scientific technology

Assistant Professor of Biology Mitch McVey and his research team report that DNA polymerase theta, or PolQ, promotes an inaccurate repair process, which can ultimately cause mutations, cell death or cancer. The research is published in the July 1 edition of the open-access journal PLoS Genetics.
"Although scientists have known for several years that the PolQ protein is somehow related to the development of cancer, its exact cellular role has been difficult to pin down," says McVey."Our finding that it acts during inaccurate DNA repair could have implications for biologists who study genomic changes associated with cancer."
DNA is a double stranded molecule shaped like a spiral staircase. Its two strands are linked together by nucleotides -- guanine, cytosine, adenine and thymine -- that naturally complement one another. Under normal conditions, a guanine matches with a cytosine, and an adenine with a thymine.

How DNA Double-Strand Breaks Are Repaired

But during the course of a cell's life, the staircase can become severed into two molecules. These breaks must be repaired if the cells are to accurately replicate and pass on their genetic material. Most breaks are quickly and accurately fixed during the process of homologous recombination (HR), which uses an intact copy of DNA as a template for repair.

However, there is a second, error-prone process called end-joining repair. Here, the broken, double-stranded ends are stitched back together without regard to the original sequence. The ends of the broken strands may be altered by removal or addition of small DNA segments, which can change the genomic architecture.

In a previous paper, McVey and doctoral student Amy Marie Yu were able to demonstrate an alternative form of end-joining by studying how repair proceeds in the absence of DNA ligase 4, an important protein that links together two broken DNA ends.

After analyzing hundreds of inaccurately repaired breaks in the fruit fly Drosophila melanogaster the scientists observed two things. One, extra nucleotides were often inserted into the DNA strands at the point of the break. Second, the insertions were closely related to the original DNA sequences directly adjacent to the break.

Polymerase Theta's Role in DNA Repair and Cancer

In the current PLoS Genetics paper, McVey, Yu and undergraduate Sze Ham Chan showed that polymerase theta plays a dominant role in this alternative repair process. First, it reads the genetic material in DNA adjacent to the break and makes a copy of it. The newly copied DNA can then be used as a molecular splint that holds the broken ends together until they can be permanently joined. In addition, the scientists speculated that the PolQ protein also has the ability to unwind DNA sequences near a break, thereby facilitating alternative end-joining.
Other research groups have previously shown that levels of the PolQ protein are higher in several types of human tumors. McVey and his team are currently working to determine if a PolQ-dependent type of alternative end-joining is involved in the development of cancer in people. If this is indeed the case, the PolQ protein could represent a novel target for the development of new cancer drugs.
"Our first goal is to determine which parts of PolQ are required for its role in alternative end-joining," McVey says. "This will give us a road map for determining how its activity might be altered in a clinical setting."
This work was funded by grants from the National Science Foundation and the Ellison Medical Foundation.

Pete Beckman, Mathematics and Computer Science Division, Argonne National Laboratory
Large-scale parallel simulation and modeling have changed our world. Today, supercomputers are not just for research and development or scientific exploration; they have become an integral part of many industries. A brief look at the Top 500 list of the world’s largest supercomputers shows some of the business sectors that now rely on supercomputers: finance, entertainment and digital media, transportation, pharmaceuticals, aerospace, petroleum, and biotechnology. While supercomputing may not yet be considered commonplace, the world has embraced high-performance computation (HPC). Demand for skilled computational scientists is high, and colleges and universities are struggling to meet the need for cross-disciplinary engineers who are skilled in both computation and an applied scientific domain. It is on this stage that a new breed of high-fidelity simulations is emerging – applications that need urgent access to supercomputing resources.

For some simulations, insights gained through supercomputer computation have immediate application. Consider, for example, an HPC application that could quickly calculate the exact location and magnitude of tsunamis immediately after an undersea earthquake. Since the evacuation of local residents is both costly and potentially dangerous, promptly beginning an orderly evacuation in only those areas directly threatened could save lives. Similarly, imagine a parallel wildfire simulation that coupled weather, terrain, and fuel models and could accurately predict the path of a wildfire days in advance. Firefighters could cut firebreaks exactly where they would be most effective. For these urgent computations, late results are useless results. As the HPC community builds increasingly realistic models, applications are emerging that need on-demand computation. Looking into the future, we might imagine event-driven and data-driven HPC applications running on-demand to predict everything from where to look for a lost boater after a storm to tracking a toxic plume after an industrial or transportation accident.
Of course, as we build confidence in these emerging computations, they will move from the scientist’s workbench and into critical decision-making paths. Where will the supercomputer cycles come from? It is straightforward to imagine building a supercomputer specifically for these emerging urgent computations. Even if such a system led the Top 500 list, however, it would not be as powerful as the combined computational might of the world’s five largest computers. Aggregating the country’s largest resources to solve a critical, national-scale computational challenge could provide an order of magnitude more power than attempting to rely on a prebuilt system for on-demand computation.

Furthermore, costly public infrastructure, idle except during an emergency, is inefficient. A better approach, when practical, is to temporarily use public resources during times of crisis. For example, rather than build a nationwide set of radio towers and transmitters to disseminate emergency information, the government requires that large TV and radio stations participate in the Emergency Alert System. When public broadcasts are needed, most often in the form of localized severe weather, broadcasters are automatically interrupted, and critical information is shared with the public.

As high-fidelity computation becomes more capable in predicting the future and being used for immediate decision support, governments and local municipalities must build infrastructures that can link together the largest resources from the NSF, DOE, NASA, and the NIH and use them to run time-critical urgent computations. For embarrassingly parallel applications, we might look to the emerging market for “cloud computing.” Many of the world’s largest Internet companies have embraced a model for providing software as a service. Amazon’s elastic computing cloud (EC2), for example, can provide thousands of virtual machine images rapidly and cost effectively. For applications with relatively small network communication needs, it might be most effective for urgent, on-demand computations simply to be injected into the nation’s existing Internet infrastructure supported by Amazon, Yahoo, Google, and Microsoft.
In April 2007, an urgent computing conference at Argonne National Laboratory brought together an international group of scientists to discuss how on-demand computations for HPC might be supported and change the landscape of predictive modeling. The organizers of that workshop realized that CTWatch Quarterly would be the ideal venue for exploring this new field. This issue describes how applications, urgent-computing infrastructures, and computational resources can support this new role for computing.

Biomimicry, imitating nature’s designs and processes to create products for humans, has been heralded as key to creating our sustainable future. Innovations such as self-cleaning paint based on lotus leaves, swimsuits made like sharkskin, and wind turbines in the likeness of whale flippers have all been inspired by parts of nature. But why stop there? A number of developers are capturing the movement and grace of entire animals, giving us robots that crawl, walk, and swim just like their biological counterparts. If this research one day spawns an uncomplaining robotic mule to carry our physical burdens or dogs that can save children from fiery buildings without fear of harm, man’s best friend may also be humanity’s own invention.

Electron microscopes have given scientists unprecedented views of atomic and molecular structures. Now those vistas are evolving from still photographs into motion pictures. Physicist Ahmed Zewail of Caltech, who won the 1999 Nobel Prize in Chemistry for his use of lasers to study chemical reactions, is pioneering 4-D electron microscopy, which allows direct observation of atomic-scale changes in real time. His filmmaking technique relies on applying a short laser pulse to the subject, followed by an ultrafast pulse of electrons, which scatter off the material to produce an image for the microscope. A series of these images can be collected in rapid succession and viewed as a movie. The extremely brief electron pulses ensure that the image remains sharp, much like a short-exposure photograph of a speeding object.

In late 2008 Zewail and his colleagues announced that they had observed atomic motion in gold and in graphite (a sheet of carbon atoms). They discovered that atoms in heated graphite began to pulse in an unexpected synchronized “drumming” action, much like a heartbeat. Last summer the lab reported capturing changes in the pattern of bonding among graphite’s carbon atoms following intense compression of the sample. And in December they described watching nanotubes briefly glow after being hit with laser light. “You can see things evolve over time in a way that you never could with a snapshot,” says physicist and collaborator Brett Barwick. Eventually the group hopes to study chemical reactions in living cells.
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ALTHOUGH the technology of continuous casting has been around for two decades, most domestic steel producers had found it uneconomical and impractical until recently.
But steelmaking energy costs have doubled since the 1973 oil embargo and pressure has intensified from such competitors as the Japanese, who in 1980 cast 58 percent of their steel through the new process. Some of the large domestic steelmakers are now making a major effort to build new continuous casters. The domestic industry now casts about 17 percent of its steel through the process.

The process was patented by Henry Bessemer in 1865 but was not developed on a large scale until after World War II. Its use in the 1980's is expected to be significant, however. ''The most important technological change for integrated steelmakers during the next 10 years will be greater adoption of continuous casting,'' according to a report by the Federal Office of Technology Assessment.

The United States Steel Corporation, for example, announced last year that it would install a continuous slab caster at its historic Edgar Thomson Works and at its Lorain Works in Ohio. David M. Roderick, chairman, said that the nation's largest steel company would then have eight such casters and would be able to cast about 29 percent of its raw steel through the process.
The National Steel Corporation, which installed the first large continuous caster in this country in 1968 at its Weirton Works in West Virginia, will be able to cast more than 50 percent of its steel continuously by 1982.

And such other large steelmakers as Armco are adding casters. In continuous casting, freshly refined molten steel is transformed directly into steel products such as slabs, billets and blooms, which can then be finished in mills into various steel products such as sheet, rods and beams.
In the process, molten steel is poured into a vessel called a tundish, which allows the steel to flow at a constant rate into a water-cooled mold. A solid skin is formed and the hardened steel is pulled continuously out of the bottom of the mold. It is then cut into various lengths.
In the traditional method, molten steel is poured into ingot molds. When it cools and hardens, the mold is stripped away. The ingot can then be stored. It must be reheated, however, before it can be formed into slabs, billets and blooms suitable for rolling.
During heating in the old process, the surface oxidizes and part of the steel must be removed through a process called scarfing. These various steps lead to the loss of some of the steel, which becomes scrap and is recycled.

The savings in energy, manpower and waste in continuous casting come mostly from the elimination of various steps needed under traditional methods.
The total energy saving is estimated to be about 10 percent in making semifinished steel products. The average saving on a ton of steel has been estimated to be about 3 million British thermal units, or about $12.

The other major advantage is that the process eliminates much of the scrap and increases the yield from the raw steel of semifinished steel products by about 10 to 15 percent. Continuous casters thus fit in with current industry strategy of seeking to raise capacity by making plants more efficient.

The manpower savings are estimated to be 10 to 15 percent by the Department of Labor. In older plants some workers are absorbed in running the caster and in the finishing mills.
There are a few potential disadvanages. If a continuous caster breaks down, the primary steelmaking process has to be held up also. There are also a small number of steels that have not yet been cast through the process - basically because the casting methods have not been perfected -though the list has been decreasing.

Milton Deaner, vice president of engineering for National Steel, which has had one the most extensive and longest experiences with continous casting, said that the company has been very satsified with the process. He said that executives of plants without casters were eager to have them installed. ''No one has reservations to build them, it's just to get the money to build one,'' he said. A caster can cost from $120 million to $150 million