Posts tagged science
Articles and news from the latest research reports.
How Cone Snail Venom Minimizes Pain
The venom from marine cone snails, used to immobilize prey, contains numerous peptides called conotoxins, some of which can act as painkillers in mammals. A recent study in The Journal of General Physiology provides new insight into the mechanisms by which one conotoxin, Vc1.1, inhibits pain. The findings help explain the analgesic powers of this naturally occurring toxin and could eventually lead to the development of synthetic forms of Vc1.1 to treat certain types of neuropathic pain in humans.
Neuropathic pain, a form of chronic pain that occurs in conjunction with injury to—or dysfunction of—the nervous system, can be debilitating and difficult to treat, and the medical community is eager to find better methods to minimize what can be a serious condition. Neuropathic pain is associated with changes in the transmission of signals between neurons, a process that depends on several types of voltage-gated calcium channels (VGCCs). However, given the importance of these VGCCs in mediating normal neurotransmission, using them as a pharmacological target against neuropathic pain could potentially lead to undesirable side effects.
In previous studies, David Adams and colleagues from RMIT University in Melbourne showed that Vc1.1 acted against neuropathic pain in mice; they found that, rather than acting directly to block VGCCs, Vc1.1 acts through GABA type B (GABAB) receptors to inhibit N-type (Cav2.2) channels.
Now, Adams and colleagues show that Vc1.1 also acts through GABAB receptors to inhibit a second, mysterious class of neuronal VGCCs that have been implicated in pain signaling but have not been well understood—R-type (Cav2.3) channels. Their new findings not only help solve the mystery of Cav2.3 function, but identify them as targets for analgesic conotoxins.
Training the Brain to Focus
About one in 10 school children suffers from attention deficit/hyperactivity disorder (ADHD), according to the Centers for Disease Control and Prevention. Linked to measurable differences in children’s brain structures and brain waves, ADHD can have dire effects on children’s academic achievements and lead to disrupted classrooms.
The CDC reports that as many as 3 million American elementary school children now take medications to control their symptoms. But these drugs don’t work for everyone. Worse, their potential side effects can have serious consequences for kids who also have heart conditions, eating or digestive problems or mood disorders such as depression.
In a recent study, Naomi J. Steiner, director of the CATS Project (Computer Attention Training in Schools for children with ADHD) at Tufts Medical Center, and her colleagues found that computer-based attention-training exercises significantly improved the ability of kids with ADHD to focus and pay attention.
The team tested two kinds of computer training systems. The first, computer cognitive attention training, uses computerized brain exercises to strengthen key mental skills such as short-term memory, eye-hand coordination and visual processing through a series of game-like activities. The second, neurofeedback, measures children’s brain waves in real time and provides visual and auditory feedback that can help them harness their ability to focus. The researchers found that both systems ameliorated the symptoms of ADHD, with neurofeedback outperforming computer cognitive attention training.
What’s more, the team found that the effect lasted months after the computer-based training sessions ended. The results of the large-scale clinical trial, published earlier this year in the journal Pediatrics, bolster the positive findings Steiner and her colleagues saw in a pilot study they conducted previously.
That’s encouraging news, because these therapies—some of which are commercially available to the public and many of which have been adopted by school systems in every state—aren’t yet covered by health insurance policies, nor will they be without a data showing their efficacy. Steiner’s body of research is one more step down that road. (See the story “Your Brain on Video Games.”)
(Image: Shutterstock)
A National Institutes of Health-sponsored study published in the Journal of the American Medical Association (JAMA) showed that lorazepam - a widely used but not yet Food and Drug Administration (FDA) approved drug for children - is no more effective than an approved benzodiazepine, diazepam, for treating pediatric status epilepticus.
Status epilepticus is a state in which the brain is in a persistent state of seizure. By the age of 15, 4 to 8 percent of children experience a seizure episode, which can be life threatening if they aren’t stopped immediately. Status epilepticus is a continuous, unremitting seizure lasting longer than five minutes or recurrent seizures without regaining consciousness between seizures for more than five minutes.
Before this current study, published April 23, there was no evidence indicating which of the two treatments might prove more effective. Although it is not yet approved by the FDA, James M. Chamberlain, MD, Division Chief of Emergency Medicine at Children’s National Health System, the study’s principal investigator, estimates that lorazepam is used as first-line therapy in most emergency departments.
“The study results provide reassurance to emergency medicine personnel who must act within minutes,” said Chamberlain. The study was conducted at 11 hospitals in the United States using the infrastructure of the Pediatric Emergency Care Applied Research Network (PECARN), under a contract from the National Institutes of Health’s (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
Both lorazepam and diazepam are used to treat status epilepticus. Diazepam, also known as Valium, is the only one of the two drugs to have been approved by the FDA for use in adults and children.
Lorazepam, marketed under the trade name Ativan, has been approved by the FDA only for use in adults. Once the FDA has approved a drug for use in adults, physicians may then prescribe it for other uses and in pediatric patients if, in their best judgment, they believe their patients will benefit.
“Sometimes physicians are forced to rely on their best judgment alone,” said George Giacoia, MD, of the NICHD’s Obstetric and Pediatric Pharmacology and Therapeutics Branch. “However, it’s always better to make treatment decisions on the evidence that comes only from conducting large comparison studies. We now know that lorezapam offers no advantage over diazepam in treating pediatric seizure disorder, and that diazepam is more suited to use by emergency teams.”
In 2007, the National Institutes of Health’s Pediatric Seizure study sought to determine which of two drugs—diazepam or lorazepam—was more effective in treating the life-threatening condition, status epilepticus. This condition can occur without warning. For reasons not fully understood, a child may be gripped by continuous seizures, which, if not stopped within minutes, may lead to brain damage or even death.
Because of the random nature of seizures and their significantly life altering affects, lorezapam is commonly prescribed to treat status epilepticus in children, even though it hasn’t been specifically approved for that use. The results of the Pediatric Seizure study do not support the use of lorezapam instead of diazepam for treating status epilepticus, Dr. Chamberlain said. Also, because lorezapam needs to be refrigerated and diazepam does not, diazepam is more suited for use by ambulance crews.
A few previous studies indicated that lorazepam might be more effective at ending a seizure and might be less likely than diazepam to depress breathing—a side effect of benzodiazapines, the category of medications that includes both drugs.
In their study, Chamberlain and colleague wrote, “There is no conclusive evidence to support lorazepam as a superior treatment and there is little consensus as to which is the preferred agent.”
The current study was the largest, most comprehensive comparison study of the two treatments for pediatric seizure disorder. Dr. Chamberlain and his colleagues enrolled 310 children at the 11 institutions, between 2008 and 2012. The researchers found that both medications successfully halted seizures in 70 percent of cases, and each had rates of severe respiratory depression of less than 20 percent.
It’s important that “we get the most important scientific information about such medications so there are government approvals for pediatric use,” Chamberlain said. “Pediatric patients are not just small adults.”
(Image: Alamy)
Preventing Alzheimer’s disease — with an antidepressant
Citalopram, an antidepressant better known by its commercial name Celexa, has a remarkable side effect, a new study has found: In both mice bred to develop Alzheimer’s disease and in healthy human volunteers, the selective serotonin reuptake inhibitor, or SSRI, drives down the production of a protein called beta-amyloid, which in the brains of those with Alzheimer’s clumps together in sticky plaques and is thought to short-circuit the brain’s wiring.
In study participants free of Alzheimer’s disease or any other neuropsychiatric affliction, citalopram was found to reduce the concentration of beta-amyloid in the cerebrospinal fluid (outside of the brain) by 38%. Researchers see that as a clear sign that beta-amyloid protein in the brain, too, declines in those taking the antidepressant.
(Image caption: Omega-3 fatty acid DHA transporter protein Mfsd2a is shown here as red fluorescence along mouse brain capillaries. Credit: Long N. Nguyen)
Researchers discover how DHA omega-3 fatty acid reaches the brain
It is widely believed that DHA (docosahexaenoic acid) is good for your brain, but how it is absorbed by the brain has been unknown. That is - until now. Researchers from Duke-NUS Graduate Medical School Singapore (Duke-NUS) have conducted a new study identifying that the transporter protein Mfsd2a carries DHA to the brain. Their findings have widespread implications for how DHA functions in human nutrition.
People know that DHA is an essential dietary nutrient that they can get from seafood and marine oils. Baby formula companies are especially attuned to the benefits of DHA, with nary a baby formula marketed without it.
DHA is an omega-3 fatty acid most abundantly found in the brain that is thought to be crucial to its function. However, the brain does not produce DHA. Instead, DHA uptake in the brain happens in two ways. The developing brain receives DHA during fetal development, from a mother to her baby. The adult brain gets it through food or DHA produced by the liver.
Though DHA is postulated to benefit the brain, the mechanics of how the brain absorbs the fatty acid has remained elusive. Senior author of the research, Associate Professor David L. Silver of Duke-NUS explained the importance of unlocking this mystery.
"If we could show the link by determining how DHA gets into the brain, then we could use this information to more effectively target its absorption and formulate an improved nutritional agent."
In the study, led by post-doctoral fellow Long N. Nguyen of Duke-NUS, researchers found that mice without the Mfsd2a transporter had brains a third smaller than those with the transporter, and exhibited memory and learning deficits and high levels of anxiety. The team recognized that the learning, memory and behavioral function of these mice were reminiscent of omega-3 fatty acid deficiency in mice starved of DHA in their diet.
Then, using biochemical approaches, the team discovered that mice without Mfsd2a were deficient in DHA and made the surprising discovery that Mfds2a transports DHA in the chemical form of lysophosphatidlycholine (LPC). LPCs are phospholipids mainly produced by the liver that circulate in human blood at high levels. This is an especially significant finding as LPCs have been considered toxic to cells and their role in the body remains poorly understood. Based on this surprising new information, Dr Silver’s team showed that Mfsd2a is the major pathway for the uptake of DHA carried in the chemical form of LPCs by the growing fetal brain and by adult brain.
The findings, published online in Nature the week of May 12, 2014 marks the first time a genetic model for brain DHA deficiency and its functions in the brain has been made available.
"Our findings can help guide the development of technologies to more effectively incorporate DHA into food and exploit this pathway to maximize the potential for improved nutritionals to improve brain growth and function. This is especially important for pre-term babies who would not have received sufficient DHA during fetal development," said Dr Silver, who is from the Cardiovascular and Metabolic Disorders Program at Duke-NUS.
(Image caption: Tracer dye (red) leaked through capillaries (green) in the brains of mice that lacked the gene Mfsd2a, helping to reveal the gene’s role in regulating blood-brain barrier permeability. Credit: Gu Lab)
Like a bouncer at an exclusive nightclub, the blood-brain barrier allows only select molecules to pass from the bloodstream into the fluid that bathes the brain. Vital nutrients get in; toxins and pathogens are blocked. The barrier also ensures that waste products are filtered out of the brain and whisked away.
The blood-brain barrier helps maintain the delicate environment that allows the human brain to thrive. There’s just one problem: The barrier is so discerning, it won’t let medicines pass through. Researchers haven’t been able to coax it to open up because they don’t know enough about how the barrier forms or functions.
Now, a team from Harvard Medical School has identified a gene in mice, Mfsd2a, that may be responsible for limiting the barrier’s permeability—and the molecule it produces, Mfsd2a, works in a way few researchers expected.
“Right now, 98 percent of small-molecule drugs and 100 percent of large-molecule drugs and antibodies can’t get through the blood-brain barrier,” said Chenghua Gu, associate professor of neurobiology at HMS and senior author of the study. “Less than 1 percent of pharmaceuticals even try to target the barrier, because we don’t know what the targets are. Mfsd2a could be one.”
Most attempts to understand and manipulate blood-brain barrier function have focused on tight junctions, seals that prevent all but a few substances from squeezing between barrier cells. Gu and her team discovered that Mfsd2a appears to instead affect a second barrier-crossing mechanism that has received much less attention, transcytosis, a process in which substances are transported through the barrier cells in bubbles called vesicles. Transcytosis occurs frequently at other sites in the body but is normally suppressed at the blood-brain barrier. Mfsd2a may be one of the suppressors.
“It’s exciting because this is the first molecule identified that inhibits transcytosis,” said Gu. “It opens up a new way of thinking about how to design strategies to deliver drugs to the central nervous system.”
Because Mfsd2a has a human equivalent, blocking its activity in people could allow doctors to open the blood-brain barrier briefly and selectively to let in drugs to treat life-threatening conditions such as brain tumors and infections.
Conversely, because researchers have begun to link blood-brain barrier degradation to several brain diseases, boosting Mfsd2a or Mfsd2a could allow doctors to strengthen the barrier and perhaps alleviate diseases such as Alzheimer’s, amyotrophic lateral sclerosis (ALS) and multiple sclerosis. The findings may also have implications for other areas of the body that rely on transcytosis, such as the retina and kidney.
The study was published May 14 in Nature.
Back to the beginning
As developmental biologists, Gu and her colleagues believed watching the barrier develop in young organisms would reveal molecules important for its formation and function.
The team introduced a small amount of dye into the blood of embryonic mice at different stages of development and watched whether it leaked through the walls of the tiny capillaries of the mice’s brains, suggesting that the blood-brain barrier hadn’t formed yet, or stayed contained within the capillaries, indicating that the barrier was doing its job. This allowed them to define a time window during which the barrier was being built.
The team was able to do this by devising a new dye injection technique. Researchers studying blood-brain barrier leakage in adult organisms can inject dye directly into blood vessels, but the capillaries of embryos are too small and delicate. Instead, researchers typically inject dye into the heart. However, according to Gu, this can raise blood pressure and burst brain capillaries, making it difficult to tell whether leakage is due to blood-brain barrier immaturity or the dye procedure itself. She and her team used their vascular biology expertise to identify an alternate injection site that would avoid such artifacts: the liver.
“This allowed us to provide definitive evidence that the blood-brain barrier comes into play during embryonic development,” said Ayal Ben-Zvi, a postdoctoral researcher in the Gu lab and first author of the study. “That changes our understanding of the development of the brain itself.”
Telltale pattern
Now that they knew when the barrier formed in the mice, the team compared endothelial cells—the cells that line blood vessel walls and help form the blood-brain barrier—from peripheral blood vessels and cortical (brain) vessels and looked for differences in gene expression. They made a list of genes that were expressed only in the cortical endothelial cells. From that list, they validated about a dozen in vivo.
The team could have studied any of the genes first, but they were most intrigued by Mfsd2a because of its expression pattern. In addition to being switched on in brain vessels, it was active in the placenta and testis, two other organs that have barrier-type functions. Also, the gene is shared across vertebrate organisms that have blood-brain barriers, including humans.
Gu and the team then conducted experiments in mice that lacked the Mfsd2a gene. They found that without Mfsd2a, the blood-brain barrier leaked (although it didn’t prevent the blood vessels themselves from forming in the first place). The next question was why.
“We focused on two basic characteristics: tight junctions between cells, which prohibit passage of water-soluble molecules, and transcytosis, which happens all the time in peripheral vessels but very little in the cortical vessels,” said Gu. “We found the surprising result that Mfsd2a regulates transcytosis without affecting tight junctions. This is exciting because conceptually it says this previously unappreciated feature may be even more important than tight junctions.”
“At first we were looking at tight junctions, because we were also biased by the field,” said Ben-Zvi, who will be starting his own lab later this year at The Hebrew University of Jerusalem. “We weren’t finding anything on the electron micrographs even though we knew the vessels leaked. Then we noticed there were tons of vesicles.
“It really shows that if you do systematic science and see something strange, you shouldn’t dismiss it, because maybe that’s what you’re looking for.”
Next steps
The team also began to study the relationship between the cortical endothelial cells and another contributor to the blood-brain barrier, cells called pericytes. So far, they have found that pericytes regulate Mfsd2a. Next, they want to learn what exactly the pericytes are telling the endothelial cells to do.
Other future work in the Gu lab includes testing the dozen other potential molecular players and trying to piece together the entire network that regulates transcytosis in the blood-brain barrier.
“In addition to Mfsd2a, there may be several other molecules on the list that will be good drug targets,” said Gu. “The key here is we are gaining tools to manipulate transcytosis either way: opening or tightening.”
As important as the molecules themselves, she added, is the concept.
“I personally hope people in the blood-brain barrier field will consider the mind-shifting paradigm that transcytosis could be targeted or modulated,” said Ben-Zvi.
Better understanding—and potentially being able to manipulate—the molecular underpinnings of transcytosis could aid in the study and treatment of diseases in tissues beyond the brain, from the intestines absorbing nutrients to the kidneys filtering waste.
Being able to open and close the blood-brain barrier also promises to benefit basic research, enabling scientists to investigate how abnormal barrier formation affects brain development and what the relationship may be between barrier deterioration and disease.
US experts urge focus on ethics in brain research
Ethics must be considered early and often as the field of modern neuroscience forges ahead, to avoid repeating a dark period in history when lobotomies were common, experts said on Wednesday.
President Barack Obama sought the recommendations of the Presidential Commission for the Study of Bioethical Issues, as part of his $100 million Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative announced last year.
It is “absolutely critical… to integrate ethics from the get-go into neuroscience research,” and not “for the first time after something has gone wrong,” said Amy Gutmann, Bioethics Commission Chair.
Primates and patience — the evolutionary roots of self control
A chimpanzee will wait more than two minutes to eat six grapes, but a black lemur would rather eat two grapes now than wait any longer than 15 seconds for a bigger serving.
It’s an echo of the dilemma human beings face with a long line at a posh restaurant. How long are they willing to wait for the five-star meal? Or do they head to a greasy spoon to eat sooner?
A paper published today in the scientific journal Proceedings of the Royal Society B explores the evolutionary reasons why some primate species wait for a bigger reward, while others are more likely to grab what they can get immediately.
"Natural selection has shaped levels of patience to deal with the types of problems that animals face in the wild," said author Jeffrey R. Stevens, a comparative psychologist at the University of Nebraska-Lincoln and the study’s lead author. "Those problems are species-specific, so levels of patience are also species-specific."
Studying 13 primate species, from massive gorillas to tiny marmosets, Stevens compared species’ characteristics with their capacity for “intertemporal choice.” That’s a scientific term for what some might call patience, self-control or delayed gratification.
He found the species with bigger body mass, bigger brains, longer lifespans and larger home ranges also tend to wait longer for a bigger reward.
Chimpanzees, which typically weigh about 85 pounds, live nearly 60 years and range about 35 square miles, waited for a reward for about two minutes, the longest of any of the primate species studied. Cotton-top tamarins, which weigh less than a pound and live about 23 years, waited about eight seconds before opting for a smaller, immediate reward.
The findings are based partially on experiments Stevens performed during the past ten years with lemurs, marmosets, tamarins, chimpanzees and bonobos at Harvard’s Department of Psychology and at the Berlin and Leipzig zoos in Germany. In those experiments, individual animals chose between a tray containing two grapes that they could eat immediately and a tray containing six grapes they could eat after waiting. The wait times were gradually increased until the animal reached an “indifference point” when it opted for the smaller, immediate reward instead of waiting.
Stevens combined those results with those of scientists who performed similar experiments with other primates. He scoured primate-research literature to gather data on the biological characteristics of each species.
In addition to characteristics related to body mass, Stevens analyzed but found no correlation with two other hypotheses for patience: cognitive ability and social complexity.
"In humans, the ability to wait for delayed rewards correlates with higher performance in cognitive measures such as IQ, academic success, standardized test scores and working memory capacity," he wrote. "The cognitive ability hypothesis predicts that species with higher levels of cognition should wait longer than those with lower levels."
But Stevens found no correlation between patience levels and an animal’s relative brain size compared to its body size, the measure he used to quantify cognitive ability.
Researchers also have argued that animals in complex social groups have reduced impulsivity and more patience to adapt to the social hierarchies of dominance and submission. But Stevens did not find correlations between species’ social group sizes and their patience levels.
Stevens said he believes metabolic rates may be the driving factor connecting patience with body mass and related physical characteristics. Smaller animals tend to have higher metabolic rates.
"You need fuel and you need it at a certain rate," he said. "The faster you need it, the shorter time you will wait."
Metabolic rates also may factor in human beings’ willingness to wait. Stevens said human decisions about food, their environment, their health care and even their finances all relate to future payoffs. The mental processes behind those decisions have not yet been well identified.
"To me, this offers us interesting avenues to start thinking about what factors might influence human patience," he said. "What does natural selection tell us about decision making? That applies to humans as well as to other animals."
Human hibernation: Secrets behind the big sleep
Imagine it: you have been rushed into the emergency room and you are dying. Your injuries are too severe for the surgeons to repair in time. Your blood haemorrhages unseen from ruptured vessels. The loss of blood is starving your organs of vital nutrients and oxygen. You are entering cardiac arrest.
But this is not the end. A decision is made: tubes are connected, machines whir into life, pumps shuffle back and forth. Ice-cold fluid flows through your veins, chilling them. Eventually, your heart stops beating, your lungs no longer draw breath. Your frigid body remains there, balanced on the knife-edge of life and death, neither fully one nor the other, as if frozen in time.
The surgeons continue their work, clamping, suturing, repairing. Then the pumps stir into life, coursing warm blood back into your body. You will be resuscitated. And, if all goes well, you will live.
Novel Protein Fragments May Protect Against Alzheimer’s
The devastating loss of memory and consciousness in Alzheimer’s disease is caused by plaque accumulations and tangles in neurons, which kill brain cells. Alzheimer’s research has centered on trying to understand the pathology as well as the potential protective or regenerative properties of brain cells as an avenue for treating the widespread disease.
Now Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of Tel Aviv University’s Sagol School of Neuroscience, has discovered novel protein fragments that have proven protective properties for cognitive functioning.
In a study published in the Journal of Alzheimer’s Disease, Prof. Gozes examined the protective effects of two newly discovered protein fragments in mice afflicted with Alzheimer’s disease-like symptoms. Her findings have the potential to serve as a pipeline for new drug candidates to treat the disease.
NAP time for Alzheimer’s
"Several years ago we discovered that NAP, a snippet of a protein essential for brain formation, which later showed efficacy in Phase 2 clinical trials in mild cognitive impairment patients, a precursor to Alzheimer’s," said Prof. Gozes. "Now, we’re investigating whether there are other novel NAP-like sequences in other proteins. This is the question that led us to our discovery."
Prof. Gozes’ research focused on the microtubule network, a crucial part of cells in our bodies. Microtubules act as a transportation system within nerve cells, carrying essential proteins and enabling cell-to-cell communications. But in neurodegenerative diseases like Alzheimer’s, ALS, and Parkinson’s, this network breaks down, hindering motor abilities and cognitive function.
"NAP operates through the stabilization of microtubules — tubes within the cell which maintain cellular shape. They serve as ‘train tracks’ for movement of biological material," said Prof. Gozes. "This is very important to nerve cells, because they have long processes and would otherwise collapse. In Alzheimer’s disease, these microtubules break down. The newly discovered protein fragments, just like NAP before them, work to protect microtubules, thereby protecting the cell."
Down the tubes
In her new study, Prof. Gozes and her team looked at the subunit of the microtubule — the tubulin — and the protein TAU (tubulin-associated unit), important for assembly and maintenance of the microtubule. Abnormal TAU proteins form the tangles that contribute to Alzheimer’s; increased tangle accumulation is indicative of cognitive deterioration. Prof. Gozes decided to test both the tubulin and the TAU proteins for NAP-like sequences. After confirming NAP-like sequences in both tubulin subunits and in TAU, she tested the fragments in tissue cultures for nerve-cell protecting properties against amyloid peptides, the cause of plaque build up in Alzheimer patients’ brains.
"From the tissue culture, we moved to a 10-month-old transgenic mouse model with frontotemporal dementia-like characteristics, which exhibits TAU pathology and cognitive decline," said Prof. Gozes. "We tested one compound — a tubulin fragment — and saw that it protected against cognitive deficits. When we looked at the ‘dementia’-afflicted brain, there was a reduction in the NAP parent protein, but upon treatment with the tubulin fragment, the protein was restored to normal levels."
Prof. Gozes and her team also measured the brain-to-body mass ratio, an indicator of brain degeneration, and saw a significant decrease in the mouse model compared to normal mice. Following the introduction of the tubulin fragments, however, the mouse’s brain to body ratio returned to normal. “We clearly see here the protective effect of the treatment,” said Prof. Gozes. “We witnessed the restorative and protective effects of totally new protein fragments, derived from proteins critical to cell function, in tissue cultures and on animal models.”
(Image: Getty Images)