Thursday, July 7, 2011

Researchers decipher protein structure of key molecule in DNA transcription system

Scientists have deciphered the structure of an essential part of Mediator, a complex molecular machine that plays a vital role in regulating the transcription of DNA.


The research adds an important link to discoveries that have enabled scientists to gain a deeper understanding of how cells translate into the proteins and processes of life. The findings, published in the July 3 advance online issue of the journal Nature, were reported by a research team led by Yuichiro Takagi, Ph.D., assistant professor of biochemistry and molecular biology at Indiana University School of Medicine.


The fundamental operations of all are controlled by the genetic information – the genes –stored in each cell's , a long double-stranded chain. Information copied from sections of the DNA – through a process called transcription – leads to synthesis of messenger RNA, eventually enabling the production of proteins necessary for cellular function. Transcription is undertaken by the enzyme called RNA polymerase II.


As cellular operations proceed, signals are sent to the DNA asking that some genes be activated and others be shut down. The Mediator transcription regulator accepts and interprets those instructions, telling RNA polymerase II where and when to begin the transcription process.


Mediator is a gigantic molecular machine composed of 25 proteins organized into three modules known as the head, the middle, and the tail. Using X-ray crystallography, the Takagi team was able to describe in detail the structure of the Mediator Head module, the most important for interactions with RNA polymerase II.


"It's turned out to be extremely novel, revealing how a molecular machine is built from multiple proteins," said Takagi.


"As a molecular machine, the Mediator head module needs to have elements of both stability and flexibility in order to accommodate numerous interactions. A portion of the head we named the neck domain provides the stability by arranging the five proteins in a polymer-like structure," he said.


"We call it the alpha helical bundle," said Dr. Takagi. "People have seen structures of alpha helical bundles before but not coming from five different proteins."


"This is a completely noble structure," he said.


One immediate benefit of the research will be to provide detailed mapping of previously known mutations that affect the regulation of the transcription process, he said.


The ability to solve such complex structures will be important because multi-protein complexes such as Mediator will most likely become a new generation of drug targets for treatment of disease, he said.


Previously, the structure of RNA polymerase II was determined by Roger Kornberg of Stanford University, with whom Dr. Takagi worked prior to coming to IU School of Medicine. Kornberg received the Nobel Prize in 2006 for his discoveries. The researchers who described the structure of the ribosome, the production machine, were awarded the Nobel Prize in 2009. The structure of the entire Mediator has yet to be described, and thus remains the one of grand challenges in structure biology. Dr. Takagi's work on the Mediator head module structure represents a major step towards a structure determination of the entire .


Provided by Indiana University School of Medicine

Cellulose breakdown

Ionic liquids have emerged as promising new solvents capable of disrupting the cellulose crystalline structure in a wide range of biomass feedstocks.

Such biomass is of particular interest as a renewable and sustainable source of fuels and chemicals, and the crystallinity of the cellulose is one of the major obstacles to fermentation and yields.

Researchers at ORNL pretreated four different feedstocks -- microcrystalline cellulose (Avicel), switchgrass, pine, and eucalyptus -- with an ionic liquid and found such pretreatment results in a loss of cellulose crystalline structure and the transition of the feedstock surface from cellulose I to the more readily digested cellulose II.

The impact of the pretreatment on the structure was analyzed by . The impact on the surface roughness was determined by small-angle neutron scattering, using the General Purpose SANS instrument at the at ORNL.

Researchers believe the results for some samples suggest another factor, likely lignin-carbohydrate complexes, also impacts cellulose breakdown.

Provided by Oak Ridge National Laboratory (news : web)

Nanowire-based sensors offer improved detection of volatile organic compounds

A team of researchers from the National Institute of Standards and Technology (NIST), George Mason University and the University of Maryland has made nano-sized sensors that detect volatile organic compounds -- harmful pollutants released from paints, cleaners, pesticides and other products -- that offer several advantages over today's commercial gas sensors, including low-power room-temperature operation and the ability to detect one or several compounds over a wide range of concentrations.


The recently published work is proof of concept for a gas sensor made of a single nanowire and metal oxide nanoclusters chosen to react to a specific organic compound. This work is the most recent of several efforts at NIST that take advantage of the unique properties of nanowires and metal oxide elements for sensing dangerous substances.


Modern commercial gas sensors are made of thin, conductive films of metal oxides. When a volatile organic compound like benzene interacts with titanium dioxide, for example, a reaction alters the current running through the film, triggering an alarm. While thin-film sensors are effective, many must operate at temperatures of 200° C (392° F) or higher. Frequent heating can degrade the materials that make up the films and contacts, causing reliability problems. In addition, most thin-film sensors work within a narrow range: one might catch a small amount of toluene in the air, but fail to sniff out a massive release of the gas. The range of the new nanowire sensors runs from just 50 parts per billion up to 1 part per 100, or 1 percent of the air in a room.


These new sensors, built using the same fabrication processes that are commonly used for silicon computer chips, operate using the same basic principle, but on a much smaller scale: the gallium nitride wires are less than 500 nanometers across and less than 10 micrometers in length. Despite their microscopic size, the nanowires and titanium dioxide nanoclusters they're coated with have a high surface-to-volume ratio that makes them exquisitely sensitive.


"The electrical current flowing through our nanosensors is in the microamps range, while traditional sensors require milliamps," explains NIST's Abhishek Motayed. "So we're sensing with a lot less power and energy. The nanosensors also offer greater reliability and smaller size. They're so small that you can put them anywhere." Ultraviolet light, rather than heat, promotes the titanium dioxide to react in the presence of a volatile organic compound.


Further, each nanowire is a defect-free single crystal, rather than the conglomeration of crystal grains in thin-film sensors, so they're less prone to degradation. In reliability tests over the last year, the nano-sized sensors have not experienced failures. While the team's current experimental sensors are tuned to detect benzene as well as the similar volatile organic compounds toluene, ethylbenzene and xylene, their goal is to build a device that includes an array of nanowires and various metal oxide nanoclusters for analyzing mixtures of compounds. They plan to collaborate with other NIST teams to combine their ultraviolet light approach with heat-induced nanowire sensing technologies.


The portion of this work conducted at George Mason University was funded by the National Science Foundation.


Story Source:


The above story is reprinted (with editorial adaptations ) from materials provided by National Institute of Standards and Technology (NIST).

Journal Reference:

Geetha S Aluri, Abhishek Motayed, Albert V Davydov, Vladimir P Oleshko, Kris A Bertness, Norman A Sanford, Mulpuri V Rao. Highly selective GaN-nanowire/TiO2-nanocluster hybrid sensors for detection of benzene and related environment pollutants. Nanotechnology, 2011; 22 (29): 295503 DOI: 10.1088/0957-4484/22/29/295503

The genius of a disorderly enzyme

 USC Dornsife researchers uncover how the inefficiency of activation-induced deoxycytidine deaminase is good for your immune system.


Why is antibody diversity important? Think about it like this, said Myron Goodman: “Why don’t you die when I sneeze? It’s because you have a powerful immune system. And the way to get a decent immune system is for your body to have a way to respond to insults it has never seen before.”


Random patterns of deamination by the activation-induced deoxycytidine deaminase (AID) are the key to generating antibody diversity, a crucial component to a healthy , according to a new study by USC Dornsife researchers published in The Journal of Biological Chemistry.


Having variation in the types of antibodies produced by your body gives it a fighting chance to respond to those “insults.” Antibodies protect against invasion by antigens such as bacteria or viruses by locating them in the body and neutralizing them. To do that, antibodies must bind to antigens. The more variation in the types of antibodies produced by the body, the more likely they will be able to bind to and fight off antigens, which come in many forms.


To create antibody diversity, mutations must occur in the variable region of immunoglobulin genes, the region where antibodies bind to invaders. Generating those mutations has to be a really random process according to Goodman, professor of biological sciences and chemistry in USC Dornsife. This is where AID steps in.


Goodman and his colleagues monitored the actions of AID as it scanned single-stranded or transcribed double-stranded DNA. The enzyme essentially moves back and forth along the DNA strand and sporadically deaminates, or converts, cytosine to uracil triggering a mutation in tri-nucleotide motifs – sequences comprising three bases – found along the DNA.

This video is not supported by your browser at this time.

A visual representation of single-stranded DNA deamination by AID. This video was originally published in The Journal of Biological Chemistry, vol. 286: 24931-24942.

Unlike most enzymes that are exquisitely efficient in targeting favored motifs, they found that AID was extremely inefficient. AID initiated chemical reactions in favored motifs only about 3 percent of the time. By mutating the motifs so haphazardly, the researchers suggest that AID produces antibody diversity.

The study also sheds light on a little-studied group of enzymes. Enzymes like AID that scan single-stranded DNA have been studied far less extensively than enzymes that scan double-stranded DNA.


“This is the first really clear picture of what AID is doing during the scanning process,” Goodman said.


To identify and describe AID’s complex process during scanning, the team used a genetic assay to measure the distribution of AID-induced mutations on individual DNA molecules and then analyzed the mutational data computationally using a random walk model, developed for the study by USC Dornsife researcher Peter Calabrese. By combining the genetic and computational analyses, they were able to calculate the distribution of mutations that occurred with a remarkable fit to their experimental data. The fit entailed matching theory to experiment for the patterns of closely spaced mutations and separately for the distances between mutated and non-mutated target motifs.


Their paper, “An Analysis of a Single-stranded DNA Scanning Process in which AID Deaminates C to U Haphazardly and Inefficiently to Ensure Mutational Diversity” published online May 12, was selected by The Journal of Biological Chemistry as a “Paper of the Week” to appear in the July 15 print issue.


Provided by USC College

Discovery alters conventional understanding of sight

A discovery by a team of researchers led by a Syracuse University physicist sheds new light on how the vision process is initiated. For almost 50 years, scientists have believed that light signals could not be initiated unless special light-receptor molecules in the retinal cells first changed their shape in a process called isomerization. However, the SU research team, which includes researchers from Columbia University, has demonstrated that visual signals can be initiated in the absence of isomerization.

"We have demonstrated that chromophores (light-absorbing substances in retinal photoreceptor molecules), do not have to change shape in order to trigger the visual signal," says Kenneth Foster, professor of physics in SU's College of Arts and Sciences. "The shape-change that results from isomerization is actually the second step in the process. Historically, scientists have focused on isomerization without realizing there is an earlier and more crucial first step."

The research was published online June 23 in the journal and is the cover article for the print version to appear June 24. The work was done in collaboration with Juree Saranak, research assistant professor in the Department of Physics; and Koji Nakanishi, professor of chemistry at Columbia University. Nakanishi's group was responsible for the synthetic chemistry that went into the compounds tested at SU. The National Institutes of Health funded the research.

Chromophores absorb light after it enters the eye, setting off an extremely rapid series of complex that enable to be transmitted to, and interpreted by, the brain so that we can visually perceive the world around us. Visual chromophores are composed of retinal (a type of vitamin A), which attaches to a protein (opsin) to form rhodopsin.

Foster's team of researchers discovered that the visual process is initiated by the redistribution of electrons on the chromophores, which occurs during the first few femptoseconds (one-quadrillionth of a second) after light enters the eye. Their experiments showed that when a chromophore absorbs a photon of light, electrons move from the chromophore's "free" end to the place where it attaches to opsin. The movement of the electrons causes a change in the electrical field surrounding the chromophore. That change is detected by nearby amino acids that are highly sensitive to changes in the electrical field. These amino acids, in turn, signal the rest of the rhodopsin molecule to initiate the visual process.

"We found that the complete blocking of isomerization of the chromophore does not preclude vision in our model organism," Foster says. "The signal is triggered as a result of an electronic coupling instead of a geometric change in the chromophore's structure as previously hypothesized. We believe this is a universal mechanism that activates all rhodopsins present in organisms from bacteria to mammals."

Foster attributes his findings to new technologies and scientific information not available 50 years ago when scientists first tried to understand how people see. "Fifty years ago, scientists had little knowledge of the structure of rhodopsins," he says. "Advances in technology have enabled scientists to determine the rhodopsin structure at the level of the , which enables us to design sensitive experiments to test our hypotheses."

Provided by Syracuse University

Pigment patterns from the prehistoric past

An international collaboration led by researchers at the University of Manchester has for the first time revealed chemical traces of pigments in bird, fish and squid fossils, some over 100 million years old.


Publishing their findings in Science, the researchers have been able to show a remarkable relationship between copper and pigment within exceptionally preserved feathers and other soft tissues.


Results include important species such as the oldest beaked bird yet found, the 120 million year old Confuciusornis sanctus, and also the 110 million year old Gansus yumenensis, which looks similar to the modern Grebe and represents the oldest example of modern birds.


Pigment is a critical component of colour. The team can map the presence of pigments over whole fossils, revealing original patterns. The team's findings indicate that pigment chemistry holds the future key to the ultimate goal of discovering the colour palette of past life, from dodos to dinosaurs and beyond.


Colour has played a key role in the processes of evolution by natural selection that have steered all life on Earth for hundreds of millions of years.


This unique scientific breakthrough can allow paleontologists to reconstruct colour patterns in extinct animals, as well as provide an understanding of the way in which biological compounds are preserved in specific environments over deep time.


This could give them a far greater understanding of the feeding habits and environments occupied by extinct creatures, as well as shedding light on the evolution of colour pigments in modern species.


The X-ray team, led by Dr Roy Wogelius, Dr Phil Manning and Dr Uwe Bergmann, took the unique approach of using the synchrotron to analyse the soft tissue regions of fossil organisms.


The application of X-ray physics to palaeontology has shed new light on the tangled tale of prehistoric pigments in deep time and how to recognise its chemistry in fossils that are hundreds of millions years old.


Dr Wogelius, lead author on the paper and University of Manchester geochemist, said: "Every once in a while we are lucky enough to discover something new, something that nobody has ever seen before.


"For me, learning that copper can be mapped to reveal astonishing details about colour in animals that are over 100 million years old is simply amazing. But even more amazing is to realize that such biological pigments, which we still manufacture within our own bodies, can now be studied throughout the fossil record, probably back much further than the 120 million years we show in this publication."


To unlock the stunning colour patterns, the Manchester researchers teamed up with scientists at SLAC National Accelerator Laboratory (USA) and used the Stanford Synchrotron Radiation Lightsource to bathe fossils in intense synchrotron X-rays.


The interaction of these X-rays with the chemistry of each fossil allowed the team to recognise the chemistry of eumelanin, the molecule that provides the dark coloured pigmentation, in feathers from some of the most pivotal species of dino-birds and even pigment from within the eye of a 50 million year old fish.


The key to their work was identifying and imaging trace metals incorporated by ancient and living organisms into their soft tissues, in the same way that all living species do today, including humans.


Without essential trace metals, key biological processes in life would fail and animals either become sick or die. It is these essential trace metals that the team has pinned down for the first time.


Dr Phil Manning, a senior author on the paper and University of Manchester palaeontologist, added:"The fossils we excavate have vast potential to unlock many secrets on the original organism's life, death and subsequent events impacting its preservation before and after burial.


"To unpick the complicated chemical archive that fossils represent requires a multidisciplinary team that can bring in to focus many areas of science.


"In doing this, we unlock much more than just palaeontological information, we now have a chemical roadmap to track similar pigments in all life."


Results show that chemical remnants of pigments may survive even after the melanosome (biological paint pots) containing pigment has been destroyed. Some of the samples they publish clearly preserve a chemical fossil, where almost all structure has been lost in the sands of time. The chemical residue can be mapped to reveal details of the distribution of dark pigment (eumelanin), probably the most important pigment in the animal kingdom.


This pigment gives dark shading to human hair, reptile skin, and bird feathers. Using rapid scan X-ray fluorescence imaging, a technique recently developed at SLAC, the team was able to map the residue of dark pigment over the entire surface of a large fossil, for the first time giving clear information about fundamental colour patterning in extinct animals. It turns out that the presence of copper and other metals derived from the original pigment gives a non-biodegradeable record of colour that can last over deep geological time.


Dr Uwe Bergmann, SLAC physicist and co-author on the paper said: "Synchrotron radiation has been successfully applied for many years to many problems.


"It is very exciting to see that it is now starting to have an impact in palaeontology, in a way that may have important implications in many other disciplines. To work in a team of such diverse experts is a privilege and incredibly stimulating. This is what science is all about."


Using this novel method to accurately and non-destructively measure the accumulation of trace metals in soft tissues and bone, the team also studied the chemistry of living species, including birds.


Dr Wogelius added: "This advance in chemical mapping will help us to understand modern animals as well as fossils. We may also be able to use this research to improve our ability to sequester toxic materials such as radioactive waste and to devise new strategies for stabilizing man-made organic compounds."


Some of the results are also presented in an upcoming National Geographic special, for more details see http://channel.nationalgeographic.com/episode/in-living-color-4493/Overview


Story Source:


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

Journal Reference:

R. A. Wogelius, P. L. Manning, H. E. Barden, N. P. Edwards, S. M. Webb, W. I. Sellers, K. G. Taylor, P. L. Larson, P. Dodson, H. You, L. Da-Qing, U. Bergmann. Trace Metals as Biomarkers for Eumelanin Pigment in the Fossil Record. Science, 2011; DOI: 10.1126/science.1205748

Tapping titanium's colorful potential

 

A new method to color titanium developed by Gregory Jerkiewicz, a professor in the Queen's University Department of Chemistry, uses an electrochemical solution to produce colored titanium, improving on an older, time-consuming and expensive method where heat was used to develop a colored layer. Credit: Queen's University

A new, cost-effective process for colouring titanium can be used in manufacturing products from sporting equipment to colour-coded nuclear waste containers.


"The new method uses an electrochemical solution to produce coloured , improving on an older, time-consuming and expensive method where heat was used to develop a coloured layer," says Gregory Jerkiewicz, a professor in the Department of Chemistry.


Dr. Jerkiewicz's new technique can be finely tuned to produce over 80 different shades of basic colours. In addition, the coloured titanium produced using the new method remains crack-free and stable for many years.


Colourful titanium has the potential to be used in the production of everyday objects like spectacle frames, jewelry, golf clubs and high-performance bicycles.


Industries including healthcare, aviation and the military could use the technology to create items like colour-coded , brightly coloured airplane parts, and stealth submarines made from blue titanium.


Provided by Queen's University (news : web)

Boosting research into new drugs: 'Smart materials' make proteins form crystals

Scientists have developed a new method to make proteins form crystals using 'smart materials' that remember the shape and characteristics of the molecule. The technique, reported today in Proceedings of the National Academy of Sciences, should assist research into new medicines by helping scientists work out the structure of drug targets.

The process of developing a new drug normally works by identifying a protein that is involved in the disease, then designing a molecule that will interact with the protein to stimulate or block its function. In order to do this, scientists need to know the structure of the protein that they are targeting.

A technique called can be used to analyse the arrangement of atoms within a crystal of protein, but getting a protein to come out of solution and form a crystal is a major obstacle. The number of proteins identified as potential is increasing exponentially as scientists make progress in the fields of genomics and proteomics, but with current methods, scientists have successfully obtained useful for less than 20 per cent of proteins that have been tried.

Now researchers at Imperial College London and the University of Surrey have developed a more effective method for making proteins crystallise using materials called 'molecularly imprinted polymers' (MIPs). MIPs are made up of small units that bind together around the outside of a molecule. When the molecule is extracted, it leaves a cavity that retains its shape and has a strong affinity for the .

This property makes MIPs ideal nucleants – substances that bind protein molecules and make it easier for them to come together to form crystals. Many substances have been used as nucleants before, but none are designed specifically to attract a particular protein.

"Proteins are very comfortable in solution," said Professor Naomi Chayen, from the Department of Surgery and Cancer at Imperial College London, who led the research. "They need some convincing to come out and form a crystal.

"MIPs help this process by using the protein as a template for forming its own crystal. Once the first molecule or group of molecules is held in place, other molecules can arrange themselves around it and start to build a crystal."

In the study, Professor Chayen and her colleagues found that six different MIPs induced crystallisation of nine proteins, yielding crystals in conditions that do not give crystals otherwise. They also tested whether MIPs would be effective at producing crystals from a series of preliminary trials for three target proteins for which scientists have not previously been able to obtain crystals of sufficient quality. The presence of MIPs gave rise to crystals in eight to 10 per cent of such trials, yielding valuable crystals that would have been missed using other known nucleants.

"Rational drug design depends on knowing the structure of the you're trying to target, and getting good crystals is essential for studying the structure," Professor Chayen said. "With MIPs we can get better crystals than we can with other methods, and also improve the probability of getting crystals from new proteins. This is a really significant innovation that could have a major impact on research leading to the development of new drugs."

More information: Saridakis et al. 'Protein crystallization facilitated by molecularly imprinted polymers' Proceedings of the National Academy of Sciences, published online 20 June 2011.

Provided by Imperial College London (news : web)

Metal particle generates new hope for hydrogen energy

Tiny metallic particles produced by University of Adelaide chemistry researchers are bringing new hope for the production of cheap, efficient and clean hydrogen energy.


Led by Associate Professor Greg Metha, Head of Chemistry, the researchers are exploring how the metal nanoparticles act as highly efficient catalysts in using solar radiation to split water into hydrogen and oxygen.


"Efficient and direct production of hydrogen from solar radiation provides a renewable energy source that is the pinnacle of clean energy," said Associate Professor Greg Metha. "We believe this work will contribute significantly to the global effort to convert solar energy into portable chemical energy."


The latest research is the outcome of 14 years of fundamental research by Associate Professor Metha's research group investigating the synthesis and properties of metal nanoparticles and how they work as catalysts at the molecular level.


The group works with metal "clusters" of about one-quarter of a nanometre in size -- less than 10 atoms. Associate Professor Metha said these tiny "magic clusters" act as super-efficient catalysts. Catalysts drive chemical reactions, reducing the amount of energy required.


"We've discovered ways of producing these tiny metallic clusters, we've explored their fundamental chemical activity, and now we are applying their catalytic properties to reactions which have great potential benefit for industrial use and the environment," said Associate Professor Metha.


PhD student Jason Alvino is exploring splitting water to make hydrogen (and oxygen) using solar energy -- a process that is not viable for industry development at the moment.


"We know this catalysis works very efficiently at the molecular level and now need to demonstrate it works on the macroscopic scale," said Associate Professor Metha.


"Splitting water to make hydrogen and oxygen requires a lot of energy and is an expensive process. We will be using solar radiation as the energy source, so there will be no carbon emissions and because the clusters work so efficiently as a catalyst, it will be a much better process.


"The ultimate aim is to produce hydrogen from water as a cheap portable energy source."


Associate Professor Metha said there were also other industrial chemical reactions that could be made feasible by these catalysts, using solar radiation as the energy source -- with potentially significant environmental benefits. One example was converting carbon dioxide into methane or methanol with water.


This project 'Solar Hydrogen: photocatalytic generation of hydrogen from water', has been funded under the three-year clean energy partnership between Adelaide Airport Ltd and the University's Centre for Energy Technology.


Story Source:


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

High-energy density magnesium batteries for smart electrical grids

Magnesium-based batteries are, in theory, a very attractive alternative to other batteries.


Magnesium (Mg) is cheap, safe, lightweight, and its compounds are usually non-toxic. Mg is less expensive (metallic [Li] costs about 24 times more than metallic Mg) because Mg is abundant in the Earth’s crust. Mg is safer because it is stable when exposed to the atmosphere. Mg provides a theoretical specific capacity of 2,205 ampere-hours/kilogram, making it an attractive high-energy density system.


Furthermore, it provides two electrons per atom and has electrochemical characteristics similar to Li (12 grams-per-Faraday [g/F], compared to 7 g/F for Li or 23 g/F for sodium).


Proper design and architecture should lead to Mg-based batteries with densities of 400-1,100 watt-hour per kilogram for an open circuit voltage in the range of 0.8 – 2.1 V, which would make it an attractive candidate for electrical grid energy storage and stationary back-up energy.


To make Mg-based batteries practical, researchers at DOE’s National Energy Technology Laboratory are developing novel alloys of Mg doped with different elements such as calcium, zinc, and yttrium. These alloys are being produced by melting and casting as well as powder metallurgy.


A new displacement reaction hypothesis, based on the reaction of nanostructured transition metal with Mg, has resulted in a thermodynamically favorable reversible displacement reaction of transition metals and Mg-alloys.


Recent accomplishments include a new, intermetallic anode compound formulated by melting/casting and synthesis of a new MgMn1-xFexSiO4/C composite, and other transition metal oxide spinel cathode systems. Mg-based electrolytes and other ionic electrolytes have also been developed and are being tested.


Provided by National Energy Technology Laboratory

Compound may provide drug therapy approach for Huntington's disease

UT Southwestern Medical Center researchers have identified compounds that appear to inhibit a signaling pathway in Huntington's disease, a finding that may eventually lead to a potential drug therapy to help slow the progression of degenerative nerve disorders.

"Our studies have uncovered a new for Huntington's disease treatment and possibly for other ," said Dr. Ilya Bezprozvanny, professor of physiology and senior author of the study, published in today's issue of . "In addition, we now have this new series of compounds that gives us a tool to study the pathogenesis of Huntington's disease."

Huntington's disease is a fatal genetic disorder in which certain waste away. More than 250,000 people in the U.S. have the disorder or are at risk for it. The most common form is adult-onset, with symptoms usually developing in patients in their mid-30s and 40s.

The disease results in uncontrolled movements, psychiatric disturbance, gradual dementia and eventually death. There is no therapy available currently to slow the progression of the disease.

Scientists at UT Southwestern found that quinazoline-derived compounds effectively block what is known as the store-operated calcium entry signaling pathway, which was never before implicated in Huntington but that might be a therapeutic target in the disease.

Dr. Bezprozvanny's laboratory research has contributed to growing scientific evidence that suggests abnormalities in neuronal calcium signaling play an important role in the development of Huntington's disease. UT Southwestern researchers demonstrated in the current study that the quinoline compounds – supplied by EnVivo – protected brain cells.

"If this holds, this compound can be considered to have potential therapeutic application for Huntington's," he said. "As we ultimately seek a cure, we are encouraged to have found something that may slow the progress or delay the onset of the disease."

Provided by UT Southwestern Medical Center (news : web)

Gold microflowers to enhance signals from molecules

Researchers have to place objects under study on suitable substrates to obtain a strong enhancement of electromagnetic radiation emitted by single molecules. A simple and cheap method to fabricate substrates for SERS spectroscopy has been discovered at the Institute of Physical Chemistry of the Polish Academy of Sciences. A key role in substrate fabrication play spherical gold aggregates -- flower-like micrometer-sized spheres.


Surface Enhanced Raman Spectroscopy (SERS) is a promising research tool that allows to enhance signals emitted by molecules by hundreds of thousands or even millions of times. „There is, however, no joy without annoy," says Dr Marcin FiaƂkowski, associate professor at the Institute of Physical Chemistry of the Polish Academy of Sciences (IPC PAS). „To reach so high enhancement, the molecules must be placed on an appropriately shaped substrate. Under electron microscope, such substrates resemble peaked mountains, like Alps for example. The difference is that here the peak heights are measured in nanometres, and the mountains are covered not with snow but with a layer of gold."


At present no cheap, good and easy-to-use substrates for SERS analyses are available on the market and this is one of the factors inhibiting commercialization of the method. A promising solution to the problem seem to offer substrates developed recently at the Institute of Physical Chemistry of the PAS under the research project „Quantum nanostructures." The substrates are fabricated by depositing spherical, strongly ragged gold structures precipitating from solution, on a slide surface. When observed under electron microscope, these micrometer-sized spheres resemble flower buds composed of many gold petals.


The highest enhancement of a SERS signal is obtained when a molecule is placed in the meeting area of two "peaks" of the substrate. The effect can be hardly reached with existing mountain-like surfaces, as the peaks there are distinctly separated. The situation on the substrates made with gold flowers is different. „When ragged microflowers are deposited on the surface, they form thick, complex 3D structures with numerous meeting areas between the petals. That's why the signals emitted from our substrates are enhanced even by ten million times," stresses Katarzyna Winkler, a PhD student from the IPC PAS.


Equally crucial as the enhancement is the repeatability of signals obtained from a specific substrate. In that respect the layers of gold microflowers show excellent performance. The signals originating from molecules of the same type that are placed at different locations on the same substrate are very similar to each other, and this is not always the case for surfaces obtained with other methods. High signal repeatability has also been observed for substrates fabricated on various slides, using separately prepared solutions.


The fabrication of substrates using gold flowers is fast, simple and cheap, does not require to use neither robots nor clean rooms. "The reaction mixture contains only a gold salt and a reducing agent, mixed in an appropriate mixing ratio. The role of the reducing agent is to reduce gold cations to metallic gold," says Winkler. What remains is to immerse a roughened slide in so prepared solution. The deposition of gold flowers is usually completed within one hour, and the substrate is ready for use on the next day.


The method of covering surfaces with gold microflowers designed for SERS applications has been filed for patenting. The present goal of the researchers from the Institute of Physical Chemistry of the PAS is to develop substrates that can be used repeatedly in measurements involving various analytes. For that purpose, methods to wash out analytes while leaving the substrate structure intact are being developed.


Story Source:


The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Institute of Physical Chemistry of the Polish Academy of Sciences, via AlphaGalileo.