Remote Controlled With A Magnetic Field, Aggregates Of Plastic Particles On A Microchip Function Like Stirrers And Pumps

Sometimes physicists resort to tried and trusted model-making tricks. Scientists at the Max Planck Institute for Metals Research, the University of Stuttgart and the Colorado School of Mines have constructed micromachines using the same trick that model makers use to get ships into a bottle where the masts and rigging of the sailing ship are not erected until it is in the bottle. In the same way, the scientists link the valves, pumps and stirrers of a microlaboratory to create a micro device on a chip. To do this, they introduce colloidal particles - tiny magnetizable plastic spheres - as components into the channels on the chip. A rotating magnetic field is used to link the components into larger aggregates and set them into motion as micromachines. (Proceedings of the National Academy of Sciences (PNAS), December 2, 2008)



In the future, biologists and chemists want to avoid using bulky glass flasks, Bunsen burners and magnetic stirrers as far as possible in their experiments. Similarly to microelectronics, where electrons are steered through tiny conducting paths, they intend to perform chemical reactions in microfluidic systems, that is, chambers and channels just a few micrometers in diameter. These "labs on a chip" will then allow DNA sequences or blood samples to be analyzed much more quickly and more efficiently. As they only require tiny amounts of liquids, this approach costs much less than traditional methods, which require larger quantities of materials. These micro analytical systems would also be transportable, because their core parts take up very little space. Paramedics, for example, could analyze blood samples at the site of an accident.



Researchers working with Clemens Bechinger who is a Professor at the University of Stuttgart and a Fellow at the Max Planck Institute for Metals Research, and David Marr, a professor at the Colorado School of Mines, have now found a new way to equip these miniaturized laboratories with moving parts and how to drive the tiny machines. They introduce colloidal particles, tiny plastic spheres with a diameter of just about five micrometers, into the channels and cavities on the chip.



As the particles contain iron oxide, they group together when they are magnetized by an external magnetic field. The scientists construct the magnetic field with four coils so that the microparticles are literally remote controlled and form diamond shapes or cog wheels. "The shape they assemble into depends crucially on the geometry of the channels," explains Tobias Sawetzki, who a doctoral student is working on the project. The microparticles then remain in this shape as long as the magnetic field is switched on.



The geometry also determines the function of the aggregates. By tipping backwards and forwards, a rhombus creates openings and acts like a valve. On the other hand, if it rotates in a chamber with two inflows, it mixes the incoming liquids. The micro stirrer is also driven by a magnetic field that rotates clockwise or anticlockwise parallel to the chip. In the same way, the researchers in Stuttgart roll a cog wheel through a channel with a serrated wall. The cog wheel, which completely shuts the channel off, agitates liquid back and forth and only in combination with two valves, acts like a pump.
















"Compared to other approaches to equipping microlaboratories with moving parts, our ship-in-a-bottle technique has several advantages," says David Marr. Some scientists use pneumatic systems to pump liquids through microchannels, for example. However, this requires each component to be connected with a separate hose to the outside so that it can be supplied with compressed air. This is very complex and limits the integration density on microfluidic devices considerably, i.e. the total number of components on the chip.



With the new method, it is possible to accommodate up to 5,000 pumps on one square centimetre. Moreover, the new approach does not rely on elastic materials as are required for pneumatic pumps. "It is much easier to produce suitable chips for applications if they only consist of a single material, silicon, if at all possible," says Clemens Bechinger. As the electrical control components like the mini-coils can be fabricated based on silicon, it would be ideal to make the microchannels from the same material. This would allow for integration of all the components on one chip, as in microelectronics," says Bechinger.



Currently the researchers are still using large coils, so that all the components are driven by a single magnetic field and they all move in time with each other. However, this need not be a disadvantage as processes in many applications run in parallel; for example when the pharmaceutical industry searches for a new active ingredient amongst many thousands of substances. Furthermore, the researchers can choose the geometry of the channels so skilfully that different aggregates fulfil completely different functions in the same magnetic field. This means that the Stuttgart physicists' method offers the option of driving a complex network of individual, standalone components with only one magnetic field.







Related links:



[1] Microspheres in a magnetic field (mpg-Video: 3.2 MB) mpg/video/107819s.mpg



Original work:



Tobias Sawetzki, Sabri Rahmouni, Clemens Bechinger, David W.M. Marr

In-Situ Assembly of Linked Geometrically-Coupled Microdevices

Proceedings of the National Academy of Sciences (PNAS), December 2, 2008



Source: Clemens Bechinger


Max-Planck-Gesellschaft

Researchers Develop Vaccine Candidate That Is Successful In Blocking Simian Version Of HIV

Researchers have successfully blocked SIV, the simian version of HIV, using a new technique that could help lead to the development of an effective HIV/AIDS vaccine, the






Hildegund Ertl, a virus expert at the Wistar Institute in Philadelphia, said, "It is a very innovative approach but currently, in my mind, still far from clinical use." Ertl added that because most people have been exposed to adeno-associated viruses through cold viruses, they would be "likely to mount an immune response" to the vaccine. According to Phillip Johnson, most people have not been exposed to the strain of the adeno-associated virus that the researchers used as the carrier. He added that they "will be certainly looking at that as part of our Phase I testing in humans" (Philadelphia Inquirer, 5/18).


Reprinted with kind permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation.

© 2009 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

First Science From The Compact Light Source: A Miniature Synchrotron For Your Home Lab

In 2004 Lyncean Technologies announced the construction of the Compact Light Source (CLS), a miniature synchrotron which uses inverse Compton scattering to produce high-intensity, tunable, near-monochromatic x-ray beams. The CLS was designed to bring state-of-the-art protein structure determination to the home laboratory - but it has also promised to have a broad impact across the spectrum of x-ray science.



Today, 7th January, at the 39th Winter Colloquium on the Physics of Quantum Electronics, Ronald Ruth, Ph.D., president of Lyncean Technologies, announced that the CLS has started delivering on this promise by achieving three key milestones using its unique x-ray beam: First scientific publication from the CLS featured by the Journal of Synchrotron Radiation on its January 2009 cover; first micro-tomographic images from the CLS; and first protein crystallography data set from the CLS.



The Compact Light Source prototype effort was funded by the National Institute of General Medical Sciences (NIGMS) Small Business Innovation Research (SBIR) program as an advanced technology related to the NIGMS Protein Structure Initiative (PSI). The CLS technology is based on an electron beam stored in a miniature storage ring colliding repeatedly with an opposing infrared light pulse stored in a high-finesse cavity. Each collision produces x-rays through inverse Compton scattering. The entire x-ray source fits in a 10x25 ft room similar in size to those used for Magnetic Resonance Imaging in medical clinics.



The first scientific publication using the CLS x-ray beam employs a technique called Differential Phase Contrast Imaging (DPCI) developed by Professor Franz Pfeiffer and collaborators at the Paul Scherrer Institute in Switzerland. DPCI uses a pair of micron-scale gratings to create two images, one sensitive to the phase of the x-ray wave front and the other sensitive to the local scattering power. This technique has been primarily developed at x-ray beam lines in large synchrotrons, and it relies on a small point-like x-ray source to achieve the coherence necessary for the fringes. The Compact Light Sources has an x-ray beam that is a perfect match for the technique.



Prof. Pfeiffer explained the motivation for imaging with the CLS x-ray beam, "High-resolution, soft-tissue imaging has been pursued at the large synchrotrons for the past 15 years, but to be useful to the biomedical community, the new methods must be able to use x-ray sources that are laboratory or clinical in scale. Differential Phase Contrast Imaging can use the full intensity of the CLS beam and can take advantage of its tiny source size and moderate divergence to image a field of view in the 10 cm range with very small pixel size. This will first open research and development applications such as small animal imaging, the study of tumor growth models or the development of Alzheimer's plaques in brain samples. Clinical applications might extend from mammography to osteoarthritis."
















"We are only just beginning to exploit the benefits of the CLS for DPCI," continued Pfeiffer, "The JSR paper shows results from the very first experiments using the CLS for DPCI. Since then, we have also performed the first computed tomography using the CLS x-ray beam, and we are planning our next round of experiments this spring with higher x-ray energy (20 keV), higher intensity, and finer resolution."



In the second round of the Protein Structure Initiative, further CLS development was included in the Accelerated Technology Center for Gene to 3D Structure (ATCG3D, ATCG3D) supported by both NIGMS and the National Center for Research Resources (NCRR). "The focus of the CLS development has been towards protein crystallography," said Professor Ruth, "and with the ATCG3D Beta CLS we had the opportunity to improve performance and reliability. We now have the Beta CLS nearly ready for installation and further development."



"Using many of the ATCG3D CLS subsystems together with the prototype CLS", Ruth continued, "we saw our first protein diffraction in November and on our second crystal, we collected a data set with 3 Г… resolution. This was made possible by close collaboration with ATCG3D and in particular with Dr. Michael McCormick of the Peter Kuhn and Ray Stevens laboratory at The Scripps Research Institute. After the ATCG3D Beta CLS is commissioned, we will improve performance to make data collection rapid and routine."


Dr. Lance Stewart, director of ATCG3D and President of deCODE biostructures, commented on the imaging results and the first crystallography at the CLS, "The ATCG3D is very pleased to have had the opportunity to help develop the Compact Light Source. I believe the CLS technology will be important for both soft tissue imaging and protein crystallography."



"With the publication of the first scientific results and the collection of the first set of crystallography data using the CLS, the instrument has demonstrated its potential to have a broad impact on biomedical research," said Jeremy M. Berg, Ph.D., director of NIGMS. "The wide availability of an intense, tunable x-ray tool could transform numerous fields of research by improving access to a key resource."







Lyncean Technologies, Inc. is located in Palo Alto, California. It was founded in 2001 by Stanford Professor Ronald Ruth, Jeffrey Rifkin, M.A. and Rod Loewen, Ph.D. The Compact Light Source concept is based on research performed earlier by Prof. Ruth, Dr. Zhirong Huang and Dr. Rod Loewen at Stanford Linear Accelerator Center and Stanford University. For more information visit lynceantech.



39th Winter Colloquium on the Physics of Quantum Electronics (pqeconference/pqe2009/)



Journal of Synchrotron Radiation January cover (journals.iucr/s/issues/2009/01/00/issconts.html)



Source: Ronald Ruth


Lyncean Technologies, Inc.

JDRF-Funded Research Advances Potential For Regeneration As A Possible Cure For Type 1 Diabetes

A hormone responsible for the body's stress response is also linked to the growth of insulin-producing cells in the pancreas, according to JDRF- funded researchers at the Salk Institute for Biological Studies in California. The findings are the latest advances to underscore the potential for regeneration as a key component of a possible cure for type 1 diabetes.



The research, which was published in the Proceedings of the National Academy of Sciences, was led by Wylie Vale, Ph.D., Professor and Head of the Clayton Laboratories for Peptide Biology and Mark O. Huising, Ph.D., a postdoctoral fellow at the Clayton Foundation Laboratories. The Juvenile Diabetes Research Foundation was a funder of the study.



According to Patricia Kilian, Ph.D., Program Director for Regeneration at JDRF, the study showed that the stress hormone could increase the rate at which insulin-producing cells in the pancreas expand in animal models. These findings reinforce the potential of regeneration as a cure for diabetes and provide insights for discovering new approaches to treat people with diabetes by restoring or regenerating their ability to produce insulin.



Regeneration Research



Among the fastest-growing scientific areas JDRF supports is research aimed at regenerating insulin producing cells in people who have diabetes (as opposed to transplanting cells from organ donors or other sources). This involves triggering the body to grow its own new insulin producing cells, either by copying existing ones - some are usually still active, even in people who have had diabetes for decades - or causing the pancreas to create new ones.



JDRF has become a leader in this new and exciting research field, funding a wide range of research projects such as the Salk Institute study and creating an innovative diabetes drug discovery and development partnership with the Genomics Institute of the Novartis Foundation (GNF), focused on regeneration approaches. With a team of 550 scientists and associates and an impressive track record of success in translational research, GNF applies innovative technologies to the discovery of new or improved therapeutics for people.



In addition to regenerating or replacing insulin producing cells, a cure for type 1 diabetes will also involve stopping the autoimmune attack that causes diabetes, and reestablishing excellent glucose control.



Role of Stress Hormones in Insulin Producing Cells



Research conducted by Dr. Vale's laboratory since the 1980s established the role of the hormone CRF (corticotropin-releasing factor) in regulating the stress response in people. With this research, the team now reports that CRF has a direct effect on how insulin producing cells in the pancreas function and grow.



"We found that beta cells in the pancreas actually express the receptor for CRF," explains Dr. Huising. "And once we had established the presence of CRF in these cells, we started filling in the blanks, trying to learn as much as we could."



These results showed that when beta cells are exposed to the hormone, and to high levels of blood sugar, they will produce and release insulin. Working in collaboration with researchers at the Panum Institute in Copenhagen, the investigators discovered that these insulin producing cells proliferate when exposed to CRF.



"Being able to stimulate beta cells to divide a little faster may be part of a solution that may ultimately, hopefully, allow management of type 1 diabetes," Dr. Vale says. "But because it is an autoimmune condition, making the cells divide won't be enough. That is why researchers are working hard to solve the problem of destruction of beta cells."



Source:

Jill Lubarsky

Juvenile Diabetes Research Foundation International

Study Shows How The Brain Handles Pleasant And Aversive Stimuli

Whether it's a mugger or a friend who jumps out of the bushes, you're still surprised. But your response -- to flee or to hug -- must be very different. Now, researchers have begun to distinguish the circuitry in the brain's emotion center that processes surprise from the circuitry that processes the aversive or reward "valence" of a stimulus.



C. Daniel Salzman and colleagues published their findings in the September 20, 2007 issue of the journal Neuron, published by Cell Press.



"Animals and humans learn to approach and acquire pleasant stimuli and to avoid or defend against aversive ones," wrote the researchers. "However, both pleasant and aversive stimuli can elicit arousal and attention, and their salience or intensity increases when they occur by surprise. Thus, adaptive behavior may require that neural circuits compute both stimulus valence -- or value -- and intensity."



The researchers concentrated their study on the amygdala, known to be the brain center that processes the emotional substance of sensory input and helps shape behavioral response to that input.



In their studies, which used monkeys, the researchers performed two types of experiments as they recorded the electrical activity of neurons in the animals' amygdala. In one experiment, they taught the monkeys to associate a pattern on a TV monitor with either the rewarding experience of a sip of water or an unpleasant puff of air to the face. The researchers measured how well the monkeys learned the association by recording how frequently the animals anticipated the water sip or the air puff by, respectively, licking the water spout or blinking. This experiment was intended to establish whether there were specific amygdala neurons activated by rewarding or aversive stimuli.



In the other experiment, the researchers surprised the monkeys by randomly delivering either the water sip or the air puff -- which aimed to establish whether the amygdala harbored specific surprise-processing circuitry.



The researchers' analyses of the activity of the amygdala neurons did reveal different types of neurons. Some neurons responded to either the reward or the aversive stimulus, but not both. However, the activity of distinctly different sets of neurons was affected by expectation of either a reward or an aversive experience.



"These different neuronal populations may subserve two sorts of processes mediated by the amygdala: those activated by surprising reinforcements of both valences -- such as enhanced arousal and attention -- and those that are valence-specific, such as fear or reward-seeking behavior," wrote the researchers.



They concluded that "These different types of response properties may underlie the role of the amygdala in multiple processes related to emotion, including reinforcement learning, attention, and arousal. Future work must develop experimental approaches for unraveling the complex anatomical circuitry and mechanisms by which amygdala neurons influence learning and the many emotional processes related to the valence and intensity of reinforcing stimuli."







The researchers include Marina A. Belova, Joseph J. Paton, and Sara E. Morrison of Columbia University in New York and C. Daniel Salzman of Columbia University Medical Center and the New York State Psychiatric Institute in New York.



This work was supported by the NIMH, NIDA, and the Klingenstein, Keck, Sloan, James S. McDonnell, and NARSAD foundations, and by a Charles E. Culpeper Scholarship to C.D.S. J.J.P. received support from NICHD and NEI institutional training grants. S.E.M. received support from the NSF.



Belova et al.: "Expectation Modulates Neural Responses to Pleasant and Aversive Stimuli in Primate Amygdala." Publishing in Neuron 55, 970-984, September 20, 2007. DOI 10.1016/j.neuron.2007.08.004. neuron/



Source: Nancy Wampler


Cell Press

New Findings Support Warburg Theory Of Cancer

German scientist Otto H. Warburg's theory on the origin of cancer earned him the Nobel Prize in 1931, but the biochemical basis for his theory remained elusive.



His theory that cancer starts from irreversible injury to cellular respiration eventually fell out of favor amid research pointing to genomic mutations as the cause of uncontrolled cell growth.



Seventy-eight years after Warburg received science's highest honor, researchers from Boston College and Washington University School of Medicine report new evidence in support of the original Warburg Theory of Cancer.



A descendant of German aristocrats, World War I cavalry officer and pioneering biochemist, Warburg first proposed in 1924 that the prime cause of cancer was injury to a cell caused by impairment to a cell's power plant - or energy metabolism - found in its mitochondria.



In contrast to healthy cells, which generate energy by the oxidative breakdown of a simple acid within the mitochondria, tumors and cancer cells generate energy through the non-oxidative breakdown of glucose, a process called glycolysis. Indeed, glycolysis is the biochemical hallmark of most, if not all, types of cancers. Because of this difference between healthy cells and cancer cells, Warburg argued, cancer should be interpreted as a type of mitochondrial disease.



In the years that followed, Warburg's theory inspired controversy and debate as researchers instead found that genetic mutations within cells caused malignant transformation and uncontrolled cell growth. Many researchers argued Warburg's findings really identified the effects, and not the causes, of cancer since no mitochondrial defects could be found that were consistently associated with malignant transformation in cancers.



Boston College biologists and colleagues at Washington University School of Medicine found new evidence to support Warburg's theory by examining mitochondrial lipids in a diverse group of mouse brain tumors, specifically a complex lipid known as cardiolipin (CL). They reported their findings in the December edition of the Journal of Lipid Research.



Abnormalities in cardiolipin can impair mitochondrial function and energy production. Boston College doctoral student Michael Kiebish and Professors Thomas N. Seyfried and Jeffrey Chuang compared the cardiolipin content in normal mouse brain mitochondria with CL content in several types of brain tumors taken from mice. Bioinformatic models were used to compare the lipid characteristics of the normal and the tumor mitochondria samples. Major abnormalities in cardiolipin content or composition were present in all types of tumors and closely associated with significant reductions in energy-generating activities.



The findings were consistent with the pivotal role of cardiolipin in maintaining the structural integrity of a cell's inner mitochondrial membrane, responsible for energy production. The results suggest that cardiolipin abnormalities "can underlie the irreversible respiratory injury in tumors and link mitochondrial lipid defects to the Warburg theory of cancer," according to the co-authors.



These findings can provide insight into new cancer therapies that could exploit the bioenergetic defects of tumor cells without harming normal body cells.







Seyfried, Chuang and Kiebish were joined by co-authors Xianlin Han and Hua Cheng from the Washington University School of Medicine, Department of Internal Medicine, in St. Louis.



The paper, "Cardiolipin and Electron Transport Chain Abnormalities in Mouse Brain Tumor Mitochondria: Lipidomic Evidence Supporting the Warburg Theory of Cancer," can be viewed at: jlr/cgi/content/full/49/12/2545



Source: Ed Hayward


Boston College

Seminal Finding Has Major Implications For The Development Of New And Better Vaccines

A research team led by the La Jolla Institute for Allergy & Immunology has identified the specific gene which triggers the body to produce disease-fighting antibodies -- a seminal finding that clarifies the exact molecular steps taken by the body to mount an antibody defense against viruses and other pathogens. The finding, published online today in the prestigious journal Science, has major implications for the development of new and more effective vaccines. The La Jolla Institute's Shane Crotty, Ph.D., was the lead scientist on the team, which also included researchers from Yale University.



"The finding is enormous in terms of its long-term benefit to science and society as a whole because it illuminates a pivotal piece of the vaccine development puzzle -- that is, 'what is the molecular switch that tells the body to create antibodies?' Dr. Crotty has pinpointed the BCL6 gene and, in doing so, has answered a critical question that has long been sought by the scientific community," said Mitchell Kronenberg, Ph.D., president & scientific director of the La Jolla Institute, a nonprofit biomedical research institute. Dr. Kronenberg said this knowledge opens the door to developing ways to boost antibody production, thereby creating stronger and more effective vaccines.



Rafi Ahmed, Ph.D., director of the Emory Vaccine Center, and a professor of microbiology and immunology at the Emory University School of Medicine, called the finding an "important breakthrough."



"Dr. Crotty has defined the gene that regulates the formation of certain CD4 T cells," said Dr. Ahmed. "Those cells are very critical for antibody production, so describing what regulates the birth of those cells is clearly an important discovery."



Pamela L. Schwartzberg, M.D., Ph.D., a senior investigator in the Cell Signaling Section of the National Human Genome Research Institute, part of the National Institutes of Health, called the discovery a major step forward in the area of vaccine development. "This finding defines the master regulator (gene) that triggers an elaborate cellular interaction necessary to get effective long-term antibody responses, which are required for most successful vaccines," she said. "In making this discovery, Dr. Crotty and his fellow researchers at Yale have made a major contribution that will help provide critical insight into the processes important for successful vaccination and effective immune responses."



The finding is outlined in a paper entitled, "Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper (TFH) cell differentiation." Yale scientist Joseph Craft, M.D., led the Yale research team, which contributed to the study.



Antibodies, Dr. Kronenberg explained, may be thought of as the body's smart bombs, which seek out infectious agents and tag them for destruction. Twenty-five human vaccines currently exist worldwide, 23 of those work by triggering the production of antibodies. "The scientific community has known for many years that antibodies were key to vaccine development and fighting infections," he continued. "But we didn't know exactly how the process worked at the cellular level and it has long been the subject of speculation, debate and intense interest."
















Dr. Crotty said it has been well established that antibody production is a multi-step process that involves interactions between several cellular players, key among them CD4 "helper" T cells, which are disease-fighting white blood cells that tell other cells to produce antibodies in response to infections. "There were different flavors of these CD4 helper T cells and, for many years, we, in the scientific community, thought that one of the four varieties of CD4 helper type 2 cells (known as TH-2 cells) triggered the antibody process. But about 10 years ago, scientists realized this was incorrect and that there must exist a fifth variety of CD4 helper T cell that initiated antibody production. It was named TFH."



Dr. Crotty's team set out to understand the inner workings of the TFH pathway. "We discovered that the BCL6 gene was like an on and off switch, or master regulator, in this process. In a series of experiments, we showed that if you turn on this gene, you get more CD4 T helper cells (the TFH type) and it's those cells that are telling the B cells to produce antibodies," he said.



Dr. Crotty's group also tested the finding by using a cellular mechanism to turn off the BCL6 gene. Turning off the gene stopped the production of the TFH cells. "Without this genetic trigger, no TFH cells were produced and consequently no antibodies." The researchers also found that the more TFH cells produced, the greater the antibody response.



Yale researchers, who were collaborators on the study, also tested and proved the finding by deleting the BCL6 gene. "Beautifully, they got the same results - antibody production ceased," said Dr. Crotty.



The finding also may have implications for rheumatoid arthritis and some other autoimmune diseases. "Some autoimmune diseases are triggered by antibody-induced inflammation," said Dr. Crotty. "The ability to turn antibody production off may also offer therapeutic opportunities for these people."



Source:
Bonnie Ward


La Jolla Institute for Allergy and Immunology