Neuroscience

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

Sat, 25 May 2013 19:12:52 -0400

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)

Proteins in migration

Sat, 25 May 2013 16:48:24 -0400

In Parkinson’s disease, the protein “alpha-synuclein” aggregates and accumulates within neurons....

Going live – immune cell activation in multiple...

Sat, 25 May 2013 14:24:48 -0400

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.

New neuron formation could increase capacity for new learning,...

Sat, 25 May 2013 12:02:39 -0400

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.”

Biophysicists measure mechanism that determines fate of living...

Sat, 25 May 2013 09:36:24 -0400

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.”

Motion Quotient IQ Predicted by the Brain’s Ability to...

Fri, 24 May 2013 22:30:29 -0400

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.

Scientists Discover Molecule Triggers Sensation of...

Fri, 24 May 2013 21:01:10 -0400

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)

Awoken from a persistent vegetative state: First successful...

Fri, 24 May 2013 19:30:39 -0400

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.

Cold plasma successful against brain cancer cells For the first...

Fri, 24 May 2013 18:02:00 -0400

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.

Depression Linked to Telomere Enzyme, Aging, Chronic Disease

Fri, 24 May 2013 16:30:44 -0400

The first symptoms of major depression may be behavioral, but the common mental illness is based in...

Breakthrough on Huntington’s disease

Fri, 24 May 2013 15:01:53 -0400

Researchers at Lund University have succeeded in preventing very early symptoms of Huntington’s...

Pay attention: How we focus and concentrate Scientists at...

Fri, 24 May 2013 13:30:48 -0400

Pay attention: How we focus and concentrate

Scientists at Newcastle University have shed new light on how the brain tunes in to relevant information.

Publishing in Neuron, the team reveal the interplay of brain chemicals which help us pay attention in work funded by the Wellcome Trust and BBSRC.

By changing the way neurons respond to external stimuli we improve our perceptual abilities. While these changes can affect the strength of a neuronal response, they can also affect the fidelity of that response.

Lead author Alex Thiele, Professor of Visual Neuroscience explains: “When you communicate with others, you can make yourself better heard by speaking louder or by speaking more clearly. Neurons appear to do similar things when we’re paying attention. They send their message more intensely to their partners, which compares to speaking louder. But more importantly, they also increase the fidelity of their message, which compares to speaking more clearly.

“Our earlier work has shown that attention is able to affect the intensity of responses – in effect the loudness - by means of the brain chemical acetylcholine. Now we have shown that the fidelity of the response is altered by a different brain chemical system.”

In the paper, the team reveal that the quality of the response is altered by means of glutamate coupling to NMDA receptors (a molecular device that mediates communication between neurons). Carried out in a primate model, these studies for the first time isolate different attention mechanisms at the receptor level.

The research builds on the team’s previous studies and has potentially significant implications not only for our understanding of how our brains work but also give an insight into conditions such as schizophrenia, Alzheimer’s disease and attention deficit disorder, and may aid in the development of treatments for them.

Brain uses internal ‘average voice’ prototype to identify who is...

Fri, 24 May 2013 12:02:32 -0400

Brain uses internal ‘average voice’ prototype to identify who is talking

The human brain is able to identify individuals’ voices by comparing them against an internal ‘average voice’ prototype, according to neuroscientists.

A study carried out by researchers at the University of Glasgow and reported in the journal Current Biology demonstrates that voice identity is coded in the brain by reference to two internal voice prototypes – one male, one female.

Voices that have the greatest difference from the prototype are perceived as more distinctive and produce greater neural activity than voices deemed very similar.

The researchers in the Institute of Neuroscience & Psychology conducted the study by generating a voice prototype through morphing 32 same-gender voices together resulting in a smooth, idealised voice with few irregularities.

They then generated different voices by altering the ‘distance-to-mean’ of the prototype voice – for example, changing the tone and pitch or morphing two or more voices together.

Using functional Magnetic Resonance Imaging (fMRI), the researchers were able to see increased neural activity the further from the prototype the voices were.

Professor Pascal Belin said: “Like faces, voices can be used to identify a person, yet the neural basis of this ability remains poorly understood. Here we provide the first evidence of a norm-based coding mechanism the brain uses to identify a speaker.

“The research indicates this is a similar process for the identification of faces, where the brain also uses an average face to compare against other faces it encounters in order to establish identity.

“So, rather than having to remember each single voice it hears every day for a lifetime, the brain facilitates the task of identification by remembering only the differences from the prototype it stores.

“It leads to a range of interesting and important questions, such as whether the prototypes are innate, stored templates or whether they are subject to environmental and cultural influences. Could the prototype consist of an average of all voices experiences during one’s life?”

(Image: Shutterstock)

Anti-cancer drug viewed as possible Alzheimer’s treatment doesn’t work in UF study

Fri, 24 May 2013 10:30:41 -0400

An anti-cancer drug about to be tested in a clinical trial by a biomedical company in Ohio as a...

Scientists Discover Cinnamon Compounds’ Potential Ability...

Fri, 24 May 2013 09:01:08 -0400

Scientists Discover Cinnamon Compounds’ Potential Ability to Prevent Alzheimer’s

Cinnamon: Can the red-brown spice with the unmistakable fragrance and variety of uses offer an important benefit? The common baking spice might hold the key to delaying the onset of –– or warding off –– the effects of Alzheimer’s disease.

That is, according to Roshni George and Donald Graves, scientists at UC Santa Barbara. The results of their study, “Interaction of Cinnamaldehyde and Epicatechin with Tau: Implications of Beneficial Effects in Modulating Alzheimer’s Disease Pathogenesis,” appears in the online early edition of the Journal of Alzheimer’s Disease, and in the upcoming Volume 36, issue 1 print edition.

Alzheimer’s disease is the most common form of dementia, a neurodegenerative disease that progressively worsens over time as it kills brain cells. No cure has yet been found, nor has the major cause of Alzheimer’s been identified.

However, two compounds found in cinnamon –– cinnamaldehyde and epicatechin –– are showing some promise in the effort to fight the disease. According to George and Graves, the compounds have been shown to prevent the development of the filamentous “tangles” found in the brain cells that characterize Alzheimer’s.

Responsible for the assembly of microtubules in a cell, a protein called tau plays a large role in the structure of the neurons, as well as their function.

“The problem with tau in Alzheimer’s is that it starts aggregating,” said George, a graduate student researcher. When the protein does not bind properly to the microtubules that form the cell’s structure, it has a tendency to clump together, she explained, forming insoluble fibers in the neuron. The older we get the more susceptible we are to these twists and tangles; Alzheimer’s patients develop them more often and in larger amounts.

The use of cinnamaldehyde, the compound responsible for the bright, sweet smell of cinnamon, has proven effective in preventing the tau knots. By protecting tau from oxidative stress, the compound, an oil, could inhibit the protein’s aggregation. To do this, cinnamaldehyde binds to two residues of an amino acid called cysteine on the tau protein. The cysteine residues are vulnerable to modifications, a factor that contributes to the development of Alzheimer’s.

“Take, for example, sunburn, a form of oxidative damage,” said Graves, adjunct professor in UCSB’s Department of Molecular, Cellular, and Developmental Biology. “If you wore a hat, you could protect your face and head from the oxidation. In a sense this cinnamaldehyde is like a cap.” While it can protect the tau protein by binding to its vulnerable cysteine residues, it can also come off, Graves added, which can ensure the proper functioning of the protein.

Oxidative stress is a major factor to consider in the health of cells in general. Through normal cellular processes, free radical-generating substances like peroxides are formed, but antioxidants in the cell work to neutralize them and prevent oxidation. Under some conditions however, the scales are tipped, with increased production of peroxides and free radicals, and decreased amounts of antioxidants, leading to oxidative stress.

Epicatechin, which is also present in other foods, such as blueberries, chocolate, and red wine, has proven to be a powerful antioxidant. Not only does it quench the burn of oxidation, it is actually activated by oxidation so the compound can interact with the cysteines on the tau protein in a way similar to the protective action of cinnamaldehyde.

“Cell membranes that are oxidized also produce reactive derivatives, such as Acrolein, that can damage the cysteines,” said George. “Epicatechin also sequesters those byproducts.”

Studies indicate that there is a high correlation between Type 2 diabetes and the incidence of Alzheimer’s disease. The elevated glucose levels typical of diabetes lead to the overproduction of reactive oxygen species, resulting in oxidative stress, which is a common factor in both diabetes and Alzheimer’s disease. Other research has shown cinnamon’s beneficial effects in managing blood glucose and other problems associated with diabetes.

“Since tau is vulnerable to oxidative stress, this study then asks whether Alzheimer’s disease could benefit from cinnamon, especially looking at the potential of small compounds,” said George.

Although this research shows promise, Graves said, they are “still a long way from knowing whether this will work in human beings.” The researchers caution against ingesting more than the typical amounts of cinnamon already used in cooking.

If cinnamon and its compounds do live up to their promise, it could be a significant step in the ongoing battle against Alzheimer’s. A major risk factor for the disease –– age –––– is uncontrollable. In the United States, Alzheimer’s presents a particular problem as the population lives longer and the Baby Boom generation turns gray, leading to a steep rise in the prevalance of the disease. It is a phenomenon that threatens to overwhelm the U.S. health care system. According to the Alzheimer’s Association, in 2013, Alzheimer’s disease will cost the nation $203 billion.

“Wouldn’t it be interesting if a small molecule from a spice could help?” commented Graves, “perhaps prevent it, or slow down the progression.”

(Image: iStockphoto)

The Secret Lives (and Deaths) of Neurons As the human body...

Fri, 24 May 2013 07:30:32 -0400

The Secret Lives (and Deaths) of Neurons

As the human body fine-tunes its neurological wiring, nerve cells often must fix a faulty connection by amputating an axon — the “business end” of the neuron that sends electrical impulses to tissues or other neurons. It is a dance with death, however, because the molecular poison the neuron deploys to sever an axon could, if uncontained, kill the entire cell.

Researchers from the University of North Carolina School of Medicine have uncovered some surprising insights about the process of axon amputation, or “pruning,” in a study published May 21 in the journal Nature Communications. Axon pruning has mystified scientists curious to know how a neuron can unleash a self-destruct mechanism within its axon, but keep it from spreading to the rest of the cell. The researchers’ findings could offer clues about the processes underlying some neurological disorders.

“Aberrant axon pruning is thought to underlie some of the causes for neurodevelopmental disorders, such as schizophrenia and autism,” said Mohanish Deshmukh, PhD, professor of cell biology and physiology at UNC and the study’s senior author. “This study sheds light on some of the mechanisms by which neurons are able to regulate axon pruning.”

Axon pruning is part of normal development and plays a key role in learning and memory. Another important process, apoptosis — the purposeful death of an entire cell — is also crucial because it allows the body to cull broken or incorrectly placed neurons. But both processes have been linked with disease when improperly regulated.

The research team placed mouse neurons in special devices called microfluidic chambers that allowed the researchers to independently manipulate the environments surrounding the axon and cell body to induce axon pruning or apoptosis.

They found that although the nerve cell uses the same poison — a group of molecules known as Caspases — whether it intends to kill the whole cell or just the axon, it deploys the Caspases in a different way depending on the context.

“People had assumed that the mechanism was the same regardless of whether the context was axon pruning or apoptosis, but we found that it’s actually quite distinct,” said Deshmukh. “The neuron essentially uses the same components for both cases, but tweaks them in a very elegant way so the neuron knows whether it needs to undergo apoptosis or axon pruning.”

In apoptosis, the neuron deploys the deadly Caspases using an activator known as Apaf-1. In the case of axon pruning, Apaf-1 was simply not involved, despite the presence of Caspases. “This is really going to take the field by surprise,” said Deshmukh. “There’s very little precedent of Caspases being activated without Apaf-1. We just didn’t know they could be activated through a different mechanism.”

In addition, the team discovered that neurons employ other molecules as safety brakes to keep the “kill” signal contained to the axon alone. “Having this brake keeps that signal from spreading to the rest of the body,” said Deshmukh. “Remarkably, just removing one brake makes the neurons more vulnerable.”

Deshmukh said the findings offer a glimpse into how nerve cells reconfigure themselves during development and beyond. Enhancing our understanding of these basic processes could help illuminate what has gone wrong in the case of some neurological disorders.

Common Brain Processes of Anesthetic-Induced Unconsciousness...

Thu, 23 May 2013 22:30:31 -0400

Common Brain Processes of Anesthetic-Induced Unconsciousness Identified

A study from the June issue of Anesthesiology found feedback from the front region of the brain is a crucial building block for consciousness and that its disruption is associated with unconsciousness when the anesthetics ketamine, propofol or sevoflurane are administered.

Brain centers and mechanisms of consciousness have not been well understood, resulting in a need for better monitors of consciousness during anesthesia. In addition, how anesthetics with different structures and pharmacological properties can generate unconsciousness has been a persistent question in anesthesiology since the beginning of the field in the mid-19th century.

A team of researchers from the University of Michigan, Ann Arbor, Mich., and Asan Medical Center, Seoul, South Korea, conducted a brain wave (electroencephalographic, or EEG) study of the front and back regions of the brain in 30 surgical patients who received intravenous ketamine. They compared the results of this study to the EEG data collected from 18 surgical patients who received either intravenous propofol or inhaled sevoflurane in a previous study. These three anesthetics, known to act on different parts of the brain and produce different EEG patterns, had the same effect of disrupting communication in the brain.

“Understanding a commonality among the actions of these diverse drugs could lead to a more comprehensive theory of how general anesthetics induce unconsciousness,” said study author George Mashour, M.D., Ph.D., assistant professor and associate chair for faculty affairs, Department of Anesthesiology, University of Michigan. “Our research shows that studying general anesthesia from the perspective of consciousness may be a fruitful approach and create new avenues for further investigation of anesthetic mechanisms and monitoring.”

An accompanying editorial by Jamie W. Sleigh, M.D., professor of anaesthesiology and intensive care, Department of Anaesthesia, University of Auckland, Hamilton, New Zealand, supported the study’s ability to better understand the neurobiology of consciousness.

“If the study’s findings are confirmed by subsequent work, the paper will achieve landmark status,” said Dr. Sleigh. “The study not only sheds light on the phenomenon of general anesthesia, but also how it is necessary for certain regions of the brain to communicate accurately with one another for consciousness to emerge.”

In addition, Dr. Sleigh recognized the study’s potential to lead to the development of better depth-of-anesthesia monitors that work for all general anesthetics.

(Image: Shutterstock)

Eyes on the prey: Researchers analyse the hunting behaviour of...

Thu, 23 May 2013 21:01:15 -0400

Eyes on the prey: Researchers analyse the hunting behaviour of fish larvae in virtual reality

Moving objects attract greater attention – a fact exploited by video screens in public spaces and animated advertising banners on the Internet. For most animal species, moving objects also play a major role in the processing of sensory impressions in the brain, as they often signal the presence of a welcome prey or an imminent threat. This is also true of the zebrafish larva, which has to react to the movements of its prey. Scientists at the Max Planck Institute for Medical Research in Heidelberg have investigated how the brain uses the information from the visual system for the execution of quicker movements. The animals’ visual system records the movements of the prey so that the brain can redirect the animals’ movements through targeted swim bouts in a matter of milliseconds. Two hitherto unknown types of neurons in the mid-brain are involved in the processing of movement stimuli.

In principle, the visual system of zebrafish larvae resembles that of other vertebrates. Moreover, its genome has been decoded, it is a small organism, and it has transparent skin, which is easily penetrated by light in the fluorescent microscope. Therefore, these animals are very suitable for studying visual motion perception. They also display very clear prey capture behaviour. With the help of their finely-tuned visual system, they pursue and catch small ciliates. To do this, they execute a series of swimming manoeuvres in a matter of one or two seconds, during which they repeatedly verify the direction and distance of the prey so that they can adapt their subsequent movement steps. The larva’s brain must, therefore, filter and evaluate visual information extremely rapidly so that it can select appropriate motor patterns.

Using high-speed video recordings, researchers working with Johann Bollmann at the Max Planck Institute for Medical Research began by studying the natural course of prey capture by the larvae under a variety of starting conditions. It emerged that the larvae repeatedly execute a basic motion pattern and can apply an orientation component that re-directs the hunter towards the prey with each swim bout. To do this, the larvae must process visual information in just a few hundreds of milliseconds.

Using an innovative experimental design, the scientists then modelled, in a second step, the natural swimming environment as a “virtual reality”, in which the larvae execute typical prey capture sequences without actually moving. The virtual prey consisted of computer-controlled images, which were projected onto a small screen. In this way, the role of motion parameters, for example the size and speed of the “prey”, could be studied quantitatively in relation to the processing of visual stimuli by the animals.

In the “virtual reality”, the scientists can test how the fish larvae respond to unexpected shifts in the prey after a swim bout. “When we direct our gaze at a target through movements of our eyes and head, we expect the object to appear in a central position in our field of view. In the larvae, very slight deviations from the target position or delays in the re-appearance of the virtual prey increased the reaction times. When it receives unexpected visual feedback, the larva’s brain presumably needs extra processing time to calculate the next swim bout,” explains Johann Bollmann from the Max Planck Institute in Heidelberg.

In addition, with the help of fluorescent microscopes, the researchers can examine the activity of groups of neurons in the larval brain which are likely to control the targeted prey capture movements. In a previous study, they discovered cell types that react specifically to opposing directions of movement. These previously unknown neurons in the dorsal region of the midbrain (tectum) differ in their directional sensitivity and in the structure of their finely branched projections. “It appears that different directions of motion are processed in different layers of the tectum, since the dendritic ramifications of these cell types are spatially separated from each other,” says Bollmann.

Brain can be trained in compassion

Thu, 23 May 2013 19:31:05 -0400

Until now, little was scientifically known about the human potential to cultivate compassion — the...

Insomnia may cause dysfunction in emotional brain circuitry A...

Thu, 23 May 2013 18:01:58 -0400

Insomnia may cause dysfunction in emotional brain circuitry

A new study provides neurobiological evidence for dysfunction in the neural circuitry underlying emotion regulation in people with insomnia, which may have implications for the risk relationship between insomnia and depression.

“Insomnia has been consistently identified as a risk factor for depression,” said lead author Peter Franzen, PhD, an assistant professor of psychiatry at the University of Pittsburgh School of Medicine. “Alterations in the brain circuitry underlying emotion regulation may be involved in the pathway for depression, and these results suggest a mechanistic role for sleep disturbance in the development of psychiatric disorders.”

The study involved 14 individuals with chronic primary insomnia without other primary psychiatric disorders, as well as 30 good sleepers who served as a control group. Participants underwent an fMRI scan during an emotion regulation task in which they were shown negative or neutral pictures. They were asked to passively view the images or to decrease their emotional responses using cognitive reappraisal, a voluntary emotion regulation strategy in which you interpret the meaning depicted in the picture in order to feel less negative.

Results show that in the primary insomnia group, amygdala activity was significantly higher during reappraisal than during passive viewing. Located in the temporal lobe of the brain, the amygdala plays an important role in emotional processing and regulation.

In analysis between groups, amygdala activity during reappraisal trials was significantly greater in the primary insomnia group compared with good sleepers. The two groups did not significantly differ when passively viewing negative pictures.

“Previous studies have demonstrated that successful emotion regulation using reappraisal decreases amygdala response in healthy individuals, yet we were surprised that activity was even higher during reappraisal of, versus passive viewing of, pictures with negative emotional content in this sample of individuals with primary insomnia,” said Franzen.

The research abstract was published recently in an online supplement of the journal SLEEP, and Franzen will present the findings Wednesday, June 5, in Baltimore, Md., at SLEEP 2013, the 27th annual meeting of the Associated Professional Sleep Societies LLC.

The American Academy of Sleep Medicine reports that about 10 to 15 percent of adults have an insomnia disorder with distress or daytime impairment. According to the National Institute of Mental Health, 6.7 percent of the U.S. adult population suffers from major depressive disorder. Both insomnia and depression are more common in women than in men.