Neuroscience

Articles and news from the latest research reports.

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A new strategy required in the search for Alzheimer’s drugs? In the search for medication against Alzheimer’s disease, scientists have focused – among other factors – on drugs that can break down Amyloid beta (A-beta). After all, it is the accumulation of A-beta that causes the known plaques in the brains of Alzheimer’s patients. Starting point for the formation of A-beta is APP. Alessia Soldano and Bassem Hassan (VIB/KU Leuven) were the first to unravel the function of APPL – the fruit-fly version of APP – in the brain of healthy fruit flies. (PLoS Biology) Alessia Soldano (VIB/KU Leuven): “We have discovered that APPL ensures that brain cells form a good network. We now have to ask ourselves the question whether this function of APPL is also relevant to Alzheimer’s disease.” Bassem Hassan (VIB/KU Leuven): “Since we show that APP and APPL show similar activities in cultured cells, we suspect that APP in the human brain functions in the same manner as APPL in the brain of fruit flies. Hopefully we can use this to ask and eventually answer the question whether A-beta or APP itself is the better target for new drugs.” Plaques in the brain: cause or effectThe brain of a person with Alzheimer’s disease is very recognizable due to the so-called plaques. A plaque is an accumulation of proteins that are primarily made up of Amyloid beta (A-beta), a small structure that splits off from the Amyloid Precursor Protein (APP). We have been dreaming for a long time of a drug that can break down A-beta, but we should be asking ourselves whether this is really the best strategy. After all, it is not yet clear whether the plaques are a cause or effect of Alzheimer’s disease. In order to answer this question, it is important to determine the function of APP in healthy brains. Optimum communication between brain cellsAlessia Soldano and Bassem Hassan study APPL, the fruit-fly version of APP. APPL is found throughout the fruit-fly brain, but primarily in the so-called alpha-beta neurons that are vital to learning processes and memory. The alpha-beta neurons must form functional axons for optimum functioning. Axons are tendrils projecting from the neuron, which are essential for communication between neurons. The VIB scientists had previously shown that APPL is important for memory in flies. Now, they have discovered that – in the developing brain of a fruit fly – APPL ensures that the axons are long enough and grow in the correct direction. APPL is therefore essential in the formation of a good network of neurons. The question is whether or not it is a good strategy to target a protein with such an important function in the brain in order to combat Alzheimer’s disease. (PLoS Biology)

A new strategy required in the search for Alzheimer’s drugs?

In the search for medication against Alzheimer’s disease, scientists have focused – among other factors – on drugs that can break down Amyloid beta (A-beta). After all, it is the accumulation of A-beta that causes the known plaques in the brains of Alzheimer’s patients. Starting point for the formation of A-beta is APP. Alessia Soldano and Bassem Hassan (VIB/KU Leuven) were the first to unravel the function of APPL – the fruit-fly version of APP – in the brain of healthy fruit flies. (PLoS Biology)

Alessia Soldano (VIB/KU Leuven): “We have discovered that APPL ensures that brain cells form a good network. We now have to ask ourselves the question whether this function of APPL is also relevant to Alzheimer’s disease.”

Bassem Hassan (VIB/KU Leuven): “Since we show that APP and APPL show similar activities in cultured cells, we suspect that APP in the human brain functions in the same manner as APPL in the brain of fruit flies. Hopefully we can use this to ask and eventually answer the question whether A-beta or APP itself is the better target for new drugs.”

Plaques in the brain: cause or effect
The brain of a person with Alzheimer’s disease is very recognizable due to the so-called plaques. A plaque is an accumulation of proteins that are primarily made up of Amyloid beta (A-beta), a small structure that splits off from the Amyloid Precursor Protein (APP). We have been dreaming for a long time of a drug that can break down A-beta, but we should be asking ourselves whether this is really the best strategy. After all, it is not yet clear whether the plaques are a cause or effect of Alzheimer’s disease. In order to answer this question, it is important to determine the function of APP in healthy brains.

Optimum communication between brain cells
Alessia Soldano and Bassem Hassan study APPL, the fruit-fly version of APP. APPL is found throughout the fruit-fly brain, but primarily in the so-called alpha-beta neurons that are vital to learning processes and memory. The alpha-beta neurons must form functional axons for optimum functioning. Axons are tendrils projecting from the neuron, which are essential for communication between neurons. The VIB scientists had previously shown that APPL is important for memory in flies. Now, they have discovered that – in the developing brain of a fruit fly – APPL ensures that the axons are long enough and grow in the correct direction. APPL is therefore essential in the formation of a good network of neurons. The question is whether or not it is a good strategy to target a protein with such an important function in the brain in order to combat Alzheimer’s disease. (PLoS Biology)

Filed under alzheimer's disease amyloid beta amyloid precursor protein plaques fruit flies neuroscience science

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Proteins in migration

In Parkinson’s disease, the protein “alpha-synuclein” aggregates and accumulates within neurons. Specific areas of the brain become progressively affected as the disease develops and advances. The mechanism underlying this pathological progression is poorly understood but could result from spreading of the protein (or abnormal forms of it) along nerve projections connecting lower to upper brain regions. Scientists at the German Center for Neurodegenerative Diseases (DZNE) in Bonn have developed a novel experimental model that reproduces for the first time this pattern of alpha-synuclein brain spreading and provides important clues on the mechanisms underlying this pathological process. They triggered the production of human alpha-synuclein in the lower rat brain and were able to trace the spreading of this protein toward higher brain regions. The new experimental paradigm could promote the development of ways to halt or slow down disease development in humans. The research team headed by Prof. Donato Di Monte presents these results in the scientific journal “EMBO Molecular Medicine”.

Parkinson’s disease is a disorder of the nervous system. It typically manifests itself with motor disturbances, such as an uncontrollable trembling of the limbs, as well as non-motor symptoms, including sleep disorders and depression.

At the present, no cure exists for Parkinson’s disease, although symptomatic intervention, including treatment with dopamine agonists, can alleviate patients’ motor impairment. Parkinson’s is the second most common neurodegenerative disorder, after Alzheimer’s disease; it is estimated that 100,000 to 300,000 patients are affected by Parkinson’s disease in Germany alone.

In a small percentage of cases, Parkinson’s disease is due to genetic abnormalities carried within families. For the vast majority of patients, however, the cause of the disease remains unknown; the development of this sporadic form of the disease is likely promoted by both environmental and genetic risk factors. An intriguing characteristic of the brain of patients with sporadic Parkinson’s disease is the progressive accumulation of intraneuronal inclusions that were first described by a German neurologist, Friedrich Lewy, and are therefore called Lewy bodies.

“A major discovery in the late 90’s was that Lewy bodies are formed when the protein alpha-synuclein becomes aggregated,” says Di Monte. “Since then, it was also found that aggregates of alpha-synuclein are progressively accumulated within the patients’ brains during the course of the disease”.

Pathology studies from human brains show that the deposits usually start forming in the lower part of the brain, in an area named “medulla oblongata”. In subsequent disease stages, alpha-synuclein aggregates are observed in progressively higher (more rostral) brain regions, including the midbrain and cortical areas.

“This spreading appears to follow a typical pattern based on anatomical connections between regions of the brain,” says the neuroscientist. “For this reason, it has been hypothesized that alpha-synuclein or abnormal forms of it can be transferred between two interconnected neurons and hence migrate throughout the brain. But until now, there was no way of targeting the medulla oblongata to reproduce this spreading of alpha-synuclein in the laboratory. It is also unclear what conditions could trigger the inter-neuronal passage of the protein or its aggregates. We have now developed a new experimental paradigm which enables investigations on these fundamental issues.”

From the neck into the brain
The researchers’ concept is based on reproducing alpha-synuclein spreading in rats: for this, they transferred the blueprint of the human form of alpha-synuclein into the rat brain. The blueprint was transported by specifically engineered viral particles that the scientists injected into nerve fibres in the neck of the animals. The genetic code for the protein passed along these fibres into the medulla oblongata, where transfected rat neurons began producing high quantities of human alpha-synuclein.

“We have good reasons to believe that the medulla oblongata is a primary site of early disease development. This is why we wanted to activate production of alpha-synuclein specifically in this part of the brain. The medulla oblongata is difficult to reach via surgical procedures. For this reason, we injected the viral particles into the vagus nerve. This is a long nerve stretching from the abdomen via the neck to the medulla oblongata. The nerve consequently served as an entrance into the brain and, in particular, the medulla oblongata,” Di Monte explains.

A migrating protein
The researchers monitored the production and localization of human alpha-synuclein in rats’ brains over a period of four and a half months after injection of the viral particles. As predicted, the exogenous protein was synthesized only within neurons of the medulla oblongata connected to the vagus nerve. Starting at two months, however, human alpha-synuclein was observed also in brain areas more and more distant from the medulla oblongata. Caudo-rostral spreading involved inter-neuronal passage of the protein along specific nerve tracts and was accompanied by morphological alterations (such as swellings) of the neuronal projections taking up human alpha-synuclein.

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The study, sponsored in part by the Blanche A. Paul Foundation, bears a number of critical implications. It reproduces a pattern of protein propagation that resembles the progressive spreading of pathological alpha-synuclein in Parkinson’s disease. As importantly, the process of protein transmission was triggered by overproduction of alpha-synuclein within a specific brain region.

“Overproduction of alpha-synuclein accompanies a variety of conditions, such as aging, neuronal injury or genetic polymorphisms, that could promote the development of Parkinson’s disease.” concludes Di Monte. “Thus, our results suggest a mechanistic link between disease risk factors, enhanced levels of alpha-synuclein, spreading of the protein and its pathological accumulation.”

Insight into the early stages of Parkinson’s
The new model mimics events that likely occur in the early stages of alpha-synuclein pathology in the absence of overt behavioural (in rats) or clinical (in patients) manifestations. “It will therefore become a valuable tool to investigate early mechanisms of disease pathogenesis that could be targeted for therapeutic intervention. Early intervention would have a greater probability to prevent or halt the spreading of pathology and progression of the disease,” says Di Monte.

(Source: dzne.de)

Filed under alpha-synuclein parkinson's disease proteins medulla oblongata viral particles neuroscience science

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Going live – immune cell activation in multiple sclerosis Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to examine individual cells and their activity directly in the tissue. The development of new microscopes and fluorescent dyes in recent years has brought this scientific dream tantalisingly close. Scientists from the Max Planck Institute of Neurobiology in Martinsried have now presented not one, but two studies introducing new indicator molecules which can visualise the activation of T cells. Their findings provide new insight into the role of these cells in the autoimmune disease multiple sclerosis (MS). The new indicators are set to be an important tool in the study of other immune reactions as well. Inflammation is the body’s defence response to a potentially harmful stimulus. The purpose of an inflammation is to fight and remove the stimulus – whether it be disease-causing pathogens or tissue. As an inflammation progresses, significant steps that occur thus include the recruitment of immune cells, the interactions of these cells in the affected tissue and the resulting activation pattern of the immune cells. The more scientists understand about these steps, the better they can develop more effective drugs and treatments to support them. This is particularly true for diseases like multiple sclerosis. In this autoimmune disorder cells from the body’s immune system penetrate into the central nervous system where they cause massive damage in the course of an inflammation. In order to truly understand the cellular processes involved in MS, scientists ideally need to study them in real time at the exact location where they take place – directly in the affected tissue. In recent years, new microscopic techniques and fluorescent dyes have been developed to make this possible for the first time. These coloured indicators make individual cells, their components or certain cell processes visible under the microscope. For example, scientists from the Max Planck Institute of Neurobiology have developed a genetic calcium indicator, TN-XXL, which the cells themselves form, and which highlights the activity of individual nerve cells reliably and for an unlimited time. However, the gene for the indicator was not expressed by immune cells. That is why it was previously impossible to track where in the body and when a contact between immune cells and other cells led to the immune cell’s activation. Now the Martinsried-based neuroimmunologists report two major advances in this field simultaneously. One is their development of a new indicator which visualises the activation of T cells. These cells, which are important components of the immune system, detect and fight pathogens or substances classified as foreign (antigens). Multiple sclerosis, for example, is one of the diseases in which T cells play an important role: here, however, they detect and attack the body’s brain tissue. If a T cell detects “its own” antigen, the NFAT signal protein migrates from the cell plasma to the nucleus of the T cell. “This movement of the NFAT shows us that the cell has been activated, in other words it has been ‘armed’,” explains Marija Pesic, lead author of the study published in the Journal of Clinical Investigation. “We took advantage of this to bind the fluorescent dye called GFP to the NFAT, thereby visualising the activation of these cells.” The scientists are thus now able to conclusively show in the organism whether an antigen leads to the activation of a T cell. The new indicator is an important new tool for researching autoimmune diseases and also for studying immune cells during their development, during infections or in the course of tumour reactions. In parallel to these studies, the neuroimmunologists in Martinsried developed a slightly different, complementary method. They modified the calcium indicator TN-XXL to enable, for the first time, T cell activation patterns to be observed live under the microscope, even while the cells are wandering about the body. When a T cell detects an antigen, a rapid rise in the calcium concentration within the cell ensues. The TN-XXL makes this alteration in the calcium level apparent by changing colour, giving the scientists a direct view of when and where the T cells are being activated. "This method has enabled us to demonstrate that these cells really can be activated in the brain," says a pleased Marsilius Mues, lead author of the study which has just been published in Nature Medicine. Until now, scientists had only suspected this to be the case. In the animal model of multiple sclerosis, scientists are now able to track not only the migration of the T cells, but also their activation pattern in the course of the disease. Initial investigations have already shown, besides the expected activation by antigen detection, that numerous fluctuations in calcium levels also take place which bear no relation to an antigen. “These fluctuations can tell us something about how potent the T cell is, how strong the antigen is, or it may have something to do with the environment,” speculates Marsilius Mues. These observations could indicate new research approaches for drugs – or they could even show whether a drug actually has an effect on T cell activation.

Going live – immune cell activation in multiple sclerosis

Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to examine individual cells and their activity directly in the tissue. The development of new microscopes and fluorescent dyes in recent years has brought this scientific dream tantalisingly close. Scientists from the Max Planck Institute of Neurobiology in Martinsried have now presented not one, but two studies introducing new indicator molecules which can visualise the activation of T cells. Their findings provide new insight into the role of these cells in the autoimmune disease multiple sclerosis (MS). The new indicators are set to be an important tool in the study of other immune reactions as well.

Inflammation is the body’s defence response to a potentially harmful stimulus. The purpose of an inflammation is to fight and remove the stimulus – whether it be disease-causing pathogens or tissue. As an inflammation progresses, significant steps that occur thus include the recruitment of immune cells, the interactions of these cells in the affected tissue and the resulting activation pattern of the immune cells. The more scientists understand about these steps, the better they can develop more effective drugs and treatments to support them. This is particularly true for diseases like multiple sclerosis. In this autoimmune disorder cells from the body’s immune system penetrate into the central nervous system where they cause massive damage in the course of an inflammation.

In order to truly understand the cellular processes involved in MS, scientists ideally need to study them in real time at the exact location where they take place – directly in the affected tissue. In recent years, new microscopic techniques and fluorescent dyes have been developed to make this possible for the first time. These coloured indicators make individual cells, their components or certain cell processes visible under the microscope. For example, scientists from the Max Planck Institute of Neurobiology have developed a genetic calcium indicator, TN-XXL, which the cells themselves form, and which highlights the activity of individual nerve cells reliably and for an unlimited time. However, the gene for the indicator was not expressed by immune cells. That is why it was previously impossible to track where in the body and when a contact between immune cells and other cells led to the immune cell’s activation.

Now the Martinsried-based neuroimmunologists report two major advances in this field simultaneously. One is their development of a new indicator which visualises the activation of T cells. These cells, which are important components of the immune system, detect and fight pathogens or substances classified as foreign (antigens). Multiple sclerosis, for example, is one of the diseases in which T cells play an important role: here, however, they detect and attack the body’s brain tissue. If a T cell detects “its own” antigen, the NFAT signal protein migrates from the cell plasma to the nucleus of the T cell. “This movement of the NFAT shows us that the cell has been activated, in other words it has been ‘armed’,” explains Marija Pesic, lead author of the study published in the Journal of Clinical Investigation. “We took advantage of this to bind the fluorescent dye called GFP to the NFAT, thereby visualising the activation of these cells.” The scientists are thus now able to conclusively show in the organism whether an antigen leads to the activation of a T cell. The new indicator is an important new tool for researching autoimmune diseases and also for studying immune cells during their development, during infections or in the course of tumour reactions.

In parallel to these studies, the neuroimmunologists in Martinsried developed a slightly different, complementary method. They modified the calcium indicator TN-XXL to enable, for the first time, T cell activation patterns to be observed live under the microscope, even while the cells are wandering about the body. When a T cell detects an antigen, a rapid rise in the calcium concentration within the cell ensues. The TN-XXL makes this alteration in the calcium level apparent by changing colour, giving the scientists a direct view of when and where the T cells are being activated.

"This method has enabled us to demonstrate that these cells really can be activated in the brain," says a pleased Marsilius Mues, lead author of the study which has just been published in Nature Medicine. Until now, scientists had only suspected this to be the case. In the animal model of multiple sclerosis, scientists are now able to track not only the migration of the T cells, but also their activation pattern in the course of the disease. Initial investigations have already shown, besides the expected activation by antigen detection, that numerous fluctuations in calcium levels also take place which bear no relation to an antigen. “These fluctuations can tell us something about how potent the T cell is, how strong the antigen is, or it may have something to do with the environment,” speculates Marsilius Mues. These observations could indicate new research approaches for drugs – or they could even show whether a drug actually has an effect on T cell activation.

Filed under inflammation immune cells MS CNS calcium indicator T cells autoimmune diseases neuroscience science

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New neuron formation could increase capacity for new learning, at the expense of old memories Cause of infantile amnesia revealed New research presented today shows that formation of new neurons in the hippocampus - a brain region known for its importance in learning and remembering - could cause forgetting of old memories by causing a reorganization of existing brain circuits. Drs. Paul Frankland and Sheena Josselyn, both from the Hospital for Sick Children in Toronto, argue this reorganization could have the positive effect of clearing old memories, reducing interference and thereby increasing capacity for new learning. These results were presented at the 2013 Canadian Neuroscience Meeting, the annual meeting of the Canadian Association for Neuroscience - Association Canadienne des Neurosciences (CAN-ACN). Researchers have long known of the phenomenon of infantile amnesia: This refers to the absence of long-term memory of events occurring within the first 2-3 years of life, and little long-term memories for events occurring until about 7 years of age. Studies have shown that though young children can remember events in the short term, these memories do not persist. This new study by Frankland and Josselyn shows that this amnesia is associated with high levels of new neuron production - a process called neurogenesis - in the hippocampus, and that more permanent memory formation is associated with a reduction in neurogenesis. Dr. Frankland and Dr. Josselyn’s approach was to look at retention of memories in young mice in which they suppressed the usual high levels of neurogenesis in the hippocampus (thereby replicating the circuit stability normally observed in adult mice), but also in older mice in which they stimulated increased neurogenesis (thereby replicating the conditions normally seen in younger mice). Dr. Frankland was able to show a causal relationship between a reduction in neurogenesis and increased remembering, and the converse, decreased remembering when neurogenesis increased. Dr. Frankland concludes: ” Why infantile amnesia exists has long been a mystery. We think our new studies begin to explain why we have no memories from our earliest years.”

New neuron formation could increase capacity for new learning, at the expense of old memories

Cause of infantile amnesia revealed

New research presented today shows that formation of new neurons in the hippocampus - a brain region known for its importance in learning and remembering - could cause forgetting of old memories by causing a reorganization of existing brain circuits. Drs. Paul Frankland and Sheena Josselyn, both from the Hospital for Sick Children in Toronto, argue this reorganization could have the positive effect of clearing old memories, reducing interference and thereby increasing capacity for new learning. These results were presented at the 2013 Canadian Neuroscience Meeting, the annual meeting of the Canadian Association for Neuroscience - Association Canadienne des Neurosciences (CAN-ACN).

Researchers have long known of the phenomenon of infantile amnesia: This refers to the absence of long-term memory of events occurring within the first 2-3 years of life, and little long-term memories for events occurring until about 7 years of age. Studies have shown that though young children can remember events in the short term, these memories do not persist. This new study by Frankland and Josselyn shows that this amnesia is associated with high levels of new neuron production - a process called neurogenesis - in the hippocampus, and that more permanent memory formation is associated with a reduction in neurogenesis.

Dr. Frankland and Dr. Josselyn’s approach was to look at retention of memories in young mice in which they suppressed the usual high levels of neurogenesis in the hippocampus (thereby replicating the circuit stability normally observed in adult mice), but also in older mice in which they stimulated increased neurogenesis (thereby replicating the conditions normally seen in younger mice). Dr. Frankland was able to show a causal relationship between a reduction in neurogenesis and increased remembering, and the converse, decreased remembering when neurogenesis increased.

Dr. Frankland concludes: ” Why infantile amnesia exists has long been a mystery. We think our new studies begin to explain why we have no memories from our earliest years.”

Filed under infantile amnesia neurons memory learning hippocampus neurogenesis neuroscience science

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Biophysicists measure mechanism that determines fate of living cells Cells in the human body do not function in isolation. Living cells rely on communication with their environment—neighboring cells and the surrounding matrix—to activate a wide range of cellular functions, including reproduction of new cells, differentiation of stem cells into distinct cell types, cell adhesion, and migration of white blood cells to fight bodily infections. This cellular communication occurs on the molecular level and it is reciprocal: a cell receives cues from and also transmits function-activating cues to its neighbors. The mechanics of this type of cellular interaction have been studied extensively: receptors extending through the cell membrane are activated when they form a bond to specific molecules. Now for the first time, University of Illinois biophysicists at the Center for the Physics of Living Cells and the Institute for Genomic Biology have measured the molecular force required to mechanically transmit function-regulating signals within a cell. The new laboratory method, named the tension gauge tether (TGT) approach, developed by Taekjip Ha with postdoctoral researcher Xuefeng Wang, and reported in the May 24, 2013, issue of the journal Science, has made it possible to detect and measure the mechanics of the single-molecule interaction by which human cell receptors are activated. The researchers used integrin, a cell membrane receptor protein that is activated when it bonds to a ligand molecule. In the TGT approach, Ha and Wang repurposed DNA strands, using them as tethers for ligand molecules, to test the tension required to activate cell adhesion through integrin. The integrin bonds to the tethered ligand, and adhesion is activated only if the DNA tether does not rupture (See video animation). Taking advantage of the geometric characteristics of DNA’s double helix form, the researchers were able to tune the strands to rupture at discrete tension levels: by varying the attachment points along the DNA strands, the force required for rupture was either low (unzipping the helix), high (shearing the strands), or intermediary (combination of unzipping and shearing). “If you went fishing and a fish broke your 30-lb fishing line but not the 40-lb one, you would know that its strength was in the range of 30­–40 pounds,” explained Wang. “Here we applied the same strategy to measure the molecular tension applied by cells (the fish). Mammalian cells apply a force to activate cell membrane proteins called integrins which mediate cell adhesion. We immobilized ligand molecules (the bait) on a surface through molecular tethers (the fishing line) with defined tension tolerances, tunable from 10 pico Newton (pN) to 60 pN). After integrin-ligand binding, cells apply a force on the bonds, and we compare this force to the molecular tether strength by observing cell adhesion status.” Since single-molecule interactions are difficult to monitor, the researchers observed the receptor-regulated cellular function, to gauge whether the integrin was activated. Ha and Wang discovered that integrin experiences a well-defined “quantum of force,” about 40 pico-Newton (pN), to activate cell’s adhesion to a surface. “We observed that mammalian cells adhere on the culture surface with 43 pN tension tolerance of ligands, but not on 33 pN surface. Therefore we deduced that single molecular tension is around 40 pN on integrin cell-membrane receptors during cell adhesion,” Wang added. “This is a very exciting result,” commented Ha, an Edward William and Jane Marr Gutgsell Endowed Professor at Illinois. “With the ability to define the single molecular forces required to make living cells behave as desired, we may be one step closer to a remedy for certain hard-to-cure diseases. We know that the behavior of cancer cells and stem cells can be controlled by how stiff or soft their environments are. Understanding and manipulating molecular conversation through defined forces has huge implications for the development of future medical interventions. We expect the TGT approach will have broad applications in laboratory studies of cell differentiation, cancer metastasis, as well as immunology and infectious disease.”

Biophysicists measure mechanism that determines fate of living cells

Cells in the human body do not function in isolation. Living cells rely on communication with their environment—neighboring cells and the surrounding matrix—to activate a wide range of cellular functions, including reproduction of new cells, differentiation of stem cells into distinct cell types, cell adhesion, and migration of white blood cells to fight bodily infections. This cellular communication occurs on the molecular level and it is reciprocal: a cell receives cues from and also transmits function-activating cues to its neighbors.

The mechanics of this type of cellular interaction have been studied extensively: receptors extending through the cell membrane are activated when they form a bond to specific molecules. Now for the first time, University of Illinois biophysicists at the Center for the Physics of Living Cells and the Institute for Genomic Biology have measured the molecular force required to mechanically transmit function-regulating signals within a cell.

The new laboratory method, named the tension gauge tether (TGT) approach, developed by Taekjip Ha with postdoctoral researcher Xuefeng Wang, and reported in the May 24, 2013, issue of the journal Science, has made it possible to detect and measure the mechanics of the single-molecule interaction by which human cell receptors are activated. The researchers used integrin, a cell membrane receptor protein that is activated when it bonds to a ligand molecule.

In the TGT approach, Ha and Wang repurposed DNA strands, using them as tethers for ligand molecules, to test the tension required to activate cell adhesion through integrin. The integrin bonds to the tethered ligand, and adhesion is activated only if the DNA tether does not rupture (See video animation).

Taking advantage of the geometric characteristics of DNA’s double helix form, the researchers were able to tune the strands to rupture at discrete tension levels: by varying the attachment points along the DNA strands, the force required for rupture was either low (unzipping the helix), high (shearing the strands), or intermediary (combination of unzipping and shearing).

“If you went fishing and a fish broke your 30-lb fishing line but not the 40-lb one, you would know that its strength was in the range of 30­–40 pounds,” explained Wang. “Here we applied the same strategy to measure the molecular tension applied by cells (the fish). Mammalian cells apply a force to activate cell membrane proteins called integrins which mediate cell adhesion. We immobilized ligand molecules (the bait) on a surface through molecular tethers (the fishing line) with defined tension tolerances, tunable from 10 pico Newton (pN) to 60 pN). After integrin-ligand binding, cells apply a force on the bonds, and we compare this force to the molecular tether strength by observing cell adhesion status.”

Since single-molecule interactions are difficult to monitor, the researchers observed the receptor-regulated cellular function, to gauge whether the integrin was activated. Ha and Wang discovered that integrin experiences a well-defined “quantum of force,” about 40 pico-Newton (pN), to activate cell’s adhesion to a surface.

“We observed that mammalian cells adhere on the culture surface with 43 pN tension tolerance of ligands, but not on 33 pN surface. Therefore we deduced that single molecular tension is around 40 pN on integrin cell-membrane receptors during cell adhesion,” Wang added.

“This is a very exciting result,” commented Ha, an Edward William and Jane Marr Gutgsell Endowed Professor at Illinois. “With the ability to define the single molecular forces required to make living cells behave as desired, we may be one step closer to a remedy for certain hard-to-cure diseases. We know that the behavior of cancer cells and stem cells can be controlled by how stiff or soft their environments are. Understanding and manipulating molecular conversation through defined forces has huge implications for the development of future medical interventions. We expect the TGT approach will have broad applications in laboratory studies of cell differentiation, cancer metastasis, as well as immunology and infectious disease.”

Filed under cells cellular interaction tension gauge tether ligands cell adhesion neuroscience science

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Motion Quotient IQ Predicted by the Brain’s Ability to Filter Visual Motion A brief visual task can predict IQ, according to a new study. This surprisingly simple exercise measures the brain’s unconscious ability to filter out visual movement. The study shows that individuals whose brains are better at automatically suppressing background motion perform better on standard measures of intelligence. The test is the first purely sensory assessment to be strongly correlated with IQ and may provide a non-verbal and culturally unbiased tool for scientists seeking to understand neural processes associated with general intelligence. "Because intelligence is such a broad construct, you can’t really track it back to one part of the brain," says Duje Tadin, a senior author on the study and an assistant professor of brain and cognitive sciences at the University of Rochester. "But since this task is so simple and so closely linked to IQ, it may give us clues about what makes a brain more efficient, and, consequently, more intelligent." The unexpected link between IQ and motion filtering was reported online in the Cell Press journal Current Biology on May 23 by a research team lead by Tadin and Michael Melnick, a doctoral candidate in brain and cognitive sciences at the University of Rochester. In the study, individuals watched brief video clips of black and white bars moving across a computer screen. Their sole task was to identify which direction the bars drifted: to the right or to the left. The bars were presented in three sizes, with the smallest version restricted to the central circle where human motion perception is known to be optimal, an area roughly the width of the thumb when the hand is extended. Participants also took a standardized intelligence test. As expected, people with higher IQ scores were faster at catching the movement of the bars when observing the smallest image. The results support prior research showing that individuals with higher IQs make simple perceptual judgments swifter and have faster reflexes. “Being ‘quick witted’ and ‘quick on the draw’ generally go hand in hand,” says Melnick. But the tables turned when presented with the larger images. The higher a person’s IQ, the slower they were at detecting movement. “From previous research, we expected that all participants would be worse at detecting the movement of large images, but high IQ individuals were much, much worse,” says Melnick. That counter-intuitive inability to perceive large moving images is a perceptual marker for the brain’s ability to suppress background motion, the authors explain. In most scenarios, background movement is less important than small moving objects in the foreground. Think about driving in a car, walking down a hall, or even just moving your eyes across the room. The background is constantly in motion. The key discovery in this study is how closely this natural filtering ability is linked to IQ. The first experiment found a 64 percent correlation between motion suppression and IQ scores, a much stronger relationship than other sensory measures to date. For example, research on the relationship between intelligence and color discrimination, sensitivity to pitch, and reaction times have found only a 20 to 40 percent correlation. “In our first experiment, the effect for motion was so strong,” recalls Tadin, “that I really thought this was a fluke.” So the group tried to disprove the findings from the initial 12-participant study conducted while Tadin was at Vanderbilt University working with co-author Sohee Park, a professor of psychology. They reran the experiment at the University of Rochester on a new cohort of 53 subjects, administering the full IQ test instead of an abbreviated version and the results were even stronger; correlation rose to 71 percent. The authors also tested for other possible explanations for their findings. For example, did the surprising link to IQ simply reflect a person’s willful decision to focus on small moving images? To rule out the effect of attention, the second round of experiments randomly ordered the different image sizes and tested other types of large images that have been shown not to elicit suppression. High IQ individuals continued to be quicker on all tasks, except the ones that isolated motion suppression. The authors concluded that high IQ is associated with automatic filtering of background motion. "We know from prior research which parts of the brain are involved in visual suppression of background motion. This new link to intelligence provides a good target for looking at what is different about the neural processing, what’s different about the neurochemistry, what’s different about the neurotransmitters of people with different IQs," says Tadin. The relationship between IQ and motion suppression points to the fundamental cognitive processes that underlie intelligence, the authors write. The brain is bombarded by an overwhelming amount of sensory information, and its efficiency is built not only on how quickly our neural networks process these signals, but also on how good they are at suppressing less meaningful information. “Rapid processing is of little utility unless it is restricted to the most relevant information,” the authors conclude. The researchers point out that this vision test could remove some of the limitations associated with standard IQ tests, which have been criticized for cultural bias. “Because the test is simple and non-verbal, it will also help researchers better understand neural processing in individuals with intellectual and developmental disabilities,” says co-author Loisa Bennetto, an associate professor of psychology at the University of Rochester.

Motion Quotient

IQ Predicted by the Brain’s Ability to Filter Visual Motion

A brief visual task can predict IQ, according to a new study.

This surprisingly simple exercise measures the brain’s unconscious ability to filter out visual movement. The study shows that individuals whose brains are better at automatically suppressing background motion perform better on standard measures of intelligence.

The test is the first purely sensory assessment to be strongly correlated with IQ and may provide a non-verbal and culturally unbiased tool for scientists seeking to understand neural processes associated with general intelligence.

"Because intelligence is such a broad construct, you can’t really track it back to one part of the brain," says Duje Tadin, a senior author on the study and an assistant professor of brain and cognitive sciences at the University of Rochester. "But since this task is so simple and so closely linked to IQ, it may give us clues about what makes a brain more efficient, and, consequently, more intelligent."

The unexpected link between IQ and motion filtering was reported online in the Cell Press journal Current Biology on May 23 by a research team lead by Tadin and Michael Melnick, a doctoral candidate in brain and cognitive sciences at the University of Rochester.

In the study, individuals watched brief video clips of black and white bars moving across a computer screen. Their sole task was to identify which direction the bars drifted: to the right or to the left. The bars were presented in three sizes, with the smallest version restricted to the central circle where human motion perception is known to be optimal, an area roughly the width of the thumb when the hand is extended. Participants also took a standardized intelligence test.

As expected, people with higher IQ scores were faster at catching the movement of the bars when observing the smallest image. The results support prior research showing that individuals with higher IQs make simple perceptual judgments swifter and have faster reflexes. “Being ‘quick witted’ and ‘quick on the draw’ generally go hand in hand,” says Melnick.

But the tables turned when presented with the larger images. The higher a person’s IQ, the slower they were at detecting movement. “From previous research, we expected that all participants would be worse at detecting the movement of large images, but high IQ individuals were much, much worse,” says Melnick. That counter-intuitive inability to perceive large moving images is a perceptual marker for the brain’s ability to suppress background motion, the authors explain. In most scenarios, background movement is less important than small moving objects in the foreground. Think about driving in a car, walking down a hall, or even just moving your eyes across the room. The background is constantly in motion.

The key discovery in this study is how closely this natural filtering ability is linked to IQ. The first experiment found a 64 percent correlation between motion suppression and IQ scores, a much stronger relationship than other sensory measures to date. For example, research on the relationship between intelligence and color discrimination, sensitivity to pitch, and reaction times have found only a 20 to 40 percent correlation. “In our first experiment, the effect for motion was so strong,” recalls Tadin, “that I really thought this was a fluke.”

So the group tried to disprove the findings from the initial 12-participant study conducted while Tadin was at Vanderbilt University working with co-author Sohee Park, a professor of psychology. They reran the experiment at the University of Rochester on a new cohort of 53 subjects, administering the full IQ test instead of an abbreviated version and the results were even stronger; correlation rose to 71 percent. The authors also tested for other possible explanations for their findings.

For example, did the surprising link to IQ simply reflect a person’s willful decision to focus on small moving images? To rule out the effect of attention, the second round of experiments randomly ordered the different image sizes and tested other types of large images that have been shown not to elicit suppression. High IQ individuals continued to be quicker on all tasks, except the ones that isolated motion suppression. The authors concluded that high IQ is associated with automatic filtering of background motion.

"We know from prior research which parts of the brain are involved in visual suppression of background motion. This new link to intelligence provides a good target for looking at what is different about the neural processing, what’s different about the neurochemistry, what’s different about the neurotransmitters of people with different IQs," says Tadin.

The relationship between IQ and motion suppression points to the fundamental cognitive processes that underlie intelligence, the authors write. The brain is bombarded by an overwhelming amount of sensory information, and its efficiency is built not only on how quickly our neural networks process these signals, but also on how good they are at suppressing less meaningful information. “Rapid processing is of little utility unless it is restricted to the most relevant information,” the authors conclude.

The researchers point out that this vision test could remove some of the limitations associated with standard IQ tests, which have been criticized for cultural bias. “Because the test is simple and non-verbal, it will also help researchers better understand neural processing in individuals with intellectual and developmental disabilities,” says co-author Loisa Bennetto, an associate professor of psychology at the University of Rochester.

Filed under intelligence IQ visual motion motion perception psychology neuroscience science

205 notes

Scientists Discover Molecule Triggers Sensation of Itch Scientists at the National Institutes of Health report they have discovered in mouse studies that a small molecule released in the spinal cord triggers a process that is later experienced in the brain as the sensation of itch. The small molecule, called natriuretic polypeptide b (Nppb), streams ahead and selectively plugs into a specific nerve cell in the spinal cord, which sends the signal onward through the central nervous system. When Nppb or its nerve cell was removed, mice stopped scratching at a broad array of itch-inducing substances. The signal wasn’t going through. Because the nervous systems of mice and humans are similar, the scientists say a comparable biocircuit for itch likely is present in people. If correct, this start switch would provide a natural place to look for unique molecules that can be targeted with drugs to turn off the sensation more efficiently in the millions of people with chronic itch conditions, such eczema and psoriasis. The paper, published online in the journal Science, also helps to solve a lingering scientific issue. “Our work shows that itch, once thought to be a low-level form of pain, is a distinct sensation that is uniquely hardwired into the nervous system with the biochemical equivalent of its own dedicated land line to the brain,” said Mark Hoon, Ph.D., the senior author on the paper and a scientist at the National Institute of Dental and Craniofacial Research, part of the National Institutes of Health. Hoon said his group’s findings began with searching for the signaling components on a class of nerve cells, or neurons, that contain a molecule called TRPV1. These neurons, with their long nerve fibers extending into the skin, muscle, and other tissues, help to monitor a range of external conditions, from extreme temperature changes to detecting pain. Yet little is known about how these neurons recognize the various sensory inputs and, like sorting mail, know how to route them correctly to the appropriate pathway to the brain. To fill in more of the details, Hoon said his laboratory identified in mice some of the main neurotransmitters that TRPV1 neurons produce. A neurotransmitter is a small molecule that neurons selectively release when stimulated, like a quick pulse of water from a faucet, to communicate sensory signals to other nerve cells. The scientists screened the various neurotransmitters, including Nppb, to see which ones corresponded with transmitting sensation. “We tested Nppb for its possible role in various sensations without success,” said Santosh Mishra, lead author on the study and a researcher in the Hoon laboratory. “When we exposed the Nppb-deficient mice to several itch-inducing substances, it was amazing to watch. Nothing happened. The mice wouldn’t scratch.” Further experiments established that Nppb was essential to initiate the sensation of itch, known clinically as pruritus. Equally significant, the molecule was necessary to respond to a broad spectrum of pruritic substances. Previous research had suggested that a common start switch for itch would be unlikely, given the myriad proteins and cell types that seemed to be involved in processing the sensation. Hoon and Mishra turned to the dorsal horn, a junction point in the spine where sensory signals from the body’s periphery are routed onward to the brain. Within this nexus of nerve connections, they looked for cells that expressed the receptor to receive the incoming Nppb molecules. “The receptors were exactly in the right place in the dorsal horn,” said Hoon, the receptor being the long-recognized protein Npra. “We went further and removed the Npra neurons from the spinal cord. We wanted to see if their removal would short-circuit the itch, and it did.” Hoon said this experiment added another key piece of information. Removing the receptor neurons had no impact on other sensory sensations, such as temperature, pain, and touch. This told them that the connection forms a dedicated biocircuit to the brain that conveys the sensation of itch. But the scientists had stepped into a conundrum. Previous reports had suggested that another neurotransmitter called GRP might initiate itch. If that wasn’t the case, where did GRP fit into the process? They tested the receptor neurons that express GRP, finding the previous reports were correct about this molecule relaying the signal to the central nervous system. GRP just enters the picture after Nppb already has set the sensation in motion. Based on these findings, Nppb would seem to be an obvious first target to control itch. But that’s not necessarily the case. Nppb also is used in the heart, kidneys, and other parts of the body, so attempts to control the neurotransmitter in the spine has the potential to cause unwanted side effects. “The larger scientific point remains,” said Hoon. “We have defined in the mouse the primary itch-initiating neurons and figured out the first three steps in the pruritic pathway. Now the challenge is to find similar biocircuitry in people, evaluate what’s there, and identify unique molecules that can be targeted to turn off chronic itch without causing unwanted side effects. So, this is a start, not a finish.” (Image: GETTY)

Scientists Discover Molecule Triggers Sensation of Itch

Scientists at the National Institutes of Health report they have discovered in mouse studies that a small molecule released in the spinal cord triggers a process that is later experienced in the brain as the sensation of itch.

The small molecule, called natriuretic polypeptide b (Nppb), streams ahead and selectively plugs into a specific nerve cell in the spinal cord, which sends the signal onward through the central nervous system. When Nppb or its nerve cell was removed, mice stopped scratching at a broad array of itch-inducing substances. The signal wasn’t going through.

Because the nervous systems of mice and humans are similar, the scientists say a comparable biocircuit for itch likely is present in people. If correct, this start switch would provide a natural place to look for unique molecules that can be targeted with drugs to turn off the sensation more efficiently in the millions of people with chronic itch conditions, such eczema and psoriasis.

The paper, published online in the journal Science, also helps to solve a lingering scientific issue. “Our work shows that itch, once thought to be a low-level form of pain, is a distinct sensation that is uniquely hardwired into the nervous system with the biochemical equivalent of its own dedicated land line to the brain,” said Mark Hoon, Ph.D., the senior author on the paper and a scientist at the National Institute of Dental and Craniofacial Research, part of the National Institutes of Health.

Hoon said his group’s findings began with searching for the signaling components on a class of nerve cells, or neurons, that contain a molecule called TRPV1. These neurons, with their long nerve fibers extending into the skin, muscle, and other tissues, help to monitor a range of external conditions, from extreme temperature changes to detecting pain.

Yet little is known about how these neurons recognize the various sensory inputs and, like sorting mail, know how to route them correctly to the appropriate pathway to the brain.

To fill in more of the details, Hoon said his laboratory identified in mice some of the main neurotransmitters that TRPV1 neurons produce. A neurotransmitter is a small molecule that neurons selectively release when stimulated, like a quick pulse of water from a faucet, to communicate sensory signals to other nerve cells.

The scientists screened the various neurotransmitters, including Nppb, to see which ones corresponded with transmitting sensation.

“We tested Nppb for its possible role in various sensations without success,” said Santosh Mishra, lead author on the study and a researcher in the Hoon laboratory. “When we exposed the Nppb-deficient mice to several itch-inducing substances, it was amazing to watch. Nothing happened. The mice wouldn’t scratch.”

Further experiments established that Nppb was essential to initiate the sensation of itch, known clinically as pruritus. Equally significant, the molecule was necessary to respond to a broad spectrum of pruritic substances. Previous research had suggested that a common start switch for itch would be unlikely, given the myriad proteins and cell types that seemed to be involved in processing the sensation.

Hoon and Mishra turned to the dorsal horn, a junction point in the spine where sensory signals from the body’s periphery are routed onward to the brain. Within this nexus of nerve connections, they looked for cells that expressed the receptor to receive the incoming Nppb molecules.

“The receptors were exactly in the right place in the dorsal horn,” said Hoon, the receptor being the long-recognized protein Npra. “We went further and removed the Npra neurons from the spinal cord. We wanted to see if their removal would short-circuit the itch, and it did.”

Hoon said this experiment added another key piece of information. Removing the receptor neurons had no impact on other sensory sensations, such as temperature, pain, and touch. This told them that the connection forms a dedicated biocircuit to the brain that conveys the sensation of itch.

But the scientists had stepped into a conundrum. Previous reports had suggested that another neurotransmitter called GRP might initiate itch. If that wasn’t the case, where did GRP fit into the process?

They tested the receptor neurons that express GRP, finding the previous reports were correct about this molecule relaying the signal to the central nervous system. GRP just enters the picture after Nppb already has set the sensation in motion.

Based on these findings, Nppb would seem to be an obvious first target to control itch. But that’s not necessarily the case. Nppb also is used in the heart, kidneys, and other parts of the body, so attempts to control the neurotransmitter in the spine has the potential to cause unwanted side effects.

“The larger scientific point remains,” said Hoon. “We have defined in the mouse the primary itch-initiating neurons and figured out the first three steps in the pruritic pathway. Now the challenge is to find similar biocircuitry in people, evaluate what’s there, and identify unique molecules that can be targeted to turn off chronic itch without causing unwanted side effects. So, this is a start, not a finish.”

(Image: GETTY)

Filed under somatosensory neurons sensation of itch chronic itch nervous system neural circuits neuroscience science

518 notes

Awoken from a persistent vegetative state: First successful treatment of paediatric cerebral palsy with autologous cord blood Bochum’s medics have succeeded in treating cerebral palsy with autologous cord blood. Following a cardiac arrest with severe brain damage, a 2.5 year old boy had been in a persistent vegetative state – with minimal chances of survival. Just two months after treatment with the cord blood containing stem cells, the symptoms improved significantly; over the following months, the child learned to speak simple sentences and to move. “Our findings, along with those from a Korean study, dispel the long-held doubts about the effectiveness of the new therapy”, says Dr. Arne Jensen of the Campus Clinic Gynaecology. Together with his colleague Prof. Dr. Eckard Hamelmann of the Department of Paediatrics at the Catholic Hospital Bochum (University Clinic of the RUB), he reports in the journal “Case Reports in Transplantation”. The parents searched the literature for treatment options At the end of November 2008, the child suffered from cardiac arrest with severe brain damage and was subsequently in a persistent vegetative state with his body paralysed. Up to now, there has been no treatment for the cause of what is known as infantile cerebral palsy. “In their desperate situation, the parents searched the literature for alternative therapies”, Arne Jensen explains. “They contacted us and asked about the possibilities of using their son’s cord blood, frozen at his birth.” “Threatening, if not hopeless prognosis” Nine weeks after the brain damage, on 27 January 2009, the doctors administered the prepared blood intravenously. They studied the progress of recovery at 2, 5, 12, 24, 30, and 40 months after the insult. Usually, the chances of survival after such a severe brain damage and more than 25 minutes duration of resuscitation are six per cent. Months after the severe brain damage, the surviving children usually only exhibit minimal signs of consciousness. “The prognosis for the little patient was threatening if not hopeless”, the Bochum medics say. Rapid recovery after cord blood therapy After the cord blood therapy, the patient, however, recovered relatively quickly. Within two months, the spasticity decreased significantly. He was able to see, sit, smile, and to speak simple words again. Forty months after treatment, the child was able to eat independently, walk with assistance, and form four-word sentences. “Of course, on the basis of these results, we cannot clearly say what the cause of the recovery is”, Jensen says. “It is, however, very difficult to explain these remarkable effects by purely symptomatic treatment during active rehabilitation.” In animal studies, stem cells migrate to damaged brain tissue In animal studies, scientists have been researching the therapeutic potential of cord blood for some time. In a previous study with rats, RUB researchers revealed that cord blood cells migrate to the damaged area of the brain in large numbers within 24 hours of administration. In March 2013, in a controlled study of one hundred children, Korean doctors reported for the first time that they had successfully treated cerebral palsy with allogeneic cord blood.

Awoken from a persistent vegetative state: First successful treatment of paediatric cerebral palsy with autologous cord blood

Bochum’s medics have succeeded in treating cerebral palsy with autologous cord blood. Following a cardiac arrest with severe brain damage, a 2.5 year old boy had been in a persistent vegetative state – with minimal chances of survival. Just two months after treatment with the cord blood containing stem cells, the symptoms improved significantly; over the following months, the child learned to speak simple sentences and to move. “Our findings, along with those from a Korean study, dispel the long-held doubts about the effectiveness of the new therapy”, says Dr. Arne Jensen of the Campus Clinic Gynaecology. Together with his colleague Prof. Dr. Eckard Hamelmann of the Department of Paediatrics at the Catholic Hospital Bochum (University Clinic of the RUB), he reports in the journal “Case Reports in Transplantation”.

The parents searched the literature for treatment options

At the end of November 2008, the child suffered from cardiac arrest with severe brain damage and was subsequently in a persistent vegetative state with his body paralysed. Up to now, there has been no treatment for the cause of what is known as infantile cerebral palsy. “In their desperate situation, the parents searched the literature for alternative therapies”, Arne Jensen explains. “They contacted us and asked about the possibilities of using their son’s cord blood, frozen at his birth.”

“Threatening, if not hopeless prognosis”

Nine weeks after the brain damage, on 27 January 2009, the doctors administered the prepared blood intravenously. They studied the progress of recovery at 2, 5, 12, 24, 30, and 40 months after the insult. Usually, the chances of survival after such a severe brain damage and more than 25 minutes duration of resuscitation are six per cent. Months after the severe brain damage, the surviving children usually only exhibit minimal signs of consciousness. “The prognosis for the little patient was threatening if not hopeless”, the Bochum medics say.

Rapid recovery after cord blood therapy

After the cord blood therapy, the patient, however, recovered relatively quickly. Within two months, the spasticity decreased significantly. He was able to see, sit, smile, and to speak simple words again. Forty months after treatment, the child was able to eat independently, walk with assistance, and form four-word sentences. “Of course, on the basis of these results, we cannot clearly say what the cause of the recovery is”, Jensen says. “It is, however, very difficult to explain these remarkable effects by purely symptomatic treatment during active rehabilitation.”

In animal studies, stem cells migrate to damaged brain tissue

In animal studies, scientists have been researching the therapeutic potential of cord blood for some time. In a previous study with rats, RUB researchers revealed that cord blood cells migrate to the damaged area of the brain in large numbers within 24 hours of administration. In March 2013, in a controlled study of one hundred children, Korean doctors reported for the first time that they had successfully treated cerebral palsy with allogeneic cord blood.

Filed under cerebral palsy vegetative state stem cells cord blood therapy neuroscience science

189 notes

Cold plasma successful against brain cancer cells For the first time, physicists from the Max Planck Institute for Extraterrestrial Physics (MPE), biologists and physicians demonstrated the synergistic effect of cold atmospheric plasma - a partly ionized gas - and chemo therapy on aggressive brain tumour cells. Laboratory tests showed that the proliferation of glioblastoma cells – the most common and aggressive brain tumour in adults – is arrested and that even resistant cell populations become sensitive to treatment with chemo therapy if pre-treated with cold atmospheric plasma. This could be the first step on the way to a new combination therapy, providing new hope for fighting this lethal cancer. If someone is diagnosed with the type of brain tumour called glioblastoma, the prospects are dire: median survival is just a bit over one year, and less than 16% of the patients survive more than three years. It is still unknown how this cancer is triggered – only a few rare genetic factors have been identified so far – and treatment remains largely palliative, i.e. trying to alleviate the symptoms and prolonging the life of the patient. The standard therapy proceeds in three steps: Guided by an MRT scan, the tumour is removed surgically, followed by radiation and chemo therapy. But even if the treatment is successful initially, there is a high likelihood of relapse. A recently developed new kind of treatment could offer some hope. Cold atmospheric plasma, or CAP for short, has already proven to successfully inactivate bacteria, fungi, viruses and spores, while healthy tissue remains largely unaffected. Healthcare applications such as the sterilization of surgical instruments, skin and wound disinfection paved its way into medical care. Recently also CAP sources were developed which show anti-cancer properties. "For many patients the regular treatment is just not effective, because the brain tumours contain sub-populations for which chemo therapy does not work,” says Julia Zimmermann, who manages the Plasma Healthcare group at MPE. “So we were particularly interested to see if the CAP would be effective against these resistant tumour cells – and indeed it worked!” For the study, the researchers used Glioblastoma cells and grew them in cell culture dishes, where they could be subjected to various combinations of treatments. For both normal and resistant tumour cell lines, the growth of the cells was more inhibited after the plasma treatment compared to the chemo therapy alone. The largest effect could be obtained for a short application time of 120 seconds; such an additional step could be easily incorporated into the clinical treatment if an appropriate plasma device can be developed. The researchers also found that CAP stops the cell cycle and that the individual cells lose their ability to clone themselves. A combined therapy of both - CAP treatment and chemo therapy – showed the most promising results, where the amount of chemotherapeutic needed to achieve the same result as with chemo therapy alone is strongly reduced. So far, no resistance towards CAP treatment was observed. The study also showed that even those cell lines that originally were resistant against the chemo therapy drug became sensitive again after the pre-application of CAP. “In particular, also resistant cell populations could be treated effectively with CAP, which means that there is now hope to find a therapy for the patients with a poor prognosis, i.e. those with resistant cells in the tumour,” explains Julia Köritzer, lead author of the study. Such a treatment option for resistant cells is urgently needed, because about 40% of the patients do not profit from chemo therapy. She adds: “It is a first step, now we have to further investigate the effects gained in the cell culture and integrate them for the application.” Though, even if there is still a long way ahead before CAP can actually be used in the hospital, it offers a promising new possibility. Eventually it could be applied after surgery to treat the tissue around the extracted tumour, where some cancerous cells might have been left behind, preventing the cancer from reappearing. Devices similar to an endoscope are currently under development.

Cold plasma successful against brain cancer cells

For the first time, physicists from the Max Planck Institute for Extraterrestrial Physics (MPE), biologists and physicians demonstrated the synergistic effect of cold atmospheric plasma - a partly ionized gas - and chemo therapy on aggressive brain tumour cells. Laboratory tests showed that the proliferation of glioblastoma cells – the most common and aggressive brain tumour in adults – is arrested and that even resistant cell populations become sensitive to treatment with chemo therapy if pre-treated with cold atmospheric plasma. This could be the first step on the way to a new combination therapy, providing new hope for fighting this lethal cancer.

If someone is diagnosed with the type of brain tumour called glioblastoma, the prospects are dire: median survival is just a bit over one year, and less than 16% of the patients survive more than three years. It is still unknown how this cancer is triggered – only a few rare genetic factors have been identified so far – and treatment remains largely palliative, i.e. trying to alleviate the symptoms and prolonging the life of the patient. The standard therapy proceeds in three steps: Guided by an MRT scan, the tumour is removed surgically, followed by radiation and chemo therapy. But even if the treatment is successful initially, there is a high likelihood of relapse.

A recently developed new kind of treatment could offer some hope. Cold atmospheric plasma, or CAP for short, has already proven to successfully inactivate bacteria, fungi, viruses and spores, while healthy tissue remains largely unaffected. Healthcare applications such as the sterilization of surgical instruments, skin and wound disinfection paved its way into medical care. Recently also CAP sources were developed which show anti-cancer properties.

"For many patients the regular treatment is just not effective, because the brain tumours contain sub-populations for which chemo therapy does not work,” says Julia Zimmermann, who manages the Plasma Healthcare group at MPE. “So we were particularly interested to see if the CAP would be effective against these resistant tumour cells – and indeed it worked!”

For the study, the researchers used Glioblastoma cells and grew them in cell culture dishes, where they could be subjected to various combinations of treatments. For both normal and resistant tumour cell lines, the growth of the cells was more inhibited after the plasma treatment compared to the chemo therapy alone. The largest effect could be obtained for a short application time of 120 seconds; such an additional step could be easily incorporated into the clinical treatment if an appropriate plasma device can be developed.

The researchers also found that CAP stops the cell cycle and that the individual cells lose their ability to clone themselves. A combined therapy of both - CAP treatment and chemo therapy – showed the most promising results, where the amount of chemotherapeutic needed to achieve the same result as with chemo therapy alone is strongly reduced. So far, no resistance towards CAP treatment was observed. The study also showed that even those cell lines that originally were resistant against the chemo therapy drug became sensitive again after the pre-application of CAP.

“In particular, also resistant cell populations could be treated effectively with CAP, which means that there is now hope to find a therapy for the patients with a poor prognosis, i.e. those with resistant cells in the tumour,” explains Julia Köritzer, lead author of the study. Such a treatment option for resistant cells is urgently needed, because about 40% of the patients do not profit from chemo therapy. She adds: “It is a first step, now we have to further investigate the effects gained in the cell culture and integrate them for the application.”

Though, even if there is still a long way ahead before CAP can actually be used in the hospital, it offers a promising new possibility. Eventually it could be applied after surgery to treat the tissue around the extracted tumour, where some cancerous cells might have been left behind, preventing the cancer from reappearing. Devices similar to an endoscope are currently under development.

Filed under glioblastoma cells brain tumor cold atmospheric plasma brain cancer neuroscience science

195 notes

Depression Linked to Telomere Enzyme, Aging, Chronic Disease

The first symptoms of major depression may be behavioral, but the common mental illness is based in biology — and not limited to the brain.

image

In recent years, some studies have linked major, long-term depression with life-threatening chronic disease and with earlier death, even after lifestyle risk factors have been taken into account.

Now a research team led by Owen Wolkowitz, MD, professor of psychiatry at UC San Francisco, has found that within cells of the immune system, activity of an enzyme called telomerase is greater, on average, in untreated individuals with major depression. The preliminary findings from his latest, ongoing study was reported Wednesday at the annual meeting of the American Psychiatric Association in San Francisco.

Telomerase is an enzyme that lengthens protective end caps on the chromosomes’ DNA, called telomeres. Shortened telomeres have been associated with earlier death and with chronic diseases in population studies.

The heightened telomerase activity in untreated major depression might represent the body’s attempt to fight back against the progression of disease, in order to prevent biological damage in long-depressed individuals, Wolkowitz said.

The researchers made another discovery that may suggest a protective role for telomerase. Using magnetic resonance imaging (MRI), they found that, in untreated, depressed study participants, the size of the hippocampus, a brain structure that is critical for learning and memory, was associated with the amount of telomerase activity measured in the white blood cells. Such an association at a single point in time cannot be used to conclude that there is a cause-and-effect relationship with telomerase helping to protect the hippocampus, but it is plausible, Wolkowitz said.

Telomerase Activity and Antidepressants

Remarkably, the researchers also found that the enzyme’s activity went up when some patients began taking an antidepressant. In fact, depressed participants with lower telomerase activity at baseline — as well as those in whom enzyme activity increased the most with treatment — were the most likely to become less depressed with treatment.

“Our results are consistent with the beneficial effect of telomerase when it is boosted in animal studies, where it has been associated with the growth of new nerve cells in the hippocampus and with antidepressant-like effects, evidenced by increased exploratory behavior,” Wolkowitz said. He cautions that his new findings are preliminary due to the small size of the study and must be confirmed through further research.

The researchers also measured telomere length in the same immune cells. Only very chronically depressed individuals showed telomere shortening, Wolkowitz said.

“The longer people had been depressed, the shorter their telomeres were,” he said. “Shortened telomere length has been previously demonstrated in major depression in most, but not all, studies that have examined it. The duration of depression may be a critical factor.”

Ongoing Study

The 20 depressed participants enrolled in the study had been untreated for at least six weeks and had an average lifetime duration of depression of about 13 years. After baseline evaluation and laboratory measures, 16 of the depressed participants were treated with sertraline, a member of the most popular class of antidepressants, the serotonin-selective-reuptake-inhibitors (SSRIs), and then evaluated again after eight weeks. There were 20 healthy participants who served as controls.

The ongoing study still is accepting depressed participants who are not now taking antidepressants.

Wolkowitz’s team also studies chronic inflammation and the biochemical phenomenon of oxidative stress, which he said have often been reported in major depression. Wolkowitz is exploring the hypothesis that inflammation and oxidative stress play a role in telomere shortening and accelerated aging in depression.

“New insights into the mechanisms of these processes may well lead to new treatments — both pharmacological and behavioral — that will be distinctly different from the current generation of drugs prescribed to treat depression,” he said. “Additional studies might lead to simple blood tests that can measure accelerated immune-cell aging.”

(Source: ucsf.edu)

Filed under depression chronic illness telomeres telomerase activity psychology neuroscience science

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