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  • Tamiflu: an analysis of all the data

    Jonathan Wood | 10 Apr 14 | 0 comments

    Woman sneezing

    Was the government right to spend half a billion pounds in stockpiling the antiviral drugs Tamiflu and Relenza in preparation for a flu pandemic?

    These drugs were handed out via a phoneline during the swine flu pandemic of 2009 as part of a wider public health strategy.

    Professor Carl Heneghan of Oxford University's Department of Primary Care Health Sciences and colleagues in the independent Cochrane Collaboration are clear that the money was wasted. They argue that the decision to stockpile the drugs might have been different had we had access to all the clinical data on their effectiveness.

    Now we do have that evidence, and Carl says: 'There is no credible way these drugs could prevent a pandemic.' Speaking at a media briefing at the Science Media Centre in London, he said the money spent on stockpiling had been 'thrown down the drain'.

    Since 2009, the Cochrane researchers have had a long running battle with the drug firms that manufacture Tamiflu and Relenza (Roche and GSK, respectively) to get unconditional access to their full data. They finally received everything last year, after first GSK then Roche said they would provide the materials – a significant development in the campaign to increase openness and accessibility of complete trial data.

    The Cochrane group has been significant players, along with the AllTrials campaign, the BMJ medical journal, Ben Goldacre and others, in changing the whole approach to this issue among researchers, journals, drug firms and regulators. The simple argument is that if we are to make the right decision on what are the best drugs – considering their safety, effectiveness and the balance of benefits they offer in treating conditions over their side-effects – we need to have all the evidence available.

    The researchers have now made that assessment for Tamiflu in the prevention and treatment of flu. They have reviewed a phenomenal amount of material, and with the BMJ and the Cochrane Collaboration, have published their conclusions today. They call on government and health policy decision makers to review guidance on the use of Tamiflu in light of their new evidence.

    They found that Tamiflu is effective – but it shortens symptoms of flu by only around half a day on average. And importantly, they say, there is no good evidence to support claims that it reduces complications of influenza or admissions to hospital.

    Then there are the side effects. Using Tamiflu to treat flu, the evidence confirms an increased risk of suffering from nausea and vomiting.

    When Tamiflu is used to prevent flu, the drug can reduce the risk of people suffering symptomatic influenza. But there was an increased risk of headaches, psychiatric disturbances, and kidney events.

    The review authors, Drs Tom Jefferson, Carl Heneghan and Peter Doshi, conclude that there are insufficient grounds to support the stockpiling of Tamiflu for mass use in a pandemic. From the best conducted randomised trials, there just isn’t enough evidence on the crucial elements of reducing serious complications of flu that can lead to hospitalisation and death, and the prevention of spread of flu. On the other hand we know there would be side-effects.

    Not all scientists agree on the assessment of the balance of benefits of these antivirals versus their side-effects. Virologist Professor Wendy Barclay at Imperial College London believes the shorter time that symptoms last is important: 'Although one day does not sound like a lot, in a disease that lasts only 6 days, it is…We have only two drugs with which we can currently treat influenza patients and there is some data to suggest they can save lives. It would be awful if, in trying to make a point about the way clinical trials are conducted and reported, the review ended up discouraging doctors from using the only effective anti-influenza drugs we currently have.'

    Roche, the manufacturers of Tamiflu, fundamentally disagree with the overall conclusions of the Cochrane review and criticised some of the report’s methodology. In media reports, UK Medical Director Dr Daniel Thurley has said: 'Roche stands behind the wealth of data for Tamiflu and the decisions of public health agencies worldwide, including the US and European Centres for Disease Control & Prevention and the World Health Organization.'

    Indeed, Roche have pointed to a large observational trial in the Lancet Respiratory Medicine that they funded which recently reported a reduction in deaths among those hospitalised with swine flu H1N1, though there are some who disagree with that analysis too.

    So what to make of all of this? An editorial in the Guardian concludes: 'The only way to resolve the argument is proper science. That means transforming clinical trials, harmonising the way they are carried out. It has happened with malaria drugs, and it is happening with HIV. The industry must allow access to their data. Confident that like is compared with like, trials can then be subjected to meta-analysis, allowing statisticians to drill down into sub-populations to establish when a drug performs most effectively.'

    The editorial points to the need to be able to react swiftly and carry out good research actually during pandemics, as former Oxford University professor and now director of the Wellcome Trust, Jeremy Farrar, argued in the paper last month.

    What has really changed is the ability to have these discussions based on all of the evidence. There is a real shift in the level of scrutiny and the analyses that are now possible with access to all clinical trial data (although dealing with all these reams of data also brings new challenges too). That is a phenomenal change and a real achievement by the Cochrane researchers.

    David Spiegelhalter, Winton Professor of the Public Understanding of Risk at the University of Cambridge, comments: 'This is a ground-breaking review. Since important studies have never been published, the reviewers have had to go back to clinical trial reports comprising over 100,000 pages: the effort to obtain these is a saga in itself. The poor quality of these reports clearly made extracting relevant data a massive struggle, with many pragmatic assumptions having to be made, but the final statistical methods are standard and have been used in hundreds of Cochrane reviews. Let’s hope that in future high-quality data can be routinely obtained and this type of review becomes unnecessary.'

    (Full story)
  • MeerKAT is shape of things to come

    Pete Wilton | 01 Apr 14 | 0 comments

    MeerKATantenna, the precursor to SKA

    In a remote semi-desert region of South Africa, the Karoo veld, what looks like a huge satellite dish has risen up to dominate the landscape.

    But instead of tuning into TV this dish is the first part of a giant radio telescope called MeerKAT that will play a key role in the creation of the world’s largest telescope, the Square Kilometre Array (SKA).

    Last week saw the official launch of this first dish of many, I asked Matt Jarvis of Oxford University's Department of Physics, one of the Oxford scientists involved in MeerKAT, about plans for the new telescope and where it will lead…

    OxSciBlog: What is MeerKAT and why is it important?
    Matt Jarvis: MeerKAT is actually made up of 64 dishes, each 13.5m in diameter. All of these dishes are connected to make up a single telescope that operates at radio wavelengths (around medium-wave for the people who still have analogue radios), much like a satellite dish but rather than receiving information from satellites it detects radio waves from astrophysical phenomena such as jets emanating from around black holes and sites of star formation. It is the precursor to the Square Kilometre Array which will extend MeerKAT from 64 to 254 dishes in around 2020, making it much more powerful.

    OSB: What questions will MeerKAT investigate? 
    MeerKAT will detect radio waves from the distant reaches of the cosmos. It allows us to trace a range of physical processes that occur in the Universe, such has high-speed jets (moving at close to the speed of light) which arise from accretion around black holes, both in our own galaxy and from supermassive black holes in the centres of distant galaxies. It will also be able to detect neutral hydrogen gas, the fundamental building block of all the things that we can see in the Universe, from stars to galaxies, enabling us to determine how this gas gets turned into stars over the history of the Universe. By using the radio emission from these distant galaxies we will also be able to investigate the impact of Dark Energy and Dark Matter in the Universe and how these may evolve, possibly leading us to reassess how gravity acts on very large scale.

    OSB: How are Oxford scientists involved in the project?
    Oxford has a large involvement in MeerKAT. Two of the Large Surveys to be undertaken on MeerKAT are co-led by Oxford staff. I’m the co-PI of the deep radio continuum survey (MIGHTEE) to study how galaxies evolve over the history of the Universe and Rob Fender is the co-PI of the THUNDERKAT survey which aims to detect all of the phenomena which go bang, such as stars colliding together, bursts of radiation when a star dies and accretion events on to a black hole. We have also been involved in some of the technical development for the receivers on the dishes.

    OSB: How will work with MeerKAT feed into SKA?
    MeerKAT is essentially a stepping stone to the SKA, in terms of both science and engineering. The work we will do will set the stage for the SKA to really move us forward into a whole different regime of radio astronomy. MeerKAT will be a fantastic facility in its own right, providing us with the most sensitive radio surveys in the southern hemisphere, however, the SKA will be able to take such surveys and expand them by an order of magnitude in sensitivity and ability to map large volumes of the Universe. From a more technical perspective, the lessons learned from constructing MeerKAT will feed into the design specifications of the SKA, and will also mean that we can test new algorithms to turn the raw data into scientifically useful maps and catalogues for use throughout the community.

    OSB: What are the challenges of dealing with data from MeerKAT/SKA?
    The main challenges are the sheer data volume that we need to handle. For example, we are unable to store the raw data coming from the telescope, and have to reduce it very quickly in order to keep up with the observations. This requires a large effort in data transport, supercomputers and having the necessary computer code to handle the data effectively.

    OSB: What is the next big milestone in MeerKAT's progress?
    The next big milestone will be when there are 16 dishes on the ground and all hooked up. This will then enable us to start carrying out the science, before the whole 64 dishes are in place. This is something quite unique to radio astronomy, in that we don't need the whole telescope to start doing some of the science.

    (Full story)
  • Why males stray more than females

    Pete Wilton | 24 Mar 14 | 0 comments

    Jungle fowl chicken

    Do males have more to gain than females from mating with additional partners?

    The theory that they do, and that this can help to explain different sex roles observed in the males and females of many species, is known as 'Bateman's principles', named after the work of English geneticist Angus John Bateman.

    In a recent study reported in Proceedings of the Royal Society B a team, led by Oxford University researchers, investigated Bateman's principles in relation to populations of red junglefowl (Gallus gallus), the wild ancestor of the domestic chicken.

    'Bateman's principles state that males are more variable than females in the number of offspring they produce and number of sexual partners,' explains Dr Tom Pizzari of Oxford University's Department of Zoology, one of the research team. 'This leads to a stronger relationship between number of offspring and number of partners in males than in females. In other words, males gain more reproductive success by mating with additional partners than females do.

    'This difference is explained by the fact that males produce orders of magnitude more sperm than there are eggs available for fertilisation, so their reproductive success is strongly limited by female (egg) availability. Females on the other hand tend to produce a smaller number of larger eggs, and generally mating with additional males does not influence the number of eggs that a female can afford to produce.'

    To test the principles the team studied groups of red junglefowl and carefully recorded all mating events and assigned parentage to every offspring produced. They then ran experiments to test the relationship between reproductive and mating success.

    'Studying Bateman's principles properly presents many challenges,' Tom tells me. 'First, detailed information on mating success (who mates with whom) is required. Previous studies did not measure mating behaviours, but simply inferred who mates with whom based on parentage of the offspring. This approach however, misses out all those mating events which failed to result in fertilisation.

    'Second, Bateman's principles are concerned with how males increase their reproductive success by mating with additional females. However, there are other pathways through which males can increase the number of offspring sired: mating with particularly fecund females, and defending their paternity in sperm competition. Again, most studies so far have explored Bateman's principles without controlling for these alternative pathways.

    'Finally, one must be very careful about how to interpret a positive relationship between reproductive success and mating success in females. One possibility is that females genuinely increase the number of offspring produced by mating with additional males, another is that females that are inherently more fecund are more attractive to males and so end up with more partners.' 

    The new study showed that in failing to address these challenges traditional approaches can lead to very drastic biases in estimating Bateman's principles and that future research in this area should combine independent data on mating behaviour, multivariate statistics, and experimental tests.

    'Our results suggest that once these biases are controlled for, Bateman was essentially correct: males gain more reproductive success by mating with additional partners than females, however these sex differences are much smaller than estimated by traditional methods,' Tom comments.

    'This means that males are more strongly selected to compete over access to mates than females, explaining why sexual selection is typically more intense in males, providing an answer to Darwin's original question of why it is males that often display more exaggerated traits in a species.'

    (Full story)
  • How short is your time?

    Jonathan Wood | 19 Mar 14 | 0 comments

    Time passing

    Our perception of time can depend on a number of factors – what we’re doing, how much we’re focusing on it, how we’re feeling. But there's also quite a bit of variability between us in our individual sense of time passing.

    Researchers at Oxford University have investigated what plays a part in our perception of short, fleeting times of under a second.

    In a new paper published today in the Journal of Neuroscience, they show that levels of a chemical in the brain – a neurotransmitter called GABA – accounts for some of the difference in our perceptions of subsecond intervals in what we’re seeing.

    Oxford Science Blog asked Dr Devin Terhune of the Department of Experimental Psychology about the study. So depending on who you are and your judgement of time, if you have somewhere between 2 and 5 minutes to spare, read on.

    OxSciBlog: Why is perception of time important to understand?
    Devin Terhune: Our ability to perceive duration is one of the most fundamental features of conscious experience and thus it is of great importance to our emerging understanding of how the brain generates consciousness. Second, time perception is necessary for a wide range of abilities, from playing sports and musical instruments to day-to-day decision-making. Studying time perception has considerable potential to greatly inform the broader domains of psychology and neuroscience.

    OSB: What can influence time perception?
    DT: A variety of factors can affect our perception of time. Two common factors are attention and emotion. If we focus on something, time seems to slow down somewhat (hence the common phrase 'a watched kettle never boils'), whereas it seems to go by faster if we're daydreaming or thinking about something else. In contrast, we tend to overestimate time when we’re frightened, or underestimate it when we’re experiencing joy.

    OSB: Tell us about the sort of time perception you investigated in this study
    DT: We studied people's perception of short durations of visual images lasting around half a second.

    In the specific task we used, participants were first trained on a particular image that lasted around half a second. Subsequently, they saw the same image for a range of different intervals – some shorter, some longer. Participants were asked whether each image was shorter or longer in duration than the trained interval. This task allowed us to determine whether someone is underestimating or overestimating the duration of the images, as well as their precision in the task. 

    OSB: And this judgement of time can be affected by the way neurons in the brain respond to what we are seeing?
    DT: A number of studies have recently shown that when neurons in visual regions of the brain 'fire' more strongly, a person is more likely to overestimate the duration of a visual event, whereas when the neurons 'fire' less, they are more likely to underestimate the event. Accordingly, different ways of altering these firing responses may thus affect time perception.

    OSB: What did you find?
    DT: Our study showed that participants' tendency to under- or over-estimate how long the image lasted was associated with a particular neurotransmitter in the brain known as GABA.

    Individuals who tended to underestimate the visual intervals were found to have higher GABA levels in the region of the brain responsible for visual processing.

    Importantly, GABA levels in a second region of the brain that supports movement and motor functions were unrelated to time perception. Also, GABA levels in the visual area were unrelated to time perception in a non-visual task.

    These results suggest that GABA levels in visual regions of the brain may account for variability in our perception of visual intervals.

    OSB: What does this suggest is going on in the brain?
    DT: We believe that higher GABA levels results in a greater reduction of the firing of neurons in response to a visual image, leading to underestimation.

    OSB: Do we as individuals really differ in how we perceive time and events?
    DT: It's intuitive to think that our perception of the world is similar to others, but just like many other conscious visual experiences, there is considerable variability in our ability to perceive time. This variability is more apparent for longer intervals – for instance, we all have friends who say they were only gone for two minutes when it was actually closer to ten. This variability is present for very short intervals too.

    OSB: Could this tell us anything about our perception of time in everyday situations?
    DT: This finding may account for why some people are better at judging very short durations than others. Since we used particular types of images in the lab, we have to be careful about how much we can generalize. However, these very short intervals are important to a range of tasks. For instance, running to catch a ball requires you to estimate when the ball will arrive in a particular location that you can reach. Similarly, when playing a musical instrument as part of an orchestra or band, it is important that you can accurately judge the specific time at which you need to play a particular note.

    OSB: Is it wrong to feel slightly unsettled that what we experience and think to be an accurate representation of time passing may not be?
    DT: At first glance, it could be somewhat unsettling. However, in the grand scheme of things, the vast majority of people have decent time perception. It's just that some of us are better than others, just like in a range of other cognitive, motor, and perceptual functions. Some of us have better attention or memory than others, some of us are better at riding bicycles, and so on.

    (Full story)
  • Sex, skinks, and personality

    Pete Wilton | 13 Mar 14 | 0 comments

    Easter Water Skink

    When it comes to spatial learning males are better than females, and bold and shy individuals are better than average ones, at least if you're a lizard.

    The findings, from a new study of the Easter Water Skink (Eulamprus quoyii) - a lizard that lives throughout Eastern Australia and can grow over 12cm long - are the first evidence of sexual learning differences in a reptile. A report of the research is published in this week's Proceedings of the Royal Society B.

    A team led by Oxford University and Macquarie University, Sydney, scientists took 64 skinks, 32 males and 32 females, and released them into a series of strange environments to investigate how differences in personality influence how they learn. These environments included features they would like, a 'warm' refuge made of a box with three entrances heated by an incandescent bulb, and features they wouldn't, a 'cold' refuge made of a similar box chilled with ice packs.

    By introducing the skinks to simulated predator events (being chased away into a refuge) the researchers determined which returned quickly to bask in a warm refuge ('bold' lizards) and which took longer than average to return ('shy' lizards). They then tested the lizards once a day for 20 days in a setting where they were again exposed to simulated predatory attacks and given a choice between a safe refuge (chasing stopped) and an unsafe refuge (the refuge was lifted and chasing continued) that were always located in the same place.

    'We found that male lizards were better at this spatial learning task than females, with twice as many males as females learning the spatial task within 20 trials,' explains Pau Carazo of Oxford University's Department of Zoology, who led the research.

    'While this is the first evidence ever of sexual learning differences in a reptile, we believe it reflects the fact that males are forced to spend more time moving through their environment in search for females or patrolling their territory to guard it against other rival males. We also show that, across the sexes, the boldest and shyest individuals were overall better learners than intermediate individuals.'

    According to the team this is the first evidence that individuals at the extreme ends of a personality axis are better learners than individuals with intermediate personality traits. This does not fit well with current theories about how personality and learning may co-evolve: the team proposes the idea that spatial learning ability and personality are both linked with male reproductive strategies.

    'In Eulamprus, as in many other lizard species, male lizards exhibit two alternative reproductive strategies. Some male lizards defend territories, which not only requires them to be bold but also to constantly patrol their territory and remember rival males at its boundaries (which would favour good spatial learners),' Pau tells me.

    'In contrast, other males adopt an alternative sneaker strategy whereby they are forced to navigate over long distances (which would also favour good spatial learning abilities) to sneak into other males' territories and try to mate with resident females. Because these males do not defend territories and normally avoid fights, they are likely to be shy.

    'We suggest that males that are particularly good at either of these two strategies are likely to be good spatial learners and are either extremely bold or extremely shy individuals. This new hypothesis may help to explain how personality and learning co-evolve, and to understand the evolutionary processes that may lead to the striking individual differences in learning than can be observed in most animal species studied to date.'

    (Full story)
  • Do elephants call ''human!''?

    Pete Wilton | 07 Mar 14 | 0 comments

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    African elephants make a specific alarm call in response to the danger of humans, according to a new study of wild elephants in Kenya.

    Researchers from Oxford University, Save the Elephants, and Disney's Animal Kingdom carried out a series of audio experiments in which recordings of the voices of the Samburu, a local tribe from North Kenya, were played to resting elephants. The elephants quickly reacted, becoming more vigilant and running away from the sound whilst emitting a distinctive low rumble.

    When the team, having recorded this rumble [listen to the rumble here], played it back to a group of elephants they reacted in a similar way to the sound of the Samburu voices; running away and becoming very vigilant, perhaps searching for the potentially lethal threat of human hunters.

    The new research, recently reported in PLOS ONE, builds on previous Oxford University research showing that elephants call 'bee-ware' and run away from the sound of angry bees. Whilst the 'bee' and 'human' rumbling alarm calls might sound similar to our ears there are important differences at low (infrasonic) frequencies that elephants can hear but humans can’t.

    'Elephants appear to be able to manipulate their vocal tract (mouth, tongue, trunk and so on) to shape the sounds of their rumbles to make different alarm calls,' said Dr Lucy King of Save the Elephants and Oxford University who led the study with Dr Joseph Soltis, a bioacoustics expert from Disney's Animal Kingdom, and colleagues.

    'We concede the possibility that these alarm calls are simply a by-product of elephants running away, that is, just an emotional response to the threat that other elephants pick up on,' Lucy tells me. 'On the other hand, we think it is also possible that the rumble alarms are akin to words in human language, and that elephants voluntarily and purposefully make those alarm calls to warn others about specific threats. Our research results here show that African elephant alarm calls can differentiate between two types of threat and reflect the level of urgency of that threat.'

    Lucy King and Joseph Soltis film elephants running away from human alarm call

    Elephant 'human' alarm call rumble

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    Significantly, the reaction to the human alarm call included none of the head-shaking behaviour displayed by elephants hearing the bee alarm. When threatened by bees elephants shake their heads in an effort to knock the insects away as well as running – despite their thick hides adult elephants can be stung around their eyes or up their trunks, whilst calves could potentially be killed by a swarm of stinging bees as they have yet to develop a thick protective skin.

    Lucy explains: 'Interestingly, the acoustic analysis done by Joseph Soltis at his Disney laboratory showed that the difference between the ''bee alarm rumble'' and the ''human alarm rumble'' is the same as a vowel-change in human language, which can change the meaning of words (think of ''boo'' and ''bee''). Elephants use similar vowel-like changes in their rumbles to differentiate the type of threat they experience, and so give specific warnings to other elephants who can decipher the sounds.'

    This collaborative research on how elephants react to and communicate about honeybees and humans is being used to reduce human-elephant conflict in Kenya. Armed with the knowledge that elephants are afraid of bees, Lucy and Save the Elephants have built scores of 'beehive fences' around local farms that protect precious fields from crop-raiding elephants.

    'In this way, local farmers can protect their families and livelihoods without direct conflict with elephants, and they can harvest the honey too for extra income,' says Lucy. 'Learning more about how elephants react to threats such as bees and humans will help us design strategies to reduce human-elephant conflict and protect people and elephants.'

    Elephants run away from Samburu voices - human alarm call

    Middle: Lucy King and Joseph Soltis film elephants reacting to Samburu voices. Above: elephants flee the sound of local people whilst emitting the telltale 'human' alarm call rumble.

    (Full story)
  • A sparse memory is a precise memory

    Jonathan Wood | 28 Feb 14 | 0 comments

    Dr Andrew Lin in fruit fly laboratory.

    Particular smells can be incredibly evocative and bring back very clear, vivid memories.

    Maybe you find the smell of freshly baked apple pie is forever associated with warm memories of grandma's kitchen. Perhaps cut grass means long school holidays and endless football kickabouts. Or maybe catching the scent of certain medicines sees you revisit a bout of childhood illness.

    What's remarkable about the power of these 'associative memories' – connecting sensory information and past experiences – is just how precise they are. How do we and other animals attach distinct memories to the millions of possible smells we encounter?

    There's a clear advantage in doing so: accurately discriminating smells indicating dangers while making no mistakes in following those that are advantageous. But it's a huge information processing challenge.

    Researchers at Oxford University's Centre for Neural Circuits and Behaviour have discovered that a key to forming distinct associative memories lies in how information from the senses is encoded in the brain.

    Their study in fruit flies for the first time gives experimental confirmation of a theory put forward in the 1960s which suggested sensory information is encoded 'sparsely' in the brain.

    The idea is that we have a huge population of nerve cells in many of our higher brain centres. But only a very few neurons fire in response to any particular sensation – be it smell, sound or vision. This would allow the brain to discriminate accurately between even very similar smells and sensations.

    'This "sparse" coding means that neurons that respond to one odour don't overlap much with neurons that respond to other odours, which makes it easier for the brain to tell odours apart even if they are very similar,' explains Dr Andrew Lin, the lead author of the study published in Nature Neuroscience.

    While previous studies have indicated that sensory information is encoded sparsely in the brain, there's been no evidence that this arrangement is beneficial to storing distinct memories and acting on them.

    'Sparse coding has been observed in the brains of other organisms, and there are compelling theoretical arguments for its importance,' says Professor Gero Miesenböck, in whose laboratory the research was performed. 'But until now it hasn’t been possible experimentally to link sparse coding with behaviour.'

    In their new work, the researchers demonstrated that if they interfered with the sparse coding in fruit flies – if they 'de-sparsened' odour representations in the neurons that store associative memories – the flies lost the ability to form distinct memories for similar smells.

    The flies are normally able to discriminate between two very similar odours, learning to avoid one and head for the other. This is controlled by the neurons that store associative memories, called Kenyon cells. There's a separate nerve cell that acts as a control system to dampen down the activity the Kenyon cells, preventing too many of them from firing for any particular odour.

    Dr Lin and colleagues showed that if this single nerve cell is blocked, the odour coding in Kenyon cells becomes less sparse and less able to discriminate between smells. The flies end up attaching the same memory to similar, yet different, odours.

    Sparse coding does turn out to be important for sensory memories and our ability to act on them. Although the research was carried out in fruit flies, the scientists say sparse coding is likely to play a similar role in human memory.

    Although sparse coding in the brain would seem to require much greater numbers of nerve cells, that cost appears to be worth it in being able to form distinct associative memories and act on them – thankfully. A life of experiences and memories is so much more full as a result.

    For more info on the study, check out an excellent video on the research centre's website.

    (Full story)
  • The chemistry of conservation

    Harry Dayantis | 27 Feb 14 | 0 comments

    Chemistry probably isn't the first thing that comes to mind when you see skeletons at a museum, but an understanding of chemical reactions is essential to the work of the modern museum conservator.

    Bethany Palumbo, Conservator for Life Collections in the Oxford University Museum of Natural History, used her chemical expertise to restore centuries-old whale bones for the Museum's recent reopening. The fruits of her team's hard work are now on display for all to see at the Museum, which reopened on 15 February to a staggering 30,000 visitors in the first week alone.

    'Chemistry is a key element of conservation,' says Bethany. 'When I began the whale project in mid-2013, there had been no documented preparation of the skeletons for over a century – some of them have been at the Museum since 1860! We had to examine every inch of each whale and research the chemical composition of their bones and the oils they secrete before deciding how to proceed.'

    Cleaning and preserving old bones is an intricate, technical task and each treatment must be tailored to the individual bone. Whale bones are especially challenging, as fatty oils slowly seep out over the years.

    'When we began the project, there were thick layers of oxidised natural oils on many of the bones,' says Beth. 'This unsightly residue not only attracts dust and makes specimens look dirty, but it is also acidic in nature so can damage the bone. When we tested the oils, they had an acidity of pH4 – about the same as most acid rain. The density of the oil varied across the specimens, and the skulls tended to have more oil than other areas. Whales have a hollow area in front of their skulls filled with oil to focus sonar signals which seeps into the bones where it can remain for centuries after they die. Areas of bone, still saturated with this acidic oil, were in some cases crumbling with a gritty texture similar to wet sand.'

    To remove the oily secretions, Bethany and her team brushed solutions of ammonia and purified water onto the bones. Ammonia is an alkaline chemical that works by a process known as saponification that converts fats into soap. Ammonia breaks fat molecules up into their glycerol and fatty acid elements to produce soluble salts and soap scum, which can simply be wiped or vacuumed from the surface. Concentrations of ammonia varied depending on the areas being treated.

    'Particularly oily areas, such as the humpback skull needed to be treated with 10% ammonia, whereas we used only 5% for the other specimens,' explains Beth. 'We were careful when the solution came into contact with the cartilage, as this can also disintegrate with the alkaline ammonia solution. There's always a balance to strike with conservation, the treatment method you choose on should never cause more harm than good.'

    As well as damaging the bones, the acidic oil also caused verdigris – the green pigment currently coating the Statue of Liberty – to blossom from the copper wires inside the bones used to support the skeletons. Verdigris can be build up over time when copper reacts with oxygen, and is rapidly accelerated by acids.

    'The verdigris on the copper wires was exploding from the drilled holes in the bone, causing the wires to weaken and snap when we tried to remove them,' says Beth. 'We ended up using a soldering iron to heat the wire, softening the surrounding cartilage just enough for us to pull the wires out and then vacuum out any residues.

    'We have now replaced the wires with stainless steel, which is strong and resistant to the environmental conditions of the museum. We considered alternative methods of putting the skeletons back together, but it made more sense to use the existing holes in the bones to avoid creating further damage to the skeletons.'

    Almost paradoxically, the conditions of the Museum environment are actually rather bad for the bones. Ultraviolet sunlight from the glass ceiling destroys collagen in the bones, weakening their structure, and the fluctuating temperatures cause the bones to expand and shrink, weakening joints. Before the roof was repaired, the fluctuating humidity worsened this problem.

    'Technically, the best place for these bones would be a cool, dark room,' explains Beth. 'There is often a trade-off between conservation and education, so we have to do the best we can to make sure the skeletons can cope when out in the open for all to see. The adhesives we select, for example, have to be able to withstand high heats and fluctuating temperatures.'

    Finally, when reconstructing the skeletons during the restoration process, the team tried to correct the anatomical features of the whales where possible.

    'Dried cartilage will shrink over time, pulling the bones into unnatural positions,' says Beth. 'We corrected this by repositioning bones with new wires where possible, but some areas were just too fragile. Also, since we only had six months to complete the project, we simply didn't have the time to correct everything. There are some parts of the fins and ribcages that remain slightly incorrect, which is frustrating, but the skeletons are still far more anatomically correct than when we started.

    'After a thorough restoration project, I think our whales will have a few good decades more on display. I'm extremely proud of what my team achieved in a short space of time, and hope that visitors will continue to enjoy seeing the whales in the Museum for years to come.'

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  • Homing in on the mosquito

    Pete Wilton | 13 Feb 14 | 0 comments

    Mosquito Anopheles gambiae

    In the battle against the mosquitoes that carry deadly human diseases scientists are recruiting a new ally: a genetic enemy within the mosquito's DNA.

    These new recruits are homing endonuclease genes (HEGs), 'selfish' genetic elements that have a better than normal chance of being passed on between generations despite being potentially harmful to an individual.

    HEGs can recognise and 'cut' a short sequence of DNA on one of a pair of chromosomes, then fool an organism's repair mechanism into copying the HEG across onto the other chromosome. The HEG gets inserted within the 'cut' sequence of 'normal' DNA whilst the 'cut' is repaired. It is this 'drive' that makes HEGs particularly interesting for disrupting DNA and hence mosquito control.

    Crucially HEGs can be used to recognise and disrupt a bit of DNA that really matters – that is important for an individual mosquito to survive from egg to adult.

    'HEGs occur naturally in some simple organisms, such as single-celled fungi, and have been artificially inserted into the genomes of other organisms, notably the mosquito species, Anopheles gambiae, that is the main vector of human malaria,' explains Mike Bonsall of Oxford University's Department of Zoology.

    'They can be used either to suppress mosquito populations by altering the inheritance patterns of genes (for example genes that affect survival) or to alter the genetic structure of mosquito populations by driving genes that alter the key mosquito characteristics (such as the ability to transmit a pathogen).'

    Such a genetic approach could be an important weapon against diseases like malaria, which is responsible for up to 1.6 million deaths a year worldwide, by reducing the numbers of disease-carrying adult female mosquitoes in a local area to such a level that there aren’t enough to support and pass on the infection to humans.

    But HEGs are not simply 'genetic homing missiles' that kill mosquitoes: such selfish genetic elements have to spread, the individuals carrying them have to compete, and populations respond and change.

    'While it is necessary to understand the population genetics and patterns of HEG inheritance, the effectiveness of HEGs requires an understanding of both the ecology and genetics. The population dynamics and ecology determine how individuals in a population compete, grow and disperse,' Nina Alphey of Oxford University's Department of Zoology tells me.

    'Population genetics might predict that a HEG that reduces survival will naturally spread through a population, but that does not necessarily mean the population will be reduced enough to significantly alter disease transmission. Simply knowing the genetics is not quite enough.'

    To explore how interactions between ecology and genetics can influence the effectiveness of HEG-based mosquito control Mike and Nina developed a mathematical model as part of a BBSRC-funded project. They report their findings this week in Journal of the Royal Society Interface.

    'One significant finding from our work is that we show that the type of competition affects the outcome of HEG-based control. If competition is particularly strong, alterations in early larval survival could lead to an increase in mosquito population size, rather than its decline,' Mike explains. 'This occurs as the population is 'freed' from its natural ecological control – which in mosquitoes occurs in the late-larval stage.

    'We also showed that if a HEG does not just reduce the mosquito's survival, but also changes how that mosquito fares during the larval competition, it could achieve a better reduction in mosquito numbers than an identical HEG that simply reduced survival. The effects of a HEG that affects both survival and timing of competition would need to be carefully monitored to ensure that population suppression is achieved.'

    Whilst with larger animals it might be possible to monitor individuals as a way of understanding population dynamics this is impractical for populations of thousands of insects, such as mosquitoes, linked to tiny patches of habitat – a small pond or even just a container of water.

    Mathematical models are the only practical way of studying the links between genetics and ecology and identifying potential pitfalls in any genetic insect control approach – such as HEGs acting early in an insect's lifecycle being less effective than ones acting later on.

    'We are working on extending our modelling approaches to understanding the control of mosquitoes by integrating economics and the cost-effectiveness of control programmes. This involves linking the costs of rearing modified mosquitoes, the epidemiology of the disease, the movement of people and mosquitoes and evaluating the public health benefits,' says Nina. The team have created an online game that highlights some of the issues faced by any control programme.

    There are a lot of factors to consider in a future model: another variable is that in the wild populations compete with other species.  For instance the malaria-carrying Anopheles gambiae mosquito may compete with various other species, and the dengue-carrying Aedes aegypti and the less competent Aedes albopictus compete with each other in some regions, so that reducing the numbers of one disease-carrying species could boost the numbers of another.

    Mike tells me: 'We hope to work out when and where it might be appropriate to combine these insect control strategies with other disease implementation methods (such as vaccination programmes). Also thinking on how these insect control strategies can be used to control the spread of resistance to conventional control programmes is a new BBSRC project we have very recently started.'

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  • Evolution: quantity over quality?

    Harry Dayantis | 05 Feb 14 | 0 comments

    An illustration of the possible mutations available to an RNA molecule. The blue lines represent mutations that will not change its function (phenotype), the grey are mutations to an alternative phenotype with slightly higher fitness and the red are the ‘fittest’ mutations. As there are so few possible mutations resulting in the fittest phenotype in red, the odds of this mutation are a mere 0.15%. The odds for the slightly fitter mutation in grey are 6.7%, but the most likely mutations in blue, with a 93% chance, result in no phenotype changes at all.

    When you think about evolution, 'survival of the fittest' is probably one of the first things that comes into your head. However, new research from Oxford University finds that the 'fittest' may never arrive in the first place and so aren’t around to survive.

    By modelling populations over long timescales, the study showed that the 'fitness' of their traits was not the most important determinant of success. Instead, the most genetically available mutations dominated the changes in traits. The researchers found that the 'fittest' simply did not have time to be found, or to fix in the population over evolutionary timescales.

    The findings suggest that life on Earth today may not have come about by 'survival of the fittest', but rather by the 'arrival of the frequent'. The study is published in the journal PLOS ONE and was funded by the Engineering and Physical Sciences Research Council.

    I caught up with the study's lead author Dr Ard Louis, Reader in Theoretical Physics at Oxford University, to find out more.

    OxSciBlog: How do your results challenge current popular theory?
    Ard Louis: We are arguing that some biological traits may be found in nature not because they are fitter than other potential traits but simply because they are easier to find by evolution. Darwinian evolution proceeds in two steps. Firstly, there is variation: due to mutations, different members of a population may have differences in traits. Secondly, there is selection: if the variation in a trait allows an organism to have more viable offspring, to be 'fitter', then that trait will eventually come to dominate in the population. Traditional evolutionary theory focuses primarily on the work of natural selection. We are challenging this emphasis by claiming that strong biases in the rates at which traits can arrive through variation may direct evolution towards outcomes that are not simply the 'fittest'.

    OSB: What can mathematical models tell us about biological processes?
    AL: Evolution is perhaps the field of biology where mathematics has been the most successful. For example, it was mathematically trained biologists like R. Fisher, J.B.S. Haldane and S. Wright who first worked out how to combine Mendelian genetics, which Darwin didn’t know about, with Darwinian evolution. Today, very sophisticated population genetic calculations are routinely used, for example, to work out how cancer evolves in a patient’s body.

    Of course one always needs to be careful because these models inevitably include simplifying assumptions in order to make them tractable. In our calculations we include difference in rates of the arrival of variation, something not traditionally taken into account in population genetics. But our models so far only apply to fairly simple examples of molecular evolution. Much more work is needed before we could claim that these effects are also important for more complex phenomena such as the evolution of animal behaviour.

    OSB: How do your calculations match up with real-world observations?
    We predict, for example, that RNA molecules that are more robust to the effect of mutations should naturally arise from our 'arrival of the frequent' effect. RNA can act both as an information carrier and as a catalyst, and so is thought to be very important for the origin of life on earth.  It has been known for some time that RNA found in nature is remarkably robust to mutations and we can now provide a population genetic explanation of this phenomenon.

    OSB: How have field biologists reacted to these results?
    On the one hand, biologists who work on evolution and development have not been so surprised because they have long argued that developmental processes can bias organisms to evolve in certain directions over others. Others have reacted with some caution, which is probably wise given the potentially far-reaching nature of our claims. I think we have raised a lot more questions that we have answered.
    OSB: Did the results come as a surprise to you?
    On the one hand they didn't, in part because I have long been interested in Monte Carlo simulation techniques which have many parallels to evolution. There, biases in the arrival of variation are well known to affect outcomes. But I was very surprised to find that the biasing effect could be so enormously strong, making it robust to such a wide range of different evolutionary parameters.
    OSB: How did your group come to study evolution?
    We specialise in statistical physics, and there are many beautiful parallels between evolutionary dynamics and processes in the everyday physical world. In my group we have worked for many years on self-assembly; how individual units can form well-defined composite objects without any external control. Biology is full of amazing self-assembled structures, and so we began asking: how do these structures evolve in the first place?

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