duminică, 5 august 2012
Structural Analysis Opens The Way To New Anti-Influenza Drugs
Main Category: Flu / Cold / SARS
Also Included In: Genetics; Bird Flu / Avian Flu
Article Date: 05 Aug 2012 - 0:00 PDT Current ratings for:
Structural Analysis Opens The Way To New Anti-Influenza Drugs
Researchers at the European Molecular Biology Laboratory (EMBL) in Grenoble, France, have determined the detailed 3-dimensional structure of part of the flu virus' RNA polymerase, an enzyme that is crucial for influenza virus replication. This important finding is published in PLoS Pathogens. The research was done on the 2009 pandemic influenza strain but it will help scientists to design innovative drugs against all the different influenza strains, and potentially lead to a new class of anti-flu drugs in the next 5-10 years.
The scientists focused on the endonuclease part of the viral RNA polymerase. The endonuclease is responsible for a unique mechanism called 'cap-snatching' that allows the virus to trick its host cell into producing viral proteins. In human cells the translation of messenger RNA (mRNA) strands into proteins requires a special structure, called the "cap", at the beginning of each mRNA. When the influenza virus infects a host cell its endonuclease "snatches" that cap from the cell's own mRNA. Another part of its RNA polymerase then uses it as the starting point for synthesizing viral mRNA. With the correct cap structure at the beginning, viral mRNA can then hijack the protein-production machinery of the infected cell to make viral proteins, which assemble into new viruses that will spread the infection.
The team led by Stephen Cusack, Head of EMBL Grenoble, analyzed crystals of endonuclease from the 2009 pandemic influenza strain using the high intensity X-ray beams at the European Synchrotron Radiation Facility (ESRF). The researchers were able to determine the 3D atomic structure of the enzyme and to visualize how several different small molecule inhibitors bind to and block its active site. If the active site of the endonuclease is blocked by an inhibitor the enzyme cannot bind its normal substrate, the host cell mRNA, and viral replication is prevented.
The active site of the endonuclease is shaped like a cave with two metal ions at the bottom. Cusack and colleagues found that all the inhibitors they studied bind to those two metal ions but, depending on their shapes, different inhibitors bind differently to the amino-acids of the cave's walls.
"Based on this detailed structural information we can now design new synthetic chemicals which bind even more tightly to the endonuclease active site and thus will potentially be more potent inhibitors of influenza virus replication," explains Stephen Cusack. "We can even try to build in anti-drug resistance by making sure the inhibitors only contact those amino acids that the virus cannot mutate since they are essential for the normal activity of the polymerase."
Because the cap-snatching mechanism is common to all influenza strains, new potent endonuclease inhibitors should be effective against seasonal flu, novel pandemic strains or highly pathogenic H5N1 bird flu. EMBL scientists are working with EMBL's spin-off company Savira pharmaceuticals, in partnership with Roche, to further develop influenza inhibitors. Promising candidates will be tested first for efficacy in cell culture, ultimately moving into clinical trials on humans.
Article adapted by Medical News Today from original press release. Click 'references' tab above for source.Visit our flu / cold / sars section for the latest news on this subject. This research was partly funded by the European commission, through the FP7 research grant awarded to the FluPharm project.
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5 Aug. 2012.
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'Structural Analysis Opens The Way To New Anti-Influenza Drugs'
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marți, 13 decembrie 2011
Simple, Model-Free Analysis Of Voltage-Gated Channels
Also Included In: Neurology / Neuroscience
Article Date: 13 Dec 2011 - 3:00 PST
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A new study in the Journal of General Physiology* provides fresh insight into voltage-gated channels - transmembrane ion channels that play a critical role in the function of neuronal and muscle tissue.
Voltage-gated ion channels underlie signaling of most electrically active cells. These important ion channels have long challenged physiologists with the question of how membrane voltage drives the structural transitions between closed and open states. For more than 60 years, researchers have tackled this question with elaborate models that rely on difficult-to-assess assumptions. A new study by Sandipan Chowdhury and Baron Chanda, from the University of Wisconsin-Madison, provides a key analysis of the free energy of channel opening in a virtually model-free way.
According to Christopher Miller in a commentary accompanying the article, the study gives a rare example of the power of thermodynamic reasoning and provides "a path to circumvent the tyranny and heartbreak of model fitting."
Article adapted by Medical News Today from original press release. Click 'references' tab above for source.Visit our bones / orthopedics section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:
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13 Dec. 2011.
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joi, 8 decembrie 2011
Users Of Game Designed By McGill Researchers Contributing To Analysis Of DNA Sequences
Also Included In: Genetics; Alzheimer's / Dementia
Article Date: 08 Dec 2011 - 1:00 PST
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Thousands of video game players have helped significantly advance our understanding of the genetic basis of diseases such as Alzheimer's, diabetes and cancer over the past year. They are the users of a web-based video game developed by Dr. Jérôme Waldispuhl of the McGill School of Computer Science and collaborator Mathieu Blanchette. Phylo is designed to allow casual game players to contribute to scientific research by arranging multiple sequences of coloured blocks that represent human DNA. By looking at the similarities and differences between these DNA sequences, scientists are able to gain new insight into a variety of genetically-based diseases.
The researchers are releasing the results computed from the solutions collected over the last year today, together with an improved version of Phylo for tablets.
Over the past year, Phylo's 17,000 registered users have been able to simply play the game for fun or choose to help decode a particular genetic disease. "A lot of people said they enjoyed playing a game which could help to trace the origin of a specific disease like epilepsy," said Waldispuhl. "There's a lot of excitement in the idea of playing a game and contributing to science at the same time," Blanchette agreed. "It's guilt-free playing; now you can tell yourself it's not just wasted time."
Waldispuhl and his students came up with the idea of using a video game to solve the problem of DNA multiple sequence alignment because it is a task that is difficult for computers to do well. "There are some calculations that the human brain does more efficiently than any computer can. Recognizing and sorting visual patterns fall in that category," explained Waldispuhl. "Computers are best at handling large amounts of messy data, but where we require high accuracy, we need humans. In this case, the genomes we're analyzing have already been pre-aligned by computers, but there are parts of it that are misaligned. Our goal is to identify these parts and transform the task of aligning them into a puzzle people will want to sort out."
So far, it has been working very well. Since the game was launched in November 2010, the researchers have received more than 350,000 solutions to alignment sequence problems. "Phylo has contributed to improving our understanding of the regulation of 521 genes involved in a variety of diseases. It also confirms that difficult computational problems can be embedded in a casual game that can easily be played by people without any scientific training," Waldispuhl said. "What we're doing here is different from classical citizen science approaches. We aren't substituting humans for computers or asking them to compete with the machines. They are working together. It's a synergy of humans and machines that helps to solve one of the most fundamental biological problems."
With the new games and platforms, the researchers are hoping to encourage even more gamers to join the fun and contribute to a better understanding of genetically-based diseases at the same time.
Article adapted by Medical News Today from original press release. Click 'references' tab above for source.Visit our it / internet / e-mail section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:
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8 Dec. 2011.
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Elusive Ultrafine Indoor Air Contaminants Yield To NIST Analysis
Article Date: 08 Dec 2011 - 2:00 PST
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Researchers at the National Institute of Standards and Technology (NIST) spent 75 days on the job carrying out some very important homework - measurements in a "typical dwelling" of the release, distribution and fate of particles almost as tiny as the diameter of a single DNA molecule. Particles ranging in size from 100 nanometers down to 2.5 nanometers that were emitted by gas and electric stoves, hair dryers, power tools and candles were tracked and analyzed.*
Monitoring such tiny particles was made possible by NIST advances in measurement capabilities. Measurements were carried out in weeks of experiments at a 340-square-meter (1,500-square-feet) test house on the NIST campus in Gaithersburg, Md. The researchers used the data to develop a model for predicting changes in the size and distribution of so-called ultrafine particles (technically, particles smaller than 100 nanometers) discharged by tools, appliances and other sources.
The measurements and model will further efforts to explain the dynamics of ultrafine particles, an area of growing interest among environmental and health researchers. They also will advance work to develop accurate and reliable methods for determining how changes in heating and cooling systems, often done to reduce energy consumption, will affect indoor environments.
"If we can understand and predict the dynamics of these extremely small indoor air contaminants, designers and equipment manufacturers can avoid potential negative impacts on the environment inside homes and buildings and may even devise ways to improve conditions and save energy at the same time," explains NIST engineer Andrew Persily.
Utrafine particles are produced naturally - by forest fires and volcanoes, for example - as well as by internal combustion engines, power plants and many other human-made sources. Although ever present in outdoor and indoor environments, ultrafine particles have eluded detection, and are not subject to federal or state air quality standards. However, particles with nanoscale dimensions have been associated with a variety of human health problems - especially heart, lung and blood disorders.
Because we spend most of our time indoors, however, the bulk of human exposure to ultrafine particles occurs in homes and buildings. Typically, releases of the tiny particles occur in periodic bursts - during cooking or hair drying, perhaps - but airborne concentrations during these episodes can greatly exceed outdoor levels, according to the NIST team.
The researchers measured the airborne concentrations of ultrafine particles at regular intervals after they were emitted by gas and electric stoves, candles, hair dryers and power tools. With their recently enhanced capabilities, the team could measure particles about four times smaller than in previous studies of indoor air contaminants.
Tests were conducted with the house central fan either on or off, which made a major difference in the behavior of ultrafine particles. With the fan off, these very small particles collide with each other and coagulate - or combine - during the first 2.5 minutes following a blast of ultrafine particles from an appliance or tool. In the process, they form successively larger particles, decreasing airborne concentrations of particles. As particles grow larger, they tend to settle on surfaces more quickly.
With the central fan recirculating air, ultrafine particles tend, in roughly equal proportions, to coagulate or settle on surfaces. Under both fan conditions, ventilation accounted for the removal of no more than about 5 percent of ultrafine particles.
Tests also revealed that for many indoor sources, such as stovetop cooking with gas, more than 90 percent of the particles emitted were smaller than 10 nanometers. In turn, emissions of smaller particles result in higher airborne concentrations that dissipate primarily through coagulation.
Article adapted by Medical News Today from original press release. Click 'references' tab above for source.Visit our water - air quality / agriculture section for the latest news on this subject. NIST guest researcher Donghyun Rim is lead author of the new article. Co-authors are Lance Wallace and Persily, both of NIST, and Jung-il Choi, of Yonsei University, South Korea.
*D. Rim, L. Wallace, A. Persily and J. Choi, Evolution of ultrafine particle size distributions following indoor episodic releases: Relative importance of coagulation, deposition and ventilation. Aerosol Science and Technology. Posted online Nov. 15, 2011. DOI 10.1080/02786826.2011.639317. Available online at http://www.tandfonline.com/action/showAxaArticles?journalCode=uast20.
National Institute of Standards and Technology (NIST) Please use one of the following formats to cite this article in your essay, paper or report:
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8 Dec. 2011.
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