New aging cause revealed by test tube

Chemists from The Australian National University have discovered a new way that ageing-related diseases can progress, opening up new preventative and treatment possibilities for conditions such as heart disease and Alzheimer’s disease.

Led by Professor Chris Easton and Dr. Dannon Stigers from the ARC Centre of Excellence for Free Radical Chemistry and Biotechnology at ANU, the researchers have used the test tube to simulate the living body, and revealed a new process through which ageing related diseases may develop. Their work has been published in a recent edition of The Royal Society Chemistry journal, Chemistry Communications.

“Remarkably the good old test tube has given us a fantastic window from which to look into the basic processes necessary for life and it has changed the way we think about how ageing related diseases develop,” said Dr. Stigers.

It had been assumed that lifestyle choices such as diet, exercise, and smoking caused some people to develop ageing related illnesses more rapidly than others. Poor lifestyle decisions increase exposure to free radicals which can damage proteins in the body leading to their accumulation and eventual disease. However, in this study the researchers were able to observe proteins being made with their building blocks already damaged, indicating there are two possible pathways to age-related disease development that can be exploited for future treatments.

“We are not saying that a healthy lifestyle is not important to prevent early onset of age-related disease, but we now need to acknowledge that it may not be enough to advise people to eat the right foods and exercise regularly,” said Dr. Stigers.

In their test tube of life, the researchers added all the necessary machinery to make proteins, including both damaged and healthy protein building blocks, and a type of biological proof-reader that ensures proteins are made with only the healthy building blocks. They then looked to see if any of the damaged building blocks made it into the finished protein.

“We were surprised to find that the damaged building blocks were able to effectively compete for incorporation into the final protein even when our proof-reader was present,” said Professor Chris Easton.

“It may seem subtle but from a treatment perspective the difference between preventing a protein from being damaged and dealing with one that is made from damaged goods is vast. This is a significant break through and one which we hope will prove revolutionary in terms of tackling age-related diseases,” he added.

Provided by Australian National University

UC research produces novel sensor with improved detection selectivity

 A highly sensitive sensor that combines a variety of testing means (electrochemistry, spectroscopy and selective partitioning) into one device has been developed at the University of Cincinnati. It's already been tested in a variety of settings – including testing for components in nuclear waste.

The sensor is unusual in that most sensors only have one or two modes of selectivity, while this sensor has three. In practical terms, that means the UC sensor has three different ways to find and identify a compound of interest. That's important because settings like a nuclear waste storage tank are a jumbled mix of chemical and radioactive wastes. The sensor, however, would have a variety of applications, including testing in other environments and even medical applications.

Research related to this novel sensor will be presented at the American Chemical Society biannual meeting March 27-31 in Anaheim, Calif., in a presentation titled "Using Spectroelectrochemistry to Improve Sensor Selectivity."

That presentation will be made March 28 by William Heineman, distinguished research professor of chemistry at the University of Cincinnati. He is one of six international scientists invited to speak by electrochemistry students involved in planning a conference symposium. Heineman has published more than 400 research articles on the topics of spectroelectrochemistry, electroanalytical chemistry, bioanalytical chemistry and chemical sensors, and has won numerous national and international awards for his work.

Research on this sensor concept began more than a decade ago and has received support from the United States Department of Energy for most of that time. "They wanted a sensor that can be lowered in a tank to make lots of measurements quickly or have the option of leaving it in there to monitor what's going on over months or a year," said Heineman, who added that the ideal sensor is both rugged and very selective and sensitive.

The sensor has, in fact, been tested at the Hanford site, a mostly decommissioned nuclear production complex in Washington state, where it was used to detect one important component of the radioactive and hazardous wastes stored inside the giant tanks there.

The basic design and concept for this monitor could be used in many other environmental or medical settings. These include detection of toxic heavy metals and polycyclic aromatic hydrocarbons at superfund sites.

The three-way selectivity comes from the use of coatings, electrochemistry, and spectroscopy. The selective coating only allows certain compounds to enter the sensing region. For example, all negatively charged ions might be able to enter the sensor while all positively charged ions are excluded. Next comes the electrochemistry. A potential is applied, and an even smaller group of compounds are electrolyzed. Finally, a very specific wavelength of light is used to detect the actual compound of interest.

The end result is that compounds, even those present in very low concentrations, can be detected and analyzed. This is especially important in medical monitoring and other applications requiring high selectivity and sensitivity.

"Our goal in this research was to demonstrate that the concept works, and that goal has been met as it's now been tested in several ways. Maybe that's why the students at the ACS meeting wanted to hear about it," said UC's Heineman.

Provided by University of Cincinnati (news : web)

'Lost' samples from famous origin of life researcher could send search for first life in new direction

Enlarge

Preserved samples from a 1958 experiment done by "primordial soup" pioneer Stanley Miller contain amino acids created by the experiment. The samples had not undergone analysis until recently when Miller's former student Jeffrey Bada and colleagues discovered a wide range of amino acids. The find could be an important step toward understanding how life on Earth could have originated. The vials have been relabeled but the boxes are marked with Miller's original notes. Credit: Scripps Institution of Oceanography, UC San Diego

(PhysOrg.com) -- Stanley Miller gained fame with his 1953 experiment showing the synthesis of organic compounds thought to be important in setting the origin of life in motion. Five years later, he produced samples from a similar experiment, shelved them and, as far as friends and colleagues know, never returned to them in his lifetime.

More 50 years later, Jeffrey Bada, Miller's former student and a current Scripps Institution of Oceanography, UC San Diego professor of marine chemistry, discovered the samples in Miller's laboratory material and made a discovery that represents a potential breakthrough in the search for the processes that created Earth's first life forms.

Former Scripps undergraduate student Eric Parker, Bada and colleagues report on their reanalysis of the samples in the March 21 issue of Proceedings of the National Academy of Sciences. Miller's 1958 experiment in which the gas hydrogen sulfide was added to a mix of gases believed to be present in the atmosphere of early Earth resulted in the synthesis of sulfur amino acids as well as other amino acids. The analysis by Bada's lab using techniques not available to Miller suggests that a diversity of organic compounds existed on early planet Earth to an extent scientists had not previously realized.

 

Scripps Oceanography professor of Marine Chemistry Jeffrey Bada holds a preserved sample from a 1958 experiment done by "primordial soup" pioneer Stanley Miller. The residue in the sample contains amino acids created by the experiment. The samples had not undergone analysis until recently when Bada and colleagues discovered a wide range of amino acids using modern detection methods. Credit: Scripps Institution of Oceanography, UC San Diego

The new findings support the case that volcanoes — a major source of atmospheric hydrogen sulfide today — accompanied by lightning converted simple gases into a wide array of amino acids, which are were in turn available for assembly into early proteins.

Bada also found that the amino acids produced in Miller's experiment with hydrogen sulfide are similar to those found in meteorites. This supports a widely-held hypothesis that processes such as the ones in the laboratory experiments provide a model of how organic material needed for the origin of life are likely widespread in the universe and thus may provide the extraterrestrial seeds of life elsewhere.

Successful creation of the sulfur-rich amino acids would take place in the labs of several researchers, including Miller himself, but not until the 1970s.

"Unbeknownst to him, he'd already done it in 1958," said Bada.

Miller's initial experiments in the 1950s with colleague Harold Urey used a mixture of gases such as methane, ammonia, water vapor and hydrogen and electrically charged them as lightning would. The experiment, which took place in a closed chamber meant to simulate conditions on early Earth, generated several simple amino acids and other organic compounds in what became known as "primordial soup."

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This is a photo of Stanley Miller in his UC San Diego lab in 1970. Credit: Scripps Institution of Oceanography Archives

With the gases and electrical energy they produce, many geoscientists believe the volcanoes on a young planet covered much more extensively by water than today's served as oases of raw materials that allowed prebiotic matter to accumulate in sufficient quantities to assemble into more complex material and eventually into primitive life itself. Bada had already begun reanalyzing Miller's preserved samples and drawing conclusions about the role of volcanoes in sparking early life when he came across the previously unknown samples. In a 2008 analysis of samples left from Miller's more famous experiment, Bada's team had been able to detect many more amino acids than his former mentor had thanks to modern techniques unavailable to Miller.

Miller, who became a chemistry professor at UCSD in 1960, conducted the experiments while a faculty member at Columbia University. He had collected and catalogued samples from the hydrogen sulfide mix but never analyzed them. He only casually mentioned their existence late in his life and the importance of the samples was only realized shortly before his death in 2007, Bada said. It turned out, however, that his 1958 mix more closely resembled what geoscientists now consider early Earth conditions than did the gases in his more famous previous experiment.

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The original box containing archived spark discharge samples prepared by Stanley Miller in 1958. For unknown reasons, Miller never analyzed these even though this is his first experiment using hydrogen sulfide. The label shows Miller?s original writing: p 114 refers to his notebook. Credit: Jeffrey Bada and Robert Benson/Scripps Institution of Oceanography, University of California at San Diego

"This really not only enhances our 2008 study but goes further to show the diversity of compounds that can be produced with a certain gas mixture," Bada said.

The Bada lab is gearing up to repeat Miller's classic experiments later this year. With modern equipment including a miniaturized microwave spark apparatus, experiments that took the elder researcher weeks to carry out could be completed in a day, Bada said.

Provided by University of California - San Diego (news : web)

New method for preparation of high-energy carbon-carbon double bonds

A new catalytic chemical method for the synthesis of a large and important class of carbon-carbon double bonds has been developed by scientists from Boston College and MIT, the team reports in the journal Nature. The findings substantially expand the versatility of a set of metal-based catalysts discovered only three years ago by the researchers.

With molybdenum at their core, the catalysts have now proven capable of generating the higher-energy isomer of an alkene molecule from two simpler and much more readily accessible terminal versions, the team reports in an article in the current edition of the journal.

Carbon–carbon double bonds, also referred to as alkenes or olefins, are present in many medicinally relevant and biologically active molecules. Co-author Richard Schrock of MIT shared the 2005 Nobel Prize in Chemistry for discovering one of the earliest types of olefin metathesis catalysts.

Alkenes exist as either the zigzag shaped trans olefin, or the E isomer, while others take the "U" shape of the cis olefin, or the higher-energy Z isomer. Catalytic methods for the synthesis of Z alkenes, particularly through olefin metathesis, have been sought after by many research teams in the world but had thus far proved elusive, said Amir Hoveyda, the primary author of the paper and the Joseph T. and Patricia Vanderslice Millennium Professor of Chemistry at Boston College.

Z isomers require a catalyst that must be sufficiently active to be capable of promoting the chemical reaction while maintaining the cis olefin's U-shape geometry. Preserving both characteristics in a catalyst leads to reactions that deliver Z-alkenes, which can be found in a large number of medicinally significant molecules and are used as starting materials for some of the most commonly used transformations in chemistry.

"These higher energy carbon-carbon double bonds are incredibly important to chemists and researchers in various areas such as medicinal chemistry, chemical biology, organic synthesis and materials research," said Hoveyda. "The trick here was to come up with a catalyst that is active enough to promote Z-alkene formation but not too active to also want to react with the product. So, in a way, we had to walk on a very tight rope. Olefin metathesis is a reversible reaction and you always run the risk of going back and forth between product and starting material, which forces you to end up with a lower energy and less desirable isomer. What we have found are catalysts that are sufficiently active to promote this difficult reaction but are also discriminating enough not to go after the product and cause it to isomerize."

Using the highly abundant and inexpensive metal molybdenum, Hoveyda and his colleagues show the catalyst can produce a Z-selective "cross metathesis" reaction – an olefin metathesis reaction in which two different alkene-containing molecules are fused into a single molecule, generating only ethylene, the smallest possible alkene-containing molecule, as the byproduct. By simply running their reactions in a vacuum, the team discovered that removal of generated olefin can significantly improve the desired process and yield unprecedented levels of reactivity and selectivity.

The researchers demonstrated the special versatility of their new catalytic method through synthesis of a potent antioxidant plasmalogen phospholipid, molecules critical to cellular function that have been implicated in Alzheimer's disease, as well as the potent immunostimulant KRN7000, which has been shown to combat tumors, autoimmune disease and graft-versus-host disease in mice.

The synthesis of such biologically relevant molecules further proves the far-reaching importance of olefin metathesis, Hoveyda said. In the case of the anti-oxidant, the carbon-carbon double bond marked the end-point in the creation of the compound. For the immunostimulant, the creation of the Z double bond proved to be most critical in subsequent structural modifications required to reach the final target.

Provided by Boston College (news : web)

Making skinny worms fat, fat worms skinny

Researchers exploring human metabolism at the University of California, San Francisco (UCSF) have uncovered a handful of chemical compounds that regulate fat storage in worms, offering a new tool for understanding obesity and finding future treatments for diseases associated with obesity.

As described in a paper published this month in the journal Nature Chemical Biology, the UCSF team took armies of microscopic worms called C.elegans and exposed them to thousands of different chemical compounds. Giving these compounds to the worms, they discovered, basically made them skinnier or fatter without affecting how they eat, grow, or reproduce.

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The discovery gives scientists new ways to investigate metabolism and could eventually lead to the development of new drugs to regulate excessive fat accumulation and address the metabolic issues that underlie a number of major human health problems, including, obesity, diabetes and some forms of cancer.

The work also demonstrates the value of “worm screening” as a way of finding new targets for human diseases, according to the UCSF scientists, whose work was spearheaded by postdoctoral fellow George Lemieux, PhD, in the laboratory of Professor Zena Werb, PhD, vice chair of the Department of Anatomy at UCSF.

The work was a collaboration involving Kaveh Ashrafi, PhD, an associate professor in the UCSF Department of Physiology, and Roland Bainton, MD, PhD, an associate professor in residence in the UCSF Department of Anesthesia & Perioperative Care.

Why Worms Are Fat

The UCSF team’s interest in how worms deal with fat began with a more fundamental interest in human metabolism. Worms make molecules of fat for the same reasons humans do – they are useful for storing energy and are a basic building block for body tissues. Many of the genes and mechanisms worms use to regulate fat accumulation have similar systems in humans, and not all of them are completely understood.

Starting with 3,200 different chemical compounds and 3,200 pools of tiny worms, the UCSF team used a red dye that sticks to fat molecules to pinpoint under the microscope which of the chemicals made the worms fatter (more red) or skinnier (less red). They identified a few dozen, and performing additional tests, narrowed in on about 10 compounds they believe regulate fat metabolism. Those compounds not only altered fat storage in the worms but in in insect and human cells grown in test tubes, leading Lemieux to comment that they “may be useful for understanding metabolism in other organisms.”

One of these compounds modulates a molecular complex called an AMP-activated kinase, which senses the availability of cellular energy. Versions of kinase complexes exist both in worms and humans, and some already are key targets for drug design by pharmaceutical companies.

“The compound that we get from our worm screen can act on this kinase complex as well if not better than anything else that is out there,” said Ashrafi.

The real strength of the work, he added, is that it demonstrates the value of the new worm screen over existing screening tools for identifying the genes, proteins and other molecular players involved in human health.

A large part of drug discovery involves identifying these players and designing ways to treat diseases that emerge when they don’t work correctly. But identifying the targets is only the beginning. Designing a drug involves overcoming a long list of other hurdles, Ashrafi said, and the bottom line is that most of the potential drugs that seem to work well in the test tube fail to work in people.

The value of the worm screen, he said, is that it allows scientists to select compounds for further study that already work effectively in a whole organism.

“A lot of the drugs that are in clinical use or development today were discovered basically by chance,” Ashrafi said. “If we understood everything about everything, we could probably design the right compounds. But the reality is our understanding of many of the biological principles and chemical principles are still in their infancy.”

More information: http://dx.doi.org/ … nchembio.534

Provided by University of California San Francisco

Only the weak survive? Self-healing materials strengthened by adding more 'give'

A Pitt and Carnegie Mellon team developed a new model of how self-repairing materials function and show that materials with a certain number of easily breakable bonds can absorb more stress, a natural trick found in the resilient abalone shell, according to a report in Langmuir.

Conventional rules of survival tend to favor the strongest, but University of Pittsburgh-based researchers recently found that in the emerging world of self-healing materials, it is the somewhat frail that survive.

The team presents in the journal Langmuir a new model laying out the inner workings of self-healing materials made of nanoscale gel particles that can regenerate after taking damage and are being pursued as a coating or composite material. Moreover, the researchers discovered that an ideal amount of weak bonds actually make for an overall stronger material that can withstand more stress.

Although self-healing nanogel materials have already been realized in the lab, the exact mechanical nature and ideal structure had remained unknown, explained Anna Balazs, corresponding author and Distinguished Professor of Chemical Engineering in Pitt's Swanson School of Engineering. The team's findings not only reveal how self-healing nanogel materials work, but also provide a blueprint for creating more resilient designs, she said. Balazs worked with lead author and Pitt postdoctoral researcher Isaac Salib; Chet Gnegy, a Pitt chemical and petroleum engineering sophomore; German Kolmakov, a postdoctoral researcher in Balazs' lab; and Krzysztof Matyjaszewski, a chemistry professor at Carnegie Mellon University with an adjunct appointment in Pitt's Department of Chemical and Petroleum Engineering.

The team worked from a computational model Gnegy, Kolmakov, and Salib created based on a self-healing material Matyjaszewski developed known as nanogel, a composition of spongy, microscopic polymer particles linked to one another by several tentacle-like bonds. The nanogel particles consist of stable bonds -- which provide overall strength -- and labile bonds, highly reactive bonds that can break and easily reform, that act as shock absorbers.

The computer model allowed the researchers to test the performance of various bond arrangements. The polymers were first laid out in an arrangement similar to that in the nanogel, with the tentacles linked end-to-end by a single strong bond. Simulated stress tests showed, however, that though these bonds could recover from short-lived stress, they could not withstand drawn out tension such as stretching or pulling. Instead, the team found that when particles were joined by several parallel bonds, the nanogel could absorb more stress and still self-repair.

The team then sought the most effective concentration of parallel labile bonds, Balazs said. According to the computational model, even a small number of labile bonds greatly increased resilience. For instance, a sample in which only 30 percent of the bonds were labile -- with parallel labile bonds placed in groups of four -- could withstand pressure up to 200 percent greater than what could fracture a sample comprised only of stable bonds. A film shows that as this sample is stretched, the labile bonds (red) rearrange themselves to hold the material together.

On the other hand, too many labile linkages were so collectively strong that the self-healing ability was cancelled out and the nanogel became brittle, the researchers report.

The Pitt model is corroborated by nature, which engineered the same principle into the famously tough abalone shell, Balazs said. An amalgamation of microscopic ceramic plates and a small percentage of soft protein, the abalone shell absorbs a blow by stretching and sliding rather than shattering.

"What we found is that if a material can easily break and reform, the overall strength is much better," she said. "In short, a little bit of weakness gives a material better mechanical properties. Nature knows this trick."

Story Source:

The above story is reprinted (with editorial adaptations ) from materials provided by University of Pittsburgh.

Journal Reference:

Isaac G. Salib, German V. Kolmakov, Chet N. Gnegy, Krzysztof Matyjaszewski, Anna C. Balazs. Role of Parallel Reformable Bonds in the Self-Healing of Cross-Linked Nanogel Particles. Langmuir, 2011; : 110224111613065 DOI: 10.1021/la104609t

New method for preparation of high-energy carbon-carbon double bonds

A new catalytic chemical method for the synthesis of a large and important class of carbon-carbon double bonds has been developed by scientists from Boston College and MIT, the team reports in the journal Nature. The findings substantially expand the versatility of a set of metal-based catalysts discovered only three years ago by the researchers.

With molybdenum at their core, the catalysts have now proven capable of generating the higher-energy isomer of an alkene molecule from two simpler and much more readily accessible terminal versions, the team reports in an article in a recent edition of the journal.

Carbon-carbon double bonds, also referred to as alkenes or olefins, are present in many medicinally relevant and biologically active molecules. Co-author Richard Schrock of MIT shared the 2005 Nobel Prize in Chemistry for discovering one of the earliest types of olefin metathesis catalysts.

Alkenes exist as either the zigzag shaped trans olefin, or the E isomer, while others take the "U" shape of the cis olefin, or the higher-energy Z isomer. Catalytic methods for the synthesis of Z alkenes, particularly through olefin metathesis, have been sought after by many research teams in the world but had thus far proved elusive, said Amir Hoveyda, the primary author of the paper and the Joseph T. and Patricia Vanderslice Millennium Professor of Chemistry at Boston College.

Z isomers require a catalyst that must be sufficiently active to be capable of promoting the chemical reaction while maintaining the cis olefin's U-shape geometry. Preserving both characteristics in a catalyst leads to reactions that deliver Z-alkenes, which can be found in a large number of medicinally significant molecules and are used as starting materials for some of the most commonly used transformations in chemistry.

"These higher energy carbon-carbon double bonds are incredibly important to chemists and researchers in various areas such as medicinal chemistry, chemical biology, organic synthesis and materials research," said Hoveyda. "The trick here was to come up with a catalyst that is active enough to promote Z-alkene formation but not too active to also want to react with the product. So, in a way, we had to walk on a very tight rope. Olefin metathesis is a reversible reaction and you always run the risk of going back and forth between product and starting material, which forces you to end up with a lower energy and less desirable isomer. What we have found are catalysts that are sufficiently active to promote this difficult reaction but are also discriminating enough not to go after the product and cause it to isomerize."

Using the highly abundant and inexpensive metal molybdenum, Hoveyda and his colleagues show the catalyst can produce a Z-selective "cross metathesis" reaction -- an olefin metathesis reaction in which two different alkene-containing molecules are fused into a single molecule, generating only ethylene, the smallest possible alkene-containing molecule, as the byproduct. By simply running their reactions in a vacuum, the team discovered that removal of generated olefin can significantly improve the desired process and yield unprecedented levels of reactivity and selectivity.

The researchers demonstrated the special versatility of their new catalytic method through synthesis of a potent antioxidant plasmalogen phospholipid, molecules critical to cellular function that have been implicated in Alzheimer's disease, as well as the potent immunostimulant KRN7000, which has been shown to combat tumors, autoimmune disease and graft-versus-host disease in mice.

The synthesis of such biologically relevant molecules further proves the far-reaching importance of olefin metathesis, Hoveyda said. In the case of the anti-oxidant, the carbon-carbon double bond marked the end-point in the creation of the compound. For the immunostimulant, the creation of the Z double bond proved to be most critical in subsequent structural modifications required to reach the final target.

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by Boston College, via EurekAlert!, a service of AAAS.

Journal Reference:

Simon J. Meek, Robert V. O’Brien, Josep Llaveria, Richard R. Schrock, Amir H. Hoveyda. Catalytic Z-selective olefin cross-metathesis for natural product synthesis. Nature, 2011; 471 (7339): 461 DOI: 10.1038/nature09957