Malignant tumors have usually lost their ability to destroy themselves by programmed cell death, or apoptosis. Therefore, tumors are often resistant to chemotherapy or radiation therapy, whose effect is based on forcing tumor cells to commit suicide.This resistance to apoptosis is caused by defects in one of the numerous molecular switches regulating the self-destruction process. This is why scientists have been trying for a long time to restore the formation of these switches in cancer cells and, thereby, to restore their apoptotic ability. Among the key molecular switches is cell surface protein CD95, which is activated by the binding of its partner, CD95L. This triggers a whole cascade of biochemical signals leading to the death of the cell.

At the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Dr. Ana Martin-Villalba and her team have been studying the function of CD95 on glioblastoma cells. Glioblastoma is an extremely aggressive malignant brain tumor that resists all treatments. The cancer grows like a coral and invades surrounding brain tissue with very fine protrusions. Individual, isolated tumor cells can penetrate even further. Thus, surgeons have no chance to completely remove the tumor tissue. In addition, glioblastoma is highly resistant to both chemotherapy and radiotherapy.

Martin-Villalba’s team found large amounts of CD95 on glioblastoma cells, while CD95L was localized primarily at the so-called invasive front – the border between tumor tissue and healthy brain tissue. Despite the presence of both molecules, the cells are resistant to programmed cell death. But this is not all: If CD95 on the surface of glioblastoma cells is activated by CD95L, this leads to the production of a protein called MMP9, which is known to be a molecular scissors. MMP9 cuts through the network of interwoven protein fibers that separate different tissue layers of the body from each other. With the aid of these protein scissors, tumor cells invade healthy tissue and form the dangerous protrusions that penetrate deep into the brain tissue.

The result showed the scientists a way how to stop the invasion of glioblastoma: They treated mice that had been transplanted glioblastoma with an antibody that blocks CD95. As a result, the migration of cancer cells ceded.

“This is almost a paradigm shift,” says Ana Martin-Villalba. “Up to now, the goal has been to promote formation of CD95 and CD95L in tumor cells. In the case of glioblastoma, we now have to warn against this approach: This would only additionally support the spread of the tumor. The goal is rather to block activation of CD95.” However, it is currently not possible to investigate this treatment approach in humans, because a useable antibody against human CD95 protein is not yet available.

Susanne Kleber, Ignacio Sancho-Martinez, Benedict Wiestler, Alexandra Beisel, Christian Gieffers, Oliver Hill, Meinolf Thiemann, Wolf Müller, Jaromir Sykora, Nina Schreglmann, Elisabeth Letellier, Cecilia Zuliani, Stefan Klussmann, Marcin Teodorczyk, Hermann-Josef Gröne, Tom M. Ganten, Holger Sültmann, Jochen Tüttenberg, Andreas von Deimling, Anne Regnier-Vigouroux, Christel Herold-Mende and Ana Martin-Villalba: Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell, 11 March 2008

Molecular biologists at the University of California, San Diego have found one piece of the complex puzzle of autophagy, the process of “self-eating” performed by all eukaryotic cells — cells with a nucleus — to keep themselves healthy.

Their finding, published in the March 11 issue of the journal Developmental Cell, is important because it allows scientists to control this one aspect of cellular autophagy, and may lead to the ability to control other selective “self-eating” processes. This, in turn, could help illuminate autophagy’s role in aging, immunity, neurodegeneration and cancer.

All eukaryotic cells dispose of bacteria, viruses, damaged organelles and other non-essential components through this self-eating process. A part of the cell called the lysosome engulfs and degrades subcellular detritus. The ability of cells to recycle and reuse the cellular raw materials, as well as to “re-model” themselves in response to changing conditions, allows them to adapt and survive.

Autophagy was first described about 40 years ago, but has recently become a topic of great interest in cell biology because it is linked to cell growth, development aging and homeostasis — helping cells to maintain a balance among synthesis, degradation and recycling.

The UC San Diego researchers report in their paper that they identified a novel protein called Atg30 (one of 31 required for autophagy-related processes) from the yeast Pichia pastoris, that controls the degradation of a sub-compartment of cells, the peroxisomes.

Peroxisomes generate and dispose of harmful peroxides that are by-products of oxidative chemical reactions.

Different organelles within the cell are degraded by lysosomes when the organelles are damaged or not necessary, said Jean-Claude Farré, the biologist who identified Atg30. The team is investigating peroxisomes, and working to understand how and why they are selected by the lysosome for degradation.

What the biologists found, he said, is that “this new protein can mediate peroxisome selection during pexophagy – that is, it is necessary for pexophagy, but not for other autophagy-related processes.”

Suresh Subramani, a professor of biology who headed the team, said they have established that Atg30 is a “key player” in the selection of peroxisomes for delivery to “the autophagy machinery” for re-cycling.

“For the first time, we can use a protein to control the process,” Subramani said. “It’s an important step in understanding the workings of cells.”

Subramani and Farré were assisted by Ravi Manjithaya and Richard D. Mathewson, all of the Division of Biological Sciences at UC San Diego.

The study was funded by grants from the National Institutes of Health.

UPTON, NY - Biologists at the U.S. Department of Energy’s Brookhaven National Laboratory, Stony Brook University, and the University of Wurzburg, Germany, have deciphered the structure of a large protein complex responsible for adding sugar molecules to newly formed proteins - a process essential to many proteins’ functions. The structure offers insight into the molecular “sugar-coating” mechanism, and may help scientists better understand a variety of diseases that result when the process goes awry. The research will appear in the March 12, 2008, issue of the journal Structure.”Proteins perform their functions by interacting at their surfaces with other molecules. So you can imagine that adding or removing sugar molecules will change the protein’s surface structure, and therefore its function,” said Huilin Li, a biologist at Brookhaven Lab who holds a joint appointment at Stony Brook and is co-corresponding author on the Structure paper. “Messing up this process can lead to the production of malformed proteins that are unable to do their jobs,” he added.

The results can be devastating. Failure of glycosylation, as the “sugar-coating” process is known, can lead to a variety of genetic disorders characterized by neurological problems including seizures and stroke-like episodes, feeding disorders, and possibly even some forms of muscular dystrophy.

“We studied one enzyme involved in glycosylation, the one that recognizes the protein sequence and adds the sugar chains to the protein as it is being synthesized by the cell,” said William J. Lennarz of Stony Brook University, a coauthor on the paper. “The challenge is that the enzyme, known as oligosaccharide transferase (OT), is large by protein standards, has eight intricately linked components, and sits embedded in a membrane within the cell’s protein-manufacturing machinery.”

“Membrane proteins, particularly large ones, are very difficult to study structurally,” added Li.

So the scientists turned to a technique called cryo-electron microscopy (cryo-EM), which shows great promise in deciphering large membrane protein structures.

“We imaged the purified OT complex by cryo-EM and obtained a first snapshot of the complex by computer reconstruction of the micrographs,” said Li, a cryo-EM expert.

In cryo-EM, he explained, samples are frozen in vitreous ice and maintained at cryogenic temperatures (-274° Fahrenheit) using liquid nitrogen while the samples are photographed in the high vacuum of an electron microscope. The sophisticated cryo-EM machine resides in Brookhaven Lab’s biology department. Li and his collaborators also measured the mass of the OT complex at Brookhaven’s Scanning Transmission Electron Microscope (STEM) facility.

The structure deciphered by the group helps to explain many biochemical phenomena observed about the enzyme complex over the past two decades. It also offers hints as to how the enzyme performs its various jobs, from recognizing the sugar molecules to be added to the protein, scanning the protein as it is formed to identify the sites where sugars should be attached, and transferring the sugar molecules to the protein at the right positions.

“OT physically associates with the protein translocation channel which moves a protein across a membrane and the cell’s protein synthesis machinery, forming an efficient three-machine assembly line for protein translation, translocation, and glycosylation,” Li said.

The researchers say further research is needed to illuminate the molecular mechanisms of disorders of glycosylation involving oligosaccharide transferase. For example, they would like to do structural studies of the enzyme at higher resolution in complex with substrates or in association with the cell’s protein translocation and protein synthesis machinery. A new facility Brookhaven Lab hopes to begin construction on next year, known as the National Synchrotron Light Source II, would greatly increase the precision of this work.

This research was supported by the National Institutes of Health and by Brookhaven National Laboratory’s Laboratory-Directed Research and Development funds.

Combination of tests could identify women’s ovarian cancer risk for a more accurate diagnosis and treatment

The results of a study presented today at the Society of Gynecologic Oncology’s 39th Annual Meeting on Women’s Cancer offer a promising development on the path toward better management of ovarian cancer. Researchers say testing women suspected of having ovarian cancer for a combination of proteins, or biomarkers in the blood called HE4 and CA 125, could be the key to predicting a woman’s risk for the disease dubbed the “silent killer.” Currently there is no adequate diagnostic test for ovarian cancer.

“Roughly 20 percent of women will be diagnosed with an ovarian cyst or tumor at some point in their life, and only a small percentage of these women will be diagnosed with ovarian cancer,” said Lead Researcher Richard Moore, M.D., assistant professor at The Warren Alpert Medical School of Brown University and a gynecologic oncologist in the Program in Women’s Oncology at Women & Infants’ Hospital of Rhode Island. “The problem is that current methods for distinguishing benign ovarian tumors from malignant ones are limited and as a result, women must undergo surgery without an accurate assessment as to their risk for having ovarian cancer prior to their surgery.”

Dr. Moore notes that fewer than half of all ovarian cancer patients have their initial surgery performed by a gynecologic oncologist or surgeon with specialized training in the management of ovarian cancer. “Our research is aimed at identifying patients at high risk for harboring an ovarian cancer so that they receive the right care from the right physician.”

Currently, CA 125 is the only blood test that can be used to help predict a woman’s risk for ovarian cancer and to help with the clinical management of the disease. However, CA 125 alone lacks the sensitivity required for the detection of ovarian cancer prompting researchers to look at the ability of combinations of biomarkers to predict the presence of ovarian cancer. Earlier this year, Dr. Moore published results of a pilot study in the journal of Gynecologic Oncology evaluating nine potential biomarkers and the ability of multiple marker combinations to predict the risk for ovarian cancer in women. His findings showed the combination of HE4 and CA 125 provided the highest level sensitivity and specificity out of all marker combinations for predicting the presence of ovarian cancer.

In a prospective, double-blinded, multicenter clinical trial, Dr. Moore and his team studied 496 women presenting with pelvic mass or ovarian cysts to determine if tests targeting multiple markers utilizing HE4 and CA 125 and a predictive algorithm could accurately assess the risk for epithelial ovarian cancer prior to surgery. Researchers measured levels of the biomarkers within the women’s blood and then compared the results with biopsies of their tumors. The combination of biomarkers performed well in both pre- and post-menopausal women, accurately stratifying 95 percent of patients with epithelial cancer as high risk and 75 percent of benign cases as low risk.

“Studies suggest women with ovarian cancer have better outcomes and increased survival when treated by surgeons trained in the management of ovarian cancer and at institutions specializing in the care of women with this disease,” adds Dr. Moore. “By using the combination of HE4 and CA 125 as a model to assess a women’s risk for ovarian cancer, physicians can better triage patients for care and refer them to the appropriate specialist – whether at a community hospital or large academic institution.”

“Together, HE4 and CA 125 offer a powerful combination that could dramatically change the way ovarian cancer is managed at all stages of care,” said Dr. Olle Nilsson, vice president and chief scientific officer of Fujirebio Diagnostics, the developers of the CA 125 test. “As research continues to progress, it is our hope that a test for HE4 and CA 125 could eventually lead to a plausible screening tool.”

Fujirebio Diagnostics has developed a manual test for HE4 and will be developing automated formats of the test for Fujirebio instruments. The HE4 test is CE marked in Europe. The company has applied to the U.S. Food and Drug Administration (FDA) and hopes to see availability of the test in late 2008.

PITTSBURGH, March 10 – Using X-ray crystallography, researchers at the University of Pittsburgh School of Medicine led by structural biologist Joanne I. Yeh, Ph.D., have become the first to decipher the three-dimensional structure of a membrane-bound enzyme that plays a crucial role in glycerol metabolism – a discovery that could lead to important advances against obesity, diabetes and a potential host of other diseases. Their findings are reported in the March 4 issue of the Proceedings of the National Academy of Sciences.The sugar-alcohol glycerol is an essential source of energy that is required to help drive cellular respiration. In addition to powering some of the most central reactions of the body, glycerol also provides key precursors needed to regulate fatty acid and sugar metabolism. Figuring out the complex ways that cells break down or produce glycerol and use this vital chemical could be critical to combating obesity, diabetes and other chronic disorders. Recent findings also have linked glycerol metabolism to cellular processes related to aging, infectivity in certain organisms such as Mycobacterium tuberculosis, and in other energy-related illnesses.

“Everybody wants a golden bullet for obesity, and certainly we need better ways of controlling diabetes,” said Dr. Yeh, the study’s senior author and associate professor of structural biology at Pitt. “I think that glycerol metabolism will be on the forefront of developing treatments for these diseases, and so many others, since it is a pivotal yet underappreciated link among some very important metabolic pathways.”

The protein structure Dr. Yeh’s team solved is a large enzyme called Sn-glycerol-3-phosphate dehydrogenase – known simply as GlpD – found in abundance in the cell membranes of almost all organisms, including humans. GlpD is a monotopic membrane protein, which means that although it is embedded partially into the cell membrane, the protein does not span the entire membrane to the interior of the cell. As a result, it is technically challenging to produce enough highly purified and active protein to obtain clear, relevant information about the enzyme’s atomic structure. This study marks the highest resolution structure of a monotopic membrane protein that scientists have solved to date, and is one of only a handful of structures of this important class of membrane proteins that have been determined.

“These findings and data help to fill an important scientific and technical gap in the structural field and present new information and ideas about how the enzyme works and the importance of the cell membrane in stabilizing the enzyme and in processes related to energy production,” said Dr. Yeh, who published the paper along with postdoctoral research associate Unmesh N. Chinte, Ph.D., and research assistant professor, Shoucheng Du, Ph.D., both in Pitt’s Department of Structural Biology.

Studying the proteins and enzymes involved in oxidative and glycerol metabolism, as well as characterizing their structures, functions and regulatory relationships, has been a major research interest of Dr. Yeh’s lab. It took Dr. Yeh and her colleagues only three months – an unusually short time – to decipher the set of 3-D structures of GlpD isolated from E. coli bacteria, thanks to other methodologies they developed in earlier studies.

Rather than make conclusions based on a single structure, the team additionally determined the structures of GlpD bound with its metabolic product and several substrate analogues to evaluate the enzyme in its native and combined forms. By careful unraveling of this collection of structures, researchers could gain a more complete understanding of how the enzyme functions, details about how GlpD interacts with the membrane, works to catalyze the enzymatic reaction, and links to cellular-energy production.

As part of these challenging studies, the Pitt researchers used novel peptide-based detergents called “peptergents” that they developed in their lab to carefully separate GlpD from the cell membrane and keep it in an active form to ensure that their studies revealed a physiologically relevant enzyme structure. The team then used detergents to crystallize the enzyme and screened the protein crystals in Pitt’s new state-of-the-art X-ray crystallography facility, directed by Dr. Yeh.

Next, they applied beams of high intensity parallel X-rays to the protein crystals in order to collect the diffraction data necessary to determine the protein’s atomic configuration. These experiments were performed using cyclic particle accelerators at the Argonne National Laboratory in Illinois and the Paul Scherrer Institute in Switzerland. Called synchrotrons, these accelerators are the size of a football field and produce X-ray beams millions of times more intense than those generated by conventional X-ray machines. Highly advanced computational techniques were then used to analyze the diffraction data and to uncover, through complex mathematical approaches, the atomic matter in the crystals responsible for the diffraction. Ultimately, the unique 3-D topology of GlpD was deciphered, atom by atom.

The main role of GlpD in the cell is to remove hydrogen from a form of glycerol called glycerol-3-phosphate (G3P) to generate dihydroxyacetone phosphate (DHAP), a biochemical compound vital to the process of metabolizing the sugar-alcohol. In the process, electrons are produced and shuttled to a molecule called ubiquinone that works to power cellular respiration. Based on the structural information acquired in their study, Dr. Yeh’s team proposed mechanisms by which the enzyme carries out this fundamental metabolic reaction.

Their data revealed that GlpD is a dimer, or a protein with two subunits, that is embedded into and interacts substantially with the lipids that make up the cell membrane. This interaction with the membrane is required to keep the enzyme energetically and functionally stable so that it doesn’t collapse on itself, the PNAS study reports.

Dr. Yeh’s team also found that the enzyme is made up of two major domains: a soluble extracellular “cap” and a FAD-binding region, whose base is rooted in the membrane. The location of the enzyme’s active site – where the chemical reaction actually occurs – is at this FAD-binding region. G3P fastens tightly here, much like a key fitting into a lock, and is then transformed into DHAP. The researchers also proposed a docking site for where ubiquinone binds to the enzyme to accept electrons produced in the reaction. Eventually, ubiquinone feeds these electrons into respiration to produce the crucial energy to fuel cellular processes.

In addition, Dr. Yeh’s team discovered a never-before-seen type of protein fold consisting of about 100 amino acids in the “cap” domain of GlpD. They also identified areas where other proteins might bind to regulate the enzyme’s activity and transmit chemical signals.

With the GlpD structure in hand, Dr. Yeh’s team is already examining how mutating, or changing, certain amino acids in the enzyme affects its function and fold. These studies target the roles that these specific amino acids play in enzymatic function and regulation of activity. These questions are important because glycerol metabolism is a key link between sugar and fatty acid metabolism. The Pitt group also has determined the atomic resolution structures of other enzymes involved in mediating glycerol and oxidative metabolism. In all, these structural results provide some of the first three-dimensional views of these highly important proteins and enzymes.

The study was funded by the National Institutes of Health. Use of the Advanced Photon Source at Argonne National Laboratory was supported by the U.S. Department of Energy, Office of Basic Energy Sciences.

A link to the online paper is available at http://www.pnas.org/cgi/reprint/0712331105v1.

Stockholm, Sweden and Seattle, Wash.  — March 17, 2008 — The International Neuroinformatics Coordinating Facility (INCF) and the Allen Institute for Brain Science announced today that the INCF will contribute infrastructure and support services to enhance global access to the Institute’s Allen Brain Atlas—Mouse Brain.  Publicly available for free to encourage widespread use and collaboration, the Allen Brain Atlas—Mouse Brain is a Web-based, genome-wide map of gene expression.  It is actively used by scientists worldwide to advance research on the brain in health and disease.

Through the partnership agreement, the INCF is operating a mirror, or direct copy, of the atlas from its Secretariat in Stockholm, Sweden.  The INCF will ensure the sustainability and technical maintenance of the mirror site, as well as optimal Internet connectivity, in order to guarantee the highest possible service performance and quality in Europe.

The Allen Institute is providing INCF with all content and data required for the mirror site.  The Allen Brain Atlas—Mouse Brain contains expression patterns of approximately 20,000 genes mapped throughout the entire adult mouse brain, revealing where in the brain each gene is expressed, or “turned on” down to the cellular level.

“Helping brain researchers worldwide augment and accelerate their research programs is central to our mission,” said Elaine Jones, chief operating officer at the Allen Institute for Brain Science.  “Providing free and easy global access to our data is, thus, a top priority for the Allen Institute.  We are thrilled to work with INCF to mirror the Allen Brain Atlas—Mouse Brain in Europe and thus enhance its performance for researchers overseas.”

“The Allen Brain Atlas—Mouse Brain is a unique neuroinformatics resource”, said Jan Bjaalie, executive director of the INCF.  “The INCF sees a future of highly valuable services like this becoming more and more interoperable and interlinked, to the benefit of neuroscience researchers.  By entering this collaboration with the Allen Institute for Brain Science the INCF aims to play a key role in making this happen.”

Challenge and the benefits

The Allen Brain Atlas—Mouse Brain is a uniquely comprehensive source of information about gene activity in the brain.  Each month, approximately 10,000 unique users from universities, research institutes, pharmaceutical companies and government laboratories, and others worldwide access the atlas.  The INCF’s mirroring of the atlas aims to balance the load of the global demands and relieve the Seattle-based servers, thus allowing for faster responses to queries.  Redirection to the European mirror will occur automatically and in response to traffic and load of the servers.  The service should counterbalance any increases in traffic and significantly improve the efficiency of the overall services provided by the Allen Brain Atlas—Mouse Brain.

This collaboration brings together an international outreach organization, the INCF, and a U.S.-based non-profit medical research organization, the Allen Institute for Brain Science.  Together, these organizations share the mission to provide new and improved resources and infrastructure intended to accelerate scientific progress towards a better understanding of the brain.

The launch of the brain atlas mirror inaugurates a three-year partnership with a main objective to extend and enhance the quality of services provided by the Allen Brain Atlas—Mouse Brain for neuroscientists within Europe.  In addition, the atlas database is undeniably a valuable resource that presents opportunities for further development of tools, models and resource integration services, a key element of the INCF mission.

Technical operation and server hosting is located at the Royal Institute of Technology (KTH) in Stockholm, Sweden, an organization with strong technology expertise and advanced computer operation facilities.

Imagine the power of knowing the three-dimensional structures of all proteins.  The 3D-structure can provide information about critical protein-protein interactions both from a global perspective as well as all the way down to the level of minuscule molecular and biochemical detail.  In much the same way, structural information can reveal a lot about the protein’s evolutionary relationships and functions.  Even to provide this information about all the proteins in one organism—its proteome—would offer a more global view of these relationships, but solving each structure individually would be a formidable task.

However, in a new study published online this week in the open access journal PloS Biology, Lars Malmström, David Baker, and colleagues have done precisely this for the model organism yeast.  These researchers divided all Saccharomyces cerevisiae proteins into nearly 15,000 distinct “domains” (regions of a protein that fold into a distinct quaternary globular structure).  They then applied their own de novo structure prediction methods together with worldwide distributed computing to predict three-dimensional structures for all domains lacking sequence similarity to proteins of known structure.

To overcome the uncertainties in de novo structure prediction, Lars Malmström and colleagues combined these predictions with data on the biological process, function, and localization of the proteins from previous experimental studies to assign the domains to families of evolutionarily related proteins.  These genome-wide domain predictions and superfamily assignments provide the basis for the generation of experimentally testable hypotheses about the mechanism of action for a large number of yeast proteins.

Citation: Malmstro¨m L, Riffle M, Strauss CEM, Chivian D, Davis TN, et al.  (2007) Superfamily assignments for the yeast proteome through integration of structure prediction with the gene ontology.  PloS Biol 5(4): e76.  Doi:10.1371/journal.pbio.0050076.

Uncovering the Structural Alphabet of RNA

A team of bioinformaticians at the Université de Montréal (UdeM) report in the March 6th edition of Nature the discovery of a structural alphabet that can be used to infer the 3D structure of ribonucleic acid (RNA) from sequence data, providing new tools to understand the role of this important class of cellular regulators.

The folding of a single-stranded RNA molecule is determined by the interactions between its constituent nucleotides. The classical approach to RNA modelling suffers from an important limitation: it only takes into account the canonical Watson-Crick interactions A:U and G:C, that is those where the nucleotides are facing each other. The non-canonical Hoogsteen and sugar interactions, those where the nucleotides are side by side or on top of each other, are not taken into account by conventional modelling algorithms. The result can be incomplete or erroneous models which can mislead researchers.

The attempt to remedy this problem led François Major, principal investigator at the Institute for Research in Immunology and Cancer of the UdeM and professor in the Department of Computer Science and Operations Research and Marc Parisien, a graduate student in his laboratory, to propose a radically different approach to model RNA structure. Their idea: assemble the structure in silico starting from motifs that combine all the possible interactions between a nucleotide and its neighbors.

The researchers implemented a first algorithm, MC-Fold, that systematically assigns the different motifs to each segment of the sequence and selects the most probable pair based on its frequency in known structures. A second algorithm, MC-Sym, then assembles the set of selected motifs, taking into account the constraints that are found in known structures.

“We introduced a new first-order object to represent nucleotide relationships, the nucleotide cyclic motif (NCM). We reasoned that using NCMs could allow us to arrive at better models of the 3D structure of RNA molecules, ” explains François Major. “Compared to the thermodynamic approach, our algorithms make less false positives and negatives and predict structures that are closer to the empirical data in the case of sequences for which it is available. The improvement is due to the fact that NCMs incorporate more base-pairing context-dependent information.”

The biological importance of RNA and the growing recognition of its therapeutic potential mean that the new modelling algorithms have many applications in biomedical research. For instance, Major and Parisien have shown that these tools can be used to study the biology of RNA viruses such as HIV. They have also used the MC-Fold:MC-Sym pipeline to identify microRNAs, an important class of regulatory molecules which is currently the focus of intense investigation. microRNAs inhibit target genes both efficiently and specifically and are often considered to be the next generation of therapeutic agents. Since microRNAs are notoriously difficult to identify based on sequence alone, the use of RNA modelling algorithms and structural features to do so represents an important breakthrough.

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Work in the laboratory of François Major is supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canadian Institutes of Health Research (CIHR). Marc Parisien holds Ph.D. scholarships from the NSERC, the Fonds québécois de la recherche sur la nature et les technologies (FQRNT) and the UdeM Faculty for Graduate and Postdoctoral Studies. François Major is a member of the Robert-Cedergren Centre at the Université de Montréal.

The MC-Fold and MC-Sym RNA modelling tools are available on the Internet at www.major.iric.ca.