Lariats: How RNA splicing decisions are made

June 17th, 2012 in Biology / Cell & Microbiology

Lariats are discarded byproducts of RNA splicing, the process by which genetic instructions for making proteins are assembled. A new study has found hundreds more lariats than ever before, yielding new information about how splicing occurs and how it can lead to disease.

Tiny, transient loops of genetic material, detected and studied by the hundreds for the first time at Brown University, are providing new insights into how the body transcribes DNA and splices (or missplices) those transcripts into the instructions needed for making proteins.

The lasso-shaped genetic snippets � they are called lariats � that the Brown team reports studying in the June 17 edition of Nature Structural & Molecular Biology are byproducts of gene transcription. Until now scientists had found fewer than 100 lariats, mostly by poring over very small selections of introns, which are sections of genetic code that do not directly code for proteins, but contain important signals that direct the way protein-coding regions are assembled. In the new study, Brown biologists report that they found more than 800 lariats in a publicly available set of billions of RNA reads derived from human tissues.

"We used modern genomic methods, deep sequencers, to detect these rare intermediates of splicing," said William Fairbrother, associate professor of biology and senior author of the study. "It's the first ever report of these things being discovered at a genome scale in living cells, and it tells us a lot about this step of gene processing."

That specific step is known as RNA splicing. Like film editors splicing together movie scenes, enzymes cut away the introns to assemble exons that instruct a cell's ribosome to make proteins. The body often has a choice of ways and places to make those cuts. Most of what is known about splicing has come from studying these spliced instructions, said Allison Taggart, a graduate student who is lead author of the study. What's been missing is the data hidden in the lariats, which fall apart shortly after being spliced out, but turn out to predict the body's splicing choices.

Modeling splicing

The key information uncovered in the study, Taggart said, is the location of so-called "branchpoints" on the lariats. Physically, the branchpoint is where the lariat closes on itself to form a loop during the first step of splicing, but its position and proximity to possible splice sites, the researchers learned, reliably relate to where splicing will occur.

After studying the sites of these branchpoints and their relationship to splice sites, the researchers created an algorithmic model that could predict splice sites 95.6 percent of the time. The value of the model is not in identifying splice sites � those are already well known, Fairbrother said. Instead, the model's accuracy shows that, with the new data from the lariats, scientists have gained a more general understanding of how the body chooses among alternative splicing sites.

"What it does tell us is sets of rules defining the relationship between branchpoints and the chosen splice sites, which gives clues about how the splicing machinery makes decisions," Taggart said. "Certain branchpoint locations can enforce specific splicing isoforms."

Connections to disease

In addition to ferreting out the mechanisms of alternative splicing, the team also studied the connection between branchpoints and disease. They looked through the Human Gene Mutation Database for disease-causing mutations found in introns and compared their newly found branchpoint sequences to those mutations. They found that many relate specifically to branchpoints.

"We saw a sequence motif that looked exactly like a branchpoint sequence motif," she said. "What this tells us is that these mutations are forming at branchpoints and are leading to disease, presumably through causing aberrant splicing by interfering with lariat formation."

In other words, Fairbrother said, it could well be that a consequence of mutations in branchpoints could be disease.

Provided by Brown University

"Lariats: How RNA splicing decisions are made." June 17th, 2012. http://phys.org/news/2012-06-lariats-rna-splicing-decisions.html

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The risk of carrying a cup of coffee

June 15th, 2012 in Neuroscience
Professor Dagmar Sternad and postdoctoral researcher C.J. Hasson show that we subconsciously adjust our "safety margin" when we move a dynamic object like a cup of coffee based on the amount of variability in the situation. Credit: John Guillemin

Object manipulation or tool use is almost a uniquely human trait, said Dagmar Sternad, director of Northeastern's Action Lab, a research group interested in movement coordination. "Not only does it require certain cognitive abilities but also distinct motor abilities."

Simply moving one's own body, for instance by directing a hand toward a coffee cup, requires the organization of various physiological systems including the central and peripheral nervous systems and the musculoskeletal system.

Once the hand grasps and picks up the cup, the questions become even more complicated. What if the cup is filled with liquid? At this point, the complexity of the control problem balloons - the presence of the liquid introduces nonlinear fluid dynamics with the risk of a spill because of the inherent variability in one's movement.

Sternad, a professor of , biology, electrical and computer engineering and physics and postdoctoral researcher C.J. Hasson are interested in how we adapt our movement strategies when interacting with dynamic objects in the environment.

In a recent paper published in the Journal of Neurophysiology, Hasson and Sternad explored the question by looking at the everyday task of manipulating a cup of coffee. They show that how we adapt our movement strategies is directly related to the amount of variability and reliability in our surroundings and ourselves.

"Because we're humans and not machines, we're noisy and variable," said Hasson. "We can't expect that a movement will unfold exactly as we planned it."

For the study, 18 healthy participants visited the Action Lab to play a video game, wherein they attempted to move a virtual cup filled with virtual liquid across a large video screen. Instead of a normal video-​​game controller, subjects moved the virtual cup by grasping a manipulandum - a large robotic arm. Similar to the real-​​life scenario, the robot simulated the forces one would feel from the weight of the object and the sloshing of the liquid in the cup.

They asked participants to move the cup across the screen within a comfortable time of two seconds, a task for which there is an infinite number of possibilities. You could move fast for one second and slow for one second, slow for a half second and then fast for one and a half seconds. The team hypothesized that participants would naturally adapt a safe movement strategy with practice - and they did.

But the most intriguing result, said Hasson, was that the size of each participant's safety margin -or how close they let the liquid get to the edge of the cup - could be predicted by how variable they were in their movements. Those with more variability tended to adapt a "safer" strategy with a larger safety margin.

"If you have a large safety margin and I move with a small margin, the question is, 'Why am I more risky than you?'" Hasson said. "Well, you may find that I am much more consistent in my movements, so I don't need a big safety margin. If you're more variable, you need a larger safety margin."

The results have implications in assessing elderly patients and patients of motor disorders such as cerebral palsy. "If variability determines the movements that you do, maybe that's an intervention point," said Sternad.

Provided by Northeastern University

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Bones in Bulgaria may be of John the Baptist: study

June 15th, 2012 in Other Sciences / Archaeology & Fossils
An alabaster sculpture of John the Baptist is pictured in France. Scientists have found new evidence they say supports the theory that a knuckle bone and other human remains found under a church floor in Bulgaria may be of John the Baptist.

Scientists have found new evidence they say supports the theory that a knuckle bone and other human remains found under a church floor in Bulgaria may be of John the Baptist.

The relics found in a small marble sarcophagus two years ago on a Bulgarian island called Sveti Ivan, which translates as Saint John, also included a human tooth, part of a skull and three animal bones.

A research team from Oxford University dated the right-handed knuckle bone to the first century AD, when John is believed to have lived until his beheading ordered by king Herod, the university said in a statement.

And scientists from the University of Copenhagen analysed the DNA of the bones, finding they came from a single individual, probably a man, from a family in the modern-day Middle East, where John would have lived.

While these findings do not definitively prove anything, they also don't refute the theory first proffered by the Bulgarian archaeologists who found the remains while excavating under an ancient church on the island.

Many sites around the world claim to hold relics of the saint, including the Grand Mosque in Damascus which says it has his head.

The right hand with which the prophet allegedly baptised Jesus in the River Jordan is also claimed to be held by several entities, including a Serbian Orthodox monastery in Montenegro.

"The result from the metacarpal hand bone is clearly consistent with someone who lived in the early first century AD," Oxford University professor Tom Higham said of the new study.

"Whether that person is John the Baptist is a question that we cannot yet definitely answer and probably never will."

Bulgarian archaeologists had found a small box made of hardened volcanic ash close to the sarcophagus.

The box bore inscriptions in ancient Greek that referred to John the Baptist and the date that Christians celebrate his birth, June 24.

The findings of another Oxford researcher, using historical documents, suggest that the monastery of Sveti Ivan may have received a portion of John the Baptist's relics in the fifth or early sixth centuries.

The findings are to be presented in a documentary to be aired on The National Geographic channel in Britain on Sunday.

(c) 2012 AFP

"Bones in Bulgaria may be of John the Baptist: study." June 15th, 2012. http://phys.org/news/2012-06-bones-bulgaria-john-baptist.html

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Persistence is learned from fathers, study shows

June 15th, 2012 in Psychology & Psychiatry

When the going gets tough, the tough ought to thank their fathers.

New research from Brigham Young University shows that dads are in a unique position to help their adolescent children develop persistence.

BYU professors Laura Padilla-Walker and Randal Day arrived at these findings after following 325 families over several years. And over time, the persistence gained through fathers lead to higher engagement in school and lower rates of delinquency.

"In our research we ask 'Can your child stick with a task? Can they finish a project? Can they make a goal and complete it?'" Day said. "Learning to stick with it sets a foundation for kids to flourish and to cope with the stress and pressures of life."

The scholars from BYU's School of Family Life report their findings June 15 in the Journal of Early Adolescence.

"There are relatively few studies that highlight the unique role of fathers," Padilla-Walker said. "This research also helps to establish that traits such as persistence � which can be taught � are key to a child's life success."

The key is for dads to practice what's called "authoritative" parenting � not to be confused with authoritarian. Here are the three basic ingredients:

• Children feel warmth and love from their father
• Accountability and the reasons behind rules are emphasized
• Children are granted an appropriate level of autonomy

About 52 percent of the dads in the study exhibited above-average levels of authoritative parenting. Over time, their kids were significantly more likely to develop persistence, which lead to better outcomes in school and lower levels of delinquency.

This particular study examined 11-14 year olds residing in two-parent homes. Yet the study authors suggest that single parents still may play a role in teaching the benefits of persistence, which is an avenue of future research.

"Fathers should continue to try and be involved in their children's lives and engage in high quality interactions, even if the quantity of those interactions might be lower than is desirable," Padilla-Walker said.

Provided by Brigham Young University

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Behavioral responses to a changing world

June 15th, 2012 in Biology / Ecology
Male beetles are mating with beer bottles. Credit: University of Toronto Mississauga

(Phys.org) -- Male beetles in Western Australia are mating with beer bottles in response to environmental change caused by human activity. A new book examines why, and the impacts on biodiversity.

Oxford University Press today announced the launch of Behavioral Responses to a Changing World: Mechanisms and Consequences by Dr. Bob Wong, of Monash University, and Ulrika Candolin from The University of Helsinki, Finland.

Drawing on international experts from across the globe, it is the first book of its kind devoted to understanding animal behavioral responses to environmental change. Behavioral Responses emphasises the vital links between environmental change, behavior and population dynamics which have been rarely examined in the context of one another.

Co-editor Dr. Bob Wong, Senior Lecturer at Monash University�s School of Biological Sciences and an expert in behavioural and evolutionary ecology, said how animals respond to changed conditions was a growing area of research interest.

�Due to human activities, almost all creatures live in environments that have been altered to some degree. The ability to behave accordingly under new conditions is crucial for survival,� Dr. Wong said.

�Environmental change caused by human activity is considered the greatest single threat to global biodiversity. Scientists are only now beginning to appreciate the important ecological and evolutionary implications of altered behaviours due to environmental change."

Dr. Wong said the initial response of many animals to human-induced environmental change is often behavioral, which in turn affects species� interactions, population viability, evolution, and ultimately, biodiversity.

�Some of these behaviors can be beneficial and buy more time for populations and species to genetically adapt to altered conditions. Some species might even thrive in urban environments. But behaviors can also be maladaptive,� Dr. Wong said.

�Male beetles, for example, are mating with beer bottles because they resemble female beetles and female fish in Mexico, living in polluted streams, are mating with male fish of the wrong species.�

The comprehensive text discusses impacts on both the mechanisms underlying behavioral processes, as well as the longer-term ecological and evolutionary consequences. Topics as diverse as endocrine disruption, learning, reproduction, migration, species interactions and evolutionary rescue are canvassed.

Dr. Wong will officially present �Behavioural Responses to a Changing World� at a post-congress symposia of the 14th International Behavioral Ecology Congress on 18 August in Sweden.

Provided by Monash University

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Manipulation of a specific neural circuit buried in complicated brain networks in primates

June 17th, 2012 in Neuroscience

A collaborative research team led by Professor Tadashi ISA from The National Institute for Physiological Sciences, The National Institutes of Natural Sciences and Fukushima Medical University and Kyoto University, developed a "double viral vector transfection technique" which can deliver genes to a specific neural circuit by combining two new kinds of gene transfer vectors. With this method, they found that "indirect pathways", which were suspected to have been left behind when the direct connection from the brain to motor neurons (which control muscles) was established in the course of evolution, actually plays an important role in the highly developed dexterous hand movements. This study was supported by the Strategic Research Program for Brain Sciences by the MEXT of Japan. This research result will be published in Nature (June 17th, advance online publication).

It is said that the higher primates including human beings accomplished explosive evolution by having acquired the ability to move hands skillfully. It has been thought that this ability to move individual fingers is a result of the evolution of the direct connection from the cerebrocortical motor area to motor neurons of the spinal cord which control the muscles. On the other hand, in lower animals with clumsy hands, such as cats or rats, the cortical motor area is connected to the motor neurons, only through interneurons of the spinal cord. Such "indirect pathway"remains in us, primates, without us fully understanding its functions. Is this "phylogenetically old circuit" still in operation? Or maybe suppressed since it is obstructive? The conclusion was not attached to this argument.

The collaborative research team led by Professor Tadashi ISA, Project Assistant Professor Masaharu KINOSHITA from The National Institute for Physiological Sciences, The National Institutes of Natural Sciences and Fukushima Medical University and Kyoto University developed "the double viral vector transfection technique"which can deliver genes to a specific neural circuit by combining two new kinds of gene transfer vectors.

With this method, they succeeded in the selective and reversible suppression of the propriospinal neurons (spinal interneurons mediating the indirect connection from cortical motor area to spinal motor neurons)

The results revealed that "indirect pathways" play an important role in dexterous hand movements and finally a longtime debate has come to a close.

The key component of this discovery was"the double viral vector transfection technique"in which one vector is retrogradely transported from the terminal zone back to the neuronal cell bodies and the other is transfected at the location of their cell bodies. The expression of the target gene is regulated only in the cells with double transfection by the two vectors. Using this technique, they succeeded in the suppression of the propriospinal neuron selectively and reversibly.

Such an operation was possible in mice in which the inheritable genetic manipulation of germline cells were possible, but impossible in primates until now.

Using this method, further development of gene therapy targeted to a specific neural circuit can be expected.

Professor Tadashi ISA says "this newly developed double viral vector transfection technique can be applied to the gene therapy of the human central nervous system, as we are the same higher primates.

And this is the discovery which reverses the general idea that the spinal cord is only a reflex pathway, but also plays a pivotal role in integrating the complex neural signals which enable dexterous movements."

Provided by National Institute for Physiological Sciences

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More to facial perception than meets the eye

June 15th, 2012 in Psychology & Psychiatry

People make complex judgements about a person from looking at their face that are based on a range of factors beyond simply their race and gender, according to findings of new research funded by the Economic and Social Research Council (ESRC).

The findings question a long-held belief that people immediately put a person they meet into a limited number of social categories such as: female or male; Asian, Black, Latino or White; and young or old.

Dr Kimberly Quinn at the University of Birmingham found that people 'see' faces in a multiple of ways. This could have wider importance in understanding stereotyping and discrimination because it has implications on whether and how people categorise others.

Categorisation is not done purely on the physical features of the face in front of us, but depends on other information as well, including whether the person is already known and whether the person is believed to share other important identities with us.

"How we perceive faces is not just a reflection of what's in those faces," Dr Quinn said. "We are not objective; we bring our current goals and past knowledge to every new encounter. And this happens really quickly - within a couple of hundred milliseconds of seeing the face."

Dr Quinn and her colleagues explored social categories such as sex, race and age; physical attributes such as attractiveness; personality traits such as trustworthiness; and emotional states such as anger, sadness and happiness.

She found that although social categories are used to gather information on faces, these can be easily undermined. This research found that we reject simple stereotypes when something about the situation alerts us to the fact the stereotype does not tell the whole story. If we take, for example, a racial group and the corresponding stereotype of members of that group as unintelligent, seeing a person in that group playing an intellectual game such as chess would tell us to cancel out the stereotype.

In order to investigate the causes, mechanisms, and results of social categorisation, Dr Quinn used techniques from cognitive psychology and neuroscience to investigate how people process faces. The research was designed to provide insight into when and why people categorise others according to social group membership.

Their findings differ from previous research that adopted a 'dual process' approach and assumed people initially categorised faces based on factors such as gender, race or age before determining whether to stereotype them or to see them as unique individuals.

Dr Quinn's findings were more consistent with a single process that initially focuses on 'coarse' information that is easy to detect, and then immediately starts to include more fine-grained processing as time elapses. This model allows for either categorisation or more individuated processing to emerge, and does not assume that categorisation always comes before recognising unique identities � thereby allowing for more diverse outcomes than previously thought.

Provided by Economic & Social Research Council

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Bugs have key role in farming approach to storing CO2 emissions

June 15th, 2012 in Space & Earth / Environment

Tiny microbes are at the heart of a novel agricultural technique to manage harmful greenhouse gas emissions.

Scientists have discovered how microbes can be used to turn carbon dioxide emissions into soil-enriching limestone, with the help of a type of tree that thrives in tropical areas, such as West Africa.

Researchers have found that when the Iroko tree is grown in dry, acidic soil and treated with a combination of natural fungus and bacteria, not only does the tree flourish, it also produces the mineral limestone in the soil around its roots.

The Iroko tree makes a mineral by combining calcium from the earth with CO2 from the atmosphere. The bacteria then create the conditions under which this mineral turns into limestone. The discovery offers a novel way to lock carbon into the soil, keeping it out of the atmosphere.

In addition to storing carbon in the trees' leaves and in the form of limestone, the mineral in the soil makes it more suitable for agriculture.

The discovery could lead to reforestation projects in tropical countries, and help reduce carbon dioxide emissions in the developing world. It has already been used in West Africa and is being tested in Bolivia, Haiti and India.

The findings were made in a three-year project involving researchers from the Universities of Edinburgh, Granada, Lausanne and Neuchatel, Delft University of Technology, and commercial partner Biomim-Greenloop. The project examined several microbiological methods for locking up CO2 as limestone, and the Iroko-bacteria pathway showed best results. Work was funded by the European Commission under the Future & Emerging Technologies (FET) scheme.

Dr Bryne Ngwenya of the University of Edinburgh's School of GeoSciences, who led the consortium, said: "By taking advantage of this natural limestone-producing process, we have a low-tech, safe, readily employed and easily maintained way to lock carbon out of the atmosphere, while enriching farming conditions in tropical countries."

Provided by University of Edinburgh

"Bugs have key role in farming approach to storing CO2 emissions." June 15th, 2012. http://phys.org/news/2012-06-bugs-key-role-farming-approach.html

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Researchers solve Roman Empire historical mystery

June 15th, 2012 in Other Sciences / Archaeology & Fossils
Palmyra�s main street was one of the longest and most monumental in the eastern Roman Empire. Credit: J.C. Meyer

In ancient Roman times A.D., Palmyra was the most important point along the trade route linking the east and west, reaching a population of 100 000 inhabitants. But its history has always been shrouded in mystery: What was a city that size doing in the middle of the desert? How could so many people live in such an inhospitable place nearly 2 000 years ago? Where did their food come from? And why would such an important trade route pass directly through the desert?

Norwegian researchers collaborated with Syrian colleagues for four years to find answers.

�These findings provide a wealth of new insight into Palmyra�s history,� says project manager J�rgen Christian Meyer, a professor at the University of Bergen. The project has received funding of over NOK 9 million from the Research Council of Norway�s comprehensive funding scheme for independent basic research projects (FRIPRO).

New research using modern archaeological methods

The Bergen-based archaeologists approached the problem from a novel angle � instead of examining the city itself, they studied an enormous expanse of land just to the north. Along with their Syrian colleagues from the Palmyra Museum and aided by satellite photos, they catalogued a large number of ancient remains visible on the Earth�s surface.

�In this way,� explains Professor Meyer, �we were able to form a more complete picture of what occurred within the larger area.�

The team detected a number of forgotten villages from ancient Roman times. But what finally solved the riddle of Palmyra was the discovery of the water reservoirs these villages had utilized.

The archaeologists located this and other reservoirs used nearly 2 000 years ago.

Not a desert

Professor Meyer and his colleagues came to realise that what they were studying was not a desert, but rather an arid steppe, with underground grass roots that keep rain from sinking into the soil. Rainwater collects in intermittent creeks and rivers called wadi by the Arabs.

The archaeologists gathered evidence that residents of ancient Palmyra and the nearby villages collected the rainwater using dams and cisterns. This gave the surrounding villages water for crops and enabled them to provide the city with food; the collection system ensured a stable supply of agricultural products and averted catastrophe during droughts.

Local farmers also cooperated with Bedouin tribes, who drove their flocks of sheep and goats into the area to graze during the hot season, fertilising the farmers� fields in the process.

Safe trade route

Palmyra�s location also had a political foundation. Important east-west trade routes, including along the Euphrates River to the north, were not under the control of the Romans to the west or the Persians to the east. Local lords and chieftains demanded high fees for passage.

This practice of extortion translated into a tremendous opportunity for the Palmyrians; they joined forces with the Bedouins to provide security, beasts of burden and guides through the desert.

�Tradesmen from Palmyra made the most of the city�s unique location to build up a comprehensive trade network,� says the professor. �This explains much of the city�s prosperity.�

Arable land in this time of need

The solution to the mystery of Palmyra can also teach us something today. As the world seeks arable land to feed its billions, we can learn from the Palmyrians� experience. If they were able to cultivate the desert soil almost 2 000 years ago, surely we can do the same with all the available modern aids and methods.

�Occasionally an enormous amount of rain falls in the desert,� says Professor Meyer. �Anyone can see how green the desert becomes after the rain. The Palmyrians must have realised the potential of this type of land, which covers large areas of our planet.�

Provided by The Research Council of Norway

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British researchers create robot that can learn simple words by conversing with humans (w/ Video)

June 16th, 2012 in Electronics / Robotics
The iCub robot named DeeChee learning basic language with Professor Chrystopher Nehaniv and Dr Joe Saunders

In an attempt to replicate the early experiences of infants, researchers in England have created a robot that can learn simple words in minutes just by having a conversation with a human.

The work, published this week in the journal PLoS One, offers insight into how babies transition from babbling to speaking their first words.

The three-foot-tall robot, named DeeChee, was built to produce any syllable in the English language. But it knew no words at the outset of the study, speaking only babble phrases like "een rain rain mahdl kross."

During the experiment, a human volunteer attempted to teach the robot simple words for shapes and colors by using them repeatedly in regular speech.

This video is not supported by your browser at this time.

At first, all DeeChee could comprehend was an unsegmented stream of sounds. But DeeChee had been programmed to break up that stream into individual syllables and to store them in its memory. Once there, the words were ranked according to how often they came up in conversation; words like "red" and "green" were prized.

DeeChee also was designed to recognize words of encouragement, like "good" and "well done," from its human conversation partner. That feedback helped transform the robot's babble into coherent words, sometimes in as little as two minutes.

If repetition of sounds helps infants learn a language, then it's not surprising that our first words are often mainstays like "mama" and "dada." But why don't we start using common and simple words like "and" or "the" at the same time?

The answer, said study leader Catherine Lyon, a computer scientist at the University of Hertfordshire, is that the words that form the connective tissue of our language - words like "at," "with" and "of" - are spoken in hundreds of different ways, making them difficult for newbies to recognize. On the other hand, more concrete words like "house" or "blue" tend to be spoken in the same way nearly every time.

Because the study relied on the human volunteers speaking naturally, Lyon said it was crucial that the robot resemble a person. DeeChee was programmed to smile when it was ready to pay attention to its teacher and to stop smiling and blink when it needed a break. (Though DeeChee was designed to have a gender-neutral appearance, humans tended to treat it as a boy, according to the study.)

"When we asked people to talk to the robot as a small child, it seemed to come quite naturally to them," she said. "When they talk to a bit of disembodied software, you don't get the same response."

Paul Goldstein, a psychologist at Cornell University who has also used robots to study infant learning but wasn't involved in this study, said the work was highly innovative - and that if the researchers' theory about language acquisition is correct, they can use robots to prove it.

"If we really think we understand how infants learn," he said, "then we should be able to build a robot that can do it."

More information: Lyon C, Nehaniv CL, Saunders J (2012) Interactive Language Learning by Robots: The Transition from Babbling to Word Forms. PLoS ONE 7(6): e38236. doi:10.1371/journal.pone.0038236

(c)2012 Los Angeles Times
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