Thursday, December 10, 2009

NEW RESEARCH HELPS EXPLAIN WHY BIRD FLU HAS NOT CAUSED A PANDEMIC

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Bird flu viruses would have to make at least two simultaneous genetic mutations before they could be transmitted readily from human to human, according to research published in PLoS ONE.

The authors of the new study, from Imperial College London, the University of Reading and the University of North Carolina, USA, argue that it is very unlikely that two genetic mutations would occur at the same time. Today's new study adds to our understanding of why avian influenza has not yet caused a pandemic.

Earlier this year, the Imperial researchers also showed that avian influenza viruses do not thrive in humans because, at 32 degrees Celsius, the temperature inside a person's nose is too low.

H5 strains of influenza are widespread in bird populations around the world. The viruses occasionally infect humans and the H5N1 strain has infected more than 400 people since 2003.

H5N1 has a high mortality rate in humans, at around 60 per cent, but to date there has been no sustained human to human transmission of the virus, which would need to happen in order for a pandemic to occur.

The study suggests that one reason why H5N1 has not yet caused a pandemic is that two genetic mutations would need to happen to the virus at the same time in order to enable it to infect the right cells and become transmissible. At present, H5 viruses can only infect one of the two main types of cell in the mouth and nose, a type of cell known as a ciliated cell. In order for H5 to transmit from human to human, it would need to be able to infect the other, non-ciliated type of cell as well.

To infect a cell, the influenza virus uses a protein called HA to attach itself to a receptor molecule on the cell's surface. However, it can only do this if the HA protein fits that particular receptor. Today's research shows that H5 would only be able to make this kind of adaptation and fit the receptor on the cells that are important for virus transmission if it went through two simultaneous genetic mutations.

Professor Wendy Barclay, corresponding author of the study from the Division of Investigative Science at Imperial College London, said: "H5N1 is a particularly nasty virus, so when humans started to get infected with bird flu, people started to panic. An H5N1 pandemic would be devastating for global health. Thankfully, we haven't yet had a major outbreak, and this has led some people to ask, what happened to bird flu? We wanted to know why the virus hasn't been able to jump from human to human easily.

"Our new research suggests that it is less likely than we thought that H5N1 will cause a pandemic, because it's far harder for it to infect the right cells. The odds of it undergoing the kind of double mutation that would be needed are extremely low. However, viruses mutate all the time, so we shouldn't be complacent. Our new findings do not mean that this kind of pandemic could never happen. It's important that scientists keep working on vaccines so that people can be protected if such an event occurs," added Professor Barclay.

Professor Ian Jones, leader of the collaborating group at the University of Reading, added: "It would have been impossible to do this research using mutation of the real H5N1 virus as we could have been creating the very strain we fear. However, our novel recombinant approach has allowed us to safely address the question of H5 adaptation and provide the answer that it is very unlikely."

In addition to explaining why bird flu's ability to transmit between humans is limited, the new research also gives scientists a better understanding of the virus. They believe that this could help the development of a better vaccine against bird flu, in the unlikely event that one was needed in the future.

The researchers used a realistic model of the inside of a human airway to study H5 binding to human cells. They made genetic changes to the H5 HA protein to change its shape, to see if they could make the virus recognise and infect the right types of cells. Results showed that the virus would need two genetic changes occurring at once in its genome before it could infect these cells.

The researchers then investigated intermediate forms of the virus, with one or the other mutation, to see if the change could occur gradually. They found that intermediate versions of the virus could not infect human cells, so would die out before they could be transmitted. The researchers say this means the two genetic mutations would need to occur simultaneously.

(Photo: ICL)

PROTON'S PARTY PALS MAY ALTER ITS INTERNAL STRUCTURE

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A recent experiment at the Department of Energy's Thomas Jefferson National Accelerator Facility has found that a proton's nearest neighbors in the nucleus of the atom may modify the proton's internal structure.

The result was published in the November 13 issue of the journal Physical Review Letters.

When comparing large nuclei to small nuclei, past measurements have shown a clear difference in how the proton's constituent particles, called quarks, are distributed. This difference is called the EMC Effect.

Many models of the EMC Effect predict that it is caused by the mass or density of the nucleus in which the proton resides. To test these predictions, experimenters made precise new measurements of the EMC effect in a variety of light nuclei, such as isotopes of helium.

"What we found is that there is a large modification of the quark structure in helium-4, and there was a much smaller effect in helium-3. And even though they were both light nuclei, they had a very different EMC Effect," said John Arrington, a spokesperson for the experiment and a nuclear physicist at DOE's Argonne National Lab.

The results, Arrington added, rules out the idea that the size of the EMC effect scales with the mass of the nucleus.

Next, the experimenters turned their attention to density. They compared the EMC Effect in beryllium to various other nuclei. Beryllium has a mass similar to carbon but a much lower density, roughly the same as helium-3. They found that the size of the EMC Effect in beryllium is similar to that of carbon, which is twice as dense.

"So you have one set of data that tells you the mass-dependence picture doesn’t work and another that tells you the density-dependence picture doesn't work," Arrington explained. “So, if both of these pictures are wrong, what's really going on?"

Interestingly, the result did indicate a possible new cause for the effect: the microscopic structure of nuclei. This possible result is hinged on the unusual structure of beryllium. Most of the time, beryllium’s configuration consists of two orbiting clusters that look like helium-4 nuclei (each with two protons and two neutrons), and one additional neutron orbiting around.

The orbiting clusters yield a large radius and a low average density for the beryllium nucleus, but most protons and neutrons are contained within the high local densities of the clusters. This suggests that the EMC effect may be entirely generated within these small, high-density clusters.

"That's a hypothesis, but it's certainly clear that it's small groups of nucleons that get together and change things, rather than the whole collection," Arrington said. “In a way, it’s not really surprising. If you’re at a party, it doesn’t matter how many people are in the room, most of the time you’re interacting with the people that you’re closest to.”

Arrington says the next step is to take a new measurement that directly examines the impact of the local density. This can be done by looking at the quark structure of the deuteron, a nucleus consisting of just one proton and one neutron. Most of the time, the proton and neutron are pretty far apart.

"We want to isolate the quark structure during the moment when the proton and neutron are very close together. If we find a large effect in such a small and simple nucleus by looking when the proton and neutron are closest together, it will demonstrate that the EMC effect does not require a large, dense nucleus – it simply requires two nucleons coming into extremely close contact," Arrington explained.

The experiment, E03-103, ran for 21 days in Hall C in October of 2004. It measured the momenta of protons knocked out of the nuclei of hydrogen, helium, beryllium and carbon atoms by electrons from the CEBAF Accelerator.

(Photo: Peter Mueller/Argonne National Lab)

EXPLAINED: RNA INTERFERENCE

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Exploiting the recently discovered mechanism could allow biologists to develop disease treatments by shutting down specific genes.

Every high school biology student learns the basics of how genes are expressed: DNA, the cell’s master information keeper, is copied into messenger RNA, which carries protein-building instructions to the ribosome, the part of the cell where proteins are assembled.

But it turns out the picture is far more complicated than that. In recent years, biologists have discovered a myriad of other molecules that fine-tune this process, including several types of RNA (ribonucleic acid). Through a naturally occurring phenomenon known as RNA interference, short strands of RNA can selectively intercept and destroy messenger RNA before it delivers its instructions.

Scientists are now pursuing disease treatments based on RNA interference (RNAi), which offers the tantalizing ability to shut down any gene in the body.

“With RNAi, we have the possibility to design small RNA that matches any gene, or any part of that gene, and silence it. Then we can ask what is the potential benefit of silencing that gene in the disease process,” says MIT Institute Professor Phillip Sharp, whose lab is pursuing such studies.

In 2006, the Nobel Prize in Physiology or Medicine was awarded to two scientists, including Andrew Fire, who earned his MIT PhD in 1983 under Sharp’s supervision, for the discovery of RNA interference. Fire and Craig Mello showed in 1998 that when short, double-stranded RNA molecules with sequences complementary to a specific messenger RNA were injected into the worm C. elegans, production of the protein encoded by that messenger RNA was halted.

Here’s how it works: Double-stranded RNA molecules called siRNA (short interfering RNA) bind to complementary messenger RNA, then enlist the help of proteins, the RNA-induced silencing complex. Those proteins cleave the chemical bonds holding messenger RNA together and prevent it from delivering its protein-building instructions.

This mechanism occurs naturally and may have evolved to give cells additional control over gene expression, particularly during embryonic development. It may also serve as a defense mechanism against viruses that try to insert their genetic material into cells.

RNA interference can also be mediated by microRNA, which is a short, single-stranded RNA molecule. RNA interference has been observed in a wide range of species, including plants, bacteria and fruit flies as well as humans.

Scientists have shown that synthetic siRNA injected into human cells in the lab can successfully shut off genes, raising hopes that diseases such as cancer, cystic fibrosis, Huntington’s disease and others caused by malfunctioning genes could be treated with RNA interference.

Before such therapies can become useful, scientists must figure out how to efficiently deliver small RNA molecules into target cells. Sharp and others at MIT, including Institute Professor Robert Langer and research scientist Daniel Anderson, are working on a delivery method that packages RNA inside a layer of fat-like molecules called lipidoids, which can cross cells’ fatty outer membrane. They have used the lipidoids to successfully deliver RNA to liver and lung cells in mice and monkeys, and hope to begin clinical trials within the next two years.

Sharp is also working with Sangeeta Bhatia, professor in the Harvard-MIT Division of Health Sciences and Technology, on better ways to target the RNA-carrying nanoparticles to specific cells, such as tumor cells.

There is a long way to go, says Sharp, but the potential of RNA interference is very large. “The discovery of RNA interference opened our eyes to a whole new aspect of biomedical science and biology that we just had never been aware of.”

(Photo: National Institutes of Health)

SCIENTISTS WATCH AS PEPTIDES CONTROL CRYSTAL GROWTH WITH SWITCHES, THROTTLES AND BRAKES

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By producing some of the highest resolution images of peptides attaching to mineral surfaces, scientists have a deeper understanding how biomolecules manipulate the growth crystals. This research may lead to a new treatment for kidney stones using biomolecules.

The research, which appears in the Nov. 23 online edition of the journal Proceedings of the National Academy of Science, explores how peptides interact with mineral surfaces by accelerating, switching and inhibiting their growth.

The team, made up of researchers from Lawrence Livermore National Laboratory, the Molecular Foundry at Lawrence Berkeley, the University of California, Davis and the University of Alabama, for the first time produced single-molecule resolution images of this peptide-mineral interaction.

Inorganic minerals play an important role in most biological organisms. Bone, teeth, protective shells or the intricate cell walls of marine diatoms are some displays of biomineralization, where living organisms form structures using inorganic material. Some minerals also can have negative effects on an organism such as in kidney and gallstones, which lead to severe suffering and internal damage in humans and other mammals.

Understanding how organisms limit the growth of pathological inorganic minerals is important in developing new treatment strategies. But deciphering the complex pathways that organisms use to create strong and versatile structures from relatively simple materials is no easy feat. To better understand the process, scientists attempt to mimic them in the laboratory.

By improving the resolution power of an Atomic Force Microscope (AFM), the PNAS authors were able to image individual atomic layers of the crystal interacting with small protein fragments, or peptides, as they fell on the surface of the crystal.

“Imaging biomolecules that are weakly attached to a surface, while simultaneously achieving single-molecule resolution, is normally difficult to do without knocking the molecules off,” said Raymond Friddle, an LLNL postdoctoral fellow.

But the team improved upon previous methods and achieved unprecedented resolution of the molecular structure of the crystal surface during the dynamic interaction of each growing layer with peptides. “We were able to watch peptides adhere to the surface, temporarily slow down a layer of the growing crystal, and surprisingly ‘hop’ to the next level of the crystal surface.”

The images also revealed a mechanism that molecules can use to bind to surfaces that would normally repel them. The high resolution images showed that peptides will cluster together on crystal faces that present the same electronic charge. Under certain conditions the peptides would slow down growth, while under other conditions the peptides could speed up growth.

On another face of the crystal, where the peptides were expected to bind strongly, the researchers found instead that the peptides did not attach to the surface unless the crystal growth slowed. The peptides needed to bind in a specific way to the face, which takes more time than a non-specific attachment. As a result, the growing layers of the crystal were able to shed off the peptides as they attempted to bind.

But when the researchers slowed down the crystal growth rate, the peptides collapsed onto the surface so strongly that they completely stopped growth. The researchers proposed that the phenomenon is due to the unique properties of bio-polymers, such as peptides or polyelectrolytes, which fluctuate in solution before resting in a stable configuration on a surface.

“The results of the catastrophic drop in growth by peptides suggest ways that organisms achieve protection against pathological mineralization,” said Jim De Yoreo, the project lead and deputy director of research at LBNL’s Molecular Foundry. “Once growth is halted, a very high concentration of the mineral will be needed before growth can again reach significant levels.”

He said designing polyelectrolyte modifiers in which the charge, size and ability to repel water can be systematically varied would allow researchers to create the equivalent of “switches, throttles and brakes” for directing crystallization.

(Photo: LLNL)

Lawrence Livermore National Laboratory

ACTIVE HEARING PROCESS IN MOSQUITOES

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A mathematical model has explained some of the remarkable features of mosquito hearing. In particular, the male can hear the faintest beats of the female's wings and yet is not deafened by loud noises.

The new research from the University of Bristol is published in the Journal of the Royal Society Interface.

Insects have evolved diverse and delicate morphological structures in order to hear the naturally low energy of a transmitting sound wave. In mosquitoes, the hearing of acoustic energy, and its conversion into neuronal signals, is assisted by multiple individual sensory units called scolopidia.

The researchers have developed a simple microscopic mechanistic model of the active amplification in the Tanzanian mosquito species Toxorhynchites brevipalpis. The model is based on the description of the antenna as a forced-damped oscillator attached to a set of active threads (groups of scolopidia) that provide an impulsive force when they twitch. The twitching is controlled by channels that are opened and closed if the antennal oscillation reaches critical amplitude. The model matches both qualitatively and quantitatively with recent experiments: spontaneous oscillations, nonlinear amplification, hysteresis, 2:1 resonances, frequency response, gain loss due to hypoxia.

The numerical simulations also generate new hypotheses. In particular, the model seems to indicate that scolopidia located toward the tip of the Johnston's organ are responsible for the entrainment of the other scolopidia, and that they give the largest contribution to the mechanical amplification.

Dr Daniele Avitabile, Research Assistant in the Bristol Centre for Applied Nonlinear Mathematics in the Department of Engineering Maths, said: "The numerical results presented also generate new questions. In our description of the system, for instance, all threads have the same material properties, but their impact on the dynamics of the antenna varies according to the spatial location of the threads: intuitively, an external thread induces a much larger torque than an internal one.

"However, the true physiology of the threads is more complex, due to the curved arrangement of Johnston's organ, and further research into the effect of the subsequent mechanical variation of each thread needs to be carried out."

(Photo: Journal of the Royal Society Interface)

University of Bristol

HUMAN EMISSIONS RISE 2% DESPITE GFC

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Despite the economic effects of the global financial crisis (GFC), carbon dioxide emissions from human activities rose 2 per cent in 2008 to an all-time high of 1.3 tonnes of carbon per capita per year, according to a paper published in Nature Geoscience.

The paper – by scientists from the internationally respected climate research group, the Global Carbon Project (GCP) – says rising emissions from fossil fuels last year were caused mainly by increased use of coal but there were minor decreases in emissions from oil and deforestation.

“The current growth in carbon dioxide (CO2) emissions is closely linked to growth in Gross Domestic Product (GDP),” said one of the paper’s lead authors, CSIRO’s Dr Mike Raupach.

“CO2 emissions from fossil fuel combustion are estimated to have increased 41 per cent above 1990 levels with emissions continuing to track close to the worst-case scenario of the Intergovernmental Panel on Climate Change (IPCC).

"There will be a small downturn in emissions because of the GFC, but anthropogenic emissions growth will resume when the economy recovers unless the global effort to reduce emissions from human activity is accelerated."

The GCP estimates that the growth in emissions from developing countries increased in part due to the production of manufactured goods consumed in developed countries. In China alone, 50 per cent of the growth in emissions from 2002 to 2005 was attributed to the country’s export industries.

According to the GCP’s findings, atmospheric CO2 growth was about four billion metric tonnes of carbon in 2008 and global atmospheric CO2 concentrations reached 385 parts per million – 38 per cent above pre-industrial levels.

According to co-author and GCP Executive Director, CSIRO’s Dr Pep Canadell, the findings also indicate that natural carbon sinks, which play an important role in buffering the impact of rising emissions from human activity, have not been able to keep pace with rising CO2 levels.

“On average only 45 per cent of each year’s emissions remain in the atmosphere,” Dr Canadell said.

“The remaining 55 per cent is absorbed by land and ocean sinks.

“However, CO2 sinks have not kept pace with rapidly increasing emissions, as the fraction of emissions remaining in the atmosphere has increased over the past 50 years. This is of concern as it indicates the vulnerability of the sinks to increasing emissions and climate change, making natural sinks less efficient ‘cleaners’ of human carbon pollution.”

More than 30 experts from major international climate research institutions contributed to the GCP’s annual Global Carbon Budget report – now considered a primary reference on the human effects on atmospheric CO2 for governments and policy-makers around the world.

(Photo: © Danicek Dreamstime.com)

CSIRO

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