Memory Lane in the Brain

PASADENA, Calif.- Biologist Erin Schuman is interested in how memories are formed--or forgotten. The landscape the professor of biology at the California Institute of Technology explores is the hippocampus, the part of the brain known to be crucial for memory in humans and other animals.

In 2002, Schuman and Miguel Remondes, her graduate student, published a paper in the journal Nature that suggested a possible role for a well-known but poorly understood part of the brain known as the temporoammonic (TA) pathway. Using rat hippocampal slices, they suggested two possible roles for the TA pathway that were not previously known: to serve as a memory gatekeeper that can either enhance or diminish memories, and to provide information to help animals know where they are in their environments.

The researchers' next step was to prove their theories by looking at a possible role for the TA in memory at a behavioral level. That is, says Remondes, now a postdoctoral fellow at MIT, "to do the real test."

To understand how memories are formed, many scientists have focused on the "trisynaptic circuit," which involves three areas of the hippocampus: input from the senses is first sent from the cortex to the dentate gyrus, where this signal is processed by two sets of synapses, then sent back to the cortex. That's the circuit. An often overlooked separate input to the hippocampus, though, is the TA pathway. It makes direct contact with the neurons that are at the last station in the trisynaptic circuit, thus short-circuiting the traditional trisynaptic pathway.

Reporting in the October 7 issue of the journal Nature, Remondes and Schuman, also an associate investigator for the Howard Hughes Medical Institute, now show they were correct in their belief that the TA Pathway is important in spatial or location memory. The scientists used rats as their experimental animal, and the Morris Water Maze, a standard test for location memory in rodents. The animals swim in a pool of opaque water until they find a hidden goal--a platform which allows them to escape the water. To find the platform, the animals rely on the geometrical relationships of cues away from the pool (e.g., on the walls of the maze). In other words, says Remondes, "they have to navigate and remember where the platform is in order to escape the water."

The researchers tested both short-term (24 hours) and long-term memory (four weeks). The TA pathway was lesioned (disabled) in one set of rats; another set was used as a control. Having learned the location of the platform, both sets of rats still remembered where it was 24 hours later. But when tested four weeks later, only the control rats remembered where it was. The lesioned rats forgot, which showed that the TA pathway played some role in the retention of long-term memories. But what was the role?

"It led to a second question," says Schuman. "Because long-term memories require something called consolidation, an exchange of information between the cortex and hippocampus, we wanted to know if the TA pathway was working in the acquisition phase of memory or in its consolidation."

Using two other groups of rats, the pair conducted a second set of tests. After confirming the rat's memory of the platform after 24 hours, one group was immediately lesioned. These animals lost their long-term memory when tested 4 weeks later, indicating to Schuman and Remondes that ongoing TA pathway activity was required on days after learning to stabilize or consolidate the long-term memory.

The second group of rats was also lesioned, but not until three weeks later. The researchers found that this group remembered the platform's location, showing their memory had already been adequately consolidated after three weeks. This proved the TA pathway is required to consolidate long-term location memory.

"These data indicate there must be a dialogue between the hippocampus and the cortex during long-term memory consolidation," says Schuman. "Clearly, the TA pathway plays an important role in this discussion." Further, she notes, "understanding the mechanisms of memory formation and retention may shed light on diseases like Alzheimers, where memory is impaired. "

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New Target for Future Therapeutic Drugs

PASADENA, Calif. - "Sometimes letting nature tell you what's important is the better way to go," says Raymond Deshaies, an associate professor of biology at the California Institute of Technology. Deshaies is referring to new work to come out of his lab and the lab of Randall King at Harvard that defies conventional thinking--they've discovered a chemical that stops a key cell function, but, more importantly, suggests a new possible target within a cell, once thought to be untenable, for future therapeutic drugs.

In a report in this week's issue of the journal Science, lead author Rati Verma, a Howard Hughes Medical Institute (HHMI) Research Specialist in the Deshaies lab, Deshaies, also an assistant investigator for the HHMI, and nine other authors report that a small molecule called ubistatin blocked an important step in the so-called cell cycle, a process fundamental to life where a cell makes duplicate copies of its own DNA for distribution to two daughter cells. Knowing how to stop cell duplication is critical in preventing diseases like cancer, when mutated cells go out of control and proliferate madly. Further, ubistatin blocked the cell cycle by preventing two proteins from interacting together. Prior to this, it was thought unlikely that a compound with low molecular weight like ubistatin--or any future drug--would have much impact on the interaction of proteins with each other.

While ubistatin has other properties that preclude it from being a drug candidate, its stoppage of the cell cycle provides an important clue for future drug development, says Deshaies. "We've found a chemical Achilles' heel in this cell pathway, at least from the viewpoint of these small molecules that comprise most therapeutic drugs."

Because the cell cycle is maddeningly complex, researchers usually pick a single pathway (a pathway is a series of chemical events within a cell that perform some task), then try to make a chemical to block it. They may find such a chemical, but often find it difficult to discover where in the pathway--the target--their drug hit. Finding the target is like finding the proverbial needle in a haystack.

Deshaies's colleague Rati Verma found the needle. Instead of using the typical "top down" approach of starting with a specific target, then looking for a drug to block it, the researchers took a "bottom up" approach of starting with a drug and then searching for the target it blocks. They decided to test a large number of molecules to see if any of them might block any step in one particular pathway called the ubiquitin-proteasome pathway (UP pathway): within the cell cycle, when a protein's job is done, another chain of proteins called ubiquitin attaches to it. That serves as a signal to yet another protein called proteasome. The proteasome, says Deshaies, is the biological equivalent of a Cuisinart. "It attaches to these ubiquitin-marked proteins, then ingests them and chews them up."

The researchers examined an entire cell, specifically that of a frog's egg. The King group decided to screen 110,000 molecules to see if any had an impact on the cell. First, they weeded out those molecules that had no effect on cellular function in the UP pathway. King attached a molecule of luciferase ("the stuff that makes a firefly light up," says Deshaies) to certain proteins that are normally destroyed during cell division. Next, he added this newly created protein (now a readily detectable biological "flashlight") to droplets of cellular material extracted from the frog's egg that had been placed in individual chambers. As the egg extract conducted its normal cell division, the luciferase flashlight was destroyed and the chambers went dark. That meant those proteins had been destroyed as part of the normal progress of the cell cycle. He then separately added the 110,000 small molecules to see if any of them would prevent the loss of the luciferase--essentially looking for a lit-up reaction chamber in a field of darkness.

Using this approach, the researchers eventually narrowed the molecules they were testing down to a few that were operating in a specific part of the pathway--downstream from where ubiquitin attaches to the soon-to-be doomed protein, but before the proteasome ingested and chewed it up. But given that numerous proteins are involved in this process, the question remained--where specifically was the molecule they were testing working? In short, where was the target?

To find out, Deshaies turned to work they had done over the last five years with ubiquitin, which examined how it interacted with various other proteins, including proteasome. Through a process of elimination, says Deshaies, "we figured out that these small molecules called ubistatins were blocking the recognition of the ubiquitin chain by the proteasome." Graphic evidence for how this occurs was provided by a 'picture' taken by David Fushman at the University of Maryland with a nuclear magnetic resonance spectrometer.

This step blocked by ubistatin involves a protein-protein interaction, a surprise to Deshaies. "One interesting thing about our discovery is that it is further evidence that you can affect a protein-protein interaction with a small molecule. The conventional thinking was that if you look at a footprint of a drug binding a protein, the drugs are small, but the footprint that corresponds to one protein binding to another is big. So most people thought that the idea of trying to block the huge footprint of protein-protein interaction with a tiny drug was extremely unlikely. So if I were asked to predict what we would find, I would never have proposed that a drug could prevent the ubiquitin chain from binding to the proteasome, because I was also influenced by this conventional wisdom."

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Caltech Bioinformatics Experts DevelopNew Literature Search Engine for Biologists

PASADENA, Calif.—When it comes to finding a used book on the Internet, one merely needs to Google the title, and a few suitable items for sale will soon be just a click away. But for the biologist or medical researcher looking for information on how two nematode genes interrelate in hopes of better understanding human disease, there is a clear need for a more focused search engine.

Bioinformatics experts from the California Institute of Technology are formally announcing today the Textpresso search engine, which they hope will revolutionize the way that genetic information is retrieved by researchers worldwide. The Textpresso search engine is specifically built to serve researchers who work on the small worm known as C. elegans, but the basic design should lead to the creation of new search engines for researchers who specialize in other living organisms that are intensively studied.

In the current issue of the journal PLOS, published by the Public Library of Science, Caltech biology professor Paul Sternberg and his colleagues--research associate Hans-Michael Muller and bioinformatics specialist Eimear Kenny--write that the new "text-mining system for scientific literature" will be invaluable to specialists trying to cope with the vast amount of information now available on C. elegans. This information has vastly increased in recent years due to the large-scale gene-sequencing initiative as well as the more traditional small-scale projects by individual researchers. As a result, the need for a way to scan the vast literature has become much more important.

"Textpresso gives me, as a researcher, more time to actually read papers because I don't have to skim papers anymore," says Sternberg, who is leader of the federally funded WormBase project that has already put online the entire genome sequence of C. elegans and the closely related organism C. briggsae, as well as genes for some 20 other nematode species.

The four-year-old WormBase project, a linchpin in the worldwide effort to better understand how genes interrelate, also makes a host of other information freely available in addition to the 100.2 million base-pairs that make up the millimeter-long worm's genome. There are now 28,000 gene-disruption experiments in WormBase, along with 2 million DNA expression ("chip") microarray observations, as well as detailed information on the expression of more than 1,700 of the worm's 20,000 genes. The Textpresso search engine is a logical product for the WormBase team to develop in the ongoing quest to put genetic information to work in curing and preventing human disease.

Lest anyone assume that the genes of a millimeter-long nematode have little to do with humans, it should be pointed out that the two organisms are similar in about 40 percent of their genes. A very realistic motivation for funding the genome sequencing of the fruit fly, the small mustardlike plant known as Arabidopsis, the chimp, and various other species, has been the expectation of finding underlying common mechanisms.

Thus, a cancer researcher who discovers that a certain gene is expressed in cancer cells can use the WormBase to see if the gene exists in nematodes, and if so, what is known about the gene's function. And now that Textpresso is available, the researcher can do so much more efficiently.

"The idea is distilling down the information so it can be extracted easier," says Muller, the lead author of the paper and codeveloper of Textpresso with Kenny. The idea for the name of the search engine, in fact, comes from its resemblance to "espresso," which is a process used to get the caffeine and flavor out of coffee in a minimal volume.

According to Kenny, the search engine is designed with a special kind of search in mind, which establishes categories of terms and organizes them as an ontology--that is, a catalog of types of objects and concepts and their relationships. For example, if the researcher wants to find out whether any other researcher has worked on the relationship between the nematode gene called "lin-12" and the anchor cell, then typing the two terms into a conventional search engine like Google results in more than 400 hits. And if the researcher wants to know which genes are important in the anchor cell, the task is even more arduous. But Textpresso is designed to get the information in a much simpler, more efficient, more straightforward way.

Textpresso is a text-processing system that splits research papers into sentences, and sentences into words or phrases. All words and phrases are labeled so that they are searchable, and the labels are then condensed into 33 ontological categories. So far, the database includes 4,420 scientific papers on C. elegans, as well as bibliographic information from WormBase, information on various scientific meetings, the "Worm Breeder's Gazette," and various other links and WormBase information. Therefore, the engine already searches through millions of sentences to allow researchers to find a paper of interest or information of interest with great efficiency.

Finally, the Textpresso search engine should be a useful prototype for search engines to serve other biological databases--some of which have even larger piles of data for the specialist to cope with. "Yeast currently has 25,000 papers," Kenny says.

Textpresso can be accessed at www.textpresso.org or via WormBase at www.wormbase.org.

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Robert Tindol
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Research uncovers new facts about odor detection in insects; findings could lead to more effective repellents

PASADENA, Calif.--If you think it doesn't do much good to swipe the fly that's going after the potato salad, guess again. You may be discouraging the fly's colleagues from taking up the raid.

New evidence shows that a stressed fly emits an odor that makes other flies avoid the space in which the stressful event occurred. Reporting in an advance on-line publication of the September 15 issue of the journal Nature, California Institute of Technology professors David Anderson and Seymour Benzer, along with Professor Richard Axel of Columbia University, discuss their findings about how flies may communicate information about their internal state to one another.

According to the authors, the act of shaking or shocking flies causes a repellent odor to be emitted that contains carbon dioxide as one of its active components. The research involved the fruit fly, Drosophila melanogaster, which has been used for decades in genetics experiments. However, the mechanism could be more widespread.

"We showed that CO2 is itself a potent repellent for Drosophila," says Anderson, a professor of biology at Caltech and also a Howard Hughes Medical Institute investigator.

The researchers also succeeded in mapping the initial neural circuitry that leads to CO2 avoidance. The team, led by Caltech postdoctoral scholar Greg Suh, found that CO2 activates a single class of sensory neurons in the fruit flies, and that these neurons seem to be dedicated to the sole task of responding to this odor. By inhibiting the synapses of these neurons using fancy genetic trickery, the researchers were able to block the ability of flies to avoid CO2, in behavioral experiments.

"These results show that there is probably a genetically determined, or 'hard-wired' circuit mediating CO2 avoidance behavior in the fly," Anderson says.

But even though the research is primarily aimed at furthering the understanding of the neural circuitry underlying innate behaviors, there might also be practical results. For one, the fact that mosquitoes are attracted to their warm-blooded hosts by CO2 exhalations has been known for years.

Although fruit flies are repelled by CO2, while mosquitoes are attracted to it, "given the evolutionary conservation of olfactory mechanisms in insects, if we learn about the molecular details involved in CO2 sensing in fruit flies, it could potentially lead to repellents that act by interfering with the reception of CO2," Anderson adds.

Such a repellent could be of benefit in third-world countries where mosquitoes are vectors of diseases like malaria--or even in the United States, where the mosquito-borne West Nile virus has been a serious health concern this year.

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Robert Tindol
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Caltech Physicists Achieve Measurement on a Single Magnetic Domain Wall

PASADENA, Calif.--Physicists for several years have been predicting a new age of semiconductor devices that operate by subtle changes in the orientation of electron spins. Known as "spintronics," the field relies on an intricate knowledge of the magnetic properties of materials and of how magnetic moments can be manipulated.

Now, scientists at the California Institute of Technology have developed a novel method of measuring the resistance of "domain walls," which are the nanoscale boundaries separating areas of a magnetized material that possess different magnetic alignments, or a "twist" of magnetic spins. Reporting in the September 2 issue of the journal Nature, Caltech physicists Hongxing Tang, Michael Roukes, and their colleagues show that their approach leads to an unparalleled precision in isolating, manipulating, and trapping domain walls one by one.

The authors have been able to trap individual domain walls between electrical probes for periods longer than a week. During that time, they are able to carry out extremely sensitive electrical measurements to identify the tiny amounts of resistance generated by this trapped single magnetic domain wall.

"We have demonstrated how a single magnetic domain wall can be monitored as it is made to traverse a patterned array of electrical probes in a microdevice made from single-crystal manganese-doped gallium arsenide," says Professor Roukes. Manganese- doped gallium arsenide belongs to a new class of ferromagnetic semiconductors that isexpected to have great potential for new spintronics devices.

This work also resolves an issue that has puzzled scientists for some time, according to Tang. Many physicists have thought that domain walls were a natural barrier to electron transport and that they cause positive resistance--in other words, the magnetic moments with different alignments created a natural opposition to the flow of charge from one side of the wall to the other. However, the new results show that the resistance is actually negative, which can be attributed to quantum effects in the locale of the domain wall itself. The very fact that the resistance is negative means that electrons can flow more easily under certain conditions, manifesting quantum mechanical origin in this novel phenomenon.

"We are certain that both this result and our new measurement methodology will be of interest to those working on future semiconductor devices based on spintronics," Tang says.

Understanding the dynamics of magnetic domain walls is crucial for magnetic storage devices such as magnetic hard drives, and for future magnetic memories. The methods have the potential to significantly alter the theoretical and experimental research for some time to come.

The work has been made possible through the Caltech team's earlier discovery of a phenomenon dubbed the "giant planar Hall effect." To reach the ultra-high resolution required to resolve the resistance of a domain wall, the authors advance a nanofabrication process for precise alignments of materials at the microscopic level and deploy an innovative way of manipulating domain walls.

"Using these advances, we have made careful measurements on many devices having domain walls of varying lengths and thicknesses," says Roukes. "All show negative resistance at the domain wall."

In addition to being a professor of physics, applied physics, and bioengineering at Caltech, Roukes is also founding director of Caltech's new Kavli Nanoscience Institute. Dr. Hongxing Tang is a senior research scientist at Caltech. Other authors of the paper are Sotiris Masmanidis, a Caltech graduate student in applied physics, and Roland Kawakami and Prof. David Awschalom, both of the UC Santa Barbara department of physics.

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Robert Tindol

International Team of Scientists Establishes New Internet Land-Speed Benchmark

PASADENA, Calif.—Scientists at the California Institute of Technology (Caltech) and the European Organization for Nuclear Research (CERN), along with colleagues at AMD, Cisco, Microsoft Research, Newisys, and S2io have set a new Internet2 land-speed record. The team transferred 859 gigabytes of data in less than 17 minutes at a rate of 6.63 gigabits per second between the CERN facility in Geneva, Switzerland, and Caltech in Pasadena, California, a distance of more than 15,766 kilometers. The speed is equivalent to transferring a full-length DVD movie in just four seconds.

The technology used in setting this record included S2io's Xframe® 10 GbE server adapter, Cisco 7600 Series Routers, Newisys 4300 servers utilizing AMD Opteron processors, Itanium servers, and the 64-bit version of Windows Server 2003.

The performance is also remarkable because it is the first record to break the 100 petabit meter per second mark. One petabit is 1,000,000,000,000,000 bits.

This latest record by Caltech and CERN is a further step in an ongoing research-and-development program to create high-speed global networks as the foundation of next-generation data-intensive grids.

Multi-gigabit-per-second IPv4 and IPv6 end-to-end network performance will lead to new research and business models. People will be able to form "virtual organizations" of planetary scale, sharing in a flexible way their collective computing and data resources. In particular, this is vital for projects on the frontiers of science and engineering, projects such as particle physics, astronomy, bioinformatics, global climate modeling, and seismology.

Harvey Newman, professor of physics at Caltech, said, "This is a major milestone towards our dynamic vision of globally distributed analysis in data-intensive, next-generation high-energy physics (HEP) experiments. Terabyte-scale data transfers on demand, by hundreds of small groups and thousands of scientists and students spread around the world, is a basic element of this vision; one that our recent records show is realistic." Olivier Martin, head of external networking at CERN and manager of the DataTAG project said, "As of 2007, when the Large Hadron Collider, currently being built at CERN, is switched on, this huge facility will produce some 15 petabytes of data a year, which will be stored and analyzed on a global grid of computer centers. This new record is a major step on the way to providing the sort of networking solutions that can deal with this much data."

The team used the optical networking capabilities of the LHCnet, DataTAG, and StarLight and gratefully acknowledges support from the DataTAG project sponsored by the European Commission (EU Grant IST-2001-32459), the DOE Office of Science, High Energy and Nuclear Physics Division (DOE Grants DE-FG03-92-ER40701 and DE-FC02-01ER25459), and the National Science Foundation (Grants ANI 9730202, ANI-0230967, and PHY-0122557).

About Caltech:

With an outstanding faculty, including three Nobel laureates, and such off-campus facilities as Palomar Observatory, and the W. M. Keck Observatory, the California Institute of Technology is one of the world's major research centers. The Institute also conducts instruction in science and engineering for a student body of approximately 900 undergraduates and 1,000 graduate students who maintain a high level of scholarship and intellectual achievement. Caltech's 124-acre campus is situated in Pasadena, California, a city of 135,000 at the foot of the San Gabriel Mountains, about 10 miles northeast of the Los Angeles Civic Center. Caltech is an independent, privately supported university. More information is available at http://www.caltech.edu.

About CERN:

CERN, the European Organization for Nuclear Research, has its headquarters in Geneva, Switzerland. At present, its member states are Austria, Belgium, Bulgaria, the Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Slovakia, Spain, Sweden, Switzerland, and the United Kingdom. Israel, Japan, the Russian Federation, the United States of America, Turkey, the European Commission, and UNESCO have observer status. For more information, see http://www.cern.ch.

About the European Union DataTAG project:

The DataTAG is a project co-funded by the European Union, the U.S. Department of Energy, and the National Science Foundation. It is led by CERN together with four other partners. The project brings together the following European leading research agencies: Italy's Istituto Nazionale di Fisica Nucleare (INFN), France's Institut National de Recherche en Informatique et en Automatique (INRIA), the UK's Particle Physics and Astronomy Research Council (PPARC), and Holland's University of Amsterdam (UvA). The DataTAG project is very closely associated with the European Union DataGrid project, the largest grid project in Europe also led by CERN. For more information, see http://www.datatag.org.

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Robert Tindol
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Geobiologists create novel method for studying ancient life forms

PASADENA, Calif.--Geobiologists are announcing today their first major success in using a novel method of "growing" bacteria-infested rocks in order to study early life forms. The research could be a significant tool for use in better understanding the history of life on Earth, and perhaps could also be useful in astrobiology.

Reporting in the August 23 edition of the journal Geology, California Institute of Technology geobiology graduate student Tanja Bosak and her coauthors describe their success in growing calcite crusts in the presence and absence of a certain bacterium in order to show that tiny pores found in such rocks can be definitively attributed to microbial presence. Micropores have long been known to exist in certain types of carbonate rocks that built up in the oceans millions of years ago, but researchers have never been able to say much more than that the pores were likely caused by microbes.

The new results show that there is a definite link between microbes and micropores. In the experiment, Bosak and her colleagues grew a bacterium known as Desulfovibrio desulfuricans in a supply of nutrients, calcium, and bicarbonate that built up just like a carbonate deposit in the ancient oceans. The mix that contained the bacteria tended to form rock with micropores in recognizable patterns, while the "sterile" mix did not.

"Ours is a very reductionist approach," says Dianne Newman, the Clare Boothe Luce Assistant Professor of Geobiology and Environmental Science and Engineering at Caltech and a coauthor of the paper. "This work shows that you can study a single species to see how it behaves in a controlled environment, and from that draw conclusions that apply to the rock record. The counterpart is to go to nature and infer what's going on in a system you can't control."

"We were primarily interested in directly observing how the microbes disrupt the crystal growth of the carbonate rocks," adds Bosak. In essence, the microbes are large enough to displace a bit of "real estate" with their bodies, resulting in a tiny cavity that is left behind in the permanent record. The micropores in the study tend to be present throughout the crystals, and they not only mirror the shape and size of the bacteria, but also tend to form characteristic swirling patterns. If the micropores had been formed by some kind of nonliving particles, the patterns would likely not be present.

The next step in the research is to run the growth experiments with photosynthetic microbes. The information could help scientists determine which shapes found in certain types of rocks can be used as evidence of early life on Earth. In the future, the information could also be used to study samples from other rocky planets and moons for evidence of primitive life.

Primarily, however, Newman says the technique will be of immediate benefit in studying Earth. "If you really want to look at life billions of years ago, in the Precambrian, you need to study microbial life.

"Even today the diversity of life is predominantly microbial," Newman adds, "so if we expand our perspective of what life is beyond macroscopic organisms, it's clear that microbes have been the dominant life form throughout Earth history."

In addition to Bosak and Newman, the other authors of the paper are Frank Corsetti of USC's department of earth sciences, and Virginia Souza-Egipsy of USC and the Center of Astrobiology in Madrid, Spain.

The paper is titled "Micron-scale porosity as a biosignature in carbonate crusts," and is available online at http://www.gsajournals.org/.

 

 

 

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Robert Tindol
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Chemists at Caltech devise new, simpler wayto make carbohydrates

PASADENA, Calif.--Chemists at the California Institute of Technology have succeeded in devising a new method for building carbohydrate molecules in a simple and straightforward way that requires very few steps. The new synthesis strategy should be of benefit to scientists in the areas of chemistry and biology and in the pharmaceutical industry.

In an article published online August 12 by the journal Science on the Science Express Website, Caltech chemistry professor David MacMillan and his graduate student Alan Northrup describe their new method of making carbohydrates in two steps. This is a major improvement over current methods, which can require up to a dozen chemical steps.

"The issue with carbohydrate utilization is that, for the last 100 years, scientists have needed many chemical reactions to differentiate five of the six oxygen atoms present in the carbohydrate structure," explains MacMillan, a specialist in organic synthesis. "We simplified this to two steps by the invention of two new chemical reactions that are based on an old but powerful chemical transformation known as the aldol reaction. Furthermore, we have devised methods to selectively build oxygen differentiated glucose, mannose, or allose in just two chemical steps."

MacMillan has also demonstrated that this new method for carbohydrate synthesis allows easy access to unnatural carbohydrates for use in medicinal chemistry and glycobiology as well as in a number of diagnostic techniques. One application involves a rare form or carbon known as carbon-13, which is easier to identify with magnetism-based analytical methods.

By using the readily available and inexpensive 13C-labeled form of ethylene glycol, MacMillan and Northrup have been able to construct the all-13C-labeled versions of carbohydrates in only four chemical steps. For comparison, the previous total synthesis of this all-13C-labeled carbohydrate was accomplished in 44 chemical steps.

"Carbohydrates are essential to human biology, playing key roles in everything from our growth and development to our immune system and brain functions," says John Schwab, a chemist at the National Institute of General Medical Sciences, which supported the research. "They also play critical roles in plants, bacteria, and viruses, where they have huge implications for human health. But because they are so difficult to work with, carbohydrates are not nearly as well understood as DNA and proteins.

"MacMillan's technique will allow scientists to more easily synthesize and study carbohydrates, paving the way for a deeper understanding of these molecules, which in turn may lead to new classes of drugs and diagnostic tools," Schwab adds.

"One of the central goals of chemical synthesis is to design new ways to build molecules that will greatly benefit other scientific fields and ultimately society as a whole," MacMillan says. "We think that this new chemical sequence will help toward this goal; however, there is a bounty of new chemical reactions that are simply waiting to be discovered that will greatly impact many other areas of research in the biological and physical sciences."

The title of the paper is "Two Step Synthesis of Carbohydrates by Selective Aldol Reactions." The paper will be published in the journal Science at a later date.

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RT

Fish, Frog, and Fly Share a Molecular Mechanism to Control Embryonic Growth

PASADENA, Calif. — Oriented cell division is a fundamental process in developing organisms, whether you are a worm, a fruit fly--or a human. As an embryo begins to grow, cells divide again and again, from the single fertilized egg to the countless cells present at birth. These cell divisions are not haphazard; instead, they are often precisely oriented, playing an important role in building an embryo of the right size and shape, and with the right body "parts"--the control of cell division also plays a central role in placing cells in the proper positions to build organs that will contain the correct cell types.

The orientation of cell divisions has been well studied in invertebrates, especially in Caenorhabditis elegans (worm) and Drosophila melanogaster (fruit fly), but relatively little has been known about oriented cell division in vertebrates. Now for the first time, researchers at the California Institute of Technology report that the molecular machinery that underlies oriented cell division in invertebrates serves a similar but twofold purpose in the development of the vertebrate embryo. For one, it is responsible for orienting cell division, or mitosis. For another, it's responsibile for the movements that elongate the round egg into the vertebrate body plan; that is, the shape of the particular animal. The research appears in the August 5 edition of the journal Nature (http://www.nature.com/).

The researchers are recent graduates Ying Gong '04 and Chunhui Mo '03, working with Scott Fraser, the Anna L. Rosen Professor of Biology and director of the Biological Imaging Center. Using the zebrafish, a card-carrying vertebrate, as their animal model, the researchers first marked certain cells with fluorescent proteins. Then, using a four-dimensional confocal microscope, they were able to follow the motions of these cells in real time, as the body plan of the zebrafish took shape during development, or gastrulation. The researchers found that cells in dorsal tissue divide in an oriented fashion, with one of the two daughter cells from each division moving towards the head, and the other towards the future tail. They were able to determine that such oriented cell division is a major driving force for the extension of the body axis--the growth of the embryo into the animal's final shape.

By combining their advanced imaging tools with molecular biological techniques, the researchers were able to show that the driving force for these oriented divisions is the Wnt "pathway," a ubiquitous cascade of specific proteins that trigger cellular function. Research over the past decade has shown that the Wnt pathway controls the patterns, fates, and movements of cells in both vertebrates and invertebrates. One major branch of this biochemical communication network is the planar cell polarity (PCP) pathway. In previous work from the Fraser lab and their collaborators, the PCP pathway has been shown to guide the tissue motions that convert the spherical frog embryo into the familiar shape of the elongated tadpole. This is a key process in the life of the frog, termed convergent extension. Each cell attempts to "elbow between" the row of cells to its left or its right. "This simple motion has a profound effect on the length and width of the embryo," says Fraser; "think of a band marching shoulder to shoulder on a football field. If half of the rows of marchers merged with the adjacent row, the band would be half as wide and twice as long."

The trio of researchers explored the effects in fish embryos of altering the many proteins in the Wnt-PCP signaling pathway, including some of the potential signals and co-receptors (proteins called Silberblick/Wnt11, Dishevelled, and Strabismus). They were expecting to see an alteration in the convergent-extension motions. Instead, what they found was a major alteration in the orientation of cell division. When they blocked the Wnt pathway, cell division did not take place along the head-tail axis, but randomly. In normal fish embryos, the oriented divisions lengthened the body axis by nearly twofold. With randomization, though, a short and squat embryo was created.

Given that the same PCP pathway is involved in controlling cell division in the invertebrates, C. elegans and D. melanogaster, and the vertebrate zebrafish, the results suggest that the pathway has an evolutionary conserved role. That is, that across a wide variety of animal species, such pathways share a common function, perhaps reflecting a common origin in the biological past.

"The amazing thing about these studies is that they show that the many varied mechanisms that can create the long and narrow body plan of a fish, frog, or fly come under a common molecular control mechanism," Fraser says. "Work in frog embryos from John Wallingford (formerly of UC Berkeley, currently at University of Texas, Austin) and Richard Harland (UC Berkeley) have established a link between these motions and neural tube defects (such as craniorachischisis and spina bifida). Our new experiments have already prompted a new round of collaborative experiments to determine if the same molecular pathway controls convergent extension, cell division, or both in mammals. The answers to these questions promise new insights into the underlying cause for some of the devastating birth defects seen in humans. "

MEDIA CONTACT: Mark Wheeler (626) 395-8733 wheel@caltech.edu

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Gamma-ray burst of December 3 was a new type of cosmic explosion

PASADENA, Calif.—Astronomers have identified a new class of cosmic explosions that are more powerful than supernovae but considerably weaker than most gamma-ray bursts. The discovery strongly suggests a continuum between the two previously-known classes of explosions.

In this week's issue of Nature, astronomers from the Space Research Institute of the Russian Academy of Sciences and the California Institute of Technology announce in two related papers the discovery of the explosion, which was first detected on December 3, 2003, by the European-Russian Integral satellite and then observed in detail at ground-based radio and optical observatories. The burst, known by its birthdate, GRB031203, appeared in the constellation Puppis and is about 1.6 billion light-years away.

Although the burst was the closest gamma-ray burst to Earth ever studied (all the others have been several billion light-years away), researchers noticed that the explosion was extremely faint--releasing only about one-thousandth of the gamma rays of a typical gamma-ray burst. However, the burst was also much brighter than supernovae explosions, which led to the conclusion that a new type of explosion had been found.

Both supernovae and the rare but brilliant gamma-ray bursts are cosmic explosions marking the deaths of massive stars. Astronomers have long wondered what causes the seemingly dramatic differences between these events. The question of how stars die is currently a major focus of stellar research, and is particularly directed toward the energetic explosions that destroy a star in one cataclysmic event.

Stars are powered by the fusion ("burning'') of hydrogen in their interiors. Upon exhaustion of fuel in the interior, the core of massive stars collapse to compact objects--typically a neutron star and occasionally a black hole. The energy released as a result of the collapse explodes the outer layers, the visible manifestation of which is a supernova. In this process, new elements are added to the inventory of matter in the universe.

However, this nuclear energy may be insufficient to power the supernova explosions. One theory is that additional energy is generated from the matter falling onto the newly produced black hole. Many astronomers believe that this is what powers the luminous gamma-ray bursts.

But the connection between such extreme events and the more common supernovae is not yet clear, and if they are indeed closely related, then there should be a continuum of cosmic explosions, ranging in energy from that of "ordinary" supernovae to that of gamma-ray bursts.

In 1998, astronomers discovered an extremely faint gamma-ray burst, GRB 980425, coincident with a nearby luminous supernova. The supernova, SN 1998bw, also showed evidence for an underlying engine, albeit a very weak one. The question that arose was whether the event, GRB 980425/SN 1998bw, was a "freak" explosion or whether it was indicative of a larger population of low-powered cosmic explosions with characteristics in between the cosmological gamma-ray bursts and typical supernovae.

"I knew this was an exciting find because even though this was the nearest gamma-ray burst to date, the gamma-ray energy measured by Integral is one thousand times fainter than typical cosmological gamma-ray bursts," says Sergey Sazonov of the Space Research Institute, the first author of one of the two Nature papers.

The event was studied in further detail by the Chandra X-Ray Observatory and the Very Large Array, a radio telescope facility located in New Mexico.

"I was stunned that my observations from the Very Large Array showed that this event confirmed the existence of a new class of bursts," says graduate student Alicia Soderberg, who is the principal author of the other Nature paper. "It was like hitting the jackpot."

There are several exciting implications of this discovery, including the possible existence of a significant new population of low-luminosity gamma-ray bursts lurking within the nearby universe, said Shrinivas Kulkarni, who is the MacArthur Professor of Astronomy and Planetary Science at Caltech and Soderberg's faculty adviser.

"This is an intriguing discovery," says Kulkarni. "I expect a treasure trove of such events to be identified by NASA's Swift mission scheduled to be launched this fall from Cape Canaveral. I am convinced that further discoveries and studies of this new class of hybrid events will forward our understanding of the death of massive stars."

 

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