Posts tagged science
Articles and news from the latest research reports.
Switching Brain Cells with Less Light
Networked nerve cells are the control center of organisms. In a nematode, 300 nerve cells are sufficient to initiate complex behavior. To understand the properties of the networks, researchers switch cells on and off with light and observe the resulting behavior of the organism. In the Science journal, scientists now present a protein that facilitates the control of nerve cells by light. It might be used as a basis of studies of diseases of the nervous system.
(Image caption: Nerve cells form networks that can process signals. Photo: J. Wietek/HU Berlin).
To switch a nerve cell with light, certain proteins forming ion channels in the cell membrane are used. These proteins are called channelrhodopsins. If light strikes the channels, they open and ions enter and render the cell specifically active or inactive. In this way, a very fine tool is obtained to study functions in the network of nerve cells. So far, however, large amounts of light have been required and only closely limited areas in the network could be switched. The ChlocC channelrhodopsin presented now reacts about 10,000 times more sensitively to light than other proteins used so far for switching off nerve cells.
“For the modification of the protein, we analyzed its structure on the computer,” Marcus Elstner, KIT, explains. The theoretical chemist and his team modeled the proteins that consist of about 5000 atoms. For this purpose, they used the highest-performance computers of KIT’s computing center, the Steinbuch Centre for Computing, SCC. Together with the protein environment, i.e. the cell membrane and cell water, about 100,000 atoms had to be considered for the computations that took several weeks. “It was found that ion conductivity of the channel is essentially based on three amino acids in the central region, i.e. on about 50 atoms in the channel only.” By exchanging the amino acids, scientists have now succeeded in increasing the sensitivity of the ion channel.
Light-activated ion channels, the so-called channelrhodopsins, from microalgae have been used since 2005. In neural sections or living transgenic model organisms, such as flies, zebrafish, or mice, they allow for the specific activation of selected cells with light. Thus, understanding of their role in the cell structure can be improved. This technology is known as optogenetics and applied widely. In the past years, it contributed to the better understanding of the biology of signal processing. So far inaccessible neural pathways were mapped and many relationships were discovered among proteins, cells, tissues, and functions of the nervous system.
Within the framework of the study reported in the latest Science issue, researchers from Karlsruhe, Hamburg, and Berlin developed the ion channels further. Jonas Wietek and Nona Adeishvili working in the team of Peter Hegemann at the Humboldt-Universität Berlin have succeeded in identifying the selectivity filter of the channelrhodopsins and in modifying it such that negatively charged chloride ions are conducted. These chloride-conducting channels have been called ChlocC by the scientists. Hiroshi Watanabe from the team of Marcus Elstner, Karlsruhe Institute of Technology (KIT), computed ion distribution in the protein and visualized the increased chloride distribution. Simon Wiegert from the team of Thomas Oertner of the Center for Molecular Neurobiology, Hamburg, demonstrated that ChlocC can be introduced into selected neurons for the inactivation of the latter with very small light intensities similar to the processes taking place in the living organism. With ChloC a novel optogenetic tool is now available that can be used in neurosciences to study the switching of neural networks together with the already known light-activated cation channels that mainly conduct sodium ions and protons. This fundamental knowledge might help better understand the mechanisms of diseases like epilepsy and Parkinson’s. In some years from now, this may give rise to therapy concepts, which might be much more specific than the medical drugs used today.
(Source: kit.edu)
Some innate preferences shape the sound of words from birth
Languages are learned, it’s true, but are there also innate bases in the structure of language that precede experience? Linguists have noticed that, despite the huge variability of human languages, here are some preferences in the sound of words that can be found across languages. So they wonder whether this reflects the existence of a universal, innate biological basis of language. A SISSA study provides evidence to support this hypothesis, demonstrating that certain preferences in the sound of words are already active in newborn infants.
Take the sound “bl”: how many words starting with that sound can you think of? Blouse, blue, bland… Now try with “lb”: how many can you find? None in English and Italian, and even in other languages such words either don’t exist or are extremely rare. Human languages offer several examples of this kind, and this indicates that in forming words we tend to prefer certain sound combinations to others, irrespective of which language we speak. The fact that this occurs across languages has prompted linguists to hypothesize the existence of biological bases of language (in born and universal) which precede language learning in humans. Finding evidence to support his hypothesis is, however, far from easy and the debate between the proponents of this view and those who believe that language is merely the result of learning is still open. But proof supporting the “universalist” hypothesis has now been provided by a new study conducted by a research team of the International School for Advanced Studies (SISSA) in Trieste and just published in the journal PNAS.
David Gomez, a SISSA research scientist working under the supervision of Jacques Mehler and first author of the paper, and his coworkers decided to observe the brain activity of newborns. “In fact, if it is possible to demonstrate that these preferences are already present within days from birth, when the newborn baby is still unable to speak and presumably has very limited language knowledge, then we can infer that there is an inborn bias that prefers certain words to others”, comments Gomez.
“To monitor the newborns’ brain activity we used a non-invasive technique, i.e., functional near-infrared spectroscopy”, explains Marina Nespor, a SISSA neuroscientist who participated in the study. During the experiments the newborns would listen to words starting with normally “preferred” sounds (like “bl”) and others with uncommon sounds (“lb”). “What we found was that the newborns’ brains reacted in a significantly different manner to the two types of sound” continues Nespor.
“The brain regions that are activated while the newborns are listening react differently in the two cases”, comments Gomez, “and reflect the preferences observed across languages, as well as the behavioural responses recorded in similar experiments carried out in adults”. “It’s difficult to imagine what languages would sound like if humans didn’t share a common knowledge base”, concludes Gomez. “We are lucky that this common base exists. This way, our children are born with an ability to distinguish words from “non-words” ever since birth, regardless of which language they will then go on to learn”.
Team finds a better way to grow motor neurons from stem cells
Researchers report they can generate human motor neurons from stem cells much more quickly and efficiently than previous methods allowed. The finding, described in Nature Communications, will aid efforts to model human motor neuron development, and to understand and treat spinal cord injuries and motor neuron diseases such as amyotrophic lateral sclerosis (ALS).
The new method involves adding critical signaling molecules to precursor cells a few days earlier than previous methods specified. This increases the proportion of healthy motor neurons derived from stem cells (from 30 to 70 percent) and cuts in half the time required to do so.
“We would argue that whatever happens in the human body is going to be quite efficient, quite rapid,” said University of Illinois cell and developmental biology professor Fei Wang, who led the study with visiting scholar Qiuhao Qu and materials science and engineering professor Jianjun Cheng. “Previous approaches took 40 to 50 days, and then the efficiency was very low – 20 to 30 percent. So it’s unlikely that those methods recreate human motor neuron development.”
Qu’s method produced a much larger population of mature, functional motor neurons in 20 days.
The new approach will allow scientists to induce mature human motor neuron development in cell culture, and to identify the factors that are vital to that process, Wang said.
Stem cells are unique in that they can adopt the shape and function of a variety of cell types. Generating neurons from stem cells (either embryonic stem cells or those “induced” to revert back to an embryo-like state) requires adding signaling molecules to the cells at critical moments in their development.
Wang and other colleagues previously discovered a molecule (called compound C) that converts stem cells into “neural progenitor cells,” an early stage in the cells’ development into neurons. But further coaxing these cells to become motor neurons presented unusual challenges.
Previous studies added two important signaling molecules at Day 6 (six days after exposure to compound C), but with limited success in generating motor neurons. In the new study, Qu discovered that adding the signaling molecules at Day 3 worked much better: The neural progenitor cells quickly and efficiently differentiated into motor neurons.
This indicates that Day 3 represents a previously unrecognized neural progenitor cell stage, Wang said.
The new approach has immediate applications in the lab. Watching how stem cells (derived from ALS patients’ own skin cells, for example) develop into motor neurons will offer new insights into disease processes, and any method that improves the speed and efficiency of generating the motor neurons will aid scientists. The cells can also be used to screen for drugs to treat motor neuron diseases, and may one day be used therapeutically to restore lost function.
“To have a rapid, efficient way to generate motor neurons will undoubtedly be crucial to studying – and potentially also treating – spinal cord injuries and diseases like ALS,” Wang said.
‘Sewing machine’ idea gives insight into origins of Alzheimer’s
Researchers at Lancaster University have invented a new imaging tool inspired by the humble sewing machine which is providing fresh insight into the origins of Alzheimer’s and Parkinson’s disease.
These diseases are caused by tiny toxic proteins too small to be studied with traditional optical microscopy.
Previously it was thought that Alzheimer’s was caused by the accumulation of long ‘amyloid’ fibres at the centre of senile plaques in the brain, due to improper folding of a protein called amyloid-β.
But new research suggests that these fibres and plaques are actually the body’s protective response to the presence of even smaller, more toxic structures made from amyloid-β called ‘oligomers’.
Existing techniques are not sufficient to get a good look at these proteins; optical microscopy does not provide enough resolution at this scale, and electron microscopy gives the resolution but not the contrast.
To solve the problem, Physicist Dr Oleg Kolosov and his team at Lancaster have developed a new imaging technique - Ultrasonic Force Microscopy (UFM) - inspired by the motion of a sewing machine. Their work has been published in Scientific Reports.
Dr Kolosov said: “By using a vibrating scanner, which moves quickly up and down like the foot of a sewing machine needle, the friction between the sample and the scanner was reduced – resulting in a better quality, and high contrast nanometre scale resolution image.”
It is one of a new generation of tools being developed worldwide to bring the oligomers into focus, enabling medical researchers to understand how they behave.
At Lancaster, Claire Tinker used UFM to image these oligomers. To help see them more clearly she needed to increase the contrast of the image and used poly-L-lysine (PLL) which kept the proteins stuck to the slides as the vibrating scanner was passed over them.
Lancaster University Biomedical Scientist Professor David Allsop said: “These high quality images are vitally important if we are to understand the pathways involved in formation of these oligomers, and this new technique will now be used to test the effects of inhibitors of oligomer formation that we are developing as a possible new treatment for Alzheimer’s disease.”
The technique worked so well that the team now hopes to develop it so that oligomer formation can be monitored as they are made in real time.
This would give researchers a clearer understanding of the early phases of Alzheimer’s and Parkinson’s and could potentially be one way of developing a future test for these diseases.
(Source: alphagalileo.org)
When we watch a movie, our brains react to it immediately in a way similar to other people’s brains.
Researchers at Aalto University in Finland have succeeded in developing a method fast enough to observe immediate changes in the function of the brain even when watching a movie. By employing movies it was possible to investigate the function of the human brain in experimental conditions that are close to natural. Traditionally, in neuroscience research, simple stimuli, such as checkerboard patterns or single images, have been used.
Viewing a movie creates multilevel changes in the brain function. Despite the complexity of the stimulus, the elicited brain activity patterns show remarkable similarities across different people – even at the time scale of fractions of seconds.
The analysis revealed important similarities between brain signals of different people during movie viewing. These similar kinds or synchronized signals were found in brain areas that are connected with the early-stage processing of visual stimuli, detection of movement and persons, motor coordination and cognitive functions. The results imply that the contents of the movie affected certain brain functions of the subjects in a similar manner, explains Kaisu Lankinen the findings of her doctoral research.
So far, studies in this field have mainly been based on functional magnetic resonance imaging (fMRI). However, given the superior temporal resolution, within milliseconds, magnetoencephalography (MEG) is able to provide more complete picture of the fast brain processes. With the help of MEG and new analysis methods, investigation of significantly faster brain processes is possible and it enables detection of brain activity in frequencies higher than before.
In the novel analysis, brain imaging was combined with machine-learning methodology, with which signals of a similar form were mined from the brain data.
The research result was recently published in the NeuroImage journal.
A new study in a mutant fruitfly called sleepless (sss) confirmed that the enzyme GABA transaminase, which is the target of some epilepsy drugs, contributes to sleep loss. The findings, published online in Molecular Psychiatry, were led by Amita Sehgal, PhD, head of the Chronobiology Program at the University of Pennsylvania’s Perelman School of Medicine. The findings shed light on mechanisms that may be shared between sleep disruption and some neurological disorders. A better understanding of this connection could enable treatments that target both types of symptoms and perhaps provide better therapeutic efficacy.
“Epilepsy is essentially an increase-in-firing disorder of the brain and maybe a decrease in activity of the neurotransmitter GABA, too,” says Sehgal, who is also a professor of Neuroscience and an investigator with the Howard Hughes Medical Institute (HHMI). “This connects our work to drugs that inhibit GABA transaminase. Changes in GABA transaminase activity are implicated in epilepsy and some other psychiatric disorders, which may account for some of the associated sleep problems.”
The team looked at the proteomics of the sss mutant brain – a large-scale study of the structure and function of related proteins — and found that GABA transaminase is increased in the sss brain compared to controls. This enzyme breaks down GABA, so GABA is decreased in the sss brain. Because GABA promotes sleep, there is a decrease in sleep in the sss mutant fly, as the name implies.
The relationship between the SSS protein and GABA is not fully understood. The SSS protein controls neural activity, and its absence results in increased neural firing, which likely uses up a lot of energy, says Sehgal. GABA transaminase works in the mitochondria, the energy-production organelle in the glial cells of the brain, which provide fuel for neurons. The large energy demand created by the increased neural firing in sss brains probably alters mitochondrial metabolism, including GABA transaminase function in glia.
In the sss mutant fly, there is a stream of connections that leads to its signature loss of sleep: The sss mutant has increased neuron firing caused by downregulation of a potassium channel protein called Shaker. Recently, the Sehgal lab showed that SSS also affects activity of acetylcholine receptors. Both of these actions may directly cause an inability to sleep. In addition, increased energy demands on glia, which increase GABA transaminase and decrease GABA, may further contribute to sleep loss. On the other hand, if GABA is increased, then sleep is increased, as in flies that lack GABA transaminase.
Anaesthetic technique important to prevent damage to brain
Researchers at the University of Adelaide have discovered that a commonly used anaesthetic technique to reduce the blood pressure of patients undergoing surgery could increase the risk of starving the brain of oxygen.
Reducing blood pressure is important in a wide range of surgeries - such as sinus, shoulder, back and brain operations - and is especially useful for improving visibility for surgeons, by helping to remove excess blood from the site being operated on.
There are many different techniques used to lower patients’ blood pressure for surgery - one of them is known as hypotensive anaesthesia, which slows the arterial blood pressure by up to 40%.
Professor PJ Wormald, a sinus, head and neck surgeon from the University’s Discipline of Surgery, based at the Queen Elizabeth Hospital, led a world-first study looking at both the effectiveness of hypotensive anaesthesia from the surgeon’s point of view and its impact on the patients.
The study followed 32 patients who underwent endoscopic sinus surgery. The results have now been published online in the journal The Laryngoscope.
"There is an important balance in anaesthesia where the blood pressure is lowered so that the surgeon has good visibility and is able to perform surgery safely. There are numerous sensitive areas in sinus surgery - the brain, the eye and large vessels such as the carotid. However, if the blood pressure is lowered too far this may cause damage to the brain and other organs," says Professor Wormald.
"We know from previous research that a person’s brain undergoing anaesthesia has lower metabolic requirements than the awake brain, and therefore it can withstand greater reductions in blood flow.
"There is also a widely accepted concept that the brain has the ability to autoregulate - to adapt and maintain a constant blood flow as needed, despite a wide range of blood pressure conditions. Our studies challenge this; they show that the brain can only autoregulate up to a point, and cannot completely adapt to such low blood pressures.
"This drop in blood pressure poses a risk of starving the brain of much-needed oxygen and nutrients, which could result in injury. There have been cases, for example, where patients have reported memory loss following surgery.
"Given that hypotensive anaesthesia is a widely used technique, not just in sinus surgery but in many different types of surgery, we’ve made recommendations in our paper that suggest a safer approach to this technique. This would reduce risk to the patient while enabling the surgeon to carry out their work effectively," Professor Wormald says.
(Image: Shutterstock)
Using your loaf to fight brain disease
Experts analyse baker’s yeast to discover potential for combatting neurological conditions like Parkinson’s and even cancer
A humble ingredient of bread – baker’s yeast – has provided scientists with remarkable new insights into understanding basic processes likely involved in diseases such as Parkinson’s and cancer.
In a new study published in the prestigious journal PNAS (Proceedings of the National Academy of Science), the team from Germany, Leicester, and Portugal detail a new advance – describing for the first time a key feature in cellular development linked to the onset of these devastating diseases.
The research team is from the University Medical Center Goettingen, University of Leicester, and Instituto de Medicina Molecular, Lisbon, directed by long-time collaborators and senior authors Professor Tiago Outeiro and Dr Flaviano Giorgini.
Professor Outeiro, of the University Medical Center Goettingen, Goettingen and Instituto de Medicina Molecular, Lisbon, said: “This work shows how taking advantage of simple model organisms might help us speed up the discovery of more complex biological processes. Yeast cells are really excellent living test tubes, with a powerful toolbox that enabled us to learn about the underpinnings of complex human disorders.”
Dr Giorgini, of the world-renowned Department of Genetics, at the University of Leicester, added: “We are tremendously excited by our results. The family of proteins under investigation have always been a bit of a “black box”, and a true understanding of what these proteins do at a cellular level - and why they are important - has remained elusive. This work provides a step into this darkness.”
The current research takes advantage of the simplicity and genetic power of the baker’s yeast Saccharomyces cerevisiae to understand basic cellular processes underlying Parkinson’s disease. The team studied a family of proteins in yeast (Hsp31, Hsp32, Hsp33, and Hsp34) which are related to a human protein known as DJ-1. Mutations in the human DJ-1 protein cause early-onset inherited forms of Parkinson’s disease, and alterations in the human protein have been associated with more common forms of Parkinson’s disease as well. In addition, changes in DJ-1 function are also associated with certain forms of cancer.
Claire Bale, Research Communications Manager at Parkinson’s UK, commented: “This important research sheds new light on the root causes of Parkinson’s.
“Although mutations in the DJ-1 gene cause rare inherited forms of the condition, we believe that understanding the role of this crucial protein and how it helps keep nerve cells healthy could be important for developing treatments that can help all people with Parkinson’s. We look forward to hearing the results of future investigations in this emerging new area.”
Professor Outeiro continued: “We reasoned that, by studying the yeast cousins of the human protein we would gain important insight into the function these proteins play, and understand why they may cause disease.
Dr Giorgini added: “Though the human protein DJ-1 has been linked to Parkinson’s disease, its central cellular role is not well understood, and thus it is not clear why mutations in this protein cause this devastating disease. Our study sheds new light on what DJ-1 and related proteins are doing at a cellular level, and may thus ultimately have importance for better understanding Parkinson’s.”
The scientists discovered that the yeast versions of the human protein are important for maintenance of normal lifespan of the yeast cell and are involved in regulation of autophagy – a process which the cell employs to breakdown and recycle damaged cellular components. Lifespan and autophagy are central processes in the context of both Parkinson’s disease and cancer. This work is critical because it provides a precise cellular role for DJ-1 family proteins, which links to some of the molecular functions previously ascribed to these proteins. This work could ultimately provide new insight into the mechanisms that contribute to Parkinson’s and cancer.
Leonor Miller-Fleming, of the Instituto de Medicina Molecular, Lisbon and University of Leicester, said: “Our work is important because it suggests that human DJ-1 may function in a similar manner to the yeast version of this protein. We feel that similar studies should be performed with human DJ-1 in nerve cells, to clarify its function and to see if this contributes to the formation of Parkinson’s disease. Ultimately, the detailed understanding of how these proteins function may enable us to come up with novel strategies to treat Parkinson’s disease, cancer, and other related disorders.”
The collaborators believe the next steps in the research are to better understand the details of how the DJ-1 family of proteins regulates autophagy, and if this applies in human neurons, particularly dopaminergic neurons, which are the nerve cells most sensitive to loss in the Parkinson’s brain. Once the researchers build up on the findings they have now described, they will be in a better position to design novel strategies for therapeutic intervention.
Professor Outeiro explained: “This study highlights the importance of international collaborations and networks, in which different strengths are combined to yield novel insights into science. Importantly, this scientific collaboration is also based upon personal friendship between the two senior authors, which makes science ever more exciting and fun.”
Dr Giorgini added: “In addition, this work was primarily spearheaded by a single PhD student – Leonor Miller-Fleming – who drove the project forward with passion and creativity, showing the importance of promoting, supporting and funding doctoral research.”
Professor Outeiro said: “We were pioneers in the development of the first model of Parkinson’s disease in yeast cells. With this work, we explored the powerful toolbox of yeast cells to learn about DJ-1 proteins, also intimately linked to Parkinson’s disease. We are basically adding pieces to this complicated puzzle, and getting one step closer to understanding the origin of this disorder.”
(Image: © Wikipedia)
Researchers Reveal a New Pathway Through the Sodium Pump
A study in The Journal of General Physiology provides new evidence that the ubiquitous sodium pump is more complex—and more versatile—than we thought.
(Image caption: Structure of the sodium pump, which researchers reveal to be more versatile than previously thought)
The sodium pump is present in the surface membrane of all animal cells, using energy derived from ATP to transport sodium and potassium ions in opposite directions across the cell boundary. By setting up transmembrane gradients of these two ions, the pump plays a vital role in many important processes, including nerve impulses, heartbeats, and muscular contraction.
Now, Rockefeller University researchers Natascia Vedovato and David Gadsby demonstrate that, in addition to its role as a sodium and potassium ion transporter, the pump can simultaneously import protons into the cell. Their study not only provides evidence of “hybrid” function by the pump, it also raises important questions about whether the inflow of protons through sodium pumps might play a role in certain pathologies.
The sodium pump exports three sodium ions out of the cell and imports two potassium ions into the cell during each transport cycle. Vedovato and Gadsby show that, during this normal cycle, the pump develops a passageway that enables protons to cross the membrane. When the pump releases the first of the three sodium ions to the cell exterior, a newly emptied binding site becomes available for use by an external proton, allowing it to then make its way into the cytoplasm. The protons travel a distinct route, and proton inflow is not required for successful transport of sodium and potassium.
Import of protons is high when their extracellular concentration is high (pH is low) and membrane potential is negative. The authors therefore speculate that proton inflow might have important implications under conditions in which extracellular pH is lowered, such as in muscle during heavy exercise, in the heart during a heart attack, or in the brain during a stroke.
(Source: newswise.com)
Researcher discovers two new genes linked to intellectual disability
Researchers at the Centre for Addiction and Mental Health have discovered two new genes linked to intellectual disability, according to two research studies published concurrently in early March in the journals Human Genetics and Human Molecular Genetics.
“Both studies give clues to the different pathways involved in normal neurodevelopment,” says CAMH Senior Scientist Dr. John Vincent, who heads the MiND (Molecular Neuropsychiatry and Development) Laboratory in the Campbell Family Mental Health Research Institute at CAMH. “We are building up a body of knowledge that is informing us which kinds of genes are important to, and involved in, intellectual disabilities.”
In the first study, Dr. Vincent and his team used microarray genotyping to map the genes of a large consanguineous (intermarriage within the extended family) Pakistani family, in which five members of the youngest generation were affected with mild to moderate intellectual disability. Dr. Vincent identified a truncation in the FBXO31 gene, which plays a role in the way that proteins are processed during neuronal development, particularly in the cerebellar cortex.
In the second study, using the same techniques, Dr. Vincent and his team analyzed the genes of two consanguineous families, one Austrian and one Pakistani, and identified a disruption in the METTL23 gene linked to mild recessive intellectual disability. The METTL23 gene is involved in methylation—a process important to brain development and function.
About one per cent of children worldwide are affected by non-syndromic (i.e., the absence of any other clinical features) intellectual disability, a condition characterized by an impaired capacity to learn and process new or complex information, leading to decreased cognitive functioning and social adjustment. Although trauma, infection and external damage to the unborn fetus can lead to an intellectual disability, genetic defects are a principal cause.
These studies were part of an ongoing study of affected families in Pakistan, where the cultural tradition of large families and consanguineous marriages among first cousins increases the likelihood of inherited intellectual disability in offspring.
“Although it is easier to find and track genes in consanguineous families, these genes are certainly not limited to them,” Dr. Vincent points out. A recent study estimated that 13–24 per cent of intellectual disability cases among individuals of European descent have autosomal recessive causes, meaning that results of this study are very relevant to populations such as Canada.
Autosomal recessive gene mutations have traditionally been more difficult to trace, resulting in a paucity of research in this area. Parents of affected children show no symptoms, and the child must inherit one defective copy of the gene from each parent, so that only one in four offspring are likely to be affected. Smaller families, therefore, show a decreased incidence and are less amenable to this kind of study.
Dr. Vincent is currently engaged in a study that will screen Canadian populations with autism and intellectual disability for autosomal recessive gene mutations. Results will be available later this year.
A total of 42 genes linked to non-syndromic autosomal recessive forms of intellectual disability have now been identified; estimates suggest that up to 2,500 autosomal genes might be linked with intellectual disability, the majority being recessive.
(Source: camh.ca)