Scientists a step closer to understanding 'natural antifreeze' molecules

Scientists have made an important step forward in their understanding of cryoprotectants -- compounds that act as natural 'antifreeze' to protect drugs, food and tissues stored at sub-zero temperatures.

Researchers from the Universities of Leeds and Illinois, and Columbia University in New York, studied a particular type of cryoprotectants known as osmolytes. They found that small osmolyte molecules are better at protecting proteins than larger ones.

The findings, published in Proceedings of the National Academy of Sciences, could help scientists develop better storage techniques for a range of materials, including human reproductive tissue used in IVF.

Biological systems can usually only operate within a small range of temperatures. If they get too hot or too cold, the molecules within the system can become damaged (denatured), which affects their structure and stops them from functioning.

But certain species of fish, reptiles and amphibians can survive for months below freezing by entering into a kind of suspended animation. They are able to survive these extreme conditions thanks to osmolytes -- small molecules within their blood that act like antifreeze -preventing damage to their vital organs.

These properties have made osmolytes attractive to scientists. They are used widely in the storage and testing of drugs and other pharmaceuticals; in food production; and to store human tissue like egg and sperm cells at very low temperatures (below -40oC) for a long period of time.

"If you put something like human tissue straight in the freezer, ice crystals start to grow in the freezing water and solutes -- solid particles dissolved in the water -- get forced out into the remaining liquid.

This can result in unwanted high concentrations of solutes, such as salt, which can be very damaging to the tissue," said Dr Lorna Dougan from the University of Leeds, who led the study. "The addition of cryoprotectants, such as glycerol, lowers the freezing temperature of water and prevents crystallisation by producing a 'syrupy' semi-solid state. The challenge is to know which cryoprotectant molecule to use and how much of it is necessary.

"We want to get this right so that we recover as much of the biological material as possible after re-thawing. This has massive cost implications, particularly for the pharmaceutical industry because at present they lose a large proportion of their viable drug every time they freeze it."

Dr Dougan and her team tested a range of different osmolytes to find out which ones are most effective at protecting the 3D structure of a protein. They used an atomic force microscope to unravel a test protein in a range of different osmolyte environments to find out which ones were most protective. They discovered that smaller molecules, such as glycerol, are more effective than larger ones like sorbitol and sucrose.

Dr Dougan said: "We've been able to show that if you want to really stabilise a protein, it makes sense to use small protecting osmolytes. We hope to use this discovery and future research to develop a simple set of rules that will allow scientists and industry to use the best process parameters for their system and in doing so dramatically increase the amount of material they recover from the freeze-thaw cycle."

The research was funded by the UK Engineering and Physical Sciences Research Council, the US National Institutes of Health and the China National Basic Research Program.

Story Source:

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

Journal Reference:

L. Dougan, G. Z. Genchev, H. Lu, J. M. Fernandez. Probing osmolyte participation in the unfolding transition state of a protein. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1101934108

Self-assembling electronic nano-components

Magnetic storage media such as hard drives have revolutionized the handling of information: huge quantities of data are magnetically stored while relying on highly sensitive electronic components. And data capacities are expected to increase further through ever smaller components. Together with experts from Grenoble and Strasbourg, researchers of KIT's Institute of Nanotechnology (INT) have now developed a nano-component based on a mechanism observed in nature.

What if the very tininess of a component prevented one from designing the necessary tools for its manufacture? One possibility could be to "teach" the individual parts to self-assemble into the desired product. For fabrication of an electronic nano-device, a team of INT researchers headed by Mario Ruben adopted a trick from nature: Synthetic adhesives were applied to magnetic molecules in such a way that the latter docked on to the proper positions on a nanotube without any intervention. In nature, green leaves grow through a similar self-organizing process without any impetus from subordinate mechanisms. The adoption of such principles to the manufacture of electronic components is a paradigm shift, a novelty.

The nano-switch was developed by a European team of scientists from Centre National de la Recherche Scientifique (CNRS) in Grenoble, Institut de Physique et Chimie des Matériaux at the University of Strasbourg, and KIT's INT. It is one of the invention's particular features that, unlike the conventional electronic components, the new component does not consist of materials such as metals, alloys or oxides but entirely of soft materials such as carbon nanotubes and molecules.

Terbium, the only magnetic metal atom that is used in the device, is embedded in organic material. Terbium reacts highly sensitively to external magnetic fields. Information as to how this atom aligns along such magnetic fields is efficiently passed on to the current flowing through the nanotube. The Grenoble CNRS research group headed by Dr. Wolfgang Wernsdorfer succeeded in electrically reading out the magnetism in the environment of the nano-component. The demonstrated possibility of addressing electrically single magnetic molecules opens a completely new world to spintronics, where memory, logic and possibly quantum logic may be integrated.

The function of the spintronic nano-device is described in the July issue of Nature Materials (DOI number: 10.1038/Nmat3050)for low temperatures of approximately one degree Kelvin, which is -272 degrees Celsius. Efforts are taken by the team of researchers to further increase the component's working temperature in the near future.

Story Source:

The above story is reprinted (with editorial adaptations) from materials provided by Karlsruhe Institute of Technology.

Journal Reference:

M. Urdampilleta, S. Klyatskaya, J-P. Cleuziou, M. Ruben, W. Wernsdorfer. Supramolecular spin valves. Nature Materials, 2011; DOI: 10.1038/nmat3050

Astronomers reach for the stars to discover new cancer therapy

ScienceDaily (June 25, 2011) — Astronomers' research on celestial bodies may have an impact on the human body.

Ohio State University astronomers are working with medical physicists and radiation oncologists to develop a potential new radiation treatment -- one that is intended to be tougher on tumors, but gentler on healthy tissue.

In studying how chemical elements emit and absorb radiation inside stars and around black holes, the astronomers discovered that heavy metals such as iron emit low-energy electrons when exposed to X-rays at specific energies.

Their discovery raises the possibility that implants made from certain heavy elements could enable doctors to obliterate tumors with low-energy electrons, while exposing healthy tissue to much less radiation than is possible today. Similar implants could enhance medical diagnostic imaging.

On June 24, at the International Symposium on Molecular Spectroscopy, Ohio State University senior research scientist Sultana Nahar announces the team's computer simulations of the elements gold and platinum, and the design of a prototype device that generates X-rays at key frequencies.

Their simulations suggest that hitting a single gold or platinum atom with a small dose of X-rays at a narrow range of frequencies -- equal to roughly one tenth of the broad spectrum of X-ray radiation frequencies -- produces a flood of more than 20 low-energy electrons.

"As astronomers, we apply basic physics and chemistry to understand what's happening in stars. We're very excited to apply the same knowledge to potentially treat cancer," Nahar said.

"We believe that nanoparticles embedded in tumors can absorb X-rays efficiently at particular frequencies, resulting in electron ejections that can kill malignant cells," she continued. "From X-ray spectroscopy, we can predict those energies and which atoms or molecules are likely to be most effective."

Nahar and Anil Pradhan, professor of astronomy at Ohio State, discovered that particular frequencies of X-rays cause the electrons in heavy metal atoms to vibrate and break free from their orbits around the nucleus, creating what amounts to an electrically charged gas, or plasma, around the atoms at the nanometer scale.

They have thus dubbed their medical concept Resonant Nano-Plasma Theranostics (RNPT) -- the latter word a merger of "therapy" and "diagnostics."

"From a basic physics point of view, the use of radiation in medicine is highly indiscriminate," Pradhan added. "Really, there has been no fundamental advance in X-ray production since the 1890s, when Roentgen invented the X-ray tube, which produces X-rays over a very wide range."

No fundamental advance, that is, until now.

"Together with long-time collaborator and medical physicist Yan Yu from Thomas Jefferson University Medical College, we've developed the RNPT methodology, which we hope will have far-reaching consequences for X-ray imaging and radiation therapy," Pradhan said.

He explained why metals such as gold or platinum display this behavior, and how hospitals can take advantage of it. The basic physics, he said, has been well understood since the 1920s.

Physicists have long known that electrons orbit the nuclei of atoms at different distances, some close to the nucleus and some farther away. When one of the close-in electrons is lost, a far-out electron may drop in to take its place, which releases energy. This is called the Auger effect, which was discovered in 1922.

Often the energy is strong enough to kick out a second electron, called an Auger electron. The same process could also result in the emission of light particles, or photons, at specific energies or frequencies, the most prominent of which are called K-alpha X-rays.

The astronomers believe that K-alpha X-ray frequencies kick the close-in electrons out of heavy metal atoms such as platinum, causing many far-out electrons to fall in, and many more electrons to be kicked out. These free Auger electrons are low in energy but great in number, and could feasibly bombard nearby malignant cells and shatter their DNA.

While typical therapeutic X-ray machines such as CT scanners generate full-spectrum X-rays, hospitals could employ RNPT using only K-alpha X-rays, which would greatly reduce a patient's radiation exposure.

That's the function of the proof-of-principle device that the team has constructed. Though the working tabletop prototype needs to be further developed, these first experiments show that the Auger effect can be used to deliver specific frequencies of X-ray radiation to heavy metal nanoparticles embedded in diseased tissue for imaging or therapy.

Gold and Platinum are only the first two elements that the team is studying in detail for the application of the RNPT methodology. Both metals are safe to use in the body. Platinum is already used in the chemotherapy drug cisplatin, where it helps deliver the drug by binding to malignant DNA.

"This work could eventually lead to a combination of radiation therapy with chemotherapy using platinum as the active agent," Pradhan said.

Cancer therapy is new territory for the astronomers. Together with Yu, they came upon the idea for RNPT when they were trying to understand the abundance of different chemical elements inside stars.

Their goal at the time was to help astronomers understand what different stars are made of, based on how radiation flows through them and emanates from them.

Astronomers already have several methods for doing this, but their results vary widely. By simulating how different elements behave when exposed to the radiation inside stars, Nahar and Pradhan hope to help astronomers determine precisely what our sun is made of.

Even for a profession as mathematically rigorous as astronomy, Nahar and Pradhan's undertaking is staggeringly large. They must calculate how every possible atom contained in a star will react to every possible wavelength of energy. They rely on the Ohio Supercomputer Center for these calculations and simulations; in fact, their research team has ranked among the biggest users of computational resources ever since the center's establishment more than two decades ago.

The simulations have started to pay off, in an astrophysical sense. They have revealed that previous observations and calculations of chemical abundances of the sun may in fact be off by as much as 50 percent.

Even more surprising to the astronomers were the results for simulating the radiation absorption by heavy metal atoms, such as iron. Iron plays the dominant role in controlling radiation flow through stars, but it is also observed in some black hole environments, where K-alpha X-rays can be detected from Earth.

"That's when we realized that the implications went way beyond atomic astrophysics," Pradhan said. "X-rays are used all the time in radiation treatments and imaging, and so are heavy metals -- just not in this way. If we could target heavy metal nanoparticles to certain sites in the body, X-ray imaging and therapy could be more powerful, reduce radiation exposure, and be much more precise."

Leading a multi-disciplinary team, Nahar, Pradhan, and Yu are working with several colleagues in the departments of radiation oncology at Ohio State and Thomas Jefferson University Medical College to further explore these medical applications.

The Ohio State collaborators include Russell Pitzer, professor emeritus of chemistry, Enam Chowdhury, senior research associate in physics, and Sara Lim, a graduate student in biophysics. They also worked with Kaile Li and Jian Wang, assistant professors in radiation oncology; former postdoctoral researchers Max Montenegro (now of the Pontificia Universidad Católica de Chile), and Chiranjib Sur (now of the high-performance computing group of IBM's India Software Lab); and graduate student Mike Mrozik in chemical physics.

This research was funded by a Large Interdisciplinary Grant award from Ohio State, and computational resources were provided by the Ohio Supercomputer Center.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Ohio State University. The original article was written by Pam Frost Gorder.

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Probing the secrets of the ryegrasses: Chemists design a route for synthesis of loline alkaloids

Loline alkaloids protect plants from attack by insects and have other interesting features that have yet to be studied in detail. Chemists from Ludwig-Maximilians-Universitaet in Munich have developed a method for the effective synthesis of these compounds, which will facilitate further investigations in biology and medicine.

Chemists from Ludwig-Maximilians-Universitaet in Munich led by Professor Dirk Trauner have developed a concise and efficient method for the synthesis of the alkaloid loline and related compounds.

Loline alkaloids are a biologically interesting group of natural products, which have unusual physicochemical and pharmacological characteristics, but are as of yet poorly understood. They are produced by fungal symbionts that infect weeds and forage grasses, and act as deterrents of insects and other herbivores.

Some of the agents synthesized by endophytic fungi are toxic to grazing animals, producing a syndrome known as the staggers. Indeed, such toxic weeds (commonly called ryegrass or cockle) were much feared in antiquity and are mentioned both by Virgil and in the New Testament.

Lolines however are comparatively innocuous to mammalian herbivores, and might therefore be of some therapeutic use. The loline alkaloid temuline has attracted particular attention in another context because it can strongly bind carbon dioxide.

Lolines are relatively small molecules and have a fairly simple structure, but chemical synthesis of the compounds has proven to be quite challenging. "Our synthetic route is highly efficient and, with a maximum of 10 steps, very short," says Dirk Trauner, who led the project. "It will allow us to make these compounds in sufficient quantities to enable their various aspects to be investigated in detail. We should then be able to dissect the complex network of interactions of the plants and their fungal parasites with insects and bacteria. We now plan to use our synthetic material to identify the receptor for loline alkaloids."

The project was carried out in the Center for Integrated Protein Science Munich (CIPSM), an LMU Cluster of Excellence.

Story Source:

The above story is reprinted (with editorial adaptations ) from materials provided by Ludwig-Maximilians-Universitaet Muenchen (LMU).

Journal Reference:

Mesut Cakmak, Peter Mayer, Dirk Trauner. An efficient synthesis of loline alkaloids. Nature Chemistry, 2011; DOI: 10.1038/nchem.1072