Tuesday, August 31, 2010

SCIENTISTS UNCOVER ACHILLES HEEL OF CHRONIC INFLAMMATORY PAIN

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Researchers have made a discovery that could lead to a brand new class of drugs to treat chronic pain caused by inflammatory conditions such as arthritis and back pain without numbing the whole body.

The team, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and working at UCL (University College London), have shown for the first time that genes involved in chronic pain are regulated by molecules inside cells called small RNAs. This mechanism is so different from what has already been discovered about the biology underpinning pain that it could be the Achilles heel of chronic inflammatory pain, which is notoriously difficult to treat. The research appears in The Journal of Neuroscience.

Lead researcher Professor John Wood from UCL said "When a person experiences chronic pain as a result of some sort of inflammation - as in arthritis - their pain threshold goes down very dramatically. What they can normally do without pain, such as walking or putting on clothes, becomes very painful.

"Chronic inflammatory pain can be treated with pain-killing drugs - analgesics - but these usually have an impact on the whole body and may also dull our experience of acute pain, which is actually very important as it protects us from injury. Just imagine if you didn't get a sharp pain when you accidentally touch the oven - you wouldn't be compelled to take your hand away quickly and could end up with a serious burn.

"What we would really like to be able to do is return the pain thresholds to normal in a person who has chronic inflammatory pain, rather than just numbing the whole body. This would mean that they still get the protection of acute pain. Currently, aspirin-like drugs that can do this have a number of side effects but the present discovery might make it possible to invent a class of drugs that act in a completely novel way."

The researchers studied mice that lack an enzyme called Dicer in some of their nerve cells and found that they respond normally to acute pain but don't seem to be bothered by anything that would usually cause chronic inflammatory pain. This is because Dicer makes small RNAs, which they now know are required for regulation of genes involved in chronic inflammatory pain. Without Dicer the small RNAs aren't made and without the small RNAs many of these genes are expressed at low levels. So, for example, molecules such as sodium channels that make pain nerves responsive to inflammation are produced at low levels and therefore inflammatory pain is not detected by the mouse's body.

Professor Wood concluded "Knowing that small RNAs are so important in chronic inflammatory pain provides a new avenue for developing drugs for some of the most debilitating and life-long conditions out there. We have identified small RNAs, which are possible drug targets".

Professor Douglas Kell, BBSRC Chief Executive said "It is extremely important to be able to find out as much as possible about the fundamental processes of 'normal' biology, as a vehicle for understanding what may go wrong. Because these researchers have made efforts to unpick what is happening at a molecular level in our nerves, they have been able to lay the groundwork for future drug development in the important area of chronic pain. This is an excellent example of the basic research we have to do to help ensure that our increasing lifespan does not mean that the later years of our lives are spent in ill health and discomfort."

Biotechnology and Biological Sciences Research Council

BERKELEY STUDY SHOWS OZONE AND NICOTINE A BAD COMBINATION FOR ASTHMA

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Another reason for including asthma on the list of potential health risks posed by secondhand tobacco smoke, especially for non-smokers, has been uncovered. Furthermore, the practice of using ozone to remove the smell of tobacco smoke from indoor environments, including hotel rooms and the interiors of vehicles, is probably a bad idea.

A new study by researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) shows that ozone can react with the nicotine in secondhand smoke to form ultrafine particles that may become a bigger threat to asthma sufferers than nicotine itself. These ultrafine particles also become major components of thirdhand smoke – the residue from tobacco smoke that persists long after a cigarette or cigar has been extinguished.

“Our study reveals that nicotine can react with ozone to form secondary organic aerosols that are less than 100 nanometers in diameter and become a source of thirdhand smoke,” says Mohamad Sleiman, a chemist with the Indoor Environment Department of Berkeley Lab’s Environmental Energy Technologies Division (EETD) who led this research.

“Because of their size and high surface area to volume ratio, ultrafine particles have the capacity to carry and deposit potentially harmful organic chemicals deep into the lower respiratory tract where they promote oxidative stress,” Sleiman says. “It’s been well established by others that the elderly and the very young are at greatest risk.”

Results of this study have been reported in the journal Atmospheric Environment in a paper titled “Secondary organic aerosol formation from ozone-initiated reactions with nicotine and secondhand tobacco smoke.” Co-authoring this paper with Sleiman were Hugo Destaillats and Lara Gundel, also with EETD’s Indoor Environment Department, and Jared Smith, Chen-Lin Liu, Musahid Ahmed and Kevin Wilson with the Chemical Dynamics Group of Berkeley Lab’s Chemical Sciences Division. The study was carried out under a grant from the University of California’s Tobacco-Related Disease Research Program.

The dangers of mainstream and secondhand tobacco smoke, which contain several thousand chemical toxins distributed as particles or gases, have been well documented. This past February, a study, also spearheaded by Sleiman, Destaillats and Gundel, revealed the potential health hazards posed by thirdhand tobacco smoke which was shown to react with nitrous acid, a common indoor air pollutant, to produce dangerous carcinogens. Until now, however, in terms of forming ultrafine particles, there have been no studies on the reaction of nicotine with ozone.

Released as a vapor by the burning of tobacco, nicotine is a strong and persistent adsorbent onto indoor surfaces that is released back to indoor air for a period of months after smoking ceased. Ozone is a common urban pollutant that infiltrates from outdoor air through ventilation that has been linked to health problems, including asthma and respiratory ailments.

Says co-author Gundel, “Not only did we find that nicotine from secondhand smoke reacts with ozone to make ultrafine particles – a new and stunning development – but we also found that several oxidized products of ozone and nicotine have higher values on the asthma hazard index than nicotine itself.”

Says co-author Destaillats, “In our previous study, we found that carcinogens were formed on indoor surfaces, which can lead to exposures that are likely to be dominated by dermal uptake and dust ingestion. This study suggests a different exposure pathway to aged secondhand or thirdhand smoke through the formation and inhalation of ultrafine particles. Also, our group had previously described the formation of secondary organic aerosols in reaction of indoor ozone with terpenoids, commonly present in household products. But this is the first time that nicotine has been tagged as a potential candidate to form ultrafine particles or aerosols through a reaction with ozone.”

To identify the products formed when nicotine in secondhand smoke is reacted with ozone, Sleiman and his co-authors utilized the unique capabilities of Berkeley Lab’s Advanced Light Source (ALS), a premier source of x-ray and ultraviolet light for scientific research. Working at ALS Beamline 9.0., which is optimized for the study of chemical dynamics using vacuum ultraviolet (VUV) light and features an aerosol chemistry experimental station, the researchers found new chemical compounds forming within one hour after the start of the reaction.

“The tunable VUV light of Beamline 9.0.2’s custom-built VUV aerosol mass spectrometer minimized the fragmentation of organic molecules and enabled us to chemically characterize the secondhand smoke and identify individual constituents of secondary organic aerosols,” says Sleiman. “The identification of multifunctional compounds, such as carbonyls and amines, present in the ultrafine particles, made it possible for us to estimate the Asthma Hazard Index for these compounds.”

While the findings in this study support recommendations from the California EPA and the Air Resources Board that discourage the use of ozone-generating “air purifiers,” which among other applications, have been used for the removal of tobacco odors, the Berkeley Lab researchers caution that the levels of both ozone and nicotine in their study were at the high end of typical indoor conditions.

Says Sleiman, “In addition, we need to do further investigations to verify that the formation of ultrafine particles occurs under a range of real world conditions. However, given the high levels of nicotine measured indoors when smoking takes place regularly and the significant yield of ultrafine particles formation in our study, our findings suggest new link between asthma and exposure to secondhand and thirdhand smoke.”

(Photo: Roy Kaltschmidt, Berkeley Lab Public Affairs)

Lawrence Berkeley National Laboratory

ASTEROID FOUND IN GRAVITATIONAL DEAD ZONE

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There are places in space where the gravitational tug between a planet and the Sun balance out, allowing other smaller bodies to remain stable. These places are called Lagrangian points. So-called Trojan asteroids have been found in some of these stable spots near Jupiter and Neptune. Trojans share their planet’s orbit and help astronomers understand how the planets formed and how the solar system evolved. Now Scott Sheppard at the Carnegie Institution’s Department of Terrestrial Magnetism and Chad Trujillo have discovered the first Trojan asteroid, 2008 LC18, in a difficult-to-detect stability region at Neptune, called the Lagrangian L5 point.

They used the discovery to estimate the asteroid population there and find that it is similar to the asteroid population at Neptune’s L4 point. The research is published in the August 12, 2010, online issue of Science Express.

Sheppard explained: “The L4 and L5 Neptune Trojan stability regions lie about 60 degrees ahead of and behind the planet, respectively. Unlike the other three Lagrangian points, these two areas are particularly stable, so dust and other objects tend to collect there. We found 3 of the 6 known Neptune Trojans in the L4 region in the last several years, but L5 is very difficult to observe because the line-of-sight of the region is near the bright center of our galaxy.”

The scientists devised a unique observing strategy. Using images from the digitized all-sky survey they identified places in the stability regions where dust clouds in our galaxy blocked out the background starlight from the galaxy’s plane, providing an observational window to the foreground asteroids. They discovered the L5 Neptune Trojan using the 8.2-meter Japanese Subaru telescope in Hawaii and determined its orbit with Carnegie’s 6.5-meter Magellan telescopes at Las Campanas, Chile.

“We estimate that the new Neptune Trojan has a diameter of about 100 kilometers and that there are about 150 Neptune Trojans of similar size at L5,” Sheppard said. “It matches the population estimates for the L4 Neptune stability region. This makes the Neptune Trojans in the 100-kilometer range more numerous than those bodies in the main asteroid belt between Mars and Jupiter. There are fewer Neptune Trojans known simply because they are very faint since they are so far from the Earth and Sun.”

The L5 Trojan has an orbit that is very tilted to the plane of the solar system, just like several in L4. This suggests they were captured into these stable regions during the very early solar system when Neptune was moving on a much different orbit than it is now. Capture was either through a slow, smooth planetary migration process or as the giant planets settled into their orbits, their gravitational attraction could have caught and “frozen” asteroids into these spots. The solar system was likely a much more chaotic place during that time with many bodies stirred up onto unusual orbits.

The region of space surveyed also included a volume through which the New Horizons spacecraft will pass after its encounter with Pluto in 2015.The work was funded in part by the New Horizon’s spacecraft mission to Pluto.

(Photo: Carnegie I.)

Carnegie Institution

SCIENTISTS CALL FOR A GLOBAL NUCLEAR RENAISSANCE IN NEW STUDY

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Scientists outline a 20-year master plan for the global renaissance of nuclear energy that could see nuclear reactors with replaceable parts, portable mini-reactors, and ship-borne reactors supplying countries with clean energy, in research published in the journal Science.

The scientists, from Imperial College London and the University of Cambridge, suggest a two-stage plan in their review paper that could see countries with existing nuclear infrastructure replacing or extending the life of nuclear power stations, followed by a second phase of global expansion in the industry by the year 2030. The team say their roadmap could fill an energy gap as old nuclear, gas and coal fired plants around the world are decommissioned, while helping to reduce the planet’s dependency on fossil fuels.

Professor Robin Grimes, from the Department of Materials at Imperial College London, says: “Our study explores the exciting opportunities that a renaissance in nuclear energy could bring to the world. Imagine portable nuclear power plants at the end of their working lives that can be safely shipped back by to the manufacturer for recycling, eliminating the need for countries to deal with radioactive waste. With the right investment, these new technologies could be feasible. Concerns about climate change, energy security and depleting fossil fuel reserves have spurred a revival of interest in nuclear power generation and our research sets out a strategy for growing the industry long-term, while processing and transporting nuclear waste in a safe and responsible way.”

The researchers suggest in their study that based on how technologies are developing, new types of reactors could come online that are much more efficient than current reactors by 2030. At the moment, most countries have light water reactors, which only use a small percentage of the uranium for energy, which means that the uranium is used inefficiently. The team suggest that new ‘fast reactors’ could be developed that could use uranium approximately 15 times more efficiently, which would mean that uranium supplies could last longer, ensuring energy security for countries.

Another idea is to develop reactors with replaceable parts so that they can last in excess of 70 years, compared to 40 or 50 years that plants can currently operate at. Reactors are subjected to harsh conditions including extreme radiation and temperatures, meaning that parts degrade over time, affecting the life of the reactor. Making replaceable parts for reactors would make them more cost effective and safe to run over longer periods of time.

Flexible nuclear technologies could be an option for countries that do not have an established nuclear industry, suggest the scientists. One idea involves ship-borne civil power plants that could be moored offshore, generating electricity for nearby towns and cities. This could reduce the need for countries to build large electricity grid infrastructures, making it more cost effective for governments to introduce a nuclear industry from scratch.

The researchers also suggest building small, modular reactors that never require refuelling. These could be delivered to countries as sealed units, generating power for approximately 40 years. At the end of its life, the reactor would be returned to the manufacturer for decommissioning and disposal. Because fuel handling is avoided at the point of electricity generation, the team say radiation doses to workers would be reduced, meaning that the plants would be safer to operate.

The scientists believe the roll out of flexible technologies that could be returned to the manufacturer at their end of their shelf life could also play an important role in preventing the proliferation of nuclear armaments, because only the country of origin would have access to spent fuel, meaning that other countries could not reprocess the fuel for use in weapons.

In the immediate future, the researchers suggest the first stage of the renaissance will see countries with existing nuclear energy infrastructure extending the life of current nuclear power plants. The researchers suggest this could be made possible by further developing technologies for monitoring reactors, enabling them to last longer because engineers can continually assess the safety and performance of the power plants.

The researchers say new global strategies for dealing with spent fuel and radioactive components will have to be devised. Until now, countries have not developed a coordinated strategy for dealing with waste. One suggestion is to develop regional centres, where countries can send their waste for reprocessing, creating new industries in the process.

Professor Grimes adds: “In the past, there has been the perception in the community that nuclear technology has not been safe. However, what most people don’t appreciate is just how much emphasis the nuclear industry places on safety. In fact, safety is at the very core of the industry. With continual improvements to reactor design, nuclear energy will further cement its position as an important part of our energy supply in the future.”

However, the authors caution that governments around the world need to invest more in training the next generation of nuclear engineers. Otherwise, the nuclear industry may not have enough qualified personnel to make the renaissance a reality.

Dr William Nuttall, University Senior Lecturer in Technology Policy at Cambridge Judge Business School, University of Cambridge, concludes: “The second phase of the ‘Two-Stage Nuclear Renaissance’ is not inevitable, but we would be foolish if we did not provide such an option for those that must make key energy technology decisions in the decades ahead. Too often, decisions shaping the direction of research and development in the nuclear sector are made as part of a strategy for eventual deployment. As such small research capacities can become confused with multi-billion dollar plans and stall as a result. Relatively modest research and development can, however, provide us with important options for the future. Such research and development capacities need to be developed now if they are to be ready when needed. While some good measures are already underway, the possible challenge ahead motivates even greater efforts.”

(Photo: ICL)

Imperial College London

NEW EVIDENCE THAT MATTER AND ANTIMATTER MAY BEHAVE DIFFERENTLY

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Neutrinos, elementary particles generated by nuclear reactions in the sun, suffer from an identity crisis as they cross the universe, morphing between three different “flavors.” Their antimatter counterparts (which are identical in mass but opposite in charge and spin) do the same thing.

A team of physicists including some from MIT has found surprising differences between the flavor-switching behavior of neutrinos and antineutrinos. If confirmed, the finding could help explain why matter, and not antimatter, dominates our universe.

“People are very excited about it because it suggests that there are differences between neutrinos and antineutrinos,” says Georgia Karagiorgi, an MIT graduate student and one of the leaders of the analysis of experimental data produced by the Booster Neutrino Experiment (MiniBooNE) at the Fermi National Accelerator Laboratory.

The new result, announced in June and submitted to the journal Physical Review Letters, appears to be one of the first observed violations of CP symmetry: the theory that matter and antimatter should behave in the same way. CP symmetry violation has been seen before in quarks, another type of elementary particle that makes up protons and neutrons, but never in neutrinos or electrons.

The finding could also force physicists to revise their Standard Model, which catalogs all of the known particles that make up matter. The model now posits only three flavors of neutrino, but a fourth (or fifth or sixth) may be necessary to explain the new results.

“If this should be proven to be correct, it would have major implications for particle physics,” says John Learned, professor of physics at the University of Hawaii, who is not part of the MiniBooNE team.

So far, the researchers have enough data to present their results with a confidence level of just below 99.7 percent (also called 3 sigma), which is not high enough to claim a new discovery. To reach that level, 5-sigma confidence (99.99994 percent) is required. “People are going to rightfully demand a really clean, 5-sigma result,” says Learned.

Since the 1960s, physicists have been gathering evidence that neutrinos can switch, or oscillate, between three different flavors — muon, electron and tau, each of which has a different mass. However, they have not yet been able to rule out the possibility that more types of neutrino might exist.

In an effort to help nail down the number of neutrinos, MiniBooNE physicists send beams of neutrinos or antineutrinos down a 500-meter tunnel, at the end of which sits a 250,000-gallon tank of mineral oil. When neutrinos or antineutrinos collide with a carbon atom in the mineral oil, the energy traces left behind allow physicists to identify what flavor of neutrino took part in the collision. Neutrinos, which have no charge, rarely interact with other matter, so such collisions are rare.

MiniBooNE was set up in 2002 to confirm or refute a controversial finding from an experiment at the Liquid Scintillator Neutrino Detector (LSND) at Los Alamos National Laboratory. In 1990, the LSND reported that a higher-than-expected number of antineutrinos appeared to be oscillating over relatively short distances, which suggests the existence of a fourth type of neutrino, known as a “sterile” neutrino.

In 2007, MiniBooNE researchers announced that their neutrino experiments did not produce oscillations similar to those seen at LSND. At the time, they assumed the same would hold true for antineutrinos. “In 2007, I would have told you that you can pretty much rule out LSND,” says MIT physics professor Janet Conrad, a member of the MiniBooNE collaboration and an author of the new paper.

MiniBooNE then switched to antineutrino mode and collected data for the next three years. The research team didn’t look at all of the data until earlier this year, when they were shocked to find more oscillations than would be expected from only three neutrino flavors — the same result as LSND.

Already, theoretical physicists are posting papers online with theories to account for the new results. However, “there’s no clear and immediate explanation,” says Karsten Heeger, a neutrino physicist at the University of Wisconsin. “To nail it down, we need more data from MiniBooNE, and then we need to experimentally test it in a different way.”

The MiniBooNE team plans to collect antineutrino data for another 18 months. Conrad also hopes to launch a new experiment that would use a cyclotron, a type of particle accelerator in which particles travel in a circle instead of a straight line, to help confirm or refute the MiniBooNE results.

(Photo: Fermilab)

Massachusetts Institute of Technology

PROBING THE NANOPARTICLE: PREDICTING HOW NANOPARTICLES WILL REACT IN THE HUMAN BODY

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Researchers at North Carolina State University have developed a method for predicting the ways nanoparticles will interact with biological systems – including the human body. Their work could have implications for improved human and environmental safety in the handling of nanomaterials, as well as applications for drug delivery.

NC State researchers Dr. Jim Riviere, Burroughs Wellcome Distinguished Professor of Pharmacology and director of the university’s Center for Chemical Toxicology Research and Pharmacokinetics, Dr. Nancy Monteiro-Riviere, professor of investigative dermatology and toxicology, and Dr. Xin-Rui Xia, research assistant professor of pharmacology, wanted to create a method for the biological characterization of nanoparticles – a screening tool that would allow other scientists to see how various nanoparticles might react when inside the body.

“We wanted to find a good, biologically relevant way to determine how nanomaterials react with cells,” Riviere says. “When a nanomaterial enters the human body, it immediately binds to various proteins and amino acids. The molecules a particle binds with will determine where it will go.”

This binding process also affects the particle’s behavior inside the body. According to Monteiro-Riviere, the amino acids and proteins that coat a nanoparticle change its shape and surface properties, potentially enhancing or reducing characteristics like toxicity or, in medical applications, the particle’s ability to deliver drugs to targeted cells.

To create their screening tool, the team utilized a series of chemicals to probe the surfaces of various nanoparticles, using techniques previously developed by Xia. A nanoparticle’s size and surface characteristics determine the kinds of materials with which it will bond. Once the size and surface characteristics are known, the researchers can then create “fingerprints” that identify the ways that a particular particle will interact with biological molecules. These fingerprints allow them to predict how that nanoparticle might behave once inside the body.

The study results appear in the Aug. 15 online edition of Nature Nanotechnology.

“This information will allow us to predict where a particular nanomaterial will end up in the human body, and whether or not it will be taken up by certain cells,” Riviere adds. “That in turn will give us a better idea of which nanoparticles may be useful for drug delivery, and which ones may be hazardous to humans or the environment.”

North Carolina State University

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