information from the brain and distributing it in the spinal cord. Up to now, researchers investigated mainly local spinal networks and their role in movement. In contrast, neurons with long projections have not been studied all that much. "However, the results of our new study show that long projecting neurons in the spinal cord exhibit a very important role for the coordination of the locomotor pattern", explains Silvia Arber. "Henceforth, we plan to investigate how the brain interacts differently with local and long projecting spinal neurons to control them specifically." In the long run, these results can be important to restore functionality after spinal cord injuries.


News Article | December 5, 2016
Site: www.eurekalert.org

A research team at the University of Basel's Biozentrum has investigated the expression of ribosomal proteins in a wide range of human tissues including tumors and discovered a cancer type specific signature. As the researchers report in Genome Biology this "cancer signature" could potentially be used to predict the progression of the disease. Proteins are the building blocks of life. They are produced by molecular machines, called ribosomes. A human ribosome contains some eighty ribosomal proteins. Prof. Mihaela Zavolan's research group at the Biozentrum of the University of Basel has now discovered that about a quarter of the ribosomal proteins have tissue-specific expression and that different cancer types have their own individual expression pattern of ribosomal proteins. In the future, these patterns may serve as a prognostic marker for cancer and may point towards new therapeutic opportunities. Ribosomes are responsible for protein synthesis and are thus essential for the cell. Therefore, it has long been assumed that the expression of the individual components of the ribosomes is strictly controlled and invariant. A few studies, however, have already suggested that the expression of individual ribosomal proteins is altered in cancers as well as in diseases of the hematopoietic system such as acute lymphoblastic leukemia. Mihaela Zavolan and her co-worker Joao Guimaraes have systematically analyzed ribosomal protein expression in thirty tissue types, three hundred different cell types and sixteen different types of tumors, such as lung and breast cancer. In contrast to previous assumptions, they found a wide variability in ribosomal protein gene expression. In particular, hematopoietic and tumor cells display the most complex expression pattern. "For us, it was really impressive to see that consistent signatures emerged for the different cancer types after the analysis of distinct data sets including patient samples," explains first author Guimaraes. "The pattern of the dysregulated proteins is very striking, whereby the expression of some ribosomal proteins is systematically reduced, and of others increased in cancer cells. This suggests that individual ribosomal proteins can either suppress or promote tumorigenesis." Furthermore, the scientists discovered a strong relationship between the "signature" in breast cancer and the relapse-free survival. "We were quite surprised to find that the expression level of just three ribosomal proteins allows a fairly accurate prognosis of disease progression, comparable to the best predictive markers that are currently known", Zavolan points out. "Our study demonstrates the potential of such expression signatures for the prognosis and perhaps a diagnosis of cancer. We are especially interested in studying the functions of individual ribosomal proteins and hopefully opening the door for new therapeutic options," explains the scientist. Joao C. Guimaraes and Mihaela Zavolan Patterns of ribosomal protein expression specify normal and malignant human cells Genome Biology (2016), doi: 10.1186/s13059-016-1104-z


News Article | December 17, 2015
Site: phys.org

For a long time it has been known that the protein TOR - Target of Rapamycin - controls cell growth and is involved in the development of diseases such as cancer and diabetes. Researchers at the University of Basel's Biozentrum together with scientists from ETH Zurich have now examined the structure of mammalian TOR complex 1 (mTORC1) in more detail. The scientists have revealed its unique architecture in their latest publication in Science.


News Article | December 27, 2016
Site: www.eurekalert.org

A combination of a diabetes medication and an antihypertensive drug can effectively combat cancer cells. The team of researchers led by Prof. Michael Hall at the Biozentrum of the University of Basel has also reported that specific cancer cells respond to this combination of drugs. The results of the study have now been published in Science Advances. Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. Besides its blood sugar lowering effect, it also displays anti-cancer properties. The usual therapeutic dose, however, is too low to effectively fight cancer. The research team led by Prof. Michael Hall, at the Biozentrum of the University of Basel, has now made an unexpected discovery: The antihypertensive drug syrosingopine potentiates the anti-cancer efficacy of metformin. Apparently, this drug combination drives cancer cells to programmed "suicide". At higher doses, the antidiabetic drug inhibits the growth of cancer cells but could also induce unwanted side effects. Therefore, the researchers screened over a thousand drugs for whether they can enhance the anticancer action of metformin. A favorite emerged from this screening: Syrosingopine, an antihypertensive drug. As the study shows, the cocktail of these two drugs is effective in a wide range of cancers. "For example, in samples from leukemia patients, we demonstrated that almost all tumor cells were killed by this cocktail and at doses that are actually not toxic to normal cells", says the first author, Don Benjamin. "And the effect was exclusively confined to cancer cells, as the blood cells from healthy donors were insensitive to the treatment." In mice with malignant liver cancer, enlargement of the liver was reduced after the therapy. Also the number of tumor nodules was less - in some animals the tumors disappeared completely. A glance at the molecular processes in the tumor cells explains the drug combination's efficacy: Metformin lowers not only the blood glucose level, but also blocks the respiratory chain in the energy factories of the cell, the mitochondria. The antihypertensive drug syrosingopine inhibits, among other things, the degradation of sugars. Thus, the drugs interrupt the vital processes which provide energy for the cell. Due to their increased metabolic activity and rapid growth, cancer cells have a particularly high energy consumption, which makes them extremely vulnerable when the energy supply is reduced. By testing a range of other compounds with the same mode of action, the scientists could demonstrate that the inhibition of the respiratory chain in the mitochondria is a key mechanism. These also reduced cancer cell growth in combination with the antihypertensive drug. "We have been able to show that the two known drugs lead to more profound effects on cancer cell proliferation than each drug alone," explains Benjamin. "The data from this study support the development of combination approaches for the treatment of cancer patients." This study may have implications for future clinical application of combination scenarios targeting the energy needs of tumor cells.


News Article | December 7, 2016
Site: www.medicalnewstoday.com

A research team at the University of Basel's Biozentrum has investigated the expression of ribosomal proteins in a wide range of human tissues including tumors and discovered a cancer type specific signature. As the researchers report in Genome Biology this "cancer signature" could potentially be used to predict the progression of the disease. Proteins are the building blocks of life. They are produced by molecular machines, called ribosomes. A human ribosome contains some eighty ribosomal proteins. Prof. Mihaela Zavolan's research group at the Biozentrum of the University of Basel has now discovered that about a quarter of the ribosomal proteins have tissue-specific expression and that different cancer types have their own individual expression pattern of ribosomal proteins. In the future, these patterns may serve as a prognostic marker for cancer and may point towards new therapeutic opportunities. Ribosomes are responsible for protein synthesis and are thus essential for the cell. Therefore, it has long been assumed that the expression of the individual components of the ribosomes is strictly controlled and invariant. A few studies, however, have already suggested that the expression of individual ribosomal proteins is altered in cancers as well as in diseases of the hematopoietic system such as acute lymphoblastic leukemia. Mihaela Zavolan and her co-worker Joao Guimaraes have systematically analyzed ribosomal protein expression in thirty tissue types, three hundred different cell types and sixteen different types of tumors, such as lung and breast cancer. In contrast to previous assumptions, they found a wide variability in ribosomal protein gene expression. In particular, hematopoietic and tumor cells display the most complex expression pattern. "For us, it was really impressive to see that consistent signatures emerged for the different cancer types after the analysis of distinct data sets including patient samples," explains first author Guimaraes. "The pattern of the dysregulated proteins is very striking, whereby the expression of some ribosomal proteins is systematically reduced, and of others increased in cancer cells. This suggests that individual ribosomal proteins can either suppress or promote tumorigenesis." Furthermore, the scientists discovered a strong relationship between the "signature" in breast cancer and the relapse-free survival. "We were quite surprised to find that the expression level of just three ribosomal proteins allows a fairly accurate prognosis of disease progression, comparable to the best predictive markers that are currently known", Zavolan points out. "Our study demonstrates the potential of such expression signatures for the prognosis and perhaps a diagnosis of cancer. We are especially interested in studying the functions of individual ribosomal proteins and hopefully opening the door for new therapeutic options," explains the scientist. Article: Patterns of ribosomal protein expression specify normal and malignant human cells, Joao C. Guimaraes and Mihaela Zavolan, Genome Biology, doi: 10.1186/s13059-016-1104-z, published 24 November 2016.


Angliker N.,Biozentrum
Bioarchitecture | Year: 2013

The mammalian target of rapamycin (mTOR) assembles into two distinct multi-protein complexes called mTORC1 and mTORC2. While mTORC1 controls the signaling pathways important for cell growth, the physiological function of mTORC2 is only partially known. Here we comment on recent work on gene-targeted mice lacking mTORC2 in the cerebellum or the hippocampus that provided strong evidence that mTORC2 plays an important role in neuron morphology and synapse function. We discuss that this phenotype might be based on the perturbed regulation of the actin cytoskeleton and the lack of activation of several PKC isoforms. The fact that PKC isoforms and their targets have been implicated in neurological disease including spinocerebellar ataxia and that they have been shown to affect learning and memory, suggests that aberration of mTORC2 signaling might be involved in diseases of the brain.


News Article | November 9, 2015
Site: phys.org

Drosophila wing size control depends on the spreading of the Dpp morphogen. Credit: University of Basel, Biozentrum Researchers at the Biozentrum of the University of Basel have developed a new technique using nanobodies. Employing the so-called "Morphotrap", the distribution of the morphogen Dpp, which plays an important role in wing development, could be selectively manipulated and analyzed for the first time in the fruit fly. In the future, this tool may be applied for many further investigations of organ growth. The results of the study have been published in the current issue of Nature. The two basic processes that control organ development are the regulation of growth and of the spatial pattern. The research group of Prof. Markus Affolter at the Biozentrum, University of Basel, has now developed a method named "Morphotrap" to study wing development in the fruit fly. Their results demonstrate that the signaling molecule Dpp, a so-called morphogen, influences growth in the center of the wing imaginal disc but not in the peripheral regions. It is the first time that an anti-GFP nanobody has been successfully employed in such an investigation. This tool also holds promise for future studies on organ development. The new method "Morphotrap": Nanobodies to study growth Nanobodies are small antibody fragments derived from camels. They enable the research team of Markus Affolter to manipulate molecules in the living organism. The so-called "Morphotrap" method employs anti-GFP nanobodies. Using these Nanobodies, the functions of GFP-tagged proteins in living organisms can be studied faster and more effectively than by conventional methods. "These anti-GFP nanobodies inhibit the dispersal of the morphogen Dpp at different locations in the wing. Therefore they allow us to identify the influence of Dpp spreading on wing growth," explains Stefan Harmansa, the first author of the study. Morphogen Dpp regulates growth in the middle of the imaginal disc To determine the influence of the morphogen Decapentaplegic (Dpp) in more detail, the Affolter group examined the wing disc of the fruit fly, called the imaginal disc. This is the precursor tissue of the wing of the adult fly and serves as a model for studies on organ development. "Our findings demonstrate that the morphogen Dpp only affects growth in the center of the imaginal disc. Growth continues in the periphery even when we fully block Dpp dispersal into this regions," explains Harmansa. "Now, by employing anti GFP nanobodies, we have been able to show to which extent the morphogen Dpp determines the wing size and consequently we could disprove one of the two predominant theories in this field," says Harmansa. The fact that anti GFP-nanobodies can successfully be applied for research in complex living organism is a great achievement. Affolter also plans to apply this technique in future research: "In a next step, we will investigate at what time in development Dpp acts to control central growth. The correlation between the spatial and temporal influence of Dpp will provide new insights into organ growth and may uncover possible causes of organ malformation," says Affolter. More information: Dpp spreading is required for medial but not for lateral wing disc growth, DOI: 10.1038/nature15712


News Article | December 21, 2016
Site: www.eurekalert.org

Neurons in the brain store RNA molecules - DNA gene copies - in order to rapidly react to stimuli. This storage dramatically accelerates the production of proteins. This is one of the reasons why neurons in the brain can adapt quickly during learning processes. The recent results of a research group at the University of Basel's Biozentrum have been published in the current issue of "Neuron". Our brain is not only the most complex organ of the human body, it is also the most flexible. But how do neurons in the brain adapt their function in response to stimuli within a very short time frame? The research group of Prof. Peter Scheiffele at the Biozentrum, University of Basel, has demonstrated that neurons store a reserve stock of RNA molecules, copies of the DNA, in the cell's nucleus. These RNA molecules form the blueprint for new proteins. After a neuronal stimulus, the stored RNA molecules are mobilized in order to adjust the function of the neuron. The process of RNA synthesis (DNA copying) is very slow, especially for large genes. Thus, this newly uncovered mechanism for mobilization of stored RNAs saves time and provides new insights regarding the fast adaptation of the brain during learning processes. The RNA blueprint for proteins is produced by a sophisticated copying process: First, a basic RNA copy of the DNA is generated. From this copy, individual sections, so-called introns, are subsequently cut out to provide a finalized blueprint for the production of a specific protein. This process is called RNA splicing. So far, it was assumed, that neuronal stimuli trigger the complete process for the production of new RNA molecules. However, the team of Peter Scheiffele now discovered that neurons in the brain pre-manufacture certain immature RNA copies which are only partially spliced. These RNA molecules still contain some introns and are stored in the cell nucleus. Signals induced by neuronal stimulation trigger the splicing completion of the immature RNA molecules. "The copying process of the DNA, the so-called transcription, is already finalized in advance by the neurons. Hence, mature RNA molecules can be produced within minutes," explains Oriane Mauger, the first author. For large genes, the production of the initial version of the RNAs itself takes dozens of hours. "The fact that the RNA molecules are already available in an immature form and only need to be completed, shortens the whole process to a few minutes", says Mauger. "Since the transcription is very time-consuming, the storage of RNA means a significant time saving. This enables neurons to quickly adapt their function." "This study reveals a completely new regulatory mechanism for the brain", declares Scheiffele. "The results provide us with a further explanation of how neurons steer rapid plasticity processes."


News Article | September 8, 2016
Site: phys.org

Vibrio cholerae bacteria (green) recycle T6SS proteins of the attacking sister cells (red) to build their own spear gun (light green intracellular structure). Credit: University of Basel Bacteria fight their competitors with molecular spear guns, the so-called Type VI secretion system. When firing this weapon they also unintentionally hit their own kind. However, as Prof. Marek Basler from the Biozentrum of the University of Basel reports in the journal Cell, the related bacteria strains benefit from coming under fire. They recycle the protein components of the spear guns and use these to build their own weapons. Many bacteria possess molecular spear guns, which they fire at enemies and rivals, thus putting them out of action. The tips of these nano-spear guns, known as Type VI secretion system (T6SS), are loaded with toxic molecules that lead to death of their adversaries. However, sometimes close related bacteria come under fire. The team of Prof. Marek Basler, infection biologist at the Biozentrum of the University of Basel, has shown for the first time, that in contrast to their enemies the harpooned sister cells actually profit from the attack: After a T6SS injection, they are able to reuse specific proteins to produce their own spear guns. Thus the related bacterial strains help each other to enlarge their arsenal of weapons and to fight their competitors. Bacteria harpoon their opponents - and their allies The T6SS is firmly attached to the bacterial cell envelop. The tiny spear with a sharp tip is surrounded by a flexible sheath. "When bacteria fire their spear guns, the sheath rapidly contracts in just a few milliseconds and ejects the spear out of the cell into by-standing bacteria," says Basler describing the mechanism. "The attackers then recycle the harpoon proteins remaining in the cell." In this maneuver, the bacteria also hit related bacterial strains that do the same as the attackers: They disassemble the harpoon into their protein components and reuse these for new T6SS assembly. Recycling is everything: Bacteria also provide unarmed allies with munitions That closely related bacteria share their proteins through this type of spear gun attack and then recycle the components, has been demonstrated by the researchers for the first time, using the cholera pathogen, Vibrio cholerae. For this, they mixed T6SS-deficient bacteria that lack the proteins needed for the spear gun production with normal T6SS-producing Vibrio bacteria. "The special thing about Vibrio cholerae is that it assembles spear guns all the time and fires them aimlessly," explains Andrea Vettiger, author of the study. "If one of T6SS-defecient bacteria is randomly hit, it disassembles the spear gun to its individual components, the shaft and tip proteins, and reassembles its own functional harpoon. Also the translocated tip-linked toxins can be recycled by the attacked cell. And even bacteria that no longer produce any proteins can assemble a T6SS by reusing the harpooned proteins provided by their neighboring sister cells." Additionally, the researchers observed the related bacterial strains also cooperate with each other and join forces in their defense against undesirable rivals. Thus, two Vibrio strains can cooperate to kill a third competitor, even if one of them lacks individual T6SS components or the toxins for the spear tip. They combine their resources and produce their weapons together. "Although we have only observed this interbacterial complementation under laboratory conditions, we are convinced that this form of cooperation plays an important role in nature and provides some bacterial communities with a survival advantage," says Basler. Explore further: Pseudomonas deploys a toxin delivery machine to breach cell walls of rivals without hurting itself

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