Structure of Neuron-Connecting Synaptic Adhesion Molecules Discovered

Figure 1: Overview of the PTPd Ig1–3/Slitrk1 LRR1 complex. Copyright : Korea Advanced Institute of Science and Technology

A research team has found the three-dimensional structure of synaptic adhesion molecules, which orchestrate synaptogenesis. The research findings also propose the mechanism of synapses in its initial formation.

Some brain diseases such as obsessive compulsive disorder (OCD) or bipolar disorders arise from a malfunction of synapses. The team expects the findings to be applied in investigating pathogenesis and developing medicines for such diseases.

The research was conducted by a Master’s candidate Kee Hun Kim, Professor Ji Won Um from Yonsei University, and Professor Beom Seok Park from Eulji University under the guidance of Professor Homin Kim from the Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), and Professor Jaewon Ko from Yonsei University. Sponsored by the Ministry of Science, ICT and Future Planning and the National Research Foundation of Korea, the research findings were published online in the November 14th issue of Nature Communications.

Figure 2: Representative negative-stained electron microscopy images of Slitrk1 Full ectodomain (yellow arrows indicate the horseshoe-shaped LRR domains). The typical horseshoe-shaped structures and the randomness of the relative positions of each LRR domain can be observed from the two-dimensional class averages displayed in the orange box. Copyright : Korea Advanced Institute of Science and Technology

A protein that exists in the neuronal transmembrane, Slitrk, interacts with the presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) and forms a protein complex. It is involved in the development of synapses in the initial stage, and balances excitatory and inhibitory signals of neurons.

It is known that a disorder in those two proteins cause a malfunction of synapses, resulting in neuropsychosis such as autism, epilepsy, OCD, and bipolar disorders. However, because the structure as well as synaptogenic function of these proteins were not understood, the development of cures could not progress.

The research team discovered the three-dimensional structure of two synaptic adhesion molecules like Slitrk and LAR-RPTPs and identified the regions of interaction through protein crystallography and transmission electron microscopy (TEM). Furthermore, they found that the formation of the synapse is induced after the combination of two synaptic adhesion molecules develops a cluster.

Figure 3: Model of the two-step presynaptic differentiation process mediated by the biding of Slitrks to LAR-RPTPs and subsequent lateral assembly of trans-synaptic LAR-RPTPs/Slitrik complexes. Copyright : Korea Advanced Institute of Science and Technology

Professor Kim said, “The research findings will serve as a basis of understanding the pathogenesis of brain diseases which arises from a malfunction of synaptic adhesion molecules. In particular, this is a good example in which collaboration between structural biology and neurobiology has led to a fruitful result.” Professor Ko commented that “this will give new directions to synaptic formation-related-researches by revealing the molecular mechanism of synaptic adhesion molecules.”

Source: KAIST

Gene discovered that reduces risk of stroke

Lab microscope (stock image). The discovery of a gene that protects people against one of the major causes of stroke could lead to new treatments and prevention strategies for the disease.
Credit: © 18percentgrey / Fotolia

Scientists have discovered a gene that protects people against one of the major causes of stroke in young and middle-aged adults and could hold the key to new treatments.

Researchers from Royal Holloway, University of London, together with an international team from across the United States and Europe, have found that people with a specific variant of a gene, known as PHACTR1, are at reduced risk of suffering cervical artery dissection, which is caused by a tear in an artery that leads to the brain.

The new discovery, published in the journal Nature Genetics, could lead to new treatments and prevention strategies for the disease, which is a major cause of stroke in young adults. The same gene variant has also been identified as a protector against migraines and affects the risk of heart attack.

Professor Pankaj Sharma, from the School of Biological Sciences at Royal Holloway, said: "This is an important breakthrough. Our findings provide us with a greater understanding of how this region of the genome appears to influence key vascular functions, which could have major implications for the treatment of these severe and disabling conditions. "

In the largest study of its kind ever undertaken, researchers from around the world screened the entire genome of 1,400 patients with cervical artery dissection, along with 14,400 people without the disease. Cervical artery dissection can lead to compression of adjacent nerves and to blood clotting, potentially causing blockage of vessels and brain damage.

Professor Sharma, Professor of Clinical Neurology at Royal Holloway, added: "Further genetic analyses and worldwide collaborations of this kind provide hope of pinpointing the underlying mechanisms that cause stroke. The Bio-Repository of DNA in Stroke (BRAINS) study I am leading is creating a large stroke DNA biobank which will give an exciting opportunity to identify the genes directly linked to the condition."

Source: University of Royal Holloway London

New genetic clues found in fragile X syndrome

Research by Vitaly Klyachko, PhD, and colleagues has shed new light on brain dysfunctions associated with fragile X syndrome. Credit: Robert Boston

Scientists have gained new insight into fragile X syndrome -- the most common cause of inherited intellectual disability -- by studying the case of a person without the disorder, but with two of its classic symptoms.

In patients with fragile X, a key gene is completely disabled, eliminating a protein that regulates electrical signals in the brain and causing a host of behavioral, neurological and physical symptoms. This patient, in contrast, had only a single error in this gene and exhibited only two classic traits of fragile X -- intellectual disability and seizures -- allowing the researchers to parse out a previously unknown role for the gene.

"This individual case has allowed us to separate two independent functions of the fragile X protein in the brain," said co-senior author Vitaly A. Klyachko, PhD, associate professor of cell biology and physiology at Washington University School of Medicine in St. Louis. "By finding the mutation, even in just one patient, and linking it to a partial set of traits, we have identified a distinct function that this gene is responsible for and that is likely impaired in all people with fragile X."

The research, appearing in the Proceedings of the National Academy of Sciences (PNAS) Online Early Edition in December and in the print issue Jan. 5, is by investigators at Washington University and Emory University School of Medicine in Atlanta.

In studying fragile X, researchers' focus long has been on the problems that occur when brain cells receive signals. Like radio transmitters and receivers, brain cells send and receive transmissions in fine tuned ways that separate the signals from the noise. Until recently, most fragile X research has focused on problems with overly sensitive receivers, those that allow in too much information. The new study suggests that fragile X likely also causes overactive transmitters that send out too much information.

"The mechanisms that researchers have long thought were the entirety of the problem with fragile X are obviously still very much in play," Klyachko said. "But this unique case has allowed us to see that something else is going on."

The finding also raises the possibility that drugs recently tested as treatments for fragile X may be ineffective, at least in part, because they only dialed down the brain's receivers, presumably leaving transmitters on overdrive.

Fragile X syndrome results from an inherited genetic error in a gene called FMR1. The error prevents the manufacture of a protein called FMRP. Loss of FMRP is known to affect how cells in the brain receive signals, dialing up the amount of information allowed in. The gene is on the X chromosome, so the syndrome affects males more often and more severely than females, who may be able to compensate for the genetic error if their second copy of FMR1 is normal.

Patients with fragile X have a range of symptoms. One of the mysteries of the syndrome is how loss of a single gene can lead to such a variety of effects in different patients. Some patients are profoundly intellectually disabled, unable to talk or communicate. Others are only mildly affected. Patients often experience seizures, anxiety and impulsive behavior. Typical physical symptoms include enlarged heads, flat feet and distinctive facial features. 

Almost one-third of patients with fragile X also show symptoms of autism spectrum disorders.

To gain insight into what else FMRP might do, the researchers plumbed genetic sequencing data from more than 900 males with intellectual disabilities but without classic fragile X syndrome. They looked for mutations in the FMR1 gene that might impair the protein but not eliminate it entirely. Even in this relatively large sample size, they only found one patient with abnormal FMRP, resulting from a change in a single letter of the gene's DNA code.

Importantly, although this individual has intellectual disability and seizures, his physical features are not typical of the syndrome, and he is not autistic.

To see what effect this mutation might have, geneticist Stephen T. Warren, PhD, and his team at Emory replicated it in mouse brain cells and tested it for the widely known functions of FMRP. To their surprise, this mutated FMRP appeared to work normally. In other words, the patient's brain cells had entirely normal receivers, which appeared to work in ways that were indistinguishable from those in healthy people.

"This single point mutation does not seem to affect the classical, well-known functions of FMRP," said Klyachko, also an associate professor of biomedical engineering. "This patient presents a case of partial fragile X syndrome associated with mutated, rather than absent, FMRP. As far as I know, this is the only known case of this. It's a unique opportunity to parse out the functions of FMRP. What does this mutation impair to cause only two symptoms of fragile X?"

To find out, Warren and his team replicated the mutation in fruit flies.

Surprisingly, according to the researchers, the fruit fly studies indicated that this single mutation increased the number of transmitters in brain cells, implicating a fundamental problem in which the brain's cells send out too many signals.

To verify this mechanism in mammals, they turned to Klyachko's lab at Washington University, which has expertise in understanding how brain cells regulate the sending of electrical signals. Indeed, in past work Klyachko showed that total loss of FMRP in mice disrupts the normal process by which brain cells send signals, causing transmitters to send out too much information. In the new study, they were able to verify the same effect from just the mutation and link it to human disease. This single mutation in FMRP has the same overactivating effect on transmissions as the total loss of the protein.

The researchers said they can't rule out the possibility that additional problems also are caused by this mutation and are present in fragile X. But this research specifies at least one additional dysfunction not previously recognized. Further studies of patients with different partial symptoms of fragile X and different mutations -- if any can be found -- might identify more.

Source: Washington University School of Medicine

Alcohol interferes with body's ability to regulate sleep

At right: Mahesh Thakkar, PhD, associate professor and director of research in the MU School of Medicine’s Department of Neurology, and Pradeep Sahota, MD, chair of the MU School of Medicine’s Department of Neurology, have studied alcohol’s effects on sleep for more than five years. Their study found that drinking interferes with the brain’s built-in system for regulating a person’s need for sleep. Credit: Image courtesy of University of Missouri-Columbia

Researchers from the University of Missouri School of Medicine have found that drinking alcohol to fall asleep interferes with sleep homeostasis, the body's sleep-regulating mechanism.

Alcohol is known to be a powerful somnogen, or sleep inducer, and approximately 20 percent of the U.S. adult population drinks alcohol to help fall asleep. The researchers, led by Mahesh Thakkar, PhD, associate professor and director of research in the MU School of Medicine's Department of Neurology, have studied alcohol's effects on sleep for more than five years. They found that alcohol interferes with the brain's built-in system for regulating a person's need for sleep.

"The prevailing thought was that alcohol promotes sleep by changing a person's circadian rhythm -- the body's built-in 24-hour clock," Thakkar said. "However, we discovered that alcohol actually promotes sleep by affecting a person's sleep homeostasis -- the brain's built-in mechanism that regulates your sleepiness and wakefulness."

Sleep homeostasis balances the body's need for sleep in relation to how long a person has been awake. If an individual loses sleep, the body produces adenosine, a naturally occurring sleep-regulating substance that increases a person's need for sleep. When a person goes to sleep early, sleep homeostasis is shifted and he or she may wake up in the middle of the night or early morning. The researchers found that alcohol alters the sleep homeostatic mechanism and puts pressure on an individual to sleep. When this happens, the sleep period is shifted, and a person may experience disrupted sleep.

"Based on our results, it's clear that alcohol should not be used as a sleep aid," said Pradeep Sahota, MD, chair of the MU School of Medicine's Department of Neurology and an author of the study. "Alcohol disrupts sleep and the quality of sleep is diminished. Additionally, alcohol is a diuretic, which increases your need to go the bathroom and causes you to wake up earlier in the morning."

In addition to studying alcohol's impact on sleep homeostasis, the researchers explored how alcohol withdrawal affects sleep. The investigators found that after extended periods of frequent drinking, subjects would fall asleep as expected, but would wake within a few hours and would be unable to fall back asleep. When the subjects were not given alcohol, the researchers found that subjects showed symptomatic insomnia.

"During acute alcohol withdrawal, subjects displayed a significant increase in wakefulness with a reduction in rapid eye movement and non-rapid eye movement sleep," Thakkar said. "This caused insomnia-like symptoms and suggests an impaired sleep homeostasis."

The researchers hope to use these findings to explore other effects of alcohol consumption.

"Sleep is an immense area of study," Thakkar said. "Approximately one-third of our life is spent sleeping. Coupled with statistics that show 20 percent of people drink alcohol to sleep, it's vital that we understand how the two interact. If you are experiencing difficulty sleeping, don't use alcohol. Talk to your doctor or a sleep medicine physician to determine what factors are keeping you from sleeping. These factors can then be addressed with individualized treatments."

The study, "Alcohol Disrupts Sleep Homeostasis," is an invited article published in the international biomedical journal Alcohol.

Source:  University of Missouri-Columbia

How to sell the drugs of the future

Drugs
Credit: Getty Images

Only a decade ago, basing medical treatment on your DNA seemed like science fiction. Not any more. Thanks in part to the sequencing of the human genome, personalized medicine (PM), a specific course of treatment developed for the individual patient, is now science fact.

PM has already shown its effectiveness in the treatment of cancer, and medical professionals are eager to expand it to treat other chronic diseases. But first patients need to understand how PM can work for them.

Will they buy into it? "Yes -- but only if patients are armed with knowledge about their own disease and understand the relative advantages of PM," says Concordia University marketing professor Lea Prevel Katsanis, the co-author of a new study on the subject, published in the International Journal of Pharmaceutical and Healthcare Marketing. She adds that if patients are going to accept PM, doctor-patient communication is vital.

For the study, Katsanis and her co-author, Anja Hitz, a former John Molson School of Business MBA student and current head of medical compliance and prevention at the Military Hospital in Hamburg, Germany, polled 307 consumers through an online survey. 
They found that knowledge and the relative advantages of PM have the most significant influence on patient acceptance of PM.

"The more a patient knows about how she is being treated, the more likely she is to accept that treatment," says Katsanis. "So it's important to educate consumers on potential benefits and risks associated with PM."

Indeed, patient understanding is a key factor in getting healthcare professionals, governments and insurance companies to adopt and pay for PM, particularly when these targeted treatments are often more costly than traditional medical methods.

With PM, the same drug isn't given to millions of people. It's a targeted treatment regime. While that reduced patient pool means an increased cost, there can be long-term benefits. Increased efficiency and prevention may result in fewer drugs being prescribed. And PM may also result in the reduction of secondary costs as a result of overdosing, incorrect prescriptions and adverse drug reactions.

"If PM can be successfully integrated into the healthcare system at a reasonable cost, it represent a significant improvement in the treatment of chronic disease," says Katsanis.

But she warns that marketers need to proceed with caution: "The promotion of personalized medications will increasingly focus on the healthy patient with a genetic disposition for a particular illness. While this might lead to new and potentially greater opportunities for marketers, it might also result in the targeting of healthy patients who don't actually need treatment for an active disease. Ultimately, this could increase healthcare costs and cause unnecessary patient treatment."

Source: Concordia University

Internet addicts often suffer from additional disorders

Chatting via WhatsApp rather than meeting friends in real life, sharing holiday photos on Facebook rather than showing them in person, playing video games rather than going out. Digital media play an important role in our everyday lives. However, some people spend an excessive amount of time online, and they are unable to break free. Credit: Image courtesy of Ruhr-Universitaet-Bochum

Internet addicts often suffer from concomitant disorders, most frequently from depressive disorders, anxiety disorders and ADHS. PD Dr med. Bert te Wildt studies this phenomenon at the Ruhr-Universität's LWL Clinic for Psychosomatic Medicine and Psychotherapy.

Spectrum of concomitant disorders similar to that in alcohol addicts

The researcher from Bochum has compiled a so-called comorbidity profile of 25 Internet addicts. Each patient presented at least one concomitant disorder. Together with his colleagues, Bert te Wildt examined 25 alcohol addicts for comparison. Their comorbidity profile was quite similar. However, only every other patient in this cohort suffered from a concomitant disorder. "These results highlight the significance of comorbidity for Internet addiction," says te Wildt. He also points out: "This is not a one-way street, the disorders interact." In another study, he found evidence that in a number of patients Internet addiction may be traced back to similar personality structures.

Large numbers presumably undetected

According to estimates, 500,000 Germans in the age bracket from 14 to 64 years suffer from Internet addiction, which most commonly takes the shape of online gaming addiction. The studies conducted by Bert te Wildt's team at the media outpatient clinic in Bochum suggest that many cases remain undetected.

Source: Ruhr-Universitaet-Bochum

A Facebook application knows if you are having a bad day and tells your teacher

Spanish scientists create algorithms to measure sentiment on social networks Computer languages and systems researchers at the Autonomous University of Madrid have developed an application called SentBuk, which is capable of deducing the emotional states of Facebook users by analysing their messages using algorithms. The authors believe that this tool could be useful to online educators, as it would furnish them with similar information to that obtained by in-person teachers when they look at their students’ faces.

Computer languages and systems researchers at the Autonomous University of Madrid have developed an application called SentBuk, which is capable of deducing the emotional states of Facebook users by analysing their messages using algorithms. The authors believe that this tool could be useful to online educators, as it would furnish them with similar information to that obtained by in-person teachers when they look at their students' faces.

Information from social networks is becoming a goldmine for marketing and advertising companies. Now, a team of computer languages and systems researchers at the Autonomous University of Madrid (UAM) has also spotted great potential for analysing the emotions transmitted by users in the most popular of these networks: Facebook.

As Álvaro Ortigosa, Director of the UAM's National Centre of Excellence in Cybersecurity, explains, he and his team have developed an application called SentBuk, which is capable of automatically deducing the emotional states of Facebook users by analysing their messages on the social network using algorithms. The results of the study have been published in the journal Computers in Human Behavior.

"SentBuk is an application external to Facebook which, with the user's permission, analyses the messages he/she publishes and calculates his/her emotional state. The tool is based on two algorithms: the first calculates the emotional load of each message and classifies it as positive, negative or neutral. The second deduces emotional state by comparing it with the emotional load of recent messages."

The tool -Ortigosa continues- "utilises a natural language analysis technique to recognise significant words with emotional load. It also uses an automatic, machine-learning-type classification system. Based on a large bank of sentences classified by humans, the application has been trained to learn to reproduce human judgment. The emotional load assigned to each sentence arises from a combination of both calculations."

Adaptive e-learning

The UAM scientists believe that this application could be used in adaptive online education, i.e. education that attempts to suggest tasks to the student at the most appropriate time.

"The information obtained via SentBuk, with the approval of the user," Ortigosa insists, "will be able to be used to avoid recommending especially complex pieces of work at times when it detects that the student is in a negative state of mind or one that is less positive than usual."

In these situations, by contrast, "activities with less pedagogical content but designed to motivate students could be assigned."

In his opinion, analysing the general trend of a group of students during internet courses "may afford the teacher similar feedback to that obtained by looking at students' faces in an in-person class -- information it is not normally possible to get online."

Field tests

Ortigosa and the study's co-authors have performed tests with SentBuk and have included the information on students' emotional states in an e-learning system.

According to the expert, in its most basic form, the application alerts professors when it detects that a significant number of students are in a negative frame of mind. "These messages are analysed in context. Although there may be many reasons for the emotional state, the hypothesis is that these negative emotions should be uniformly distributed across time."

On the other hand, he adds, the students of an online course have little to no relation to each other, beyond being classmates in that particular course. For this reason, "if at any given moment a negative emotional peak is detected in a representative sample of the students, it is highly probable that such emotional variation is due to some situation relating to the course, and thus the tool will send a warning message to the teacher."

Other applications

Álvaro Ortigosa says that it is a non-intrusive technique that "enables teachers to have an emotional state thermometer for Facebook users." Once all the necessary permissions for the application have been given, it deduces their emotional state by observing the behaviour in their interaction -- presumably normal and spontaneous -- with the social network.

This information could be used in several contexts. "For example, to complement remote monitoring of those who are ill or to measure user satisfaction. In this area, companies could use the information to alter products or services offered to potential consumers.

The UAM team's research is part of a broader project seeking to infer general characteristics, such as personality and emotional load, of those who use social networking sites like Facebook and Twitter.

Source: Plataforma SINC