Sweet insight: Discovery could speed drug development

 The surface of cells and many biologically active molecules are studded with sugar structures that are not used to store energy, but rather are involved in communication, immunity and inflammation. In a similar manner, sugars attached to drugs can enhance, change or neutralize their effects, says Jon Thorson, a professor of pharmaceutical sciences at the University of Wisconsin-Madison School of Pharmacy.

Thorson, an expert in the attachment and function of these sugars, says that understanding and controlling them has major potential for improving drugs, but that researchers have been stymied because many novel sugars are difficult to create and manipulate. "The chemistry of these sugars is difficult, so we have been working on methods to make it more user friendly," he says.

Now, in a study published online in Nature Chemical Biology on Aug. 21, Thorson, graduate student Richard Gantt and postdoctoral fellow Pauline Peltier-Pain have described a simple process to separate the sugars from a carrier molecule, then attach them to a drug or other chemical. The process also causes a color change only among those molecules that have accepted the sugar. The change in color should support a screening system that would easily select out transformed molecules for further testing. "One can put 1,000 drug varieties on a plate and tell by color how many of them have received the added sugar," Thorson says.

Attached sugars play a key role in pharmacy, says Thorson. Not only can they change the solubility of a compound, but "there are transporters in the body that specifically recognize certain sugars, and pharmaceutical companies have taken advantage of this to direct molecules toward specific tissue or cell types. If we can build a toolbox that allows us to make these molecules on demand, we can ask, 'What will sugar A do when it's attached to drug B?'"

And although the new study was focused more on an improved technique rather than the alteration of drugs, Thorson adds that it does describe the production of some "really interesting sugar-appended drugs: anti-virals, antibiotics, anti-cancer and anti-inflammatory drugs. Follow-up studies are currently under way to explore the potential of these analogs."

The new molecules included 11 variants of vancomycin, a powerful antibiotic, each distinguished by the nature and number of attached sugars.

The essence of the new process is its starting point: a molecule that changes the energy dynamics of the sugar-attachment reaction, Thorson says. "This is one of the first systematic studies of the equilibrium of the reaction, and it shows we can drive it forward or in reverse, depending on the molecule that we start with."

In a single test tube, the new technique is able to detach the sugar from its carrier and reattach it to the biological target molecule, Thorson says. "Sugars are involved a vast range of biology, but there are still many aspects that are not well understood about the impact of attaching and removing sugars, partly because of the difficulty of analyzing and accessing these species."

Making variants of potential and existing drugs is a standard practice for drug-makers, and a recently published study by Peltier-Pain and Thorson revealed that attaching a certain sugar to the anti-coagulant Warfarin destroys its anti-clotting ability. The transformed molecule, however, "suddenly becomes quite cytotoxic -- it kills cells," he says. "We don't know the mechanism, but there is some interest in using it to fight cancer because it seems to act specifically on certain cells."

Sugars are also attached to proteins, cell surfaces and many other locations in biology, Thorson says. "By simplifying the attachment, we are improving the pharmacologist's toolbox. This study provides access to new reagents and offers a very convenient screening for new catalysts and/or new drugs, and for other things we haven't yet thought of. We believe this is going to open up a lot of doors."

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by University of Wisconsin-Madison. The original article was written by David Tenenbaum.

Journal Reference:

Richard W Gantt, Pauline Peltier-Pain, William J Cournoyer, Jon S Thorson. Using simple donors to drive the equilibria of glycosyltransferase-catalyzed reactions. Nature Chemical Biology, 2011; DOI: 10.1038/nchembio.638

Scientists find easier, cheaper way to make a sought-after chemical modification to pharmaceuticals

Scientists at The Scripps Research Institute have devised a much easier technique for performing a chemical modification used widely in the synthesis of drugs and other products.

Known as "trifluoromethylation," the modification adds a CF3 molecule to the original compound, often making it more stable -- and, for a drug, keeping it in the body longer. With the new technique, chemists can perform this feat using a relatively simple, safe, room-temperature procedure and can even select the site of the modification on the target compound.

"I've been presenting this methodology at several pharma companies, and there's a lot of interest -- so much so that their chemists are starting to use it," said Scripps Research Professor Phil S. Baran, senior author of the new study, scheduled for publication the week of August 15, 2011, in an advance online edition of the Proceedings of the National Academy of Sciences.

Standard procedures for trifluoromethylation involve gases and associated hardware, high heat, metal catalysts, and oxidants. "The procedures are often prohibitively complicated, and medicinal chemists often don't have the time or the resources to get into it," said Baran.

Inspired by frequent consulting visits to pharmaceutical companies, Baran and his lab began to look for simpler ways to perform trifluoromethylation. After running more than 500 different reaction setups on a test compound, they found just one that delivered significant quantities of the desired reaction product. It was a simple setup that used a reagent known as sodium trifluoromethanesulfinate, an inexpensive chemical that is stable at room temperature.

Chemists had long believed that this reagent was unsuitable for trifluoromethylating a broad class of molecules frequently found in drug compounds, and also that the reagent required the use of catalyzing metal salts. But in this initial screening, the reagent, known as Langlois's reagent for its discoverer, the French chemist Bernard R. Langlois, seemed to work even without such constraints.

Baran and his team began collaborating with fellow Scripps Research chemistry Professor Donna Blackmond and members of her laboratory to study how Langlois's reagent works and to optimize its use, including the selection of trifluoromethylation sites on target compounds using certain solvents. With the optimized technique, they showed that they could directly and easily trifluoromethylate a variety of test compounds, including the natural malaria drug quinine and the synthetic anti-smoking drug varenicline (Chantix).

"The collaboration with Donna Blackmond and her lab was crucial in enabling us to improve the procedure and to understand why certain modifications led to those improvements," said Baran.

The new technique in principle makes it more feasible for pharmaceutical companies to modify and improve specific drug compounds of interest. It also means that these companies can expand the existing compound libraries they use for drug-discovery screening by making trifluoromethylated versions of these compounds quickly and easily.

"In one instance, a chemist at Pfizer told me that the trifluoromethylated compound we made in one step with our technique would have taken at least eight steps using standard techniques," said Baran.

The Baran and Blackmond labs are now working on new reagents that may be used in this reaction and ways to enable fine control of trifluoromethylation sites. "The interplay of the two labs at the nexus of synthesis and mechanistic analysis is driving this project forward in new and exciting directions," Baran said.

The two first authors of the paper, "Innate C-H Trifluoromethylation of Heterocycles," are Yining Ji and Tobias Brueckl of the Scripps Research Baran lab. Others who contributed are Ryan D. Baxter of the Scripps Research Blackmond lab and Yuta Fujiwara, Ian B. Seiple, and Shun Su of the Baran lab.

The work was supported in part by a grant from the National Institute of General Medical Sciences, part of the National Institutes of Health.

Story Source:

The above story is reprinted (with editorial adaptations ) from materials provided by The Scripps Research Institute.

Journal Reference:

Yining Ji, Tobias Brueckl, Ryan D. Baxter, Yuta Fujiwara, Ian B. Seiple, Shun Su, Donna G. Blackmond, Phil S. Baran. Innate C-H trifluoromethylation of heterocycles. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1109059108

Analytik Jena After Nine Months with Growth in Operating Business

 With sales growth of almost 7.0 % and an increase of nearly 6.0 % in operating earnings, Analytik Jena is now entering the final straight of the 2010/2011 financial year. After nine months the Group generated sales of EUR 63.6 m and operating income of EUR 3.4 m. This was announced by the manufacturer of analytical measuring technology, life science instruments and optoelectronics at the presentation of the quarterly and the 9-months-figures in Jena.

The Group’s growing positioning on global markets is reflected in the rise in international sales in the reporting period. In total, goods were exported for EUR 45.0 m (previous year: EUR 38.9 m). This corresponds to well over two thirds of total sales or an export rate of 70.6 % as against 65.3 % in the the previous year.

The core segment of Analytical Instrumentation again benefited from its strong market positioning in Asia and increased its sales as forecast. The division generated sales of EUR 40.1 m (previous year: EUR 35.9 m) or a sales increase of 11.9 %. In the Life Science segment the Group generated sales of EUR 20.0 m (previous year: EUR 20.3 m) and 1.5 % less income than in the same period of the previous year. This development is primarily due to the fact that the sales forecast were postponed to the fourth quarter of 2010/2011. The Optics division contributed EUR 3.5 m (previous year: EUR 3.4 m) to total consolidated sales after nine months.

Up 5.9 % year-on-year, the Group’s operating earnings development was solid. EBIT therefore amounted to EUR 3.4 m after the first nine months (previous year: EUR 3.2 m) with an EBIT margin of 5.4 %. EBITDA rose by 6.4 % to EUR 6.2 m (previous year: EUR 5.9 m). After the financial result had benefited from the favorable currency situation for Analytik Jena in the wake of rising financial income in the previous year, developments in foreign currencies, particularly the Japanese yen and the USD, had a negative effect this year due to higher financial expenses combined with lower financial income as against the same period of the previous year. Furthermore, earnings were significantly influenced by the measurement of derivatives compared to the previous year.

In the reporting period, Analytik Jena achieved a total net profit of EUR 0.6 m (previous year: EUR 2.5 m), 76.9 % less than in the previous year. This is equal to earnings per share of EUR 0.09 (previous year: EUR 0.47).

The Group’s total assets fell slightly by 3.2 % from EUR 83.6 m (September 30, 2010) to EUR 80.9 m as of June 30, 2011. In the reporting period, Analytik Jena reported equity of EUR 39.6 m (September 30, 2010: EUR 39.0 m). This corresponds to an equity ratio of 48.9 % (September 30, 2010: 46.7 %).
The Group’s cash and cash equivalents amounted to EUR 3.4 m as of the end of the reporting period.

As of June 30, 2011, the Group employed 803 staff, including 36 trainees (previous year: 780 employees, including 44 trainees).

Analytik Jena AG is retaining its forecasts for the 2010/2011 financial year and, in particular, is anticipating an increase in earnings in the fourth quarter, bringing it to its stated target for the year as a whole. The end of the financial year will be considerably influenced by the business recovery in Japan. All signals indicate that Analytik Jena on the basis of good incoming orders can significantly increase its sales as well. In the core business of Analytical Instrumentation the Company assumes a stable sales development. Specifically in the Life Science segment, the Company is forecasting a sound sales increase in the fourth quarter. The Optics consumer division will continue to recover until the end of the period.

"In light of the good sales and earnings development in the third quarter and on the basis of the continuing good incoming orders, we are assuming of achieving our demanding operating earnings target of EUR 4.5 m as of September 30, 2011", says Klaus Berka, CEO of Analytik Jena AG. "The biggest present risk for the Company is in currency effects. Regardless of this, we are predicting that the Company will enjoy a stable, positive performance overall in its last and, traditionally, strongest quarter. We are retaining our forecasts for the financial year."

 

Scientists copy the ways viruses deliver genes

Scientists at the National Physical Laboratory (NPL) have mimicked the ways viruses infect human cells and deliver their genetic material. The research hopes to apply the approach to gene therapy – a therapeutic strategy to correct defective genes such as those that cause cancer.

Gene therapy is still in its infancy, with obvious challenges around targeting damaged cells and creating corrective genes. An equally important challenge, addressed by this research, is finding ways to transport the corrective genes into the cell. This is a problem, because of the poor permeability of cell membranes.

This research describes a model peptide sequence, dubbed GeT (gene transporter), which wraps around genes, transports them through cell membranes and helps their escape from intracellular degradation traps. The process mimics the mechanisms viruses use to infect human cells.

GeT was designed to undergo differential membrane-induced folding - a process whereby the peptide changes its structure in response to only one type of membranes. This enables the peptide, and viruses, to carry genes into the cell. Interestingly, the property also makes it antibacterial and so capable of gene transfer even in bacteria-challenged environments.

To prove the concept, the researchers used GeT to transfer a synthetic gene encoding for a green fluorescent protein – a protein whose fluorescence in cells can be seen and monitored using fluorescence microscopy.

The design can serve as a potential template for non-viral delivery systems and specialist treatments of genetic disorders.

This research, performed at NPL, is a part of the NPL-led international research project 'Multiscale measurements in biophysical systems', which is jointly funded by NPL and the Scottish Universities Physics Alliance.

More information: The team's article GeT peptides: a single domain approach to gene delivery, detailing this research has just been published in Chem. Commun: http://pubs.rsc.or … C/c1cc13043a

Provided by National Physical Laboratory

Researchers improve performance of iron-based catalysts

Having pioneered the development of the first high-performance iron-based catalyst for fuel cells, researchers at INRS recently achieved a second major advance. They developed a new and improved iron-based catalyst capable of generating even more electric power in fuel cells for transportation applications. Previously, only platinum-based catalysts could produce similar performance.

The new research findings from the team of Professor Jean-Pol Dodelet were published in Nature Communications, a prestigious scientific journal part of the Nature Publishing Group. With these new and promising results, we bolster the prospect of iron-based catalysts replacing platinum ones in the electrochemical reduction of oxygen, one of two reactions needed to activate the electric power generator we call a fuel cell. Platinum is rare and very costly, whereas iron is the second most abundant metal on earth and is inexpensive.

"Thanks to this breakthrough we are nearing the day when we will be able to drive electric-electric hybrid vehicles —i.e. battery and fuel cell powered—, which can potentially free us from our current dependence on oil to power our cars," said Professor Dodelet.

Working at the Énergie Matériaux Télécommunications Research Centre in Varennes (Québec), INRS scientists are now focusing on the improvement of the long-term stability (at least 5,000 hours) of these promising new catalysts. "The next step is the most important because it will automatically lead to a high value commercial product, not only for car manufacturers but also for all industrial sectors that use electric power generators or manufacture their components," explained Mr. Dodelet.

Provided by INRS

Steering a beam of 'virtual particles' to manipulate ultra-small-scale particles in real time

The steady improvement in speed and power of modern electronics may soon hit the brakes unless new ways are found to pack more structures into microscopic spaces. Unfortunately, engineers are already approaching the limit of what light -- the choice tool for "tweezing" tiny features -- can achieve. But there may be a way of reaching beyond this so-called "diffraction limit" by precisely steering, in real time, a curve-shaped beam of weird "virtual particles" known as surface plasmons.

This technique, described in the Optical Society's (OSA) journal Optics Letters, opens the possibility of even smaller, faster communications systems and optoelectronic devices. Examples of optoelectronic devices used today include photodiodes such as solar cells, integrated optical circuits used in communications, and charged coupled imaging devices at the heart of cell phone cameras and receivers on the world's most advanced telescopes. This method also may yield new, important tools for research in chemistry, biology, and medicine.

The key to this innovation is the ability -- for the first time -- to actively manipulate a blended stream of light and plasma, known as a plasmonic Airy beam. The beam, owing to the laws of electromagnetism, travels, not in a straight line like the beams of light to which we are accustomed, but rather in an arc. "It's an odd thing for sure, as light is supposed to travel in a straight line," says Peng Zhang a member of the research team with the National Science Foundation (NSF) Nanoscale Science and Engineering Center of the University of California, Berkeley and Department of Physics and Astronomy at San Francisco State University (SFSU). "That's why people are so crazy about these kinds of interesting beams."

As the beam first strikes a metal surface (typically at an irregular feature called a grating structure), it stirs up small waves of electrons at the metal-insulator interface. These waves, which can be thought of as "virtual particles" known as surface plasmon polaritons (SPPs), then follow the curved trajectory of the Airy beams. And, just as ocean waves move objects on the surface of the water, the SPPs can be directed to manipulate ultrafine-scale features on the surface of a metal.

SPPs are already essential elements in the design and manufacture of optoelectronic devices. The reason they're so critical is that they can affect extremely small-scale objects, smaller than the diffraction limit, or half of the wavelength of light used to create SPPs.

The current systems, however, have a significant drawback: they required fixed, permanent nanostructures to direct the SPPs. This lack of flexibility severely limits their uses in nano-system design and manufacture. But by being able to manipulate the Airy beam, and therefore the SPPs, in real time, the new design gives scientists on-the-fly control.

"We have demonstrated a new way of routing the flow of surface plasmons without any guiding structures," says Xiang Zhang, who led this research and is the director of the NSF Nanoscale Science and Engineering Center at Berkeley and a faculty scientist with the Materials Sciences Division of the Lawrence Berkeley National Laboratory.

The lack of guiding structures, according to Xiang Zhang, is the critical innovation in their design. Currently, to manipulate surface plasmons over two-dimensional metal surfaces, different elements such as waveguides, lenses, beam splitters, and reflectors need to be created. This is done by either structuring metal surfaces (fabricating some permanent nanostructures) or placing insulators on metals. These permanent guiding structures cannot be reconfigured; once the structure is fabricated it cannot be changed in real time.

By using computer-controlled optics, however, the research team has developed a way to steer and manipulate the beams, precisely directing their trajectories to specific spots on an optical surface and adjusting them as needed. Due to their unique arc-shaped paths, the beams have the added ability to bypass surface roughness and defects, or even vault over obstacles.

"These on-the-fly adjustments are extremely desirable," says Zhigang Chen, a principal investigator with the Department of Physics and Astronomy at SFSU. "They enable reconfigurable optical interconnections in ultra-compact integrated photonic circuits, which are at the core of many high-speed computing technologies. They also would enable on-chip nanoparticle manipulations for chemical, medical, or biological research purposes."

The Airy beams used to direct the flow of plasmons also remain coherent, not fanning out or distorting as they travel along their curved trajectories, much in the same way that laser light remains coherent even after traveling great distances.

To create the Airy beams, the researchers used a laser beam and modulated its phase, or wave front, with a spatial light modulator (a device similar to a miniature liquid crystal display) controlled by a personal computer. By continuously changing the specially designed patterns in the computer, they were able to dynamically control the trajectories of the beam in real time.

"These results point out a new direction for dynamically routing surface energies without any permanent guiding structures," says Peng Zhang, "which could inspire researchers from different areas to develop new technologies or tools for a variety of applications." For example, in nano-photonics, researchers may design practical reconfigurable plasmonic devices for ultra-compact integrated photonic circuits. In biology and chemistry, researchers may establish new tools for dynamically manipulating nanoparticles or molecules, and improving the performance of sensors.

"The ultrafine wavelength nature of surface plasmons makes them a promising tool for future nanolithography or nanoimaging applications," says research team member Sheng Wang, also of the NSF Nanoscale Science and Engineering Center. "Now, with the dynamic tunable plasmonic Airy beams, researchers may also shed new light on ultrahigh resolution bioimaging. For example, by bypassing obstacles and directly shining a beam on a target sample, background noise can be greatly reduced, which would enable more accurate imaging."

"This method may also encourage researchers in other fields to manipulate the surface waves in other low-dimensional systems, including graphenes, topological insulators, and magnetic thin films," says fellow team member Yongmin Liu of the NSF Nanoscale Science and Engineering Center.

This research was supported by the U.S. Army Research Office, the Air Force Office of Scientific Research, and the National Science Foundation.

Story Source:

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

Journal Reference:

Peng Zhang, Sheng Wang, Yongmin Liu, Xiaobo Yin, Changgui Lu, Zhigang Chen, Xiang Zhang. Plasmonic Airy beams with dynamically controlled trajectories. Optics Letters, 2011; 36 (16): 3191 DOI: 10.1364/OL.36.003191

Study builds on plausible scenario for origin of life on Earth

A relatively simple combination of naturally occurring sugars and amino acids offers a plausible route to the building blocks of life, according to a paper published in Nature Chemistry co-authored by a professor at the University of California, Merced.

The study, "A Route to Enantiopure RNA Precursors from Nearly Racemic Starting Materials," shows how the precursors to RNA could have formed on Earth before any life existed. It was authored by Jason E. Hein, Eric Tse and Donna G. Blackmond, a team of researchers with the Scripps Research Institute. Hein is now a chemistry professor with UC Merced. The paper was published online Sunday.

Biological molecules, such as RNA and proteins, can exist in either a natural or unnatural form, called enantiomers. By studying the chemical reactions carefully, the research team found that it was possible to generate only the natural form of the necessary RNA precursors by including simple amino acids.

"These amino acids changed how the reactions work and allowed only the naturally occurring RNA precursors to be generated in a stable form," said Hein. "In the end, we showed that an amazingly simple result emerged from some very complex and interconnected chemistry."

The natural enantiomer of the RNA precursor molecules formed a crystal structure visible to the naked eye. The crystals are stable and avoid normal chemical breakdown. They can exist until the conditions are right for them to change into RNA.

More information: DOI: 10.1038/NCHEM.110

Provided by University of California - Merced

Genetically engineered spider silk for gene therapy

 Genetically engineered spider silk could help overcome a major barrier to the use of gene therapy in everyday medicine, according to a new study that reported development and successful initial laboratory tests of such a material. It appears in ACS' journal Bioconjugate Chemistry.

David Kaplan and colleagues note that gene therapy — the use of beneficial genes to prevent or treat disease — requires safe and efficient carriers or "vectors." Those carriers are the counterparts to pills and capsules, transporting therapeutic genes into cells in the body. Safety and other concerns surround the experimental use of viruses to insert genes. The lack of good gene delivery systems is a main reason why there are no FDA-approved gene therapies, despite almost 1,500 clinical trials since 1989. The new study focused on one promising prospect, silk proteins, which are biocompatible and have been used in everyday medicine and medical research for decades.

The scientists describe modifying spider silk proteins so that they attach to diseased cells and not healthy cells. They also engineered the spider silk to contain a gene that codes for the protein that makes fireflies glow in order to provide a visual signal (seen using special equipment) that the gene has reached its intended target. In lab studies using mice containing human breast cancer cells, the spider-silk proteins attached to the cancer cells and injected the DNA material into the cells without harming the mice. The results suggest that the genetically-engineered spider-silk proteins represent "a versatile and useful new platform polymer for nonviral gene delivery," the article notes.

More information: “Spider Silk-Based Gene Carriers for Tumor Cell-Specific Delivery” Bioconjugate Chem., Article ASAP. DOI: 10.1021/bc200170u

Abstract
The present study demonstrates pDNA complexes of recombinant silk proteins containing poly(l-lysine) and tumor-homing peptides (THPs), which are globular and approximately 150–250 nm in diameter, show significant enhancement of target specificity to tumor cells by additions of F3 and CGKRK THPs. We report herein the preparation and study of novel nanoscale silk-based ionic complexes containing pDNA able to home specifically to tumor cells. Particular focus was on how the THP, F3 (KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK), and CGKRK, enhanced transfection specificity to tumor cells. Genetically engineered silk proteins containing both poly(l-lysine) domains to interact with pDNA and the THP to bind to specific tumor cells for target-specific pDNA delivery were prepared using Escherichia coli, followed by in vitro and in vivo transfection experiments into MDA-MB-435 melanoma cells and highly metastatic human breast tumor MDA-MB-231 cells. Non-tumorigenic MCF-10A breast epithelial cells were used as a control cell line for in vitro tumor-specific delivery studies. These results demonstrate that combination of the bioengineered silk delivery systems and THP can serve as a versatile and useful new platform for nonviral gene delivery.

Provided by American Chemical Society (news : web)

Student brings home new expertise to answer question in antibiotic resistance

Working out the structure of a complex formed when a protein binds to DNA has proved to be key in understanding how an antibiotic-producing organism controls resistance to its own antibiotic, and may be an example of how other antibiotic producers regulate export to prevent self-toxicity.

The natural production of antibiotics by certain microorganisms is a complex and highly regulated process, not least because the organism making these compounds must protect itself from their toxic effects. Researchers at the John Innes Centre, which is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), have been studying the production of simocyclinone, produced by Streptomyces antibioticus, and in particular how the production of this potent antibiotic triggers an efficient pumping mechanism that exports the antibiotic from the cell.

Much of the work elucidating this protection mechanism has been carried out by Tung Le, a Vietnamese PhD student enrolled in the JIC's four-year rotation PhD programme. Tung, working under the supervision of Mark Buttner and David Lawson, showed that SimR, the protein Streptomyces antibioticus uses to regulate antibiotic export, can bind either to DNA or to the antibiotic itself, but crucially cannot bind to both. This means that when the antibiotic is around, SimR releases the DNA, which allows the expression of a gene that encodes a pump responsible for removing simocyclinone from the cell.

"This provides a mechanism that couples the potentially lethal biosynthesis of the antibiotic to its export, which has wider implications for resistance to clinically important antibiotics," commented Prof. Buttner. "However, we needed to know more detail about the interaction between SimR and DNA."

In this latest research, published in the journal Nucleic Acids Research, they show that the SimR protein has a novel 'arm' and that cutting off this arm unexpectedly weakened SimR binding to DNA. To determine the function of this arm, the researchers needed to work out the crystal structure of the protein bound to DNA, something which hadn't been achieved in Norwich before.

To overcome this skills gap, Tung won both a Korner Travelling Fellowship and an EMBO Short-Term Travel Fellowship to visit the University of Texas M.D. Anderson Cancer Center, home to one of the leading laboratories specialising in this technique. Tung spent three months working in the labs of Richard Brennan and Maria Schumacher, learning how to solve the structures of protein-DNA complexes. He was then able to apply this to his own project.

"I learned a lot and it was a great experience," said Tung. "The knowledge I brought back was not only useful for my project but will also be beneficial for others, and I feel very proud about that."

Usually, the SimR arm is unstructured, but in the presence of DNA they saw that it becomes ordered and binds into the minor groove of the DNA molecule. The crystal structure also shows how other parts of the SimR protein form sequence-specific interactions with a binding site in front of the export pump gene.

SimR is a member of a large family of regulatory proteins found in bacteria, and is the fifth one to have its structure solved when bound to DNA. The way these proteins recognise their target DNA sequences differs. This new example has wider implications, as a bioinformatic search of this family of regulators showed that many of them also have arms similar to the one characterised in this study.

Tung submitted his PhD thesis in early August, and his research has already produced four first-author papers. He is due to take up a post-doctoral position at the Massachusetts Institute of Technology in January.

"It can be very difficult for non-EU students to find the funding to study for a PhD in the UK, and so I was delighted to be offered a place on the JIC rotation programme. I am keen to encourage and help build relations between JIC and Vietnam. I was very happy to see the JIC is involved in joint work with Vietnam to sequence the genomes of different varieties of rice" said Tung, who left Vietnam at the age of seventeen for a bioscience career in the UK.

The researchers have also recently received a grant from the BBSRC to continue investigating the complexities of the regulation of antibiotic biosynthetic pathways, focussing on SimR and two other antibiotic-responsive transcription factors encoded in the simocyclinone biosynthetic cluster. This will establish the roles that the antibiotic plays in regulating self-resistance and its own biosynthesis. With the ever-growing problem of resistance, this kind of fundamental research is vital.

Provided by Norwich BioScience Institutes

Flexibility: The key to carbon capture

From power plants that capture their own carbon dioxide emissions to vehicles powered by hydrogen, clean energy applications often demand materials that can selectively adsorb large volumes of harmful gases. Materials known as porous coordination polymers (PCPs) have great gas-trapping potential, and now their adsorptive properties can be boosted using a new technique developed by a research team in Japan.

The key to the development is making PCPs that can flex, since it allows the team to tune the gas-adsorbing properties of these materials—whether it is to improve the ability to selectively adsorb one gas from a mixture or to fine-tune the pressure at which the gas is captured and released. 

While structural flexibility in PCPs is not new, team member Ryotaro Matsuda from the RIKEN SPring-8 Center, Harima, explains that he and his colleagues successfully incorporated this flexibility into a PCP built from molecular components known as secondary building units (SBUs). At the molecular scale, PCPs consist of vast networks of tiny interlinked cages, inside which gas molecules can sit. SBUs are made from clusters of metal atoms that can be used to form the corner of each cage. Their use gives materials scientists great control over the structure of a cage, but they can also lock the structure.

Matsuda and colleagues overcame the rigidity problem by connecting the cage corners into cubes using long, slim carbon-based linkers. In the absence of carbon dioxide, these slender linkers allow the cage framework to collapse into a non-porous solid; but in the presence of a gas, the material expands—a behavior known as gate-opening adsorption (Fig. 1). 

It is a behavior that could prove useful, Matsuda explains. “Gate-opening-type adsorption, which is induced by the structural transformations from a non-porous structure to a porous structure at a certain pressure of gas, would provide a way to enhance the efficiency of pressure swing adsorption,” he says. Pressure-swing adsorption is being investigated as a way to capture carbon dioxide emissions from power plants. The concept relies on finding materials that will release the gas in response to a drop in pressure, so that it can be piped away for long-term, underground storage.

The researchers are now looking to improve the performance of their material. “We are currently trying to tune the soft porosity of the prototype PCP to separate mixtures of gases,” says Matsuda. “We have also been working to reveal the relationship between the structure, adsorption property and separation ability of [other] PCPs.”

More information: Seo, J. et al. Soft secondary building unit: dynamic bond rearrangement on multinuclear core of porous coordination polymers in gas media. Journal of the American Chemical Society 133, 9005–9013 (2011).

Provided by RIKEN (news : web)

Deep recycling in the Earth faster than thought

 The recycling of the Earth's crust in volcanoes happens much faster than scientists have previously assumed. Rock of the oceanic crust, which sinks deep into the earth due to the movement of tectonic plates, reemerges through volcanic eruptions after around 500 million years. Researchers from the Max Planck Institute for Chemistry in Mainz obtained this result using volcanic rock samples. Previously, geologists thought this process would take about two billion years.

Virtually all of the ocean islands are volcanoes. Several of them, such as Hawaii, originate from the lowest part of the mantle. This geological process is similar to the movement of coloured liquids in a lava lamp: hot rock rises in cylindrical columns, the so-called mantle plumes, from a depth of nearly 3,000 kilometers. Near the surface, it melts, because the pressure is reduced, and forms volcanoes. The plume originates from former ocean crust which early in the Earth's history sank to the bottom of the mantle. Previously, scientists had assumed that this recycling took about two billion years.

The chemical analysis of tiny glassy inclusions in olivine crystals from basaltic lava on Mauna Loa volcano in Hawaii has now surprised geologists: the entire recycling process requires at most half a billion years, four times faster than previously thought.

The microscopically small inclusions in the volcanic rock contain trace elements originally dissolved in seawater, and this allows the recycling process to be dated. Before the old ocean crust sinks into the mantle, it soaks up seawater, which leaves tell-tale trace elements in the rock. The age is revealed by the isotopic ratio of strontium which changes with time. Strontium is a chemical element, which occurs in trace amounts in sea water. The isotopes of chemical elements have the same number of protons but different numbers of neutrons. Mainz scientists developed a special laser mass spectrometry method which allowed the detection of isotopes of strontium in extremely small quantities.

To their surprise, the Max Planck researchers found residues of sea water with an unexpected strontium isotope ratio in the samples, which suggested an age of less than 500 million years for the inclusions. Therefore the rock material forming the Hawaiian basalts must be younger.

"Apparently strontium from sea water has reached deep in the Earth's mantle, and reemerged after only half a billion years, in Hawaiian volcano lavas," says Klaus Peter Jochum, co-author of the publication. "This discovery was a huge surprise for us."

Another surprise for the scientists was the tremendous variation of strontium isotope ratios found in the melt inclusions in olivine from the single lava sample. “This variation is much larger than the known range for all Hawaiian lavas”, says Alexander Sobolev. “This finding suggests that the mantle is far more chemically heterogeneous on a small spatial scale than we thought before.” This heterogeneity is preserved only by melt inclusions but is completely obliterated in the lavas because of their complete mixing.

Sobolev, Jochum and their colleagues expect to obtain similar results for other volcanoes and therefore be able to determine the recycling age the ocean crust more precisely.

Original publication:
Alexander V. Sobolev, Albrecht W. Hofmann, Klaus Peter Jochum, Dmitry V. Kuzmin & Brigitte Stoll; A young source for the Hawaiian plume; Nature, 10. August 2011

Light unlocks fragrance in laboratory

In Anna Gudmundsdottir's laboratory at the University of Cincinnati, dedicated researchers endeavor to tame the extremely reactive chemicals known as radicals.

Highly reactive radicals are atoms, molecules or ions frantically trying to become something else. Their lifetimes are measured in fractions of seconds and typically occur in the middle of a chain of chemical reactions. They are also known as reactive intermediates. Much of Gudmundsdottir's work has focused on a family of radicals known as triplet nitrenes.

"Triplet nitrenes are reactive intermediates with high spin," Gudmundsdottir said. "You have a nitrogen molecule that has two unpaired electrons on it. We discovered they were actually very stable for intermediates. They live for milliseconds and that's when we got into this idea can we make them stable enough for various investigations."

The potential uses of relatively stable radicals have excited interest from industry. The high spin Gudmundsdottir describes suggests that triplet nitrenes, for example, might be ideal candidates for creating organic magnets that are lighter, more flexible and energy-intensive than conventional metal or ceramic magnets. Gudmundsdottir's research suggests that radicals, including triplet nitrenes, may show a pathway to materials with many magnetic, electrical and optical properties.

"I talk a lot about radicals," Gudmundsdottir said. "Nitrenes are radicals. We study the excited state of the precursors to the nitrenes. We are looking at how you use the excited state of molecules to form specific radicals."

One line of inquiry, presented by Gudmundsdottir to a recent Gordon Research Conference, described how her team used radicals to create a specific trap for a fragrance, which is then slowly released when exposed to light.

"The question was, can you actually tether a fragrance to something so that it will release slowly?" Gudmundsdottir said. "It turned out that a precursor similar to the ones we used to form the nitrenes could be used it as a photoremovable protecting group."

The "photoprotectant" acts as a sort of cap, containing the fragrance until the cap is pried off by a photon of light. For this particular purpose, Gudmundsdottir said it was important to design a photoprotectant "cap" that was somewhat difficult to pry off. For household products, such as a scented cleaning fluid, consumers want fragrance to be released slowly over a long period of time. That requires what is known as a low "quantum yield." In other words, how much fragrance gets released by how many photons.

The difficulty, Gudmundsdottir said, is that different applications need different rates of release. For medical uses, doctors might want a higher quantum yield, by which a little bit of light releases a lot of medicine.

"There are all kinds of applications for photoreactions," she said, "from household goods, perfumes, sun-protection, drug delivery and a variety of biologically reactive molecules. So we just decided, OK, we are very fundamental chemists, we'll design different systems and see if we can manipulate the rate of release."

Gudmundsdottir's research group studies the release mechanism, locates where there are limitations, and tries to determine what controls the rate. They also consider environmental factors, including how the delivery systems react with oxygen.

"We do very fundamental work to get the knowledge here before can take it into specific directions," she said. "If we don't understand it, we can't design where to take it next."

Much of this understanding develops from watching how radicals form and decay. Gudmundsdottir's group uses a laser flash photolysis system to fire a laser into a sample and to track the spectrum of radiated light as the radicals decay.

"What I like about transient spectroscopy is actually seeing the intermediates we work with on nanosecond, microsecond and millisecond timescales," she said.

The team also uses computer modeling, but the chemical operations of these short-lived and rapidly reacting chemicals are difficult to model, so Gudmundsdottir has tapped into the resources of the Ohio Supercomputer Center.

"Calculating excited states takes up quite a bit of computer resources and that's why we use the supercomputer," she said. "That's a really nice resource to have available. I can sit anywhere or my students can sit anywhere and we can do the calculations to model reactions."

Gudmundsdottir said the questions raised by applications leads to helpful fundamental questions that can be tackled through basic research.

"Going forward, we probably want to do more applied study with our photo protective groups, to collaborate with someone to see them in some other applications," she said. "I'm interested in how they act inside cells."

Provided by University of Cincinnati (news : web)

Clustering is key to lighting up the dark proteome

Enlarge

Most mass spectrometry studies attempt to identify Peptide-Spectrum Matches (PSMs) and often ignore Spectrum-Spectrum Matches (SSMs), especially if PSMs for these SSMs are not established. However, SSMs also are useful when the corresponding peptide is not identified, because they allow a researcher to cross-reference spectra generated by different researchers and to query all spectra ever generated against a single repository. Spectral libraries are essentially databases of PSMs, while spectral archives are databases of both PSMs and SSMs. Although construction of PSMs (via tandem mass spectrometry database search) is a well-studied topic, construction of all SSMs represents a formidable clustering problem. The figure reveals similarities and highlights differences between construction (left) and use (right) of spectral libraries and spectral archives. With an archive, researchers first cluster, then search the clusters against a protein database to generate Peptide-Cluster Matches (PCMs). In turn, these PCMs get propagated to all spectra in the identified clusters to generate PSMs. With the library, researchers first search the spectra against a protein database to generate PSMs, group PSMs corresponding to the same peptide, and finally deposit the curated consensus PSM in the spectral library. Then, the spectral library can be used to identify spectra from new spectral datasets.

A new approach that organizes previously unused mass spectra from proteomics studies gives scientists the ability to use these spectra to gain more information about proteins in a wide range of organisms. Scientists from the University of California-San Diego and Pacific Northwest National Laboratory have created a vast spectral archive from more than a billion mass spectra acquired at PNNL between 2001 and 2009. They describe their approach in the July issue of Nature Methods.

In recent years, the volume of tandem mass spectrometry data generated from proteomics experiments has increased dramatically. Multiple, nearly identical mass spectra of the same peptides are routinely measured by various laboratories. Scientists compare the spectra with peptides residing in a database of known protein sequences. They then evaluate the resulting matches using various scoring methods to assign an identity to the peptide spectrum. Large sets of spectra can be organized into spectral libraries where other spectra can be brought for comparison, leading to increasing effectiveness in peptide assignments used for protein identifications.

But what about those spectra not identified; that is, those not associated with a known peptide? Typically, unidentified spectra are ignored or discarded, as they have limited value to the researchers because the protein is unidentified. As a result, a significant fraction of the proteins remain unidentified, constituting an effective "dark proteome" of unknown content.

Shedding light on the dark proteome is where the UCSD/PNNL team comes in. While spectral libraries discard unidentified spectra, spectral archives use all mass spectra—identified or unidentified-as clusters (see "Spectral Archives Complement Spectral Libraries"). The scientists not only showed the feasibility of constructing large archives and their basic utility for run-of-the-mill peptide identification, they developed new applications now possible because a diverse collection of datasets can be analyzed as a whole.

"We believe that spectral archives could change the nature of proteomics by motivating researchers who are analyzing seemingly unrelated data to share this data," said senior author Dr. Pavel Pevzner, UCSD. "Doing so improves the quality of the interpretations of both of their spectral datasets."

With archives, a researcher can identify clusters of spectra from different organisms. Besides indicating that such spectra are interesting—as they are likely to indicate proteins occurring over multiple species—this fact can be used to reduce the effective protein database size, leading to new, confident peptide and protein identifications. The team also showed that short peptides (shorter than 7 amino acids) could be confidently identified, which is much more difficult with typically used approaches.

The PNNL mass spectra data used by the team included samples taken from a diverse set of more than 100 organisms, including humans, the common house mouse, and the metal-reducing bacterium Shewanella oneidensis. The research team developed a clustering tool, MS-Cluster, that generated a spectral archive from the ~1.18 billion spectra from PNNL. This archive greatly exceeds the size of existing spectral repositories.

To evaluate whether spectral archives can increase peptide identifications, the researchers selected a subset of 14.5 million spectra from the microorganism S. oneidensis and constructed an archive with them. They did this by breaking the dataset into five sets of ~2.9 million spectra then incrementally adding each set of spectra to the archive. At each stage they compared the number of protein and unique peptide identifications made by searching the clusters in the archive with the number that could be obtained with conventional database search approaches.

The archive consistently yielded more unique peptide and protein identifications. With the archive, the scientists also were able to identify many more spectra through their cluster membership. At different stages, they identified 50-75% more spectra through cluster membership than via a regular database search.

This study also highlights the large number of spectra for which peptide and protein identifications are not achieved, opening the door for use of experimental and computational approaches to identify the significant numbers of peptides effectively ignored by proteomics studies to date.

More information: Frank AM, et al. 2011. "Spectral archives: extending spectral libraries to analyze both identified and unidentified spectra." Nature Methods 8(7):587-591. DOI:10.1038/nmeth.1609

Provided by Pacific Northwest National Laboratory (news : web)

Eastman Acquires Dynaloy, LLC

: Eastman Chemical Company announced that one of its wholly owned subsidiaries has acquired from E&A Industries, Inc., the assets of Dynaloy, LLC, a specialty chemical business based in Indianapolis, Indiana. This acquisition, which includes Dynaloy’s inventory, equipment, intellectual property, and customer contracts, supports Eastman’s growth efforts for the electronic materials product line of its Coatings, Adhesives, Specialty Polymers and Inks (CASPI) segment. 

Dynaloy manufactures and sells advanced cleaning solutions for multiple applications on a global basis, with particular focus on the semiconductor industry. The business will remain headquartered in Indianapolis.

“Dynaloy brings a strong market connect along with material science capabilities that are complementary to our own,” said Scott Ballard, industry director, Electronic Materials. “As we continue to develop and grow Eastman’s presence in electronic materials, the expertise and reliability that Dynaloy customers have come to expect will be a great asset to our overall growth strategy.”

 

BASF with strong first half 2011

In the first half of 2011 – the International Year of Chemistry – BASF’s business remained dynamic. The previous year’s excellent results were exceeded. “The economic environment in the first half of 2011 was favorable for our business. Our numbers show that we successfully took advantage of this momentum,” said Dr. Kurt Bock, Chairman of the Board of Executive Directors of BASF SE at the presentation of BASF’s results in Ludwigshafen.

Following a strong start to the year, BASF had a good and very solid second quarter. Sales improved by 13.9% to €18.5 billion and income from operations (EBIT) before special items by 1.4% to €2.2 billion despite the suspension of oil production in Libya. In the second quarter of 2010, the Libyan activities contributed an EBIT before special items of €280 million. On a comparable basis, EBIT before special items thus increased by 16%.

Compared with the extraordinary growth in the first quarter, the growth rates have normalized in the second quarter as expected. In addition, for the first time since the first quarter of 2010 currency effects were negative (minus 6%) due to the weak U.S. dollar. The inclusion of the Cognis businesses made a positive contribution to sales. In the chemicals business, sales volumes increased 5%. Due to the suspension of oil production in Libya, the contribution to earnings before taxes from Oil & Gas was lower compared with the same quarter of the previous year.

For the first half of 2011, sales were €37.8 billion, an increase of 19.4% compared with the same period of the previous year. EBIT before special items rose by 19.4% to around €5 billion.

BASF continues to view the economic outlook as positive for the second half of the year, but expects growth to be less dynamic, as could be observed towards the end of the second quarter. Bock said: “The economic risks remain: We continue to be concerned about the development of the euro as well as the debt situation in some European countries and the United States. Added to this is the persistently high oil price, which is having a negative impact on margins across our value chains and is leading to some customers being more cautious in their orders.”

Price increases were necessary in several business areas and will continue to be necessary in the future. Domestic tensions – particularly in North Africa – continue to unsettle the markets. As announced at the beginning of May, due to the ongoing hostilities in Libya, BASF does not anticipate being able to resume oil production there in 2011.

In the chemical sector, the company anticipates worldwide growth in chemical production of 5% to 6%, which can differ considerably from region to region. However, BASF wants to grow faster than the market in all regions. For the full year 2011, BASF estimates an average exchange rate of $1.40 per euro. Due to the persistently high and further rise in the price of oil, the company’s forecast for the annual average price of Brent crude is being raised by $10 to $110 per barrel.

Bock said: “Based on the positive business growth in the first half, we remain confident for 2011. Despite the reduction in oil production, we expect significant sales growth for the BASF Group in 2011. Adjusted for non-compensable income taxes on oil-producing operations, we continue to aim to significantly exceed the record 2010 level in EBIT before special items. We expect to once again earn a high premium on our cost of capital in 2011.”

In the Chemicals segment, sales were significantly higher than in the second quarter of 2010. Sales prices increased in all divisions, particularly in the Petrochemicals division. EBIT before special items was impacted by scheduled and unscheduled plant shutdowns and almost reached the level of the previous year.

In the Plastics segment, sales volumes were higher in both divisions. Increased prices also contributed to sales growth. EBIT before special items improved thanks to higher volumes and margins.

The Performance Products segment posted a strong increase in sales thanks largely to a considerable contribution from the acquired Cognis businesses. They also contributed to the increase in EBIT before special items.

All divisions contributed to the strong growth in sales in the Functional Solutions segment. EBIT before special items rose slightly compared with the same quarter of 2010. This was due primarily to the volume-related strong contribution from the Catalysts division.

In the Agricultural Solutions segment, sales volumes increased. With stable prices, sales were at the same level as in the second quarter of 2010 due to the weak U.S. dollar. EBIT before special items slightly improved.

Sales in the Oil & Gas segment rose slightly compared with the second quarter of 2010, thanks to higher crude oil and natural gas prices. Due to the suspension of oil production in Libya at the end of February 2011, production volumes decreased. Therefore, EBIT before special items did not reach the level of the second quarter of 2010. However, net income improved substantially.

BASF’s business in the first half of 2011 was positive in all regions. Growth in sales and earnings was partially double-digit.

Sales and earnings in Europe rose significantly. The Performance Products segment made a strong contribution to this growth. In the Chemicals segment, higher raw materials costs were passed on to the market. Sales also grew substantially in the Plastics segment thanks to good demand from the automotive industry.

In North America, sales also increased. The inclusion of the Cognis businesses considerably bolstered sales growth in the Performance Products segment. The chemicals business developed successfully overall. In the Agricultural Solutions segment, sales declined in particular as a result of the weaker U.S. dollar and difficult weather conditions. Earnings were above the level of the first half of 2010.

Sales in Asia Pacific rose thanks to good demand. The Cognis businesses and price increases due to higher raw materials costs, especially in the Petrochemicals, Performance Polymers and Catalysts divisions, contributed to this growth. Earnings improved substantially in particular due to good margins in the Performance Products segment.

In South America, Africa, Middle East sales and earnings increased significantly. The inclusion of the Cognis businesses made a significant contribution to the sales growth. The successful business with crop protection products contributed to the substantial increase in earnings.

 

Phone losing charge? Novel technology allows LCDs to recycle energy

We've all worried about the charge on our smartphone or laptop running down when we have no access to an electrical outlet. But new technology developed by researchers at the UCLA Henry Samueli School of Engineering and Applied Science could finally help solve the problem.

The UCLA engineers have created a novel concept for harvesting and recycling energy for electronic devices — one that involves equipping these devices' LCD screens with built-in photovoltaic polarizers, allowing them to convert ambient light, sunlight and their own backlight into electricity.

LCDs, or liquid crystal displays, are used in many of today's electronic devices, including smartphones, TV screens, computer monitors, laptops and tablet computers. They work by using two polarized sheets that let only a certain amount of a device's backlight pass through. Tiny liquid crystal molecules are sandwiched between the two polarizers, and these crystals can be switched by tiny transistors to act as light valves. Manipulating each light valve, or pixel, lets a certain amount of the backlight escape; millions of pixels are combined to create images on LCDs.

The UCLA Engineering team created a new type of energy-harvesting polarizer for LCDs called a polarizing organic photovoltaic, which can potentially boost the function of an LCD by working simultaneously as a polarizer, a photovoltaic device and an ambient light or sunlight photovoltaic panel.

Their research findings are currently available in the online edition of the journal Advanced Materials and will be published in a forthcoming print issue of the journal.

"I believe this is a game-changer invention to improve the efficiency of LCD displays," said Yang Yang, a professor of materials science at UCLA Engineering and principal investigator on the research. "In addition, these polarizers can also be used as regular solar cells to harvest indoor or outdoor light. So next time you are on the beach, you could charge your iPhone via sunlight."

From the point of view of energy use, current LCD polarizers are inefficient, the researchers said. A device's backlight can consume 80 to 90 percent of the device's power. But as much as 75 percent of the light generated is lost through the polarizers. A polarizing organic photovoltaic LCD could recover much of that unused energy.

"In the near future, we would like to increase the efficiency of the polarizing organic photovoltaics, and eventually we hope to work with electronic manufacturers to integrate our technology into real products", Yang said. "We hope this energy-saving LCD will become a mainstream technology in displays."

"Our coating method is simple, and it can be applied in the future in large-area manufacturing processes," said Rui Zhu, a postdoctoral researcher at UCLA Engineering and the paper's lead author.

"The polarizing organic photovoltaic cell demonstrated by Professor Yang's research group can potentially harvest 75 percent of the wasted photons from LCD backlight and turn them back into electricity," said Youssry Boutros, program director for the Intel Labs Academic Research Office, which supported the research. "The strong collaboration between this group at UCLA Engineering and other top groups has led to higher cell efficiencies, increasing the potential for harvesting energy. This approach is interesting in its own right and at the same time synergetic with several other projects we are funding through the Intel Labs Academic Research Office."

More information: http://onlinelibra … 514/abstract

Provided by University of California Los Angeles (news : web)

Physicists explore the key energy transport process underlying solar energy harvesting

Two Lehigh physicists have developed an imaging technique that makes it possible to directly observe light-emitting excitons as they diffuse in a new material that is being explored for its extraordinary electronic properties. Called rubrene, it is one of a new generation of single-crystal organic semiconductors.

Excitons, which are created by light, play a central role in the harvesting of solar energy using plastic solar cells. The achievement by Ivan Biaggio, professor of physics, and Pavel Irkhin, a Ph.D. candidate, represents the first time that an advanced imaging technique has been used to witness the long-range diffusion of energy-carrying excitons in an organic crystal.

One way to understand the mechanics of excitons, says Biaggio, is to pour a cup of milk on the floor. The milk spreads out in all directions from the point of impact. How far it goes depends on the type of surface on which it lands. Now imagine that the milk has been replaced with particle-like bundles of energy and the floor with an ordered arrangement of organic molecules.

Biaggio's group used a focused laser beam to create the particles -- the excitons -- in a crystal made of organic molecules. They tracked the movements of the excitons over distances smaller than the size of a human hair by directly taking pictures of the light that they emit. Unlike the spilled milk, the excitons spread only in a direction corresponding to a particular arrangement of molecules.

Hope for overcoming a solar bottleneck

An understanding of exciton diffusion is critical for plastic solar cell technology, in which the absorption of light creates excitons instead of directly inducing a current, as it does in the most commonly used silicon systems.

After they are created in plastic solar cells, excitons diffuse toward specially designed interfaces where they drive electrons into an external circuit, creating the flow of electrons we know as electric current. This diffusion process is one of the technical challenges limiting the efficiency of plastic solar cells.

"This is the first time that excitons have been directly viewed in a molecular material at room temperature," said Biaggio. "We believe the technique we have demonstrated will be exploited by other researchers to develop a better understanding of exciton diffusion and the bottleneck it forms in plastic solar cells."

When will we have cheap and efficient plastic solar cells? It is the goal of researchers around the world to improve exciton diffusion lengths until they become as large as the light absorption -- that's the point when sunlight is most efficiently collected and converted into energy.

An article by Irkhin and Biaggio was published in the journal Physical Review Letters.

The work was supported by a Faculty Innovation Grant from Lehigh, which provides resources to develop novel ideas and demonstrate new approaches to important research questions.

Thanks to the direct imaging of the diffusing excitons, Irkhin and Biaggio were able to obtain precise measurement of their diffusion length. This length was found to be very large in a particular direction, reaching a value several hundreds of times larger than in the plastic solar cells that are presently used. This is the first time that excitons have been directly viewed in a molecular material at room temperature, and it is believed that the widespread adoption of the technique developed by Irkhin and Biaggio will lead to significant progress in the field.

"It is important that physicists explore the most fundamental phenomena underlying the mechanisms that enable solar energy harvesting with cheap organic materials," said Biaggio. "Organics have lots of unexplored potential and the very efficient exciton diffusion that we have observed in rubrene may build the basis for new ideas and technologies towards the development of ever more efficient and plastic solar cells."

Story Source:

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

Journal Reference:

Pavel Irkhin, Ivan Biaggio. Direct Imaging of Anisotropic Exciton Diffusion and Triplet Diffusion Length in Rubrene Single Crystals. Physical Review Letters, 2011; 107 (1) DOI: 10.1103/PhysRevLett.107.017402

Salmonella stays deadly with a 'beta' version of cell behavior

Salmonella cells have hijacked the protein-building process to maintain their ability to cause illness, new research suggests.

Scientists say that these bacteria have modified what has long been considered typical cell behavior by using a beta form of an amino acid – as opposed to an alpha form – during the act of making proteins.

Beta versions of amino acids occur in nature under rare and specific circumstances, but have never been observed as part of protein synthesis. Before this finding, in fact, researchers had determined that virtually all proteins were constructed with the alpha forms of amino acids.

This work has shown that when researchers delete any one of three genes from the process that makes use of the beta form of the amino acid, or if they insert the alpha form in the beta version's place, Salmonella cells are no longer able to cause disease. The amino acid in question is lysine, one of 22 genetically encoded amino acids that are strung together in cells to make proteins.

"When these genes were knocked out, the cells became sensitive to antibiotics. And if we put beta lysine into the medium where cells were growing, they became resistant to antibiotics," said Michael Ibba, professor of microbiology at Ohio State University and a senior author of the study. "So we could see the beta amino acid being taken up and used. The cells really do need the beta amino acid to be resistant to antibiotics, and for other aspects of their virulence."

This finding suggests that the process using this specific beta amino acid could be an attractive antibiotic target for this common pathogen, the researchers say.

The Centers for Disease Control and Prevention estimates that about 1.4 million people in the United States are infected with Salmonella each year, though only 40,000 cases are reported. Most people infected with Salmonella develop diarrhea, fever and abdominal cramps. Though recovery can occur within a week without treatment, some severe cases require antibiotic treatment and hospitalization.

The study is published in the Aug. 14 online edition of the journal Nature Chemical Biology.

This work began when University of Toronto scientists exploring the origins of Salmonella's virulence identified three genes that were clear players in the process. These three genes – called YjeK, PoxA and EF-P – were unusual in this context.

Genes that confer virulence in bacteria typically have a specific job, such as producing toxins or transporters. But these three virulence genes all looked like they should have a role in the protein synthesis machinery – which is Ibba's expertise.

Under normal circumstances in cells, an enzyme will select amino acids in the cell and place them on a molecule called transfer RNA, or tRNA, which leads to translation of the genetic code into proteins.

In Salmonella cells, these steps are similar, but with a few surprising twists, Ibba said. He and colleagues confirmed that the YjeK gene makes beta lysine, and showed that the PoxA gene takes that beta lysine and attaches it to EF-P – a protein that partially mimics the shape and function of tRNA.

"It's a really unexpected pathway," said Ibba, also an investigator in Ohio State's Center for RNA Biology. "It is a mimic of what normally makes protein in a cell. Where a cell would normally be expected to use an alpha amino acid, Salmonella puts on a beta amino acid. And it ends up making molecules that lead to the cells being virulent."

The research team first reconstructed this unusual protein synthesis process in test tube experiments, and then followed with studies in cell cultures. Even before they took on studying the mechanism, however, they knew that the effects of these virulence genes were powerful: In earlier animal studies, deleting any one of the three genes and then infecting mice with these altered Salmonella cellshad no effect on the animals. When the genes were left intact and cells were injected into mice, the resulting Salmonella infection killed the animals.

In addition, when the researchers tricked Salmonella cells into using alpha lysine for this pathway instead of beta lysine, the cells lost their ability to cause illness.

"This tells us the cell is not going to be able to easily replace the beta amino acid," Ibba said. "It is essential for virulence in Salmonella."

And that, he said, is why that amino acid might be such an effective drug target, especially as humans don't seem to make beta amino acids at all. "You have to make an antibiotic look like something natural, only different. If you have something that's already different like a beta amino acid, you've potentially got a much better drug target because it involves chemistry that's comparatively rare in the cell. It's harder for the cell to try to alter its own chemistry to develop resistance," Ibba said.

From here, the researchers are observing cell behavior later in the protein-building process to figure out how this hijacked system actually gives Salmonella its virulence.

Provided by The Ohio State University (news : web)

A systematic way to find battery materials

Lithium-ion batteries have become a leading energy source for everything from smartphones and laptops to power tools and electric cars, and researchers around the world are actively seeking ways to nudge their performance toward ever-higher levels. Now, a new analysis by researchers at MIT and the University of California at Los Angeles (UCLA) has revealed why one widely used compound works particularly well as the material for one of these batteries' two electrodes -- an understanding they say could greatly facilitate the process of searching for even better materials.

Lithium-ion batteries’ energy and power density -- that is, how much electricity they can store for a given weight, and how fast they can deliver that power -- are determined mostly by the material used for the cathode (the positive electrode). When such batteries are being used, lithium atoms are stored within the crystal structure of the cathode; when the battery is being recharged, lithium ions flow back out of it. Many different materials are currently used for these cathodes.

But one of those materials has been a bit of a mystery. Lithium iron phosphate (LiFePO4) performs well as a cathode, but this performance has been hard to explain because unlike other cathode materials, lithium ion phosphate seemed to require a two-phase process to store lithium — something that should theoretically reduce its efficiency, but for some reason does not.

That anomaly has now been explained. A more detailed analysis showed that, in fact, the compound was following a single-phase process after all, but doing so in an unusual way -- which might point the way to discovery of many other such compounds that had previously been overlooked. The new analysis was carried out by Gerbrand Ceder, the Richard P. Simmons (1953) Professor of Materials Science and Engineering at MIT, his graduate student Rahul Malik, and postdoc Fei Zhou of UCLA, and published in the journal Nature Materials.

According to accepted theory, lithium iron phosphate “should have been a low-rate” cathode material, Ceder says — meaning that it could produce electricity only at a very low current, suitable for use with very-low-power devices. Instead, “it has become one of the highest-rate materials in use,” something that “always puzzled us,” he says.

Most cathode materials are porous, absorbing lithium ions during charging like water going into a sponge. But it was thought that lithium iron phosphate required a two-phase process, first forming one compound, which then morphed into a final, stable compound. The extra step was expected to add complexity and reduce the reaction’s speed.

But the new experiments, which were able to probe the activity of the material as it absorbed the lithium, found that even though the material ends up reaching an equilibrium where it has two separate phases, in operation it actually undergoes a single-phase process. “The way it actually absorbs lithium is not two-phase,” Ceder says, “but it separates into two phases when it’s done.”

That makes it much more similar to conventional single-phase cathode materials than had been thought -- and means that it makes sense to look at a wide range of other candidate materials that had been ignored because they were also assumed to require a two-phase process. This analysis makes it possible to “understand better which of these two-phase materials will actually work,” Ceder says, opening up thousands of new candidate materials to be studied. “Now we have a way of evaluating which materials may have potential,” Ceder says. “It broadens the possibilities.”

Previously, he says, it had been known that “some two-phase materials do zilch, some do very well,” but nobody knew why. Now it is likely that the ones that work well are actually using a single-phase reaction, as turns out to be the case with lithium iron phosphate. Ceder and his colleagues have been developing computer algorithms that incorporate a wide variety of known properties of materials so that large numbers of candidates can be screened quickly and efficiently to search for very specific combinations of properties needed for a particular application.

Understanding the dynamics of how lithium ions get incorporated into different molecular structures “was the missing piece in the high-throughput screening process,” Ceder says. “Hopefully we’ll be able to do that better now.”

Brent Fultz, professor of materials science and applied physics at the California Institute of Technology, who was not involved in this work, says these findings represent a “significant” step forward in understanding the behavior of this material. 

“Some oddities in the crystal structure” of lithium iron phosphate have been known, he says, “including a solid solution phase that exists at temperatures only a bit above room temperature. What is so interesting about the work from this MIT group is that it shows how the solid solution phase is far from simple.” He says “the authors make a strong case that the solid solution phase plays a bigger role in the performance” of this material than had been expected, and adds that “the work suggests alternative directions to the design of cathode materials for lithium batteries.”
This story is republished courtesy of MIT News (http://web.mit.edu/newsoffice/), a popular site that covers news about MIT research, innovation and teaching.

Provided by Massachusetts Institute of Technology (news : web)

ECHA urges registrants to verify compliance with data sharing and joint submission obligations

The Agency has noted that for some substances companies have submitted registrations possibly without taking part in a single SIEF. Registrants who find themselves in this situation are strongly encouraged to verify their compliance with data sharing and joint submission obligations. Registrants may approach the ECHA Helpdesk to obtain the contact details of other registrants for their substance.

Under the REACH Regulation, companies have to share existing information on the same substance and submit one joint dossier. Compliance with these obligations has to take place before registration dossiers are submitted to ECHA, and is facilitated through the SIEF and inquiry processes.

However, in some cases the pre-SIEF and SIEF formation process may not have worked as expected, and multiple separate (joint) registrations for the same substance have been submitted. This can be seen from some duplicate entries in ECHA's dissemination portal.. As registrants in these situations may be found in breach of the REACH Regulation, ECHA strongly encourages the registrants concerned to verify compliance with their data sharing and joint submission obligations and remedy any deficiencies as soon as possible.

To support registrants in ensuring compliance, ECHA now facilitates contact between existing registrants in the event that the contact details cannot be found via the normal channels, ie. the (pre-)SIEF or inquiry process, as appropriate. If companies become aware that other separate (joint) registrations exist for their substance, they can contact the ECHA Helpdesk to obtain the contact details of these other registrants, subject to the verification of certain information. Note that this process is only recommended to registrants who become aware of other registration of the same substance outside of their SIEF and/or joint submission (e.g. via the dissemination portal).

This new service is open to all companies that have submitted a registration for their substance(s) to ECHA and received a registration number. In order for a request to be processed, it is mandatory to indicate the registration number and the related submission number. ECHA will then provide the requester with the contact details of other registrants of the same substance as the requester via REACH-IT. In turn, these other registrants will be informed of the identity of the requester and the fact that their contact details have been passed on. If a third party representative has been appointed, ECHA will only disclose the contact details of that representative.

 

Searching for spin liquids: Much-sought exotic quantum state of matter can exist

The world economy is becoming ever more reliant on high tech electronics such as computers featuring fingernail-sized microprocessors crammed with billions of transistors. For progress to continue, for Moore's Law -- according to which the number of computer components crammed onto microchips doubles every two years, even as the size and cost of components halves -- to continue, new materials and new phenomena need to be discovered.

Furthermore, as the sizes of electronic components shrink, soon down to the size of single atoms or molecules, quantum interactions become ever more important. Consequently, enhanced knowledge and exploitation of quantum effects is essential. Researchers at the Joint Quantum Institute (JQI) in College Park, Maryland, operated by the University of Maryland and the National Institute of Standards and Technology (NIST), and at Georgetown University have uncovered evidence for a long-sought-after quantum state of matter, a spin liquid.

The research was performed by JQI postdoctoral scientists Christopher Varney and Kai Sun, JQI Fellow Victor Galitski, and Marcos Rigol of Georgetown University. The results appear in an editor-recommended article in the 12 August issue of the journal Physical Review Letters.

You can't pour a spin liquid into a glass. It's not a material at all, at least not a material you can touch. It is more like a kind of magnetic disorder within an ordered array of atoms. Nevertheless, it has many physicists excited.

To understand this exotic state of matter, first consider the concept of spin, which is at the heart of all magnetic phenomena. For instance, a refrigerator magnet, at the microscopic level, consists of trillions of trillions of iron atoms all lined up. Each of these atoms can be thought of loosely as a tiny spinning ball. The orientation of that spin is what makes the atom into a tiny magnet. The refrigerator magnet is an example of a ferromagnet, the ferro part coming from the Latin word for iron. In a ferromagnet, all the atomic spins are lined up in the same way, producing a large cooperative magnetic effect.

Important though they may be, ferromagnets aren't the only kind of material where magnetic interactions between spins are critical. In anti-ferromagnets, for instance, the neighboring spins are driven to be anti-aligned. That is, the orientations of the spins alternate up and down (see top picture in figure). The accumulative magnetic effect of all these up and down spins is that the material has no net magnetism. The high-temperature superconducting materials discovered in the 1980s are an important example of an anti-ferromagnetic structure.

More complicated and potentially interesting magnetic arrangements are possible, which may lead to a quantum spin liquid. Imagine an equilateral triangle, with an atom (spin) at each corner. Anti-ferromagnetism in such a geometry would meet with difficulties. Suppose that one spin points up while a second spin points down. So far, so good. But what spin orientation can the third atom take? It can't simultaneously anti-align with both of the other atoms in the triangle. Physicists employ the word "frustration" to describe this baffling condition where all demands cannot be satisfied.

In everyday life frustration is, well, frustrating, and actually this condition is found throughout nature, from magnetism to neural networks. Furthermore, understanding the different manifestations of a collection of magnetically interacting spins might help in designing new types of electronic circuitry.

One compromise that a frustrated spin system makes is to simultaneously exist in many spin orientations. In a quantum system, this simultaneous existence, or superposition, is allowed.

Here's where the JQI researchers have tried something new. They have studied what happens when frustration occurs in materials with a hexagonal (six sided) unit cell lattice.

What these atoms do is interact via their respective spins. The strength of the interaction between nearest neighbor (NN) atoms is denoted by the parameter J1. Similarly, the force between next nearest neighbors (NNN) -- that is, pairs of atoms that have at least one intervening atom between them -- is denoted by J2. Letting this batch of atoms interact among themselves, even on a pretend lattice as small as this, entails an immense calculation. Varney and his colleagues have calculated what happens in an array of hexagons consisting of 30 sites where the spins are free to swing about in a two-dimensional plane (this kind of approach is called an XY model).

Christopher Varney, who has appointments at Maryland and Georgetown, said that the interactions of atoms can be represented by a matrix (essentially a two-dimensional spreadsheet) with 155 million entries on each side. This huge number corresponds to the different spin configurations that can occur on this honeycomb-structured material.

What the researchers found were a "kaleidoscope" of phases, which represent the lowest-energy states that are allowed given the magnetic interactions. Just as water can exist in different phases -- steam, liquid, and ice -- as the temperature is changed, so here a change in the strengths of the interactions among the spins (the J1 and J2 parameters) results in different phases. For example, one simple solution is an antiferromagnet (upper picture in figure).

But one phase turns out to be a true quantum spin liquid having no order at all. When J2 is between about 21% and 36% of the value of J1, frustration coaxes the spins into disorder; the entire sample co-exists in millions of quantum states simultaneously.

It's difficult for the human mind to picture a tiny two-dimensional material in so many states at the same time. JQI fellow, Victor Galitski, suggests that one shouldn't think of the spins as residing at the original atomic sites but rather as free ranging particle-like entities dubbed "spinons." These spinons bob about, just as water molecules bob about in liquid water (see lower picture in figure). Hence the name quantum spin liquid.

Another reason for using the word liquid, Galitski says, is this 'bobbing about' is analogous to what happens inside a metal. There, the outer electrons of most atoms tend to leave their home atoms and drift through the metal sample as if they constituted a fluid, called a "Fermi liquid."

Electrons in a metal are able to drift since it takes only an infinitesimal amount of energy to put them into motion. The same is true for the fluctuating spins in the hexagonal model studied by the JQI scientists. Indeed, their spin model assumes a temperature of absolute zero, where quantum effects abound.

Writing in an essay that accompanied the article in Physical Review Letters, Tameem Albash and Stephan Haas, scientists at the University of Southern California, say that the JQI/Georgetown team "present a convincing example" of the new spin liquid state.

How can this new frustration calculation be tested? The experimental verification of the spin liquid state in a 2-dimenstional hexagonal lattice, Albash and Haas suggest, "will probably be tested using cold atoms trapped in optical lattices. In the past few years, this technology has become a reliable tool to emulate quantum many body lattice systems with tunable interactions." Indeed the authors propose such an experiment.

What would such a spin liquid material be good for? It's too early to tell. But some speculations include the idea that these materials could support some exotic kind of superconductivity or would organize particle-like entities that possessed fractional electric charge.

"Kaleidoscope of Exotic Quantum Phases in a Frustrated XY Model" by Christopher N. Varney, Kai Sun, Victor Galitski, and Marcos Rigol, Physical Review Letters, 107, 077201, (12 August 2011).

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by Joint Quantum Institute, University of Maryland.

Journal Reference:

Christopher Varney, Kai Sun, Victor Galitski, Marcos Rigol. Kaleidoscope of Exotic Quantum Phases in a Frustrated XY Model. Physical Review Letters, 2011; 107 (7) DOI: 10.1103/PhysRevLett.107.077201

How receptors talk to G proteins

The mechanism by which cells respond to stimuli and trigger hormonal responses, as well as the senses of sight, smell, and taste, has for the first time been brought into focus with the help of high-brightness x-rays provided by the U.S. Department of Energy Office of Science’s Advanced Photon Source (APS) at Argonne National Laboratory. This breakthrough will pave the way to new research avenues in drug discovery, cell signaling, and cellular regulation.

Receiving a signal, interpreting it, and responding correctly: these are three activities that cells must be good at in order to respond to stimuli. For responding to hormones, and for the senses of sight, smell, and taste, the activated receptors are coupled with G proteins. These G protein-coupled receptors (GPCRs) are involved in a complex set of steps in which an extracellular hormone or neurotransmitter binds to and activates a GPCR in the cell membrane. The activated receptor passes on the signal to a G-protein inside the cell, triggering reactions that ultimately create a cellular response to the stimulus.

The intricacy of this set of reactions has been appreciated—and studied—for some time. What was lacking, however, was a finely-detailed crystal structure of the GPCR as it actually signals across the membrane. The importance of acquiring this knowledge and knowing a lot more about how GPCRs function is apparent when we consider that the human genome contains over 800 GPCR genes.

The structure of protein receptors that are involved in cellular responses to stimuli is now available thanks to experiments carried out at the National Institute of General Medical Sciences and National Cancer Institute Collaborative Access Team (GM/CA-CAT) beamline 23-ID-B at the APS, and the process of cell signaling has come into crystal clear focus. This crystal structure is the first high-resolution look at transmembrane signaling by a GPCR and adds critical insight about signal transduction across the plasma membrane.

The general model for GPCR signaling is that the G-protein is activated by a receptor that has received a stimulus from outside the cell. The research team, comprising members from Stanford University, the University of Copenhagen, the University of Michigan, the University of Wisconsin, Vrije Universiteit Brussel, and Trinity College studied a specific model system for GPCR signaling that has long been used by biochemists and about which much was already known. In this system, a ß2 adrenergic receptor (ß2AR) is bound by the outside stimulus, known as an agonist, and then activates Gs, the stimulatory G protein for adenylyl cyclase.

The researchers were able to capture the ß2AR bound to the Gs protein before the latter went on to the next step in the dance, which would be binding a nucleotide. One technical challenge, and perhaps the reason that the crystal structure had been so elusive to date, was to create a stable ß2AR-Gs complex in detergent solution. Once this problem was solved, the team could proceed to unveiling the crystal structure of this active-state ß2AR-Gs complex (see the accompanying figure).

The new data allowed the research team to construct the early stages of GPCR signaling. Using their own observations, and other data collected on this model system, a mechanism for the initial stages of complex formation came into being. The data provided a pinpoint determination of exactly which changes in the molecules permitted that binding stage to carry on to completion.

Shape changes in the Gs, particularly in the nucleotide-binding pocket, prepared the protein for the next step. In the ß2AR, the researchers were able to identify major changes in two areas of the molecule that fit well with understanding of how the ß2AR interacts with molecules outside the cell and how the two molecules—ß2AR and Gs—interact each other.

Article co-author Brian Kobilka, of Stanford University, recalled how the project reached this important milestone: “For the past five years, Roger Sunahara and I have been working together to understand how receptors and G proteins interact with each other. This was the next logical step after getting the first inactive-state structures of the ß2AR alone in 2007.

“The receptor and G protein purification procedures were well established at the time we started the project, but most of the other methods were developed during the project. The minibeam and the rastering‡ capabilities of the GM/CA-CAT beamline at the APS were essential for collecting the diffraction data on these crystals.”

Future research, Kobilka said, involves “how the complex forms and dissociates after activation.”

More information: Soren G. F. et al. “Crystal structure of the b2 adrenergic receptor–Gs protein complex,” Nature, advance online publication, 19 July 2011. DOI: 10.1038/nature10361

Provided by Argonne National Laboratory (news : web)