Posts tagged science

ScienceDaily (June 22, 2012) — The gene p53 is the most commonly mutated gene in cancer. p53 is dubbed the “guardian of the genome” because it blocks cells with damaged DNA from propagating and eventually becoming cancerous. However, new research led by Ute M. Moll, M.D., Professor of Pathology at Stony Brook University School of Medicine, and colleagues, uncovers a novel role for p53 beyond cancer in the development of ischemic stroke. The research team identified an unexpected critical function of p53 in activating necrosis, an irreversible form of tissue death, triggered during oxidative stress and ischemia.

Dr. Ute Moll, Professor of Pathology, has uncovered a novel role for p53 in the development of ischemic stroke. (Credit: Image courtesy of Stony Brook Medicine)

The findings are detailed online in Cell.

Ischemia-associated oxidative damage leads to irreversible necrosis which is a major cause of catastrophic tissue loss. Elucidating its signaling mechanism is of paramount importance. p53 is a central cellular stress sensor that responds to multiple insults including oxidative stress and is known to orchestrate apoptotic and autophagic types of cell death. However, it was previously unknown whether p53 can also activate oxidative stress-induced necrosis, a regulated form of cell death that depends on the mitochondrial permeability transition pore (PTP) pore.

"We identified an unexpected and critical function of p53 in activating necrosis: In response to oxidative stress in normal healthy cells, p53 accumulates in the mitochondrial matrix and triggers the opening of the PTP pore at the inner mitochondrial membrane, leading to collapse of the electrochemical gradient and cell necrosis," explains Dr. Moll. "p53 acts via physical interaction with the critical PTP regulator Cyclophylin D (CypD). This p53 action occurs in cultured cells and in ischemic stroke in mice. "

Of note, they found in their model that when the destructive p53-CypD complex is blocked from forming by using Cyclosporine-A type inhibitors, the brain tissue is strongly protected from necrosis and stroke is prevented.

"The findings fundamentally expand our understanding of p53-mediated cell death networks," says Dr. Moll. "The data also suggest that acute temporary blockade of the destructive p53-CypD complex with clinically well-tolerated Cyclosporine A-type inhibitors may lead to a therapeutic strategy to limit the extent of an ischemic stroke in patients."

"p53 is one of the most important genes in cancer and by far the most studied," says Yusuf A. Hannun, M.D., Director of the Stony Brook University Cancer Center, Vice Dean for Cancer Medicine, and the Joel Kenny Professor of Medicine at Stony Brook. "Therefore, this discovery by Dr. Moll and her colleagues in defining the mechanism of a new p53 function and its importance in necrotic injury and stoke is truly spectacular."

Dr. Moll has studied p53 for 20 years in her Stony Brook laboratory. Her research has led to numerous discoveries about the function of p53 and two related genes. For example, previous to this latest finding regarding p53 and stroke, Dr. Moll identified that p73, a cousin to p53, steps in as a tumor suppressor gene when p53 is lost and can stabilize the genome. She found that p73 plays a major developmental role in maintaining the neural stem cell pool during brain formation and adult learning. Her work also helped to identify that another p53 cousin, called p63, has a critical surveillance function in the male germ line and likely contributed to the evolution of humans and great apes, enabling their long reproductive periods.

Source: Science Daily

ScienceDaily (June 22, 2012) — Scientists have discovered that plant compounds from a South African flower may in time be used to treat diseases originating in the brain — including depression. At the University of Copenhagen, a number of these substances have now been tested in a laboratory model of the blood-brain barrier.

Crinum from South Africa. (Credit: Gary I. Stafford)

Scientists at the University of Copenhagen have previously documented that substances from the South African plant species Crinum and Cyrtanthus — akin to snowdrops and daffodils — have an effect on the mechanisms in the brain that are involved in depression. This research has now yielded further results, since a team based at the Faculty of Health and Medical Sciences has recently shown how several South African daffodils contain plant compounds whose characteristics enable them to negotiate the defensive blood-brain barrier that is a key challenge in all new drug development.

"Several of our plant compounds can probably be smuggled past the brain’s effective barrier proteins. We examined various compounds for their influence on the transporter proteins in the brain. This study was made in a genetically-modified cell model of the blood-brain barrier that contains high levels of the transporter P-glycoprotein. Our results are promising, and several of the chemical compounds studied should therefore be tested further, as candidates for long-term drug development," says Associate Professor Birger Brodin.

"The biggest challenge in medical treatment of diseases of the brain is that the drug cannot pass through the blood-brain barrier. The blood vessels of the brain are impenetrable for most compounds, one reason being the very active transporter proteins. You could say that the proteins pump the drugs out of the cells just as quickly as they are pumped in. So it is of great interest to find compounds that manage to ‘trick’ this line of defence."

The results of the study have been published in the Journal of Pharmacy and Pharmacology.

It will nonetheless be a long time before any possible new drug reaches our pharmacy shelves: “This is the first stage of a lengthy process, so it will take some time before we can determine which of the plant compounds can be used in further drug development,” says Birger Brodin.

Yet this does not curb his enthusiasm for the opportunities from the interdisciplinary cooperation with organic scientists from the Department of Drug Design and Pharmacology and the Natural History Museum of Denmark.

"In my research group, we have had a long-term focus on the body’s barrier tissue — and in recent years particularly the transport of drug compounds across the blood-brain barrier. More than 90 per cent of all potential drugs fail the test by not making it through the barrier, or being pumped out as soon as they do get in. Studies of natural therapies are a valuable source of inspiration, giving us knowledge that can also be used in other contexts," Birger Brodin emphasises.

Source: Science Daily

June 22, 2012 By Virat Markandeya

Listening to a single voice in a crowded cocktail party sometimes seems like picking a needle out of a haystack, but new research shows that people may be better at this than expected.

New research shows that people can comprehend one sound among many.

The results surprised the University of Washington, Seattle, research team, which tested how well people could pick out one sound from a dense collection of noises.

The researchers asked ten subjects to listen to multiple streams of letters. A stream consisted of a repeating letter, for example, Q-Q-Q-Q. If four streams were played, the listener heard four different repeating letters, say, D, C, Q and J. The letters came fast —the time interval between each letter was just one-twelfth of a second.

In front of the listener was a computer screen. Before the start of each trial, the researchers put one of the four letters on the screen to prime the subject to focus on it. If he heard an oddball letter in that stream, such as R instead of Q, he was to press a button.

To make it easier on the listener, each letter stream carried a different pitch and came from a different location in the room. R was chosen as the oddball because it doesn’t rhyme with any other letter.  

"Unlike most experiments where you try to make it difficult for the listener to do the task, we tried to give every advantage we could," said Adrian K.C. Lee, a speech and hearing researcher at the university, who worked closely with Ross Maddox.

As expected, when the number of streams went up, the ability to discern the letter came down. But even with 12 streams the letter was identified correctly around 70 percent of the time.

"We expected that 12 streams would have broken the upper limits of the [subject’s hearing] system," said Lee. "It is surprising that even with twelve things coming at you at the same time you can lock on to one with reasonably high accuracy."

The work was presented last month at the Acoustics 2012 Hong Kong conference.

Down the line, the researchers want to use these experiments to design a way for paralyzed patients to control a wheelchair or a computer using brain signals. Such devices, called brain-computer interfaces, have mostly relied on visual or motor stimuli. Typically, a subject might focus on a visual cue or imagine making a movement. Using a machine that detects brain signals, such as an electroencephalogram, researchers would attempt to characterize the brain responses connected with that task and translate them into commands. Focusing on an auditory signal too produces brain signals that can be characterized. However, the current study did not look at brain signals.

A very practical reason to look at auditory interfaces is that eye-gaze control — on which visually-controlled interfaces are based — is often absent in people in a late stage of a neurodegenerative disease, said Martijn Schreuder, a researcher at the Berlin Institute of Technology.

Schreuder, who has worked on an interface where subjects spelled words by focusing on particular sounds, pointed out that auditory interfaces allow someone who is completely blind to communicate.

Schreuder said Lee’s work provides hints on “whether or not it’s good or bad to have different [audio] streams or whether it is good to have a quicker repetition or not.” To his knowledge, this is the first time researchers have gone up to 12 streams. Previous research included only two streams.

The other part Schreuder found interesting was how quickly the listeners learned how to discriminate between letter streams.

"There is a difference between being able to spell one letter every two minutes or spelling three letters per minute, which is the range [brain-computer interfaces] go," Schreuder said. "So if one selection takes 20 seconds, it’s worse than if it goes 10 seconds."

The University of Washington researchers are planning follow-up experiments to directly investigate how the brain responds to audio streams.

Provided by Inside Science News Service

Source: medicalxpress.com

June 22nd, 2012

New research suggests that it is possible to suppress emotional autobiographical memories. The study published this month by psychologists at the University of St Andrews reveals that individuals can be trained to forget particular details associated with emotional memories.

The important findings may offer exciting new potential for therapeutic interventions for individuals suffering from emotional disorders, such as depression and post-traumatic stress disorder.

The research showed that although individuals could still accurately recall the cause of the event, they could be trained to forget the consequences and personal meaning associated with the memory.

The work was carried out by researchers Dr Saima Noreen and Professor Malcolm MacLeod of the University’s School of Psychology. Lead author Dr Noreen explained, “The ability to remember and interpret emotional events from our personal past forms the basic foundation of who we are as individuals.

Research is starting to show that autobiographical memories may be forgotten. This image is adapted from a photograph of a painting. Both are in the public domain. The original painting is translated as The Break-Up Letter and was painted by Alfred Émile Léopold Stevens (ca 1867).

“These novel findings show that individuals can be trained to not think about memories that have personal relevance and significance to them and provide the most direct evidence to date that we possess some kind of control over autobiographical memory.”

The research involved participants generating emotional memories in response to generic cue words, such as theatre, barbecue, wildlife etc. Participants were asked to recall the cause of the event, the consequence of the event and the personal meaning they derived from the event.

Subjects were then asked to provide a single word that was personal to them which reminded them of the memory. In a subsequent session, participants were shown the cue and personal word pairings and were asked to either recall the memory associated with the word pair or to not think about the associated memory.

Interestingly, the findings revealed that whilst the entire autobiographical episode was not forgotten, the details associated with the memory were. Specifically, individuals could remember what caused the event, but were able to forget what happened and how it made them feel.

Co-author Professor MacLeod commented, “The capacity to engage in this kind of intentional forgetting may be critical to our ability to maintain coherent images about who we are and what we are like”.

Source: Neuroscience News

June 22, 2012

The hormone oxytocin - often referred to as the “trust” hormone or “love hormone” for its role in stimulating emotional responses - plays an important role in Williams syndrome (WS), according to a study published June 12, 2012, in PLoS One.

The study, a collaboration between scientists at the Salk Institute for Biological Studies and the University of Utah, found that people with WS flushed with the hormones oxytocin and arginine vasopressin (AVP) when exposed to emotional triggers.

The findings may help in understanding human emotional and behavioral systems and lead to new treatments for devastating illnesses such as WS, post-traumatic stress disorder, anxiety and possibly even autism.

“Williams syndrome results from a very clear genetic deletion, allowing us to explore the genetic and neuronal basis of social behavior,” says Ursula Bellugi, the director of Salk’s Laboratory for Cognitive Neuroscience and a co-author on the paper. “This study provides us with crucial information about genes and brain regions involved in the control of oxytocin and vasopressin, hormones that may play important roles in other disorders.”

WS arises from a faulty recombination event during the development of sperm or egg cells. As a result, virtually everyone with WS has exactly the same set of genes missing (25 to 28 genes are missing from one of two copies of chromosome 7). There also are rare cases of individuals who retain one or more genes that most people with the disorder have lost.

To children with WS, people are much more comprehensible than inanimate objects. Despite myriad health problems they are extremely gregarious, irresistibly drawn to strangers, and insist on making eye contact. They have an affinity for music. But they also experience heightened anxiety, have an average IQ of 60, experience severe spatial-visual problems, and suffer from cardiovascular and other health issues. Despite their desire to befriend people, they have difficulty creating and maintaining social relationships, something that is not at all understood but can afflict many people without WS.

In the new study, led by Dr. Julie R. Korenberg, a University of Utah professor and Salk adjunct professor, the scientists conducted a trial with 21 participants, 13 who have WS and a control group of eight people without the disorder. The participants were evaluated at the Cedars-Sinai Medical Center in Los Angeles. Because music is a known strong emotional stimulus, the researchers asked participants to listen to music.

Before the music was played, the participants’ blood was drawn to determine a baseline level for oxytocin, and those with WS had three times as much of the hormone as those without the syndrome. Blood also was drawn at regular intervals while the music played and was analyzed afterward to check for real-time, rapid changes in the levels of oxytocin and AVP. Other studies have examined how oxytocin affects emotion when artificially introduced into people, such as through nasal sprays, but this is one of the first significant studies to measure naturally occurring changes in oxytocin levels in rapid, real time as people undergo an emotional response.

There was little outward response to the music, but when the blood samples were analyzed, the researchers were happily surprised. The analyses showed that the oxytocin levels, and to a lesser degree AVP, had not only increased but begun to bounce among WS participants while among those without WS, both the oxytocin and AVP levels remained largely unchanged as they listened to music.

Korenberg believes the blood analyses strongly indicate that oxytocin and AVP are not regulated correctly in people with WS, and that the behavioral characteristics unique to people with WS are related to this problem.

"This shows that oxytocin quite likely is very involved in emotional response," Korenberg says.

To ensure accuracy of results, those taking the test also were asked to place their hands in 60-degree Fahrenheit water to test for negative stress, and the same results were produced as when they listened to music. Those with WS experienced an increase in oxytocin and AVP, while those without the syndrome did not.

In addition to listening to music, study participants already had taken three social behavior tests that evaluate willingness to approach and speak to strangers, emotional states, and various areas of adaptive and problem behavior. Those test results suggest that increased levels of oxytocin are linked to both increased desire to seek social interaction and decreased ability to process social cues, a double-edged message that may be very useful at times, for example, during courtship, but damaging at others, as in WS.

"The association between abnormal levels of oxytocin and AVP and altered social behaviors found in people with Williams Syndrome points to surprising, entirely unsuspected deleted genes involved in regulation of these hormones and human sociability," Korenberg said. "It also suggests that the simple characterization of oxytocin as ‘the love hormone’ may be an overreach. The data paint a far more complicated picture."

In particular, the study results indicate that the missing genes affect the release of oxytocin and AVP through the hypothalamus and the pituitary gland. About the size of a pearl, the hypothalamus is located just above the brain stem and produces hormones that control body temperature, hunger, mood, sex drive, sleep, hunger and thirst, and the release of hormones from many glands, including the pituitary. The pituitary gland, about the size of a pea, controls many other glands responsible for hormone secretion.

Overall, the researchers say, their findings paint a very hopeful picture, and the study holds promise for speeding progress in treating WS, and perhaps Autism and anxiety through regulation of these key players in human brain and emotion, oxytocin and vasopressin.

Provided by Salk Institute

Source: medicalxpress.com

June 22, 2012

Neuropsychiatric conditions such as autism, schizophrenia and epilepsy involve an imbalance between two types of synapses in the brain: excitatory synapses that release the neurotransmitter glutamate, and inhibitory synapses that release the neurotransmitter GABA. Little is known about the molecular mechanisms underlying development of inhibitory synapses, but a research team from Japan and Canada has reported that a molecular signal between adjacent neurons is required for the development of inhibitory synapses.

Figure 1: Compared with the brains of normal animals (left), mice lacking the Slitrk3 gene (right) have a reduced density of inhibitory synapses in the hippocampus. Reproduced from Ref. 1 © 2012 Jun Aruga, RIKEN Brain Science Institute

In earlier work, the researchers—led by Jun Aruga of the RIKEN Brain Science Institute, Wako, and Ann Marie Craig of the University of British Colombia, Vancouver—showed that a membrane protein called Slitrk2 organizes signaling molecules at synapses. They therefore tested whether five related proteins are involved in inhibitory synapse development. They cultured immature hippocampal neurons with non-neural cells expressing each of the six Slitrk proteins. They found that Slitrk3, but not other Slitrk proteins, induced clustering of VGAT, a GABA transporter protein found only at inhibitory synapses.

The researchers also examined the localization of Slitrk3 by tagging it with yellow fluorescent protein and introducing it into cultured hippocampal cells. This revealed that Slitrk3 co-localizes in the dendrites of neurons with gephyrin, a scaffold protein found only in inhibitory synapses. They then blocked Slitrk3 synthesis, and found that it led to a significant reduction in the number of inhibitory synapses.

To confirm these findings, the researchers generated a strain of genetically engineered mice lacking the Slitrk3 gene. These animals had significantly fewer inhibitory synapses than normal animals (Fig. 1), and therefore impaired neurotransmission of GABA. They were also susceptible to epileptic seizures. From a screen for proteins that bind to Slitrk3, Aruga, Craig and colleagues identified the protein PTPδ as its only binding partner. Introduction of PTPδ fused to yellow fluorescent protein to cultured hippocampal neurons showed that it is expressed in neuronal dendrites and cell bodies, but not in axons. Blocking PTPδ synthesis prevented the induction of inhibitory synapses by the Slitrk3 protein.

These results demonstrated that the interaction between Slitrk3 on dendrites and PTPδ on axons of adjacent cells is required for the proper development of inhibitory synapses and for inhibitory neurotransmission in the brain.

“We are now examining whether the balance of excitatory and inhibitory synapses is affected by other members of the Slitrk protein family,” says Aruga. “It is possible that Slitrk3 and other Slitrk proteins are acting synergistically or antagonistically. We are also clarifying whether Slitrk3 is involved in any neurological disorders.”

Provided by RIKEN

Source: medicalxpress.com

ScienceDaily (June 21, 2012) — Preventing diabetes or delaying its onset has been thought to stave off cognitive decline — a connection strongly supported by the results of a 9-year study led by researchers at the University of California, San Francisco (UCSF) and the San Francisco VA Medical Center.

Earlier studies have looked at cognitive decline in people who already had diabetes. The new study is the first to demonstrate that the greater risk of cognitive decline is also present among people who develop diabetes later in life. It is also the first study to link the risk of cognitive decline to the severity of diabetes.

The result is the latest finding to emerge from the Health, Aging, and Body Composition (Health ABC) Study, which enrolled 3,069 adults over 70 at two community clinics in Memphis, TN and Pittsburgh, PA beginning in 1997. All the patients provided periodic blood samples and took regular cognitive tests over time.

When the study began, hundreds of those patients already had diabetes. A decade later, many more of them had developed diabetes, and many also suffered cognitive decline. As described this week in Archives of Neurology, those two health outcomes were closely linked.

People who had diabetes at the beginning of the study showed a faster cognitive decline than people who developed it during the course of the study — and these people, in turn, tended to be worse off than people who never developed diabetes at all. The study also showed that patients with more severe diabetes who did not control their blood sugar levels as well suffered faster cognitive declines.

"Both the duration and the severity of diabetes are very important factors," said Kristine Yaffe, MD, the lead author of the study. "It’s another piece of the puzzle in terms of linking diabetes to accelerated cognitive aging."

An important question for future studies, she added, would be to ask if interventions that would effectively prevent, delay or better control diabetes would also lower people’s risk of cognitive impairment later in life.

Yaffe is the Roy and Marie Scola Endowed Chair of Psychiatry; professor in the UCSF departments of Psychiatry, Neurology and Epidemiology and Biostatistics; and Chief of Geriatric Psychiatry and Director of the Memory Disorders Clinic at the San Francisco VA Medical Center.

Diabetes and Cognitive Decline

Diabetes is a chronic and complex disease marked by high levels of sugar in the blood that arise due to problems with the hormone insulin, which regulates blood sugar levels. It is caused by an inability to produce insulin (type 1) or an inability to respond correctly to insulin (type 2).

A major health concern in the United States, diabetes of all types affects an estimated 8.3 percent of the U.S. population — some 25.8 million Americans — and costs U.S. taxpayers more than $200 billion annually. In California alone, an estimated 4 million people (one out of every seven adults) has type 2 diabetes and millions more are at risk of developing it. These numbers are poised to explode in the next half century if more is not done to prevent the disease.

Over the last several decades, scientists have come to appreciate that diabetes affects many tissues and organs of the body, including the brain and central nervous system — particularly because diabetes places people at risk of cognitive decline later in life.

In their study the scientists looked at a blood marker known as “glycosylated hemoglobin,” a standard measure of the severity of diabetes and the ability to control it over time. The marker shows evidence of high blood sugar because these sugar molecules become permanently attached to hemoglobin proteins in the blood. Yaffe and her colleagues found that greater levels of this biomarker were associated with more severe cognitive dysfunction.

While the underlying mechanism that accounts for the link between diabetes and risk of cognitive decline is not completely understood, Yaffe said, it may be related to a human protein known as insulin degrading enzyme, which plays an important role in regulating insulin, the key hormone linked to diabetes. This same enzyme also degrades a protein in the brain known as beta-amyloid, a brain protein linked to Alzheimer’s disease.

Source: Science Daily

ScienceDaily (June 21, 2012) — Scientists have developed a small-molecule-inhibiting drug that in early laboratory cell tests stopped breast cancer cells from spreading and also promoted the growth of early nerve cells called neurites.

Researchers from Cincinnati Children’s Hospital Medical Center report their findings online June 21 in Chemistry & Biology. The scientists named their lead drug candidate “Rhosin” and hope future testing shows it to be promising for the treatment of various cancers or nervous system damage.

The inhibitor overcomes a number of previous scientific challenges by precisely targeting a single component of a cell signaling protein complex called Rho GTPases. This complex regulates cell movement and growth throughout the body. Miscues in Rho GTPase processes are also widely implicated in human diseases, including various cancers and neurologic disorders.

"Although still years from clinical development, in principle Rhosin could be useful in therapy for many kinds of cancer or possibly neuron and spinal cord regeneration," said Yi Zheng, PhD, lead investigator and director of Experimental Hematology and Cancer Biology at Cincinnati Children’s. "We’ve performed in silica (computerized) rational drug design, pharmacological characterization and cell tests in the laboratory, and we are now starting to work with mouse models."

Because the role of Rho GTPases in cellular processes and cancer formation is well established, researchers have spent years trying to identify safe and effective therapeutic targets for specific parts of the protein complex. In particular, scientists have focused on the center protein in the complex called RhoA, which is essential for the signaling function of the complex. In breast cancer for example, increased RhoA activity makes the cancer cells more invasive and causes them to spread, while a deficiency of RhoA suppresses cancer growth and progression.

Despite this knowledge, past efforts to develop an effective small-molecule inhibitor for RhoA have failed, explained Zheng, who has studied Rho GTPases for over two decades. Most roadblocks stem from a lack of specificity in how researchers have been able to target RhoA, a resulting lack of efficiency in affecting molecular processes, problems with toxicity, and the inability to find a workable drug design.

For the current study, Zheng and his colleagues started with the extensive body of research from Cincinnati Children’s and other institutions describing the processes and functions of Rho GTPases. They then used high-throughput computerized molecular screening and computerized drug design to reveal a druggable target site. This also provided a preliminary virtual simulation on the potential effectiveness of candidate drugs.

A key challenge to binding a small-molecule inhibitor to RhoA is the protein’s globular structure and lack of surface pocket areas suitable for easy binding, Zheng said. The unique chemical structure of the lead compound identified by researchers, Rhosin, allows it to effectively bind to two shallow surface grooves on RhoA. This enables the candidate drug to take root and begin affecting cells. The two-legged configuration of Rosin also describes a useful drug design strategy for more effectively targeting difficult molecular sites like RhoA.

The researchers also wanted to make sure Rhosin effectively blocked what are known as guanine nucleotide exchange factors (GEFs). Guanine nucleotide is a critical energy source and signaling component of cells. Activation of GEFs is required to set off the regulatory signaling of GTPases (GTP stands for guanosine triphosphate).

After conducting a series of laboratory cell tests to verify the targeting and binding capabilities of Rhosin to RhoA, the researchers then tested the candidate drug’s impact on cultured breast cancer cells and nerve cells.

In tests on a human breast cancer cells, Rhosin inhibited cell growth and the formation of mammary spheres in a dose dependent manner, acting specifically on RhoA molecular targets without disrupting other critical cellular processes. Rhosin does not affect non-cancerous breast cells. This, along with other tests the scientists performed, indicated Rhosin’s effectiveness in targeting RhoA-mediated breast cancer proliferation, according to the researchers.

Researchers also treated an extensively tested line of neuronal cells with Rhosin, along with nerve growth factor, a protein that is important to the growth and survival of neurons. Rhosin worked with nerve growth factor in a dose-dependent way to promote the proliferation of branching neurites from the neuronal cells. Neurites are young or early stage extensions from neurons required for neuronal communications.

Source: Science Daily