A handheld, ultra-portable device that can recognize and immediately report on a wide variety of environmental or medical compounds may eventually be possible, using a method that incorporates a mixture of biologically tagged nanowires onto integrated circuit chips, according to Penn State researchers.
"Probably one of the most important things for connecting to the circuit is to place the wires accurately," says Theresa S. Mayer, professor of electrical engineering and director of Penn State's Nanofabrication Laboratory. "We need to control spatial placement on the chip with less than a micron of accuracy."
Using standard chip manufacturing, each type of nanowire would be placed on the board in a separate operation. Using the researchers' bottom-up method, they can place three different types of DNA-coated wires where they wanted them, with an error rate of less than 1 percent.
"This approach can be used to simultaneously detect different pathogens or diseases based on their nucleic acid signatures," says Christine D. Keating, associate professor of chemistry.
"Device components such as nanowires can be synthesized from many different materials and even coated with biological molecules prior to assembling them onto a chip," the researchers note in Science. They add that positioning the nanowires accurately is still difficult using conventional methods.
Using their assembly method, the researchers can place specific nanowires in assigned areas. They begin with a chip with tiny rectangular depressions in the places they wish to place the nanowires. They then apply an electrical field between electrodes that define the area where they want the nanowires to assemble. The Penn State researchers inject a mixture of the tagged nanowires and a liquid over the top of the chip. The nanowires are attracted to the area with an electric field and they fall into the proper tiny wells.
"We do not need microfluidic channels to control where each nanowire type goes," says Mayer. "We can run the solution over the whole chip and its wires will only attach where they are supposed to attach. This is important for scale-up."
The researchers then move the electric field and position the next tagged nanowires. In this proof-of-concept experiment, the different tagged wires were placed in rows, but the researchers say that they could be placed in a variety of configurations.
After all the wires are in place, they can be made into a variety of devices including resonators or field effect transistors that can be used to detect nucleic acid targets.
While the researchers have not yet connected each individual device to the underlying circuitry, they did test their chip to ensure that the wires assembled in the proper locations. They immersed the chip in a solution containing DNA sequences complementary to the three virus-specific sequences on the nanowires. Because they tagged the complimentary DNA with three differently colored fluorescent dyes, the attached DNA showed that the wires were in the proper places.
The researchers believe that their assembly method is extremely flexible, capable of placing a variety of conducting and non-conducting wires with a wide array of coatings.
"The eventual idea would be to extend the method to more nanowire types, such as different DNA sequences or even proteins, and move from fluorescence to real-time electrical detection on the chip," says Keating.
Researchers working on this project include Mayer; Keating; Thomas J. Morrow, graduate student in chemistry; Jaekyun Kim, graduate student in electrical engineering; and Mingwei Li, recent graduate student in electrical engineering. The National Science Foundation and the National Institutes of Health supported this work.
Source: A'ndrea Elyse Messer
Penn State
вторник, 31 мая 2011 г.
понедельник, 30 мая 2011 г.
A Serial Founder Effect Model For Human Settlement Out Of Africa
The increasing abundance of human genetic data has shown that the geographic patterns of worldwide genetic diversity are best explained by human expansion out of Africa.
We model human population expansion from a single origin in Africa with multiple subsequent bottleneck events, a process called the serial founder effect.
Through improved simulations, in which we separate colonization events from exchange between neighboring populations, we estimate the range of colonization and exchange rates that best explain key statistics from published data on worldwide variation in microsatellites.
With these estimated parameter values, our results match the observed linear decay of genetic diversity with geographic distance from the origin of expansion.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
Proceedings of the Royal Society B: Biological Sciences
We model human population expansion from a single origin in Africa with multiple subsequent bottleneck events, a process called the serial founder effect.
Through improved simulations, in which we separate colonization events from exchange between neighboring populations, we estimate the range of colonization and exchange rates that best explain key statistics from published data on worldwide variation in microsatellites.
With these estimated parameter values, our results match the observed linear decay of genetic diversity with geographic distance from the origin of expansion.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
Proceedings of the Royal Society B: Biological Sciences
воскресенье, 29 мая 2011 г.
Study Reveals A "Missing Link" In Immune Response To Disease
The immune system's T cells have the unique responsibilities of being both jury and executioner. They examine other cells for signs of disease, including cancers or infections, and, if such evidence is found, rid them from the body. Precisely how T cells shift so swiftly from one role to another, however, has been a mystery.
In a new study, investigators at Dana-Farber Cancer Institute, Harvard Medical School, and the Massachusetts Institute of Technology used an array of technique including "optical tweezers" that exploit laser light to press molecules against surface structures found on T cells to find out what operates the switch. Their answer: sheer mechanical force. Hence, the T cell receptor is a mechanosensor.
When a T cell's "receptors" lock onto their targeted structures called antigens on the surface of a diseased cell, parts of the receptors bend in a way that signals the T cell to change from disease scanning to disease-fighting mode, the researchers report. (Antigens are made of peptides bound to histocompatibility proteins, or pMHCs.) They also found that after T cell receptors (TCRs) and antigens meet, an additional force generated during scanning triggers the T cell's response to disease.
Their findings will be published in the Nov. 6 issue of the Journal of Biological Chemistry and currently are available on the journal's Web site.
"The study fills a major gap in our understanding of the molecules that make up the TCR the role they play in recognizing abnormal antigens and in subsequently activating a T cell to attack diseased cells," says senior author Ellis L. Reinherz, MD, of Dana-Farber and Harvard Medical School. "Our findings explain how TCRs can detect 'a needle in a haystack,' enabling T cells to identify infected or cancerous cells that may look very similar to normal cells, and destroy the diseased cells for the good of the body. Distinguishing between cells that belong in the body from those that don't is the key function of T cells, a discriminative task mediated by their TCRs."
Understanding the details of T cell activation opens the way to development of better immune-based therapies against viral infections and cancers, the authors state. "Vaccines have shown a great deal of promise as cancer treatments, but they need to be made more efficient," says Reinherz. "This fundamental discovery offers important insights that may make it possible to target such vaccines precisely, destroying cancer cells without the harsh side effects of more traditional therapies."
Reinherz says that a broader range of tumor antigens can be selected as potential targets because of the intrinsic sensitivity of the TCR triggering mechanism revealed by this study. Likewise, the discovery offers promise for the development of T cell-based vaccines for infectious disease prevention, currently an area almost exclusively restricted to antibody-based approaches. Antibodies target regions of viruses that vary substantially in many cases, requiring alterations of vaccines, as in the annual flu vaccines. This is not the case for T cell-based therapies, since they can target antigens that don't vary among diverse strains of the same type of virus.
Disease inspectors
T cells are white blood cells that patrol the bloodstream and body's organs for signs of disease, a process termed immune surveillance. When they encounter another cell, they "frisk" it to determine if it is normal or infected, cancerous, or foreign to the body. This inspection takes the form of the T cell brushing against the surface of the other cell. The T cell's surface bristles with receptors intricate webs of proteins designed to snag specific antigens, much as a lock accepts only certain keys. Each T cell displays a distinct TCR capable of binding to a specific antigen. The millions of T cells within the bloodstream protect people from a wide variety of invading germs or cells altered by cancerous changes.
TCRs are built of eight individual molecules. Investigators have sought to uncover the basic mechanics of the coupling between TCR and antigen by exploring the role of these eight molecules in recognizing foreign antigens and activating T cells' disease-fighting abilities.
First, immunologists identified monoclonal antibodies (mAbs) that target a portion of the TCR known as CD3 subunits involved in T cell activation. They determined which anti-CD3 mAbs activate T cells and which others are non-stimulatory. Using recombinant molecular biology, they generated pMHCs specific for, or irrelevant to, a particular TCR.
Next, structural biologists led by Harvard Medical School's Gerhard Wagner, PhD, used Nuclear Magnetic Resonance techniques to determine the shape of the TCR and the arrangement of its component molecules. Biomechanics scientists led by Matthew Lang, PhD, of MIT then devised a set of experiments involving mAbs and pMHC molecules.
The experiments sought to mimic, under controlled conditions, what normally happens when the TCR encounters an antigen from a diseased cell. The mAbs or pMHCs were mounted on tiny beads called microspheres that can be guided into place by laser beams. The mAbs and pMHCs were brought into contact with TCRs on T cells. By adjusting the angle of the laser beams, researchers could subtly alter the strength and direction with which the TCR and mAb or TCR and pMHC were brought together.
They found that although certain mAbs may bind quite well to the TCR, they were unable to activate the T cells if they bound in a perpendicular fashion that is, in a mode similar to pMHC binding to the TCR. The activation occurred only after the mAb or PMHC bound to the TCR was dragged along the T cell surface with optical tweezers. Likewise, application of force to other surface molecules including the co-receptor molecule CD8, failed to activate T cells.
The authors also observed that when certain anti CD3 mAbs attached diagonally beneath a lever-like portion of the TCR, the T cell was signaled to activate without any additional force application. These mAbs bind to the most sensitive part of the TCR, suggesting how the relay of TCR signals operates via its various component parts.
"Our findings with mAbs demonstrate that TCR activation function depends on the angle at which anti-CD3 mAb binding takes place," says the study's lead author, Sun Taek Kim, PhD, of Dana-Farber and Harvard. "The mechanical energy generated by diagonal binding is converted into a signal for activating the T cell."
Kim explains that as a T cell scans the surface of antigen-displaying cells in the body looking for foreign intruders such as viruses or dangerous cancerous mutations, the binding of the TCR by pMHC pulls on the TCR. This dual "ligation plus scanning" operation converts a pull to a push, much like opening a flip lid on a can of soda. This diagonal force on the lever is equivalent to that given spontaneously by the stimulatory anti-CD3 mAb. Once the T cell recognizes its target antigen, T cell movement ceases and the cell transitions from its search mode into destroy mode.
"Immune system-based therapies such as cancer vaccines work by increasing the strength of the immune response to disease through expanding the number of T cells that see a particular tumor antigen," Reinherz explains. "Our findings concerning the mechanosensor function of the TCR imply that specific target antigens can be expressed at very low levels on tumor cells and still be recognized efficiently by these T cells. With this insight, the number of tumor target antigens for cancer-based vaccine therapies can be increased."
The study's co-authors include Maki Touma, PhD, of Dana-Farber and Harvard Medical School; Koh Takeuchi, PhD, Zhen-Yu Sun, PhD, and Amr Fahmy, PhD, of Harvard Medical School; and Carlos Castro, PhD, of MIT.
The study was supported by grants from the National Institutes of Allergy and Infectious Diseases.
Source: Dana-Farber Cancer Institute
In a new study, investigators at Dana-Farber Cancer Institute, Harvard Medical School, and the Massachusetts Institute of Technology used an array of technique including "optical tweezers" that exploit laser light to press molecules against surface structures found on T cells to find out what operates the switch. Their answer: sheer mechanical force. Hence, the T cell receptor is a mechanosensor.
When a T cell's "receptors" lock onto their targeted structures called antigens on the surface of a diseased cell, parts of the receptors bend in a way that signals the T cell to change from disease scanning to disease-fighting mode, the researchers report. (Antigens are made of peptides bound to histocompatibility proteins, or pMHCs.) They also found that after T cell receptors (TCRs) and antigens meet, an additional force generated during scanning triggers the T cell's response to disease.
Their findings will be published in the Nov. 6 issue of the Journal of Biological Chemistry and currently are available on the journal's Web site.
"The study fills a major gap in our understanding of the molecules that make up the TCR the role they play in recognizing abnormal antigens and in subsequently activating a T cell to attack diseased cells," says senior author Ellis L. Reinherz, MD, of Dana-Farber and Harvard Medical School. "Our findings explain how TCRs can detect 'a needle in a haystack,' enabling T cells to identify infected or cancerous cells that may look very similar to normal cells, and destroy the diseased cells for the good of the body. Distinguishing between cells that belong in the body from those that don't is the key function of T cells, a discriminative task mediated by their TCRs."
Understanding the details of T cell activation opens the way to development of better immune-based therapies against viral infections and cancers, the authors state. "Vaccines have shown a great deal of promise as cancer treatments, but they need to be made more efficient," says Reinherz. "This fundamental discovery offers important insights that may make it possible to target such vaccines precisely, destroying cancer cells without the harsh side effects of more traditional therapies."
Reinherz says that a broader range of tumor antigens can be selected as potential targets because of the intrinsic sensitivity of the TCR triggering mechanism revealed by this study. Likewise, the discovery offers promise for the development of T cell-based vaccines for infectious disease prevention, currently an area almost exclusively restricted to antibody-based approaches. Antibodies target regions of viruses that vary substantially in many cases, requiring alterations of vaccines, as in the annual flu vaccines. This is not the case for T cell-based therapies, since they can target antigens that don't vary among diverse strains of the same type of virus.
Disease inspectors
T cells are white blood cells that patrol the bloodstream and body's organs for signs of disease, a process termed immune surveillance. When they encounter another cell, they "frisk" it to determine if it is normal or infected, cancerous, or foreign to the body. This inspection takes the form of the T cell brushing against the surface of the other cell. The T cell's surface bristles with receptors intricate webs of proteins designed to snag specific antigens, much as a lock accepts only certain keys. Each T cell displays a distinct TCR capable of binding to a specific antigen. The millions of T cells within the bloodstream protect people from a wide variety of invading germs or cells altered by cancerous changes.
TCRs are built of eight individual molecules. Investigators have sought to uncover the basic mechanics of the coupling between TCR and antigen by exploring the role of these eight molecules in recognizing foreign antigens and activating T cells' disease-fighting abilities.
First, immunologists identified monoclonal antibodies (mAbs) that target a portion of the TCR known as CD3 subunits involved in T cell activation. They determined which anti-CD3 mAbs activate T cells and which others are non-stimulatory. Using recombinant molecular biology, they generated pMHCs specific for, or irrelevant to, a particular TCR.
Next, structural biologists led by Harvard Medical School's Gerhard Wagner, PhD, used Nuclear Magnetic Resonance techniques to determine the shape of the TCR and the arrangement of its component molecules. Biomechanics scientists led by Matthew Lang, PhD, of MIT then devised a set of experiments involving mAbs and pMHC molecules.
The experiments sought to mimic, under controlled conditions, what normally happens when the TCR encounters an antigen from a diseased cell. The mAbs or pMHCs were mounted on tiny beads called microspheres that can be guided into place by laser beams. The mAbs and pMHCs were brought into contact with TCRs on T cells. By adjusting the angle of the laser beams, researchers could subtly alter the strength and direction with which the TCR and mAb or TCR and pMHC were brought together.
They found that although certain mAbs may bind quite well to the TCR, they were unable to activate the T cells if they bound in a perpendicular fashion that is, in a mode similar to pMHC binding to the TCR. The activation occurred only after the mAb or PMHC bound to the TCR was dragged along the T cell surface with optical tweezers. Likewise, application of force to other surface molecules including the co-receptor molecule CD8, failed to activate T cells.
The authors also observed that when certain anti CD3 mAbs attached diagonally beneath a lever-like portion of the TCR, the T cell was signaled to activate without any additional force application. These mAbs bind to the most sensitive part of the TCR, suggesting how the relay of TCR signals operates via its various component parts.
"Our findings with mAbs demonstrate that TCR activation function depends on the angle at which anti-CD3 mAb binding takes place," says the study's lead author, Sun Taek Kim, PhD, of Dana-Farber and Harvard. "The mechanical energy generated by diagonal binding is converted into a signal for activating the T cell."
Kim explains that as a T cell scans the surface of antigen-displaying cells in the body looking for foreign intruders such as viruses or dangerous cancerous mutations, the binding of the TCR by pMHC pulls on the TCR. This dual "ligation plus scanning" operation converts a pull to a push, much like opening a flip lid on a can of soda. This diagonal force on the lever is equivalent to that given spontaneously by the stimulatory anti-CD3 mAb. Once the T cell recognizes its target antigen, T cell movement ceases and the cell transitions from its search mode into destroy mode.
"Immune system-based therapies such as cancer vaccines work by increasing the strength of the immune response to disease through expanding the number of T cells that see a particular tumor antigen," Reinherz explains. "Our findings concerning the mechanosensor function of the TCR imply that specific target antigens can be expressed at very low levels on tumor cells and still be recognized efficiently by these T cells. With this insight, the number of tumor target antigens for cancer-based vaccine therapies can be increased."
The study's co-authors include Maki Touma, PhD, of Dana-Farber and Harvard Medical School; Koh Takeuchi, PhD, Zhen-Yu Sun, PhD, and Amr Fahmy, PhD, of Harvard Medical School; and Carlos Castro, PhD, of MIT.
The study was supported by grants from the National Institutes of Allergy and Infectious Diseases.
Source: Dana-Farber Cancer Institute
суббота, 28 мая 2011 г.
Keeping Nerve Axons On Target
Neurons constituting the optic nerve wire up to the brain in a highly dynamic way. Cell bodies in the developing retina sprout processes, called axons, which extend toward visual centers in the brain, lured by attractive cues and making U-turns when they take the wrong path. How they find targets so accurately is a central question of neuroscience today.
Using the mouse visual system, a team of Salk Institute for Biological Studies investigators led by Dennis O'Leary, Ph.D., identified an unanticipated factor that helps keep retinal axons from going astray. They report in the Sept. 11 issue of Neuron that p75, a protein previously known to regulate whether neurons live or die, leads a double life as an axon guidance protein.
"Historically, we thought that factors that mediate cell survival and those controlling axon guidance were part of two separate processes," says O'Leary, a professor in the Molecular Neurobiology Laboratory, "But in this study we show a direct interaction between these two systems."
Collaborating with Kuo-Fen Lee, Ph.D., professor in the Clayton Foundation Laboratories for Peptide Biology, the O'Leary team observed a defect in mice genetically engineered to lack p75. Through their synaptic connections, retinal axons develop a two-dimensional map of the retina in their targets in the brain. In the mice lacking p75, retinal axons stopped short of their final target and formed a map that was shifted forward to the superior colliculus, a major visual center in the brain.
Such a defect in p75-null mice was puzzling: researchers have studied p75 for decades and found it associated with activities as varied as neuronal growth, survival, and degeneration. Axonal migration was not among them.
Todd McLaughlin, Ph.D., a senior research associate in the lab and co-first author, says that insight came in a eureka moment: "We realized that what we were observing in these mice was similar to what would happen if you deleted a gene called ephrin-A from the retina."
Unlike p75, ephrin-A was a well-characterized sender and receiver of axon guidance signals, but it lacked appendages normally seen on proteins controlling axon migration. p75, however, displayed those elements, suggesting that the proteins could pair up - one receiving the migration signal and the other transmitting it.
The research team then turned to biochemical analyses and with the added expertise of Tsung Song, a research associate in Dr. Lee's lab, obtained evidence that supported this hypothesis. The group found that ephrin-A and p75 complexes in axonal membranes and showed that when activated they could generate the signals required to guide axons and develop their map in the brain.
But the clincher was the "stripe assay," a classical screen for guidance molecules that repel growing axons. In it, an immature neuron is placed on a microscopic running track, just as it starts to develop an axon. When flanking lanes are carpeted with repellant factors, the sprouting axon bursts from the block but remains in its lane like a well-coached runner, avoiding neighboring tracks.
Constructing tracks made from the repulsive factor sensed by ephrin-A, the researchers confirmed that axons from normal retinal neurons stayed in their lanes when flanked by the repellant. But neurons from mice lacking p75 were unreceptive to repulsive cues: when placed on the track their axons meandered all over the field, crossing lanes and running down repellant-covered stripes.
Why retinal neurons missed the target in the p75-minus mice became clear: they lacked the cellular machinery to respond to critical repellant signals encountered in the brain and stopped migrating prematurely.
Among its myriad functions, p75's new role is a critical one. "Repulsion is probably the dominant force in axon guidance and a stronger influence than attraction," explains McLaughlin, noting that providing axons with a lot of options is not the way to build a brain. "Attraction is like finding the best seat in an empty movie theater, but repulsion is like picking the lone empty seat in a full theater."
"We have shown that ephrin-A cannot transduce an intracellular signal by itself and instead requires the co-receptor p75," summarizes Yoo-Shick Lim, Ph.D., a postdoctoral fellow in the O'Leary lab and co-first author. "This interaction could operate in numerous events in neural development."
O'Leary believes that identifying mechanisms underlying developmental events is fundamental to understanding the basis of any biological disorder. "These studies establish that two distinct molecular systems, neurotrophins and axon guidance, both critical for neural development directly collaborate to develop neural connectivity.
Findings such as these lend critical insight into how one might repair damage to the nervous system due to genetic defects, tumors or wounds to the brain or spinal cord," he says. "We hope one day to be able to repair these defects and get cells to form functional connections again."
Tsung-Chang Sung, Ph.D., of the Lee lab, and Alicia Santiago, Ph.D., formerly of the O'Leary lab, also contributed to the study. Salk professor Tony Hunter and Sourav Ghosh, a former postdoctoral fellow in the Hunter lab, helped with preliminary biochemical experiments. Funding was from a grant from the National Eye Institute and from the Joseph Alexander Foundation.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
Source: Gina Kirchweger
Salk Institute
Using the mouse visual system, a team of Salk Institute for Biological Studies investigators led by Dennis O'Leary, Ph.D., identified an unanticipated factor that helps keep retinal axons from going astray. They report in the Sept. 11 issue of Neuron that p75, a protein previously known to regulate whether neurons live or die, leads a double life as an axon guidance protein.
"Historically, we thought that factors that mediate cell survival and those controlling axon guidance were part of two separate processes," says O'Leary, a professor in the Molecular Neurobiology Laboratory, "But in this study we show a direct interaction between these two systems."
Collaborating with Kuo-Fen Lee, Ph.D., professor in the Clayton Foundation Laboratories for Peptide Biology, the O'Leary team observed a defect in mice genetically engineered to lack p75. Through their synaptic connections, retinal axons develop a two-dimensional map of the retina in their targets in the brain. In the mice lacking p75, retinal axons stopped short of their final target and formed a map that was shifted forward to the superior colliculus, a major visual center in the brain.
Such a defect in p75-null mice was puzzling: researchers have studied p75 for decades and found it associated with activities as varied as neuronal growth, survival, and degeneration. Axonal migration was not among them.
Todd McLaughlin, Ph.D., a senior research associate in the lab and co-first author, says that insight came in a eureka moment: "We realized that what we were observing in these mice was similar to what would happen if you deleted a gene called ephrin-A from the retina."
Unlike p75, ephrin-A was a well-characterized sender and receiver of axon guidance signals, but it lacked appendages normally seen on proteins controlling axon migration. p75, however, displayed those elements, suggesting that the proteins could pair up - one receiving the migration signal and the other transmitting it.
The research team then turned to biochemical analyses and with the added expertise of Tsung Song, a research associate in Dr. Lee's lab, obtained evidence that supported this hypothesis. The group found that ephrin-A and p75 complexes in axonal membranes and showed that when activated they could generate the signals required to guide axons and develop their map in the brain.
But the clincher was the "stripe assay," a classical screen for guidance molecules that repel growing axons. In it, an immature neuron is placed on a microscopic running track, just as it starts to develop an axon. When flanking lanes are carpeted with repellant factors, the sprouting axon bursts from the block but remains in its lane like a well-coached runner, avoiding neighboring tracks.
Constructing tracks made from the repulsive factor sensed by ephrin-A, the researchers confirmed that axons from normal retinal neurons stayed in their lanes when flanked by the repellant. But neurons from mice lacking p75 were unreceptive to repulsive cues: when placed on the track their axons meandered all over the field, crossing lanes and running down repellant-covered stripes.
Why retinal neurons missed the target in the p75-minus mice became clear: they lacked the cellular machinery to respond to critical repellant signals encountered in the brain and stopped migrating prematurely.
Among its myriad functions, p75's new role is a critical one. "Repulsion is probably the dominant force in axon guidance and a stronger influence than attraction," explains McLaughlin, noting that providing axons with a lot of options is not the way to build a brain. "Attraction is like finding the best seat in an empty movie theater, but repulsion is like picking the lone empty seat in a full theater."
"We have shown that ephrin-A cannot transduce an intracellular signal by itself and instead requires the co-receptor p75," summarizes Yoo-Shick Lim, Ph.D., a postdoctoral fellow in the O'Leary lab and co-first author. "This interaction could operate in numerous events in neural development."
O'Leary believes that identifying mechanisms underlying developmental events is fundamental to understanding the basis of any biological disorder. "These studies establish that two distinct molecular systems, neurotrophins and axon guidance, both critical for neural development directly collaborate to develop neural connectivity.
Findings such as these lend critical insight into how one might repair damage to the nervous system due to genetic defects, tumors or wounds to the brain or spinal cord," he says. "We hope one day to be able to repair these defects and get cells to form functional connections again."
Tsung-Chang Sung, Ph.D., of the Lee lab, and Alicia Santiago, Ph.D., formerly of the O'Leary lab, also contributed to the study. Salk professor Tony Hunter and Sourav Ghosh, a former postdoctoral fellow in the Hunter lab, helped with preliminary biochemical experiments. Funding was from a grant from the National Eye Institute and from the Joseph Alexander Foundation.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
Source: Gina Kirchweger
Salk Institute
пятница, 27 мая 2011 г.
Quantum Computers Could Excel In Modeling Chemical Reactions
Quantum computers would likely outperform conventional computers in simulating chemical reactions involving more than four atoms, according to scientists at Harvard University, the Massachusetts Institute of Technology, and Haverford College. Such improved ability to model and predict complex chemical reactions could revolutionize drug design and materials science, among other fields.
Writing in the Proceedings of the National Academy of Sciences, the researchers describe "software" that could simulate chemical reactions on quantum computers, an ultra-modern technology that relies on quantum mechanical phenomena, such as entanglement, interference, and superposition. Quantum computing has been heralded for its potential to solve certain types of problems that are impossible for conventional computers to crack.
"There is a fundamental problem with simulating quantum systems -- such as chemical reactions -- on conventional computers," says AlГЎn Aspuru-Guzik, assistant professor of chemistry and chemical biology in Harvard's Faculty of Arts and Sciences. "As the size of a system grows, the computational resources required to simulate it grow exponentially. For example, it might take one day to simulate a reaction involving 10 atoms, two days for 11 atoms, four days for 12 atoms, eight days for 13 atoms, and so on. Before long, this would exhaust the world's computational power."
Unlike a conventional computer, Aspuru-Guzik and his colleagues say, a quantum computer could complete the steps necessary to simulate a chemical reaction in a time that doesn't increase exponentially with the reaction's complexity.
"Being able to predict the outcomes of chemical reactions would have tremendous practical applications," says Ivan Kassal, a graduate student in chemical physics at Harvard. "A lot of research in drug design, materials science, catalysis, and molecular biology is still done by trial and error. Having accurate predictions would change the way these types of science are done."
The researchers demonstrate in PNAS that quantum computers would need to attain a size of about 100 qubits -- which are to quantum computers as bits are to conventional computers -- to outperform current classical supercomputers at a chemical simulation.
"This is still far beyond current prototype quantum computers," Kassal says. "And although it might take millions of quantum elementary operations on a few hundred quantum bits, our work suggests that with quantum computers that are as fast as modern conventional computers, one could simulate in seconds a chemical reaction that would take a conventional computer years."
Rather than using binary bits labeled as "zero" and "one" to encode data, as in a conventional computer, quantum computing stores information in qubits, which can represent both "zero" and "one" simultaneously. When a quantum computer is put to work on a problem, it considers all possible answers by simultaneously arranging its qubits into every combination of "zeroes" and "ones."
Since one sequence of qubits can represent many different numbers, a quantum computer would make far fewer computations than a conventional one in solving some problems. After the computer's work is done, a measurement of its qubits provides the answer.
Aspuru-Guzik and Kassal's co-authors on the PNAS paper are Stephen P. Jordan of MIT, Peter J. Love of Haverford College, and Masoud Mohseni of Harvard. The work was sponsored by the Army Research Office and the Joyce and Zlatko Balokovic Scholarship.
Source: Steve Bradt
Harvard University
Writing in the Proceedings of the National Academy of Sciences, the researchers describe "software" that could simulate chemical reactions on quantum computers, an ultra-modern technology that relies on quantum mechanical phenomena, such as entanglement, interference, and superposition. Quantum computing has been heralded for its potential to solve certain types of problems that are impossible for conventional computers to crack.
"There is a fundamental problem with simulating quantum systems -- such as chemical reactions -- on conventional computers," says AlГЎn Aspuru-Guzik, assistant professor of chemistry and chemical biology in Harvard's Faculty of Arts and Sciences. "As the size of a system grows, the computational resources required to simulate it grow exponentially. For example, it might take one day to simulate a reaction involving 10 atoms, two days for 11 atoms, four days for 12 atoms, eight days for 13 atoms, and so on. Before long, this would exhaust the world's computational power."
Unlike a conventional computer, Aspuru-Guzik and his colleagues say, a quantum computer could complete the steps necessary to simulate a chemical reaction in a time that doesn't increase exponentially with the reaction's complexity.
"Being able to predict the outcomes of chemical reactions would have tremendous practical applications," says Ivan Kassal, a graduate student in chemical physics at Harvard. "A lot of research in drug design, materials science, catalysis, and molecular biology is still done by trial and error. Having accurate predictions would change the way these types of science are done."
The researchers demonstrate in PNAS that quantum computers would need to attain a size of about 100 qubits -- which are to quantum computers as bits are to conventional computers -- to outperform current classical supercomputers at a chemical simulation.
"This is still far beyond current prototype quantum computers," Kassal says. "And although it might take millions of quantum elementary operations on a few hundred quantum bits, our work suggests that with quantum computers that are as fast as modern conventional computers, one could simulate in seconds a chemical reaction that would take a conventional computer years."
Rather than using binary bits labeled as "zero" and "one" to encode data, as in a conventional computer, quantum computing stores information in qubits, which can represent both "zero" and "one" simultaneously. When a quantum computer is put to work on a problem, it considers all possible answers by simultaneously arranging its qubits into every combination of "zeroes" and "ones."
Since one sequence of qubits can represent many different numbers, a quantum computer would make far fewer computations than a conventional one in solving some problems. After the computer's work is done, a measurement of its qubits provides the answer.
Aspuru-Guzik and Kassal's co-authors on the PNAS paper are Stephen P. Jordan of MIT, Peter J. Love of Haverford College, and Masoud Mohseni of Harvard. The work was sponsored by the Army Research Office and the Joyce and Zlatko Balokovic Scholarship.
Source: Steve Bradt
Harvard University
четверг, 26 мая 2011 г.
Novel Pathway For Antibiotic-Induced Cell Death
Scientists have identified unforeseen mechanisms by which quinolones a family of broad-spectrum antibiotics among the most widely prescribed induce bacterial cell death. The study is published online this week in Molecular Systems Biology.
It is well-known that quinolones inhibit bacterial DNA gyrase an enzyme essential to DNA replication - and induce cell death by stimulating DNA damage, impeding lesion repair and blocking replication processes. Using a systems biology approach, Jim Collins and colleagues reveal that, in addition to the expected DNA damage response, gyrase inhibition surprisingly triggers a genetic program characteristic of responses to oxidative stress and promotes the generation of deleterious hydroxyl radicals.
The authors confirm their findings by showing that chemical or genetic prevention of gyrase inhibitor-induced oxidative damage protects from the bactericidal action of quinolone antibiotics. This work will facilitate the identification of antibacterial therapies with improved bactericidal activity.
About The EUROPEAN MOLECULAR BIOLOGY ORGANIZATION (EMBO)
The European Molecular Biology Organization (EMBO) was established in 1964 with the aim to promote biosciences in Europe.
EUROPEAN MOLECULAR BIOLOGY ORGANIZATION (EMBO)
Postfach 1022.40
D-69012 Heidelberg
embo
It is well-known that quinolones inhibit bacterial DNA gyrase an enzyme essential to DNA replication - and induce cell death by stimulating DNA damage, impeding lesion repair and blocking replication processes. Using a systems biology approach, Jim Collins and colleagues reveal that, in addition to the expected DNA damage response, gyrase inhibition surprisingly triggers a genetic program characteristic of responses to oxidative stress and promotes the generation of deleterious hydroxyl radicals.
The authors confirm their findings by showing that chemical or genetic prevention of gyrase inhibitor-induced oxidative damage protects from the bactericidal action of quinolone antibiotics. This work will facilitate the identification of antibacterial therapies with improved bactericidal activity.
About The EUROPEAN MOLECULAR BIOLOGY ORGANIZATION (EMBO)
The European Molecular Biology Organization (EMBO) was established in 1964 with the aim to promote biosciences in Europe.
EUROPEAN MOLECULAR BIOLOGY ORGANIZATION (EMBO)
Postfach 1022.40
D-69012 Heidelberg
embo
среда, 25 мая 2011 г.
New Study Shows Potential To Treat Or Prevent Viral Cancers
A new study, presented at the SNM 55th Annual Meeting, shows that radioimmunotherapy (RIT) targeting viral antigens offers a novel option to treat - or even prevent - many viral cancers by targeting cancer cells expressing viral antigens or infected cells before they convert into malignancy.
"There is an urgent need to find new approaches to treating and preventing viral cancers," said Ekaterina (Kate) Dadachova, associate professor of nuclear medicine and microbiology and immunology at Albert Einstein College of Medicine, Bronx, N.Y. and lead researcher of the study, Viral Antigens as Novel Targets for Radioimmunotherapy of Viral Cancers. "The magnitude and global health-burden associated with viral cancers is only now being realized."
It is estimated that up to 25 percent of all cancers are currently linked to existing viral infections. Most of these cancers are extremely difficult to treat and cannot successfully be reduced or removed using conventional therapies or treatments. Viral cancers include cervical cancers caused by infection with a human papillomavirus (HPV), a sexually transmitted disease; hepatocellular carcinoma (HCC), a cancer of the liver; various lymphomas and carcomas in patients with AIDS/HIV; and other cancers.
According to Dadachova, this is the first time that researchers have attempted to target viral antigens on cancers, although the use of RIT for the treatment of cancer has been under development for thirty years. However, the targets of RIT therapy to date have included only "self" human antigens, which are overexpressed on the tumors but also expressed on normal tissues. Viral antigens, on the contrary, are expressed only on the tumors and nowhere else in the body.
The idea to perform the study was suggested by Dr. Arturo Casadevall, chair of the department of microbiology and immunology at Albert Einstein College of Medicine, who collaborates with Dadachova on developing radioimmunotherapy of infectious diseases and cancers. The study involved treating experimental cervical cancer and hepatocellular carcinoma in nude mice with antibodies to respective viral antigens expressed on these tumors. The antibodies were radiolabeled with 188-Rhenium - a powerful beta-emitting radionuclide. "This study demonstrates a real possibility for more specifically targeted cancer treatments," said Dadachova. "Targeting those antigens with radiolabeled molecules offers exquisite specificity - and will hopefully allow us to significantly increase the efficacy of treatment by administering more individualized doses while avoiding toxicity."
"Nuclear medicine and molecular imaging offer the ability to target disease on a truly molecular level that is unmatched by any other imaging or therapeutic modality," said Dadachova. "Targeting viral antigens with radiolabeled antibodies (or also with specific peptides or aptamers) will allow the extremely precise diagnosis of such cancers and their effective therapy. Furthermore, this approach will make possible 'molecular prevention' of viral cancers, when infected cells will be targeted before they become cancerous."
Dadachova and her team will also be recognized for this study by SNM's Young Professionals' Committee, which recognizes the contributions of significant studies to the fields of nuclear medicine and molecular imaging by young researchers. The Young Professionals' Committee Award was presented on Sunday, June 15, during a luncheon.
This study was supported by the National Institutes of Health (NIH), Center for AIDS Research (CFAR) and Albert Einstein Cancer Center (AECOM).
Scientific Paper 412: E. Dadachova, X. Wang, E. Revskaya, R.A. Bryan, A. Casadevall, Albert Einstein College of Medicine, Bronx, N.Y., "Viral Antigens as Novel Targets for Radioimmunotherapy of Viral Cancers," SNM's 55th Annual Meeting, June 14-18, 2008.
About SNM - Advancing Molecular Imaging and Therapy
SNM is an international scientific and medical organization dedicated to increasing understanding and sound practice of molecular imaging throughout the medical community and with the public. Due to the work of SNM members, molecular imaging is a vital element of today's medical practice, adding an additional dimension to diagnosis that can change the way common and devastating diseases are understood and treated.
Our more than 16,000 members set the standard for molecular imaging practice by creating procedure guidelines, sharing information through our Journal and meetings, and leading advocacy on key issues that affect imaging research and practice. For more information visit snm/.
Source: Amy Shaw
Society of Nuclear Medicine
"There is an urgent need to find new approaches to treating and preventing viral cancers," said Ekaterina (Kate) Dadachova, associate professor of nuclear medicine and microbiology and immunology at Albert Einstein College of Medicine, Bronx, N.Y. and lead researcher of the study, Viral Antigens as Novel Targets for Radioimmunotherapy of Viral Cancers. "The magnitude and global health-burden associated with viral cancers is only now being realized."
It is estimated that up to 25 percent of all cancers are currently linked to existing viral infections. Most of these cancers are extremely difficult to treat and cannot successfully be reduced or removed using conventional therapies or treatments. Viral cancers include cervical cancers caused by infection with a human papillomavirus (HPV), a sexually transmitted disease; hepatocellular carcinoma (HCC), a cancer of the liver; various lymphomas and carcomas in patients with AIDS/HIV; and other cancers.
According to Dadachova, this is the first time that researchers have attempted to target viral antigens on cancers, although the use of RIT for the treatment of cancer has been under development for thirty years. However, the targets of RIT therapy to date have included only "self" human antigens, which are overexpressed on the tumors but also expressed on normal tissues. Viral antigens, on the contrary, are expressed only on the tumors and nowhere else in the body.
The idea to perform the study was suggested by Dr. Arturo Casadevall, chair of the department of microbiology and immunology at Albert Einstein College of Medicine, who collaborates with Dadachova on developing radioimmunotherapy of infectious diseases and cancers. The study involved treating experimental cervical cancer and hepatocellular carcinoma in nude mice with antibodies to respective viral antigens expressed on these tumors. The antibodies were radiolabeled with 188-Rhenium - a powerful beta-emitting radionuclide. "This study demonstrates a real possibility for more specifically targeted cancer treatments," said Dadachova. "Targeting those antigens with radiolabeled molecules offers exquisite specificity - and will hopefully allow us to significantly increase the efficacy of treatment by administering more individualized doses while avoiding toxicity."
"Nuclear medicine and molecular imaging offer the ability to target disease on a truly molecular level that is unmatched by any other imaging or therapeutic modality," said Dadachova. "Targeting viral antigens with radiolabeled antibodies (or also with specific peptides or aptamers) will allow the extremely precise diagnosis of such cancers and their effective therapy. Furthermore, this approach will make possible 'molecular prevention' of viral cancers, when infected cells will be targeted before they become cancerous."
Dadachova and her team will also be recognized for this study by SNM's Young Professionals' Committee, which recognizes the contributions of significant studies to the fields of nuclear medicine and molecular imaging by young researchers. The Young Professionals' Committee Award was presented on Sunday, June 15, during a luncheon.
This study was supported by the National Institutes of Health (NIH), Center for AIDS Research (CFAR) and Albert Einstein Cancer Center (AECOM).
Scientific Paper 412: E. Dadachova, X. Wang, E. Revskaya, R.A. Bryan, A. Casadevall, Albert Einstein College of Medicine, Bronx, N.Y., "Viral Antigens as Novel Targets for Radioimmunotherapy of Viral Cancers," SNM's 55th Annual Meeting, June 14-18, 2008.
About SNM - Advancing Molecular Imaging and Therapy
SNM is an international scientific and medical organization dedicated to increasing understanding and sound practice of molecular imaging throughout the medical community and with the public. Due to the work of SNM members, molecular imaging is a vital element of today's medical practice, adding an additional dimension to diagnosis that can change the way common and devastating diseases are understood and treated.
Our more than 16,000 members set the standard for molecular imaging practice by creating procedure guidelines, sharing information through our Journal and meetings, and leading advocacy on key issues that affect imaging research and practice. For more information visit snm/.
Source: Amy Shaw
Society of Nuclear Medicine
вторник, 24 мая 2011 г.
Potential Test For Chocoholics
For the first time, scientists have linked the all-too-human preference for a food -- chocolate -- to a specific, chemical signature that may be programmed into the metabolic system and is detectable by laboratory tests. The signature reads 'chocolate lover' in some people and indifference to the popular sweet in others, the researchers say.
The study by Swiss and British scientists breaks new ground in a rapidly emerging field that may eventually classify individuals on the basis of their metabolic type, or metabotype, which can ultimately be used to design healthier diets that are customized to an individual's needs. The study is scheduled for publication in the Nov. 2 issue of American Chemical Society's Journal of Proteome Research, a monthly publication.
Sunil Kochhar and colleagues studied 11 volunteers who classified themselves as 'chocolate desiring' and 11 volunteers who were 'chocolate indifferent.' In a controlled clinical study, each subject -- all men -- ate chocolate or placebo over a five day period while their blood and urine samples were analyzed. The 'chocolate lovers' had a hallmark metabolic profile that involved low levels of LDL-cholesterol (so-called 'bad' cholesterol) and marginally elevated levels of albumin, a beneficial protein, the scientists say.
The chocolate lovers expressed this profile even when they ate no chocolate, the researchers note. The activity of the gut microbes in the chocolate lovers was also distinctively different from the other subjects, they add.
"Our study shows that food preferences, including chocolate, might be programmed or imprinted into our metabolic system in such a way that the body becomes attuned to a particular diet," says Kochhar, a scientist with NestlГ© Research Center in Switzerland.
"We know that some people can eat a diet that is high in steak and carbs and generally remain healthy, while the same food in others is unhealthy," he explains. "Knowing one's metabolic profile could open-the-door to dietary or nutritional interventions that are customized to your type so that your metabolism can be nudged to a healthier status."
Researchers have known for some time that metabolic status and food preferences can vary from person to person and even between different cultures. The recent growth of the new field of proteome research, which focuses on characterizing the structure and function of the complete set of proteins produced by our genes, has allowed scientists to gain a deeper understanding of the metabolic changes that occur when foods are digested, Kochhar says.
"There's a lot of information in metabolism that can be used to improve health and this information is just now being explored and tapped," the researcher says.
In the future, a test for determining one's metabolic type could be performed as part of a blood or urine test during a regular visit to the doctor, Kochhar predicts. But a reliable test to measure one's metabolic type may be five years away, as more research is still needed in this area, he notes.
Women were not included in the current study in order to avoid any metabolic variations linked to the menstrual cycle, which has been shown in studies by others to influence metabolic differences, Kochhar says. But the researchers plan to include women in future clinical trials on metabolic responses to chocolate to determine if there is a gender-specific response to the treat.
In addition to providing a better understanding of individual metabolic types, the current study could also lead to the discovery of additional biomarkers that can identify new health benefits linked to chocolate and other foods, says Kochhar, whose research was funded by NestlГ©.
The American Chemical Society -- the world's largest scientific society -- is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
Source: Michael Bernstein
American Chemical Society
The study by Swiss and British scientists breaks new ground in a rapidly emerging field that may eventually classify individuals on the basis of their metabolic type, or metabotype, which can ultimately be used to design healthier diets that are customized to an individual's needs. The study is scheduled for publication in the Nov. 2 issue of American Chemical Society's Journal of Proteome Research, a monthly publication.
Sunil Kochhar and colleagues studied 11 volunteers who classified themselves as 'chocolate desiring' and 11 volunteers who were 'chocolate indifferent.' In a controlled clinical study, each subject -- all men -- ate chocolate or placebo over a five day period while their blood and urine samples were analyzed. The 'chocolate lovers' had a hallmark metabolic profile that involved low levels of LDL-cholesterol (so-called 'bad' cholesterol) and marginally elevated levels of albumin, a beneficial protein, the scientists say.
The chocolate lovers expressed this profile even when they ate no chocolate, the researchers note. The activity of the gut microbes in the chocolate lovers was also distinctively different from the other subjects, they add.
"Our study shows that food preferences, including chocolate, might be programmed or imprinted into our metabolic system in such a way that the body becomes attuned to a particular diet," says Kochhar, a scientist with NestlГ© Research Center in Switzerland.
"We know that some people can eat a diet that is high in steak and carbs and generally remain healthy, while the same food in others is unhealthy," he explains. "Knowing one's metabolic profile could open-the-door to dietary or nutritional interventions that are customized to your type so that your metabolism can be nudged to a healthier status."
Researchers have known for some time that metabolic status and food preferences can vary from person to person and even between different cultures. The recent growth of the new field of proteome research, which focuses on characterizing the structure and function of the complete set of proteins produced by our genes, has allowed scientists to gain a deeper understanding of the metabolic changes that occur when foods are digested, Kochhar says.
"There's a lot of information in metabolism that can be used to improve health and this information is just now being explored and tapped," the researcher says.
In the future, a test for determining one's metabolic type could be performed as part of a blood or urine test during a regular visit to the doctor, Kochhar predicts. But a reliable test to measure one's metabolic type may be five years away, as more research is still needed in this area, he notes.
Women were not included in the current study in order to avoid any metabolic variations linked to the menstrual cycle, which has been shown in studies by others to influence metabolic differences, Kochhar says. But the researchers plan to include women in future clinical trials on metabolic responses to chocolate to determine if there is a gender-specific response to the treat.
In addition to providing a better understanding of individual metabolic types, the current study could also lead to the discovery of additional biomarkers that can identify new health benefits linked to chocolate and other foods, says Kochhar, whose research was funded by NestlГ©.
The American Chemical Society -- the world's largest scientific society -- is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
Source: Michael Bernstein
American Chemical Society
понедельник, 23 мая 2011 г.
MU Scientist's Nanotech Research Earns Him 'Outstanding Missourian' Award
University of Missouri scientist Kattesh Katti recently discovered how to make gold nanoparticles using gold salts, soybeans and water. Katti's research has garnered attention worldwide and the environmentally-friendly discovery could have major applications in several disciplines.
Gold nanoparticles are tiny pieces of gold, so small they cannot be seen by the naked eye. Researchers believe gold nanoparticles will be used in cancer detection and treatment, the production of "smart" electronic devices, the treatment of certain genetic eye diseases and the development of "green" automobiles.
While the nanotechnology industry is expected to produce large quantities of nanoparticles in the near future, researchers have been worried about the environmental impact of typical production methods. Commonly, nanoparticles have been produced using synthetic chemicals. Katti's process, which uses only naturally occurring elements, could have major environmental implications for the future. Since some of the chemicals currently used to make nanoparticles are toxic to humans, Katti's discovery also could open doors for additional medical fields. Having a 100-percent natural "green" process could allow medical researchers to expand the use of the nanoparticles.
"Typically, a producer must use a variety of synthetic or man-made chemicals to produce gold nanoparticles," said Katti, professor of radiology and physics in the School of Medicine and College of Arts and Science at MU, senior research scientist at the MU Research Reactor (MURR) and director of the University of Missouri Cancer Nanotechnology Platform. "To make the chemicals necessary for production, you need to have other artificial chemicals produced, creating an even larger, negative environmental impact. Our new process only takes what nature has made available to us and uses that to produce a technology already proven to have far-reaching impacts in technology and medicine."
The new discovery has created a large positive response in the scientific community. Researchers from as far away as Germany have commented on the discovery's importance and the impact it will have in the future.
"Dr. Katti's discovery sets up the beginning of a new knowledge frontier that interfaces plant science, chemistry and nanotechnology," said Herbert W. Roesky, a professor and world-renowned chemist from the University of Goettingen in Germany.
Katti and his long-time collaborator and colleague, Raghuraman Kannan, assistant professor of radiology, sowed the seeds of Nanomedicine at MU through their groundbreaking discoveries in 2004. MU now has an internationally recognized research program in nanomedicine. The research was funded by grants from the National Cancer Institute and the National Institutes of Health.
Katti's research in the field of nanomedicine, biomedicine, cancer diagnostics/therapeutics and optical imaging have earned him numerous awards and recognition. The latest honor bestowed upon Katti is the "Outstanding Missourian" award, which he will receive Tuesday, March 4 in Jefferson City. The award is presented as "acknowledgement of the most accomplished citizens of the state of Missouri" and for making an "outstanding contribution to his state or nation." He is scheduled to receive the award at the beginning of the morning session of the Missouri House of Representatives.
In a recent interview, he expressed his gratefulness for the recognition, but attributes much of the credit to others, including his wife, Kavita Katti, who is a senior research chemist at MU, and his parents in India who supported him in his education.
"I feel excited about the recognition, and I attribute my selection to our institution, my research group and my collaborators," Katti said. "This award is the culmination of several factors, including departmental leadership, a plethora of outstanding collaborators at MU, the deans and, of course, the chancellor. A faculty member could not possibly succeed just by his or her own efforts. We have been very blessed with this team effort. I am very excited to receive this recognition. I think it speaks highly of our school and of our nanomedicine program."
Source: Bryan E. Jones
University of Missouri-Columbia
Gold nanoparticles are tiny pieces of gold, so small they cannot be seen by the naked eye. Researchers believe gold nanoparticles will be used in cancer detection and treatment, the production of "smart" electronic devices, the treatment of certain genetic eye diseases and the development of "green" automobiles.
While the nanotechnology industry is expected to produce large quantities of nanoparticles in the near future, researchers have been worried about the environmental impact of typical production methods. Commonly, nanoparticles have been produced using synthetic chemicals. Katti's process, which uses only naturally occurring elements, could have major environmental implications for the future. Since some of the chemicals currently used to make nanoparticles are toxic to humans, Katti's discovery also could open doors for additional medical fields. Having a 100-percent natural "green" process could allow medical researchers to expand the use of the nanoparticles.
"Typically, a producer must use a variety of synthetic or man-made chemicals to produce gold nanoparticles," said Katti, professor of radiology and physics in the School of Medicine and College of Arts and Science at MU, senior research scientist at the MU Research Reactor (MURR) and director of the University of Missouri Cancer Nanotechnology Platform. "To make the chemicals necessary for production, you need to have other artificial chemicals produced, creating an even larger, negative environmental impact. Our new process only takes what nature has made available to us and uses that to produce a technology already proven to have far-reaching impacts in technology and medicine."
The new discovery has created a large positive response in the scientific community. Researchers from as far away as Germany have commented on the discovery's importance and the impact it will have in the future.
"Dr. Katti's discovery sets up the beginning of a new knowledge frontier that interfaces plant science, chemistry and nanotechnology," said Herbert W. Roesky, a professor and world-renowned chemist from the University of Goettingen in Germany.
Katti and his long-time collaborator and colleague, Raghuraman Kannan, assistant professor of radiology, sowed the seeds of Nanomedicine at MU through their groundbreaking discoveries in 2004. MU now has an internationally recognized research program in nanomedicine. The research was funded by grants from the National Cancer Institute and the National Institutes of Health.
Katti's research in the field of nanomedicine, biomedicine, cancer diagnostics/therapeutics and optical imaging have earned him numerous awards and recognition. The latest honor bestowed upon Katti is the "Outstanding Missourian" award, which he will receive Tuesday, March 4 in Jefferson City. The award is presented as "acknowledgement of the most accomplished citizens of the state of Missouri" and for making an "outstanding contribution to his state or nation." He is scheduled to receive the award at the beginning of the morning session of the Missouri House of Representatives.
In a recent interview, he expressed his gratefulness for the recognition, but attributes much of the credit to others, including his wife, Kavita Katti, who is a senior research chemist at MU, and his parents in India who supported him in his education.
"I feel excited about the recognition, and I attribute my selection to our institution, my research group and my collaborators," Katti said. "This award is the culmination of several factors, including departmental leadership, a plethora of outstanding collaborators at MU, the deans and, of course, the chancellor. A faculty member could not possibly succeed just by his or her own efforts. We have been very blessed with this team effort. I am very excited to receive this recognition. I think it speaks highly of our school and of our nanomedicine program."
Source: Bryan E. Jones
University of Missouri-Columbia
воскресенье, 22 мая 2011 г.
Magnetic Nanotags Spot Cancer In Mice Earlier Than Current Methods
Searching for biomarkers that can warn of diseases such as cancer while they are still in their earliest stage is likely to become far easier thanks to an innovative biosensor chip developed by Stanford University researchers.
The sensor is up to 1,000 times more sensitive than any technology now in clinical use, is accurate regardless of which bodily fluid is being analyzed and can detect biomarker proteins over a range of concentrations three times broader than any existing method, the researchers say.
The nanosensor chip also can search for up to 64 different proteins simultaneously and has been shown to be effective in early detection of tumors in mice, suggesting that it may open the door to significantly earlier detection of even the most elusive cancers in humans. The sensor also can be used to detect markers of diseases other than cancer.
"In the early stage [of a cancer], the protein biomarker level in blood is very, very low, so you need ultra-sensitive technology to detect it," said Shan Wang, professor of materials science and engineering and of electrical engineering, and senior author of a paper describing the sensor, which was published online on Nature Medicine's website on Oct. 11. "If you can detect it early, you can have early intervention and you have a much better chance to cure that person."
Wang said the nanosensor technology also could allow doctors to rapidly determine whether a patient is responding to a particular course of chemotherapy. "We can know on day two or day three of treatment whether it is working or not, instead of a month or two later," he said.
The sensor Wang and his colleagues have created, which uses magnetic detection nanotechnology they had developed previously, can detect a given cancer-associated protein biomarker at a concentration as low as one part out of a hundred billion (or 30 molecules in a cubic millimeter of blood).
Although the basics of the magnetic detection technology used in the new biosensor were described last year in a paper in the Proceedings of the National Academy of Sciences, the new sensor is not only more sensitive than the previous one by several orders of magnitude, it also outperforms its predecessor - and detection methods now in use - in several other ways.
Early detection of tumors in mice
The most impressive performance gain detailed in the Nature Medicine paper is that the researchers have now demonstrated that the magnetic-nano sensor can successfully detect cancerous tumors in mice when levels of cancer-associated proteins are still well below concentrations detectable using the current standard methodology, known by the acronym ELISA.
"That is a critical finding for us because it says that in a realistic biological application - that of tumor growth in mice - we can actually see tumors before anything else could have detected them," said Sam Gambhir, professor of radiology at Stanford.
"I would say that the PNAS paper is proof of concept of the technology, and the Nature Medicine paper is proof of concept of the technology working in a real-world application," he said. "It is one thing to have the technology show that it can work in principle; it is quite another to actually utilize it with real mouse blood samples from a real mouse growing a real tumor."
In the Nature Medicine paper, the researchers show that the new magnetic-nano sensor has a broad range of sensitivity, from the minute quantity described earlier to concentrations six orders of magnitude, or a million times, greater. The best existing analysis methods, or assays, in clinical use are able to detect proteins over a range of concentrations of at most two orders of magnitude.
Most of the sensing platforms currently in use are also limited to performing a single analysis at a time, but because the magnetic-nano sensors are attached to a microchip in an array of 64 sensors, each of which can be set up to detect a different protein, the researchers can search for up to 64 different proteins simultaneously during a single analysis, which typically takes one to two hours - far less than most existing assays.
The researchers also demonstrated that the sensor is equally effective in every likely biological fluid, or matrix, that a doctor would want to analyze for cancer-associated proteins. Those fluids include urine, saliva, blood plasma (blood with the blood cells removed), serum (blood plasma with the factors that promote clotting removed) and cell lysates (the name applied to the cellular stew produced by dissolution of cells).
"The idea that you could essentially, on a single assay platform, measure a broad diversity of biomolecules that are at such a wide range of concentrations with such sensitivity is really, truly remarkable," said Charles Drescher, a professor of obstetrics and gynecology at the University of Washington in Seattle, who was not involved with the research. "I think we'll all be very excited if this really does pan out."
The key to the versatility of the magnetic-nano sensor and the broad range of concentrations it can detect lies in the use of magnetism.
How magnetic nanotags reveal the quarry
The basic mechanism of detection employed in the magnetic-nano sensors is to capture antigens - deleterious compounds produced and shed by the cancer cells - using antibodies that naturally tend to bond with the antigens. The antibodies, dubbed "capture antibodies," are applied to a sensor, so that when the matrix of interest is placed onto the sensor chip, the appropriate antigens bind.
While the antigens are held fast, another dollop of the antibodies is applied. These antibodies are attracted to the antigens held on the sensors, and in bonding with them effectively seal the antigens inside an antibody sandwich. The researchers then apply a wash containing magnetic nanoparticle tags that have been tailored to fit specific antibodies. The magnetic nanotags attach themselves to the outer antibody on the sandwich, where they alter the ambient magnetic field in a small but distinct and detectable way that is sensed by the detector.
The protein-detection assays that are currently in use rely on a variety of mechanisms, such as measuring electrical charge, fluorescent signals or pH, all of which are prone to interference from the biological matrix in which the desired proteins reside. While a particular assay may be fine for assessing a protein's concentration in urine, for example, it may perform poorly when applied to a blood sample, as differences in the composition of the matrix affect properties such as pH or electrical charge.
"Our sensors are shown to be rather insensitive to matrix, so that is another key element from a scientific point of view," said Wang. As an example, he said, "We know that in saliva and blood, they have totally different pH values and different chemistry, but they are all nonmagnetic. Magnetically they are just like air. So it does not interfere with our mechanism [of detection]."
Most of the assays currently in use are only able to detect proteins over a narrow range of concentrations before interference of some kind degrades the sensitivity of the assay. That can require a series of assays to be performed on a sample diluted to different strengths, in order to assemble a complete picture of a protein's concentration in the matrix. But again, by using magnetic detection, Wang and his colleagues are able to sidestep such signal degradation.
"With the high sensitivity and the broad range we can look at a big panel of proteins over a wide range of concentrations, and with the matrix insensitivity, we can look at them in different fluids," said Richard Gaster, MD/PhD candidate in bioengineering and medicine, and first author on the Nature Medicine paper. "We don't have to tailor where we are looking; we can look at everything simultaneously." That produces savings in time, which, once the sensor comes into commercial use, will also translate into monetary savings.
Another virtue of the technology, Wang said, is that it uses existing technology already in use in the data storage and semiconductor industries and because of that, he added, "It can be made relatively cheaply."
"It is the same sensor you are using in a hard disk drive to read a hard disk back," he said. "Very similar to that."
One of the next steps in the research, Wang said, is to test the magnetic-nano sensors on human blood samples taken from a long-term study in which researchers drew blood samples from subjects prior to any of them being diagnosed with cancer. To this end, the Stanford team will be collaborating with the Fred Hutchison Cancer Research Center in Seattle and the Canary Foundation, a nonprofit organization that focuses on early diagnosis of cancer.
"We can actually use our technology to study all these samples and we may be able to tell a year before or half a year before or three months before the diagnosis," Wang said. "That work will be extremely interesting."
Funding for this research came from the National Cancer Institute, the National Science Foundation, the Defense Threat Reduction Agency, the Defense Advanced Research Projects Agency, the Department of Veterans Affairs, the Canary Foundation and the National Semiconductor Corporation.
Other authors of the paper in Nature Medicine are Drew Hall, graduate student in electrical engineering; Carsten Nielsen, visiting scholar in the molecular imaging program; Sebastian Osterfeld and Heng Yu, both researchers at MagArray Inc.; Kathleen Mach, life science research assistant in urology; Robert Wilson, senior research scientist in materials science and engineering; Boris Murmann, assistant professor in electrical engineering; and Joseph Liao, assistant professor of urology.
Stanford University has licensed part of the magnetic bioassay chip technology used in this research to MagArray Inc., an early stage startup company in Silicon Valley. Shan Wang, Sanjiv "Sam" Gambhir, Heng Yu and Sebastian Osterfeld hold financial interests in MagArray in the form of stock or stock options.
Source:
Louis Bergeron
Stanford University
The sensor is up to 1,000 times more sensitive than any technology now in clinical use, is accurate regardless of which bodily fluid is being analyzed and can detect biomarker proteins over a range of concentrations three times broader than any existing method, the researchers say.
The nanosensor chip also can search for up to 64 different proteins simultaneously and has been shown to be effective in early detection of tumors in mice, suggesting that it may open the door to significantly earlier detection of even the most elusive cancers in humans. The sensor also can be used to detect markers of diseases other than cancer.
"In the early stage [of a cancer], the protein biomarker level in blood is very, very low, so you need ultra-sensitive technology to detect it," said Shan Wang, professor of materials science and engineering and of electrical engineering, and senior author of a paper describing the sensor, which was published online on Nature Medicine's website on Oct. 11. "If you can detect it early, you can have early intervention and you have a much better chance to cure that person."
Wang said the nanosensor technology also could allow doctors to rapidly determine whether a patient is responding to a particular course of chemotherapy. "We can know on day two or day three of treatment whether it is working or not, instead of a month or two later," he said.
The sensor Wang and his colleagues have created, which uses magnetic detection nanotechnology they had developed previously, can detect a given cancer-associated protein biomarker at a concentration as low as one part out of a hundred billion (or 30 molecules in a cubic millimeter of blood).
Although the basics of the magnetic detection technology used in the new biosensor were described last year in a paper in the Proceedings of the National Academy of Sciences, the new sensor is not only more sensitive than the previous one by several orders of magnitude, it also outperforms its predecessor - and detection methods now in use - in several other ways.
Early detection of tumors in mice
The most impressive performance gain detailed in the Nature Medicine paper is that the researchers have now demonstrated that the magnetic-nano sensor can successfully detect cancerous tumors in mice when levels of cancer-associated proteins are still well below concentrations detectable using the current standard methodology, known by the acronym ELISA.
"That is a critical finding for us because it says that in a realistic biological application - that of tumor growth in mice - we can actually see tumors before anything else could have detected them," said Sam Gambhir, professor of radiology at Stanford.
"I would say that the PNAS paper is proof of concept of the technology, and the Nature Medicine paper is proof of concept of the technology working in a real-world application," he said. "It is one thing to have the technology show that it can work in principle; it is quite another to actually utilize it with real mouse blood samples from a real mouse growing a real tumor."
In the Nature Medicine paper, the researchers show that the new magnetic-nano sensor has a broad range of sensitivity, from the minute quantity described earlier to concentrations six orders of magnitude, or a million times, greater. The best existing analysis methods, or assays, in clinical use are able to detect proteins over a range of concentrations of at most two orders of magnitude.
Most of the sensing platforms currently in use are also limited to performing a single analysis at a time, but because the magnetic-nano sensors are attached to a microchip in an array of 64 sensors, each of which can be set up to detect a different protein, the researchers can search for up to 64 different proteins simultaneously during a single analysis, which typically takes one to two hours - far less than most existing assays.
The researchers also demonstrated that the sensor is equally effective in every likely biological fluid, or matrix, that a doctor would want to analyze for cancer-associated proteins. Those fluids include urine, saliva, blood plasma (blood with the blood cells removed), serum (blood plasma with the factors that promote clotting removed) and cell lysates (the name applied to the cellular stew produced by dissolution of cells).
"The idea that you could essentially, on a single assay platform, measure a broad diversity of biomolecules that are at such a wide range of concentrations with such sensitivity is really, truly remarkable," said Charles Drescher, a professor of obstetrics and gynecology at the University of Washington in Seattle, who was not involved with the research. "I think we'll all be very excited if this really does pan out."
The key to the versatility of the magnetic-nano sensor and the broad range of concentrations it can detect lies in the use of magnetism.
How magnetic nanotags reveal the quarry
The basic mechanism of detection employed in the magnetic-nano sensors is to capture antigens - deleterious compounds produced and shed by the cancer cells - using antibodies that naturally tend to bond with the antigens. The antibodies, dubbed "capture antibodies," are applied to a sensor, so that when the matrix of interest is placed onto the sensor chip, the appropriate antigens bind.
While the antigens are held fast, another dollop of the antibodies is applied. These antibodies are attracted to the antigens held on the sensors, and in bonding with them effectively seal the antigens inside an antibody sandwich. The researchers then apply a wash containing magnetic nanoparticle tags that have been tailored to fit specific antibodies. The magnetic nanotags attach themselves to the outer antibody on the sandwich, where they alter the ambient magnetic field in a small but distinct and detectable way that is sensed by the detector.
The protein-detection assays that are currently in use rely on a variety of mechanisms, such as measuring electrical charge, fluorescent signals or pH, all of which are prone to interference from the biological matrix in which the desired proteins reside. While a particular assay may be fine for assessing a protein's concentration in urine, for example, it may perform poorly when applied to a blood sample, as differences in the composition of the matrix affect properties such as pH or electrical charge.
"Our sensors are shown to be rather insensitive to matrix, so that is another key element from a scientific point of view," said Wang. As an example, he said, "We know that in saliva and blood, they have totally different pH values and different chemistry, but they are all nonmagnetic. Magnetically they are just like air. So it does not interfere with our mechanism [of detection]."
Most of the assays currently in use are only able to detect proteins over a narrow range of concentrations before interference of some kind degrades the sensitivity of the assay. That can require a series of assays to be performed on a sample diluted to different strengths, in order to assemble a complete picture of a protein's concentration in the matrix. But again, by using magnetic detection, Wang and his colleagues are able to sidestep such signal degradation.
"With the high sensitivity and the broad range we can look at a big panel of proteins over a wide range of concentrations, and with the matrix insensitivity, we can look at them in different fluids," said Richard Gaster, MD/PhD candidate in bioengineering and medicine, and first author on the Nature Medicine paper. "We don't have to tailor where we are looking; we can look at everything simultaneously." That produces savings in time, which, once the sensor comes into commercial use, will also translate into monetary savings.
Another virtue of the technology, Wang said, is that it uses existing technology already in use in the data storage and semiconductor industries and because of that, he added, "It can be made relatively cheaply."
"It is the same sensor you are using in a hard disk drive to read a hard disk back," he said. "Very similar to that."
One of the next steps in the research, Wang said, is to test the magnetic-nano sensors on human blood samples taken from a long-term study in which researchers drew blood samples from subjects prior to any of them being diagnosed with cancer. To this end, the Stanford team will be collaborating with the Fred Hutchison Cancer Research Center in Seattle and the Canary Foundation, a nonprofit organization that focuses on early diagnosis of cancer.
"We can actually use our technology to study all these samples and we may be able to tell a year before or half a year before or three months before the diagnosis," Wang said. "That work will be extremely interesting."
Funding for this research came from the National Cancer Institute, the National Science Foundation, the Defense Threat Reduction Agency, the Defense Advanced Research Projects Agency, the Department of Veterans Affairs, the Canary Foundation and the National Semiconductor Corporation.
Other authors of the paper in Nature Medicine are Drew Hall, graduate student in electrical engineering; Carsten Nielsen, visiting scholar in the molecular imaging program; Sebastian Osterfeld and Heng Yu, both researchers at MagArray Inc.; Kathleen Mach, life science research assistant in urology; Robert Wilson, senior research scientist in materials science and engineering; Boris Murmann, assistant professor in electrical engineering; and Joseph Liao, assistant professor of urology.
Stanford University has licensed part of the magnetic bioassay chip technology used in this research to MagArray Inc., an early stage startup company in Silicon Valley. Shan Wang, Sanjiv "Sam" Gambhir, Heng Yu and Sebastian Osterfeld hold financial interests in MagArray in the form of stock or stock options.
Source:
Louis Bergeron
Stanford University
суббота, 21 мая 2011 г.
ChemoCentryx Initiates Clinical Trial Of CCX168, A Novel Small Molecule C5aR Antagonist For The Treatment Of Inflammatory And Autoimmune Diseases
ChemoCentryx, Inc., announced the initiation of a Phase I clinical trial of CCX168, an orally-administered small molecule designed to treat autoimmune diseases. CCX168 is a highly potent and very selective compound that specifically targets the C5a receptor (C5aR), a component of the body's complement system and a potent driver of the inflammatory response associated with autoimmune diseases such as systemic lupus erythematosus, certain types of vasculitis, age-related macular degeneration and rheumatoid arthritis. The initiation of this Phase I trial triggered a $10 million milestone payment from GSK.
"CCX168 marks the fifth product candidate that we have generated from our drug discovery platform and successfully taken into clinical development," stated Thomas J. Schall, Ph.D., President and Chief Executive Officer of ChemoCentryx. "We have no doubt firmly established ourselves as the leaders in developing oral drugs targeting the chemokine and chemoattractant systems. Furthermore, we have demonstrated the ability to develop a compound targeting C5aR, which has up to now proved to be an enormous challenge for the pharmaceutical industry. As a result, we bring to clinical development a C5aR antagonist unlike any other compound that has been developed to date. We are very excited over the promise that this novel drug candidate may hold for the future treatment of inflammatory and autoimmune diseases."
About C5aR and CCX168
The complement system consists of a set of proteins that regulate certain types of inflammatory responses. Fragments of complement proteins, such as the chemoattractant complement fragment known as C5a, work to recruit immune system cells, including neutrophils, to sites of inflammation by means of its receptor (C5aR). This system is active in many diseases, thus making C5aR an attractive target for small molecule therapeutics. Given molecular structure similarities between the C5aR and chemokine receptors, ChemoCentryx researchers successfully applied the Company's proprietary drug discovery technologies to the design of small molecule C5aR antagonists and selected CCX168 based on its potency, selectivity and favorable pharmacokinetics. C5aR is one of four defined chemokine and chemoattractant receptor projects covered under an alliance between ChemoCentryx and GlaxoSmithKline's Center of Excellence for External Drug Discovery (CEEDD).
About ChemoCentryx
ChemoCentryx, Inc., is a clinical-stage biopharmaceutical company focused on discovering, developing and commercializing orally-administered therapeutics that target the chemokine and chemoattractant systems in order to treat autoimmune diseases, inflammatory disorders and cancer. The chemokine system is a network of secreted chemokine molecules, or ligands, and cell surface receptors that regulates inflammation. Based on its proprietary drug discovery and drug development platform, ChemoCentryx has internally generated multiple clinical and preclinical-stage programs, each targeting distinct chemokine and chemoattractant receptors with different small molecule compounds. ChemoCentryx's lead compound, Traficet-EN, a specific CCR9 antagonist, completed a Phase II multi-national clinical trial, called PROTECT-1, in patients with moderate-to-severe Crohn's disease, where it demonstrated the ability to induce a clinical response and to maintain clinical remission over the course of the trial. CCX025, also a CCR9 antagonist, has to date successfully completed a Phase I clinical program. Additional clinical programs include CCX140, which targets the CCR2 receptor, expected to enter Phase II clinical development in the first quarter of 2010 for the treatment of type 2 diabetes mellitus, CCX354, a CCR1 antagonist in a Phase II clinical trial for the treatment of rheumatoid arthritis and CCX168, a C5aR antagonist, in Phase I clinical development. ChemoCentryx also has several programs in preclinical development.
Any statements in this press release about ChemoCentryx's expectations, beliefs, plans, objectives, assumptions or future events or performance are not historical facts and are forward-looking statements. These statements are often, but not always, made through the use of words or phrases such as may, believe, will, expect, anticipate, estimate, intend, predict, seek, potential, continue, plan, should, could and would or the negative of these terms or other comparable terminology. Forward-looking statements are not guarantees of performance. They involve known and unknown risks, uncertainties and assumptions that may cause actual results, levels of activity, performance or achievements to differ materially from any results, levels of activity, performance or achievements expressed or implied by any forward-looking statement. Some of the risks, uncertainties and assumptions that could cause actual results to differ materially from estimates or projections contained in the forward-looking statements include but are not limited to (i) the initiation, timing, progress and results of ChemoCentryx's preclinical studies and clinical trials, (ii) ChemoCentryx's ability to advance product candidates into clinical trials, (iii) GSK's exercise of its license options, (iv) the commercialization of ChemoCentryx's product candidates, (v) the implementation of ChemoCentryx's business model, strategic plans for its business, product candidates and technology, (vi) ChemoCentryx's ability to maintain and establish collaborations or obtain additional government grant funding, (vii) ChemoCentryx's estimates of its expenses, future revenues, capital requirements and its needs for additional financing, (viii) the timing or likelihood of regulatory filings and approvals, (ix) the availability of corporate partners, (x) the scope of protection ChemoCentryx is able to establish and maintain for intellectual property rights covering its product candidates and technology, (xi) the impact of competitive products and technological changes, (xii) the availability of capital and the cost of capital, (xiii) ChemoCentryx's financial performance, (xiv) developments relating to ChemoCentryx's competitors and other vagaries in the biotechnology industry and (xv) other risks.
You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and ChemoCentryx undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.
Source: ChemoCentryx, Inc
"CCX168 marks the fifth product candidate that we have generated from our drug discovery platform and successfully taken into clinical development," stated Thomas J. Schall, Ph.D., President and Chief Executive Officer of ChemoCentryx. "We have no doubt firmly established ourselves as the leaders in developing oral drugs targeting the chemokine and chemoattractant systems. Furthermore, we have demonstrated the ability to develop a compound targeting C5aR, which has up to now proved to be an enormous challenge for the pharmaceutical industry. As a result, we bring to clinical development a C5aR antagonist unlike any other compound that has been developed to date. We are very excited over the promise that this novel drug candidate may hold for the future treatment of inflammatory and autoimmune diseases."
About C5aR and CCX168
The complement system consists of a set of proteins that regulate certain types of inflammatory responses. Fragments of complement proteins, such as the chemoattractant complement fragment known as C5a, work to recruit immune system cells, including neutrophils, to sites of inflammation by means of its receptor (C5aR). This system is active in many diseases, thus making C5aR an attractive target for small molecule therapeutics. Given molecular structure similarities between the C5aR and chemokine receptors, ChemoCentryx researchers successfully applied the Company's proprietary drug discovery technologies to the design of small molecule C5aR antagonists and selected CCX168 based on its potency, selectivity and favorable pharmacokinetics. C5aR is one of four defined chemokine and chemoattractant receptor projects covered under an alliance between ChemoCentryx and GlaxoSmithKline's Center of Excellence for External Drug Discovery (CEEDD).
About ChemoCentryx
ChemoCentryx, Inc., is a clinical-stage biopharmaceutical company focused on discovering, developing and commercializing orally-administered therapeutics that target the chemokine and chemoattractant systems in order to treat autoimmune diseases, inflammatory disorders and cancer. The chemokine system is a network of secreted chemokine molecules, or ligands, and cell surface receptors that regulates inflammation. Based on its proprietary drug discovery and drug development platform, ChemoCentryx has internally generated multiple clinical and preclinical-stage programs, each targeting distinct chemokine and chemoattractant receptors with different small molecule compounds. ChemoCentryx's lead compound, Traficet-EN, a specific CCR9 antagonist, completed a Phase II multi-national clinical trial, called PROTECT-1, in patients with moderate-to-severe Crohn's disease, where it demonstrated the ability to induce a clinical response and to maintain clinical remission over the course of the trial. CCX025, also a CCR9 antagonist, has to date successfully completed a Phase I clinical program. Additional clinical programs include CCX140, which targets the CCR2 receptor, expected to enter Phase II clinical development in the first quarter of 2010 for the treatment of type 2 diabetes mellitus, CCX354, a CCR1 antagonist in a Phase II clinical trial for the treatment of rheumatoid arthritis and CCX168, a C5aR antagonist, in Phase I clinical development. ChemoCentryx also has several programs in preclinical development.
Any statements in this press release about ChemoCentryx's expectations, beliefs, plans, objectives, assumptions or future events or performance are not historical facts and are forward-looking statements. These statements are often, but not always, made through the use of words or phrases such as may, believe, will, expect, anticipate, estimate, intend, predict, seek, potential, continue, plan, should, could and would or the negative of these terms or other comparable terminology. Forward-looking statements are not guarantees of performance. They involve known and unknown risks, uncertainties and assumptions that may cause actual results, levels of activity, performance or achievements to differ materially from any results, levels of activity, performance or achievements expressed or implied by any forward-looking statement. Some of the risks, uncertainties and assumptions that could cause actual results to differ materially from estimates or projections contained in the forward-looking statements include but are not limited to (i) the initiation, timing, progress and results of ChemoCentryx's preclinical studies and clinical trials, (ii) ChemoCentryx's ability to advance product candidates into clinical trials, (iii) GSK's exercise of its license options, (iv) the commercialization of ChemoCentryx's product candidates, (v) the implementation of ChemoCentryx's business model, strategic plans for its business, product candidates and technology, (vi) ChemoCentryx's ability to maintain and establish collaborations or obtain additional government grant funding, (vii) ChemoCentryx's estimates of its expenses, future revenues, capital requirements and its needs for additional financing, (viii) the timing or likelihood of regulatory filings and approvals, (ix) the availability of corporate partners, (x) the scope of protection ChemoCentryx is able to establish and maintain for intellectual property rights covering its product candidates and technology, (xi) the impact of competitive products and technological changes, (xii) the availability of capital and the cost of capital, (xiii) ChemoCentryx's financial performance, (xiv) developments relating to ChemoCentryx's competitors and other vagaries in the biotechnology industry and (xv) other risks.
You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and ChemoCentryx undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.
Source: ChemoCentryx, Inc
пятница, 20 мая 2011 г.
Bochum Cell Physiologist Honored For Outstanding Communication Of Research Into Human And Animal Senses Of Smell
This year's Communicator Award, which is presented by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and the Donors' Association for the Promotion of Sciences and Humanities in Germany (Stifterverband fГјr die Deutsche Wissenschaft) goes to cell physiologist and smell researcher Hanns Hatt. The award recognises the professor at Bochum's Ruhr University for his many years of outstanding communication of his research into both the human and animal senses of smell.
The Communicator Award ("Wissenschaftspreis des Stifterverbandes") includes prize money of 50,000 euros and is considered Germany's most prestigious award for the communication of scientific findings to the media and public. Since 2000, the DFG and the Stifterverband have been honouring researchers with this prize, which recognises those who make their research accessible to a wide audience in diverse, original and creative ways and who have earned recognition for their work in improving the increasingly essential dialogue between science and the public.
The prizewinners are selected by a jury which is composed of scientific journalists, communications and PR specialists and headed by a DFG Vice President. Once again, this year's jury had to choose from a variety of high-quality, professional applications. In total, 47 researchers from all scientific fields applied or were nominated for the prize. Fourteen candidates were short-listed, with Hanns Hatt eventually prevailing.
In the opinion of the jury, the 62-year-old professor for cell physiology is a worthy recipient of the Communicator Award, as he combines high-calibre scientific research with effective public presentation. Hanns Hatt holds doctorates in zoology and medicine and obtained his physiology qualifications at the Medical Faculty of the Technische Universität München. Hatt has held the chair for Cell Physiology at the Ruhr University Bochum since 1992 and became President of the North-Rhine-Westphalia Academy of Sciences and Humanities in 2010.
Hanns Hatt considers himself the "Ambassador of Smell". Over the past few decades, he has used a variety of different methods to bring the meaning and effects of scent to a wide audience, including, for example, the multi-part ZDF programme entitled "Vom Reiz der Sinne" ["On the Stimulation/Charm of the Senses"], a range of books and audio books, and hundreds of radio and television presentations and appearances. In 2003, the Bochum researcher achieved his greatest scientific and public success when he discovered that human sperm also possess smell receptors for lily of the valley. His book on the subject, "Das Maiglöckchen-Phänomen" ["The Lily of the Valley Phenomenon"], became an international bestseller. The latest recipient of the Communicator Award has also received numerous accolades from his students for his teaching practices.
In its rationale, the jury emphasised the scope and sustainability of Hanns Hatt's achievements in the field of communications, as well as his powers of innovation.
Hanns Hatt is the eleventh recipient of the Communicator Award. Previous prizewinners include the astrophysicist Harald Lesch, the Catholic theologian Hubert Wolf, the paleoanthropologist Friedemann Schrenk, and the Berlin social scientist Jutta Allmendinger.
The Communicator Award will be presented by DFG President Professor Matthias Kleiner and the President of the Stifterverband, Dr. Arend Oetker, in Magdeburg, Germany. The ceremony will take place on June 7, as part of this year's Summer of Science. The prize money is provided by the Stifterverband, an organisation which exists to promote science and its interaction with the public and whose membership includes more than 3000 companies and private individuals. The award ceremony will be sponsored by the Deutsche Kreditbank AG.
Source:
Dr. Eva-Maria Streier
Deutsche Forschungsgemeinschaft
The Communicator Award ("Wissenschaftspreis des Stifterverbandes") includes prize money of 50,000 euros and is considered Germany's most prestigious award for the communication of scientific findings to the media and public. Since 2000, the DFG and the Stifterverband have been honouring researchers with this prize, which recognises those who make their research accessible to a wide audience in diverse, original and creative ways and who have earned recognition for their work in improving the increasingly essential dialogue between science and the public.
The prizewinners are selected by a jury which is composed of scientific journalists, communications and PR specialists and headed by a DFG Vice President. Once again, this year's jury had to choose from a variety of high-quality, professional applications. In total, 47 researchers from all scientific fields applied or were nominated for the prize. Fourteen candidates were short-listed, with Hanns Hatt eventually prevailing.
In the opinion of the jury, the 62-year-old professor for cell physiology is a worthy recipient of the Communicator Award, as he combines high-calibre scientific research with effective public presentation. Hanns Hatt holds doctorates in zoology and medicine and obtained his physiology qualifications at the Medical Faculty of the Technische Universität München. Hatt has held the chair for Cell Physiology at the Ruhr University Bochum since 1992 and became President of the North-Rhine-Westphalia Academy of Sciences and Humanities in 2010.
Hanns Hatt considers himself the "Ambassador of Smell". Over the past few decades, he has used a variety of different methods to bring the meaning and effects of scent to a wide audience, including, for example, the multi-part ZDF programme entitled "Vom Reiz der Sinne" ["On the Stimulation/Charm of the Senses"], a range of books and audio books, and hundreds of radio and television presentations and appearances. In 2003, the Bochum researcher achieved his greatest scientific and public success when he discovered that human sperm also possess smell receptors for lily of the valley. His book on the subject, "Das Maiglöckchen-Phänomen" ["The Lily of the Valley Phenomenon"], became an international bestseller. The latest recipient of the Communicator Award has also received numerous accolades from his students for his teaching practices.
In its rationale, the jury emphasised the scope and sustainability of Hanns Hatt's achievements in the field of communications, as well as his powers of innovation.
Hanns Hatt is the eleventh recipient of the Communicator Award. Previous prizewinners include the astrophysicist Harald Lesch, the Catholic theologian Hubert Wolf, the paleoanthropologist Friedemann Schrenk, and the Berlin social scientist Jutta Allmendinger.
The Communicator Award will be presented by DFG President Professor Matthias Kleiner and the President of the Stifterverband, Dr. Arend Oetker, in Magdeburg, Germany. The ceremony will take place on June 7, as part of this year's Summer of Science. The prize money is provided by the Stifterverband, an organisation which exists to promote science and its interaction with the public and whose membership includes more than 3000 companies and private individuals. The award ceremony will be sponsored by the Deutsche Kreditbank AG.
Source:
Dr. Eva-Maria Streier
Deutsche Forschungsgemeinschaft
четверг, 19 мая 2011 г.
Certain Genes Boost Chances For Distributing Variety Of Traits, Drive Evolution, Scientists Suggest
Genes that don't themselves directly affect the inherited characteristics of an organism but leave them increasingly open to variation may be a significant driving force of evolution, say two Johns Hopkins scientists.
Their proposed amended view of evolution is based on observations of genetic patterns outside of a cell's DNA and may better explain how organisms, including people, have adapted over hundreds of thousands of years to relatively rapidly changing environments.
This view, which also offers a new explanation for the genetic basis of some persistent, common human diseases, is published the week of Dec. 14 in the early online edition of the Proceedings of the National Academy of Sciences.
"We're proposing that certain gene variants contribute to heterogeneity in populations," says Johns Hopkins professor of medicine Andrew Feinberg, M.D., Ph.D. "In a fluctuating environment, this gives generations more opportunity to survive," he adds.
For more than 100 years, mainstream science has embraced the basic tenets of Darwin's view that characteristics that increase an organism's ability to survive and reproduce will be passed from generation to generation. Scientists later demonstrated that stable, significant traits are indeed inherited in the DNA carried in parental genes on chromosomes and randomly distributed to offspring.
Characteristics that affect an organism's ability to adapt and survive in times of environmental change have been thought to arise by chance through random mutations in an organism's DNA. However, this view could not explain how such mutations, which arise only rarely, help organisms of every size and variety adapt quickly enough through time. Nor could it explain how diseases that lead to a dramatic loss of survival - such as diabetes, heart disease, autism, and schizophrenia - persist in populations. Indeed, genes that directly contribute to these conditions have been difficult to find.
Feinberg says some scientists have sought to explain gaps in Darwinian theory with epigenetics, the study of changes to genes that don't directly affect the DNA sequence, but do affect which genes are turned on or off and therefore which proteins are produced in cells. Research has shown that environmental conditions, such as diet, sunlight, or viral infections, can bring about epigenetic changes. However, it is unclear whether these changes persist through several generations in a variable environment.
In a new twist on both of these ideas, Feinberg and Johns Hopkins Bloomberg School of Public Health professor of biostatistics Rafael Irizarry, Ph.D., suggest that gene variants or alleles able to take on the challenge and increase random distribution of characteristics might drive the development of the wide variety of traits - from height to skin tone to disease risk - seen in modern populations.
The scientists developed this idea through a series of experiments examining epigenetic patterns in groups of mice littermates that were very similar genetically. From before birth to adulthood, the mice were exposed to the same conditions, living in the same cage and eating the same food. The researchers then examined the animals' livers and brains for methylation, a chemical addition to DNA that is one type of epigenetic change.
Though Feinberg and Irizarry expected to see similar methylation patterns due to the rodents' identical upbringing, they found regions in the animal's genetic makeup with strikingly different patterns. Moreover, these regions occurred among genes responsible for determining anatomy during early development.
Using samples of human liver, the researchers found that these "variably methylated regions" were the same, suggesting that these genes are affected similarly by epigenetics from species to species.
In another experiment, Feinberg and Irizarry performed a computer simulation in which they calculated the likelihood of a model organism becoming extinct over 1000 generations. This organism had a trait, Y, which affected survival. In some simulations, the researchers allowed Y to behave variably, leading some generations to have more surviving members than others. When the environment in the simulation was static, having a variable Y was a detriment. However, when the environment changed on a periodic basis, generations with a variable Y created organisms with a wider range of characteristics that were more likely to survive in the long run and not become extinct.
The researchers suggest in the study that the presence of genes that contribute to trait variability might help explain the presence of common diseases. Much as having a variable Y aided the model organism in their simulation in the long run but were detrimental in a static environment, variability in traits such as the ability to control blood sugar could have helped human ancestors survive to the present but become detrimental in the current environment.
"In the long run, it might be a good thing to have a large spread of people who handle blood sugar differently. However, in today's environment, people with a propensity to develop high blood sugar are at a disadvantage," explains Feinberg.
Feinberg and Irizarry suggest that though it's unclear how these variability genes acquire such inconsistent epigenetic changes, one mechanism may be environmental influence.
"The interaction between nature and nurture may be simpler than we've imagined," Irizarry says.
Source: Christen Brownlee
Johns Hopkins Medical Institutions
Their proposed amended view of evolution is based on observations of genetic patterns outside of a cell's DNA and may better explain how organisms, including people, have adapted over hundreds of thousands of years to relatively rapidly changing environments.
This view, which also offers a new explanation for the genetic basis of some persistent, common human diseases, is published the week of Dec. 14 in the early online edition of the Proceedings of the National Academy of Sciences.
"We're proposing that certain gene variants contribute to heterogeneity in populations," says Johns Hopkins professor of medicine Andrew Feinberg, M.D., Ph.D. "In a fluctuating environment, this gives generations more opportunity to survive," he adds.
For more than 100 years, mainstream science has embraced the basic tenets of Darwin's view that characteristics that increase an organism's ability to survive and reproduce will be passed from generation to generation. Scientists later demonstrated that stable, significant traits are indeed inherited in the DNA carried in parental genes on chromosomes and randomly distributed to offspring.
Characteristics that affect an organism's ability to adapt and survive in times of environmental change have been thought to arise by chance through random mutations in an organism's DNA. However, this view could not explain how such mutations, which arise only rarely, help organisms of every size and variety adapt quickly enough through time. Nor could it explain how diseases that lead to a dramatic loss of survival - such as diabetes, heart disease, autism, and schizophrenia - persist in populations. Indeed, genes that directly contribute to these conditions have been difficult to find.
Feinberg says some scientists have sought to explain gaps in Darwinian theory with epigenetics, the study of changes to genes that don't directly affect the DNA sequence, but do affect which genes are turned on or off and therefore which proteins are produced in cells. Research has shown that environmental conditions, such as diet, sunlight, or viral infections, can bring about epigenetic changes. However, it is unclear whether these changes persist through several generations in a variable environment.
In a new twist on both of these ideas, Feinberg and Johns Hopkins Bloomberg School of Public Health professor of biostatistics Rafael Irizarry, Ph.D., suggest that gene variants or alleles able to take on the challenge and increase random distribution of characteristics might drive the development of the wide variety of traits - from height to skin tone to disease risk - seen in modern populations.
The scientists developed this idea through a series of experiments examining epigenetic patterns in groups of mice littermates that were very similar genetically. From before birth to adulthood, the mice were exposed to the same conditions, living in the same cage and eating the same food. The researchers then examined the animals' livers and brains for methylation, a chemical addition to DNA that is one type of epigenetic change.
Though Feinberg and Irizarry expected to see similar methylation patterns due to the rodents' identical upbringing, they found regions in the animal's genetic makeup with strikingly different patterns. Moreover, these regions occurred among genes responsible for determining anatomy during early development.
Using samples of human liver, the researchers found that these "variably methylated regions" were the same, suggesting that these genes are affected similarly by epigenetics from species to species.
In another experiment, Feinberg and Irizarry performed a computer simulation in which they calculated the likelihood of a model organism becoming extinct over 1000 generations. This organism had a trait, Y, which affected survival. In some simulations, the researchers allowed Y to behave variably, leading some generations to have more surviving members than others. When the environment in the simulation was static, having a variable Y was a detriment. However, when the environment changed on a periodic basis, generations with a variable Y created organisms with a wider range of characteristics that were more likely to survive in the long run and not become extinct.
The researchers suggest in the study that the presence of genes that contribute to trait variability might help explain the presence of common diseases. Much as having a variable Y aided the model organism in their simulation in the long run but were detrimental in a static environment, variability in traits such as the ability to control blood sugar could have helped human ancestors survive to the present but become detrimental in the current environment.
"In the long run, it might be a good thing to have a large spread of people who handle blood sugar differently. However, in today's environment, people with a propensity to develop high blood sugar are at a disadvantage," explains Feinberg.
Feinberg and Irizarry suggest that though it's unclear how these variability genes acquire such inconsistent epigenetic changes, one mechanism may be environmental influence.
"The interaction between nature and nurture may be simpler than we've imagined," Irizarry says.
Source: Christen Brownlee
Johns Hopkins Medical Institutions
среда, 18 мая 2011 г.
Heated Nanoprobes Used To Destroy Breast Cancer Cells In Mice
In experiments with laboratory mice that bear aggressive human breast cancers, UC Davis researchers have used hot nanoprobes to slow the growth of tumors -- without damage to surrounding healthy tissue. The researchers describe their work in the March issue of the Journal of Nuclear Medicine.
"We have demonstrated that the system is feasible in laboratory mice. The next step will be clinical testing in patients," said Sally DeNardo, a professor of internal medicine and radiology at UC Davis and lead author of the study.
Many researchers have studied heat as a potential treatment for cancer, but the difficulty of confining heat within the tumor and predicting an effective heat dose has limited its use. The UC Davis research, carried out in collaboration with scientists from Triton BioSystems in Boston, seeks to solve this problem.
The experimental system uses bioprobes created by wedding magnetized iron-oxide nanospheres to radiolabeled monoclonal antibodies. The bioprobes are cloaked in polymers and sugars that render them nearly invisible to the body's immune system.
DeNardo and her colleagues infused trillions of the probes -- more than 10,000 can fit on the end of a straight pin -- into the bloodstreams of laboratory mice bearing human breast tumors. Once in the bloodstream, the probes began to seek out and latch onto receptors on the surface of malignant cells.
Three days later, the team applied an alternating magnetic field to the tumor region, causing the magnetic nanospheres latched onto the tumor cells to change polarity thousands of times per second, instantaneously generating heat. As soon as the AMF stopped, the bioprobes cooled down.
Mice in the study received a series of AMF bursts in a single 20-minute treatment. Dosing was calculated using an equation that included tumor concentration of bioprobes, heating rate of particles at different amplitudes, and the spacing of AMF bursts.
Tumor growth rate slowed in the treated animals, a response that correlated closely with heat dose. No toxicity related to the bioprobes was observed.
"Using heat to kill cancer cells isn't a new concept," DeNardo said. "The biggest problems have been how to apply it to the tumor alone, how to predict the amount needed and how to determine its effectiveness. By combining nanotechnology, focused AMF therapy and quantitative molecular imaging techniques, we have developed a safer technique that could join other modalities as a treatment for breast and other cancers."
DeNardo, co-director of the Radiodiagnosis and Therapy Program at UC Davis, was the first investigator to use monoclonal antibodies in the delivery of radioimmunotherapy when she generated monoclonal antibodies against mouse melanoma in 1979. She was also the first to demonstrate that radioimmunotherapy can be effective in the treatment of non-Hodgkin's B-cell lymphoma and chronic lymphocytic leukemia, and the first to describe the clinical use of radioimmunotherapy coupled with a biologically active antibody to treat breast cancer.
UC Davis Cancer Center is the nation's 61st National Cancer Institute center. Its research program unites more than 275 scientists from more than a dozen disciplines on three campuses: the University of California, Davis, the UC Davis Medical Center in Sacramento, and Lawrence Livermore National Laboratory in Livermore, Calif.
Public Affairs
UC Davis Health System
4900 Broadway, Suite 1200
Sacramento, CA 95820
Contact: Claudia Morain
University of California, Davis - Health System
"We have demonstrated that the system is feasible in laboratory mice. The next step will be clinical testing in patients," said Sally DeNardo, a professor of internal medicine and radiology at UC Davis and lead author of the study.
Many researchers have studied heat as a potential treatment for cancer, but the difficulty of confining heat within the tumor and predicting an effective heat dose has limited its use. The UC Davis research, carried out in collaboration with scientists from Triton BioSystems in Boston, seeks to solve this problem.
The experimental system uses bioprobes created by wedding magnetized iron-oxide nanospheres to radiolabeled monoclonal antibodies. The bioprobes are cloaked in polymers and sugars that render them nearly invisible to the body's immune system.
DeNardo and her colleagues infused trillions of the probes -- more than 10,000 can fit on the end of a straight pin -- into the bloodstreams of laboratory mice bearing human breast tumors. Once in the bloodstream, the probes began to seek out and latch onto receptors on the surface of malignant cells.
Three days later, the team applied an alternating magnetic field to the tumor region, causing the magnetic nanospheres latched onto the tumor cells to change polarity thousands of times per second, instantaneously generating heat. As soon as the AMF stopped, the bioprobes cooled down.
Mice in the study received a series of AMF bursts in a single 20-minute treatment. Dosing was calculated using an equation that included tumor concentration of bioprobes, heating rate of particles at different amplitudes, and the spacing of AMF bursts.
Tumor growth rate slowed in the treated animals, a response that correlated closely with heat dose. No toxicity related to the bioprobes was observed.
"Using heat to kill cancer cells isn't a new concept," DeNardo said. "The biggest problems have been how to apply it to the tumor alone, how to predict the amount needed and how to determine its effectiveness. By combining nanotechnology, focused AMF therapy and quantitative molecular imaging techniques, we have developed a safer technique that could join other modalities as a treatment for breast and other cancers."
DeNardo, co-director of the Radiodiagnosis and Therapy Program at UC Davis, was the first investigator to use monoclonal antibodies in the delivery of radioimmunotherapy when she generated monoclonal antibodies against mouse melanoma in 1979. She was also the first to demonstrate that radioimmunotherapy can be effective in the treatment of non-Hodgkin's B-cell lymphoma and chronic lymphocytic leukemia, and the first to describe the clinical use of radioimmunotherapy coupled with a biologically active antibody to treat breast cancer.
UC Davis Cancer Center is the nation's 61st National Cancer Institute center. Its research program unites more than 275 scientists from more than a dozen disciplines on three campuses: the University of California, Davis, the UC Davis Medical Center in Sacramento, and Lawrence Livermore National Laboratory in Livermore, Calif.
Public Affairs
UC Davis Health System
4900 Broadway, Suite 1200
Sacramento, CA 95820
Contact: Claudia Morain
University of California, Davis - Health System
вторник, 17 мая 2011 г.
Small Molecule MiRNAs Regulate Female Mouse Fertility
Small molecules known as miRNAs, which are generated naturally by the body, regulate the conversion of genetic information into proteins. New data, generated by Jiahuai Han and colleagues, at The Scripps Research Institute, La Jolla, have now indicated that miRNAs can control the fertility of female mice.
The generation of miRNAs is a complex process that involves a protein known as Dicer. In the study, mice expressing substantially lower levels of Dicer than normal mice (Dicerd/d mice) were found to have only one defect - the female mice were infertile. Infertility was a result of impaired functioning of the corpus luteum, the structure that forms at the site of release of the fertilized egg and that is required to maintain pregnancy at the early stages. Detailed analysis indicated that the functioning of the corpus luteum was impaired because it was unable to form new blood vessels, and that this was associated with increased expression of the protein TIMP1, which inhibits blood vessel formation. As injection of the miRNAs miR17-5p and let7b into the ovaries of Dicerd/d mice decreased expression of TIMP1 and increased the number of blood vessels in the corpus luteum, the authors concluded that the development and function of the corpus luteum in mice is tightly regulated by miRNAs.
TITLE: Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice
AUTHOR CONTACT:
Jiahuai Han
The Scripps Research Institute, La Jolla, California, USA.
View the PDF of this article at: the-jci/article.php?id=33680
Source:
Karen Honey
Journal of Clinical Investigation
The generation of miRNAs is a complex process that involves a protein known as Dicer. In the study, mice expressing substantially lower levels of Dicer than normal mice (Dicerd/d mice) were found to have only one defect - the female mice were infertile. Infertility was a result of impaired functioning of the corpus luteum, the structure that forms at the site of release of the fertilized egg and that is required to maintain pregnancy at the early stages. Detailed analysis indicated that the functioning of the corpus luteum was impaired because it was unable to form new blood vessels, and that this was associated with increased expression of the protein TIMP1, which inhibits blood vessel formation. As injection of the miRNAs miR17-5p and let7b into the ovaries of Dicerd/d mice decreased expression of TIMP1 and increased the number of blood vessels in the corpus luteum, the authors concluded that the development and function of the corpus luteum in mice is tightly regulated by miRNAs.
TITLE: Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice
AUTHOR CONTACT:
Jiahuai Han
The Scripps Research Institute, La Jolla, California, USA.
View the PDF of this article at: the-jci/article.php?id=33680
Source:
Karen Honey
Journal of Clinical Investigation
понедельник, 16 мая 2011 г.
Prostate Cancer Prevented In Mice By Reducing Intake Of Dietary Fat
Scientists with UCLA's Jonsson Cancer Center and the Department of Urology have showed that lowering intake of the type of fat common in a Western diet helps prevent prostate cancer in mice, the first finding of its kind in a mouse model that closely mimics human cancer, researchers said.
The study, which appeard in the journal Cancer Research, focused on fat from corn oil, which is made up primarily of omega-6 fatty acids, or the polyunsaturated fat commonly found in the Western diet. Omega-6 fats are found in high levels in baked and fried goods, said William Aronson, a Jonsson Cancer Center researcher and the study's senior author.
Researchers fed one group of mice a diet with about 40 percent of calories coming from fat, a percentage typical in men eating a Western diet. The other group received 12 percent of their calories from fat, a figure considered to be a very low fat diet. Researchers found there was a 27 percent reduced incidence of prostate cancer in the low-fat diet group. Aronson also studied cells in the prostate that were precancerous, or would soon become cancer, and found that the cells in the mice eating the low-fat diet were growing much more slowly than those in the high-fat group.
Previous studies in Aronson's lab showed that a low-fat diet slowed the growth of aggressive human prostate cancers in mice and helped the mice live longer. However, whether such a diet could prevent prostate cancer was unknown.
"We didn't know what to expect in terms of the role of reducing dietary fat in preventing prostate cancer," said Aronson, a professor of urology. "We think this is an important finding and we are presently performing further studies in animal models and conducting clinical trials in men."
Using a novel mouse model that develops cancer within the prostate over a period of six to nine months, Aronson and his team were able to study cancer incidence and cell growth. The mice were assigned to a dietary fat group at three weeks of age, when they first started ingesting food. The prostates and prostate cells were studied at seven months.
During the growth phase when the precancerous lesions develop, called PIN or prostate intraepithelial neoplasia, Aronson found that mice on the low-fat diet had higher levels of a protein in their bloodstreams that binds to insulin like growth factor, which spurs prostate cancer growth. Aronson believes that lowering dietary fat and increasing levels of the binding protein slows prostate cancer development by cutting off the growth factor that allows prostate cancer to thrive.
"A low-fat, high-fiber diet combined with weight loss and exercise is well known to be healthy in terms of heart disease and is known to reduce the risk of heart attacks and strokes, so that would be a healthy choice to make," Aronson said. "Whether or not it will prevent prostate cancer in humans remains to be seen."
Aronson is now conducting a short term study in men who are randomly assigned to a Western diet higher in polyunsaturated fat or a low-fat diet with fish oil supplements. The next step is to see how these diets affect malignant and benign human prostate tissue, Aronson said.
"We're looking at specific markers and growth factors in human tissue known to be important for development and progression of prostate cancer," he said. "It's this work we hope will lead to longer term prevention strategies incorporating dietary changes."
UCLA's Jonsson Comprehensive Cancer Center comprises about 235 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2007, the Jonsson Cancer Center was named the best cancer center in California by U.S. News & World Report, a ranking it has held for eight consecutive years. For more information on the Jonsson Cancer Center, visit our Web site at cancer.ucla/.
Source: Kim Irwin
University of California - Los Angeles
The study, which appeard in the journal Cancer Research, focused on fat from corn oil, which is made up primarily of omega-6 fatty acids, or the polyunsaturated fat commonly found in the Western diet. Omega-6 fats are found in high levels in baked and fried goods, said William Aronson, a Jonsson Cancer Center researcher and the study's senior author.
Researchers fed one group of mice a diet with about 40 percent of calories coming from fat, a percentage typical in men eating a Western diet. The other group received 12 percent of their calories from fat, a figure considered to be a very low fat diet. Researchers found there was a 27 percent reduced incidence of prostate cancer in the low-fat diet group. Aronson also studied cells in the prostate that were precancerous, or would soon become cancer, and found that the cells in the mice eating the low-fat diet were growing much more slowly than those in the high-fat group.
Previous studies in Aronson's lab showed that a low-fat diet slowed the growth of aggressive human prostate cancers in mice and helped the mice live longer. However, whether such a diet could prevent prostate cancer was unknown.
"We didn't know what to expect in terms of the role of reducing dietary fat in preventing prostate cancer," said Aronson, a professor of urology. "We think this is an important finding and we are presently performing further studies in animal models and conducting clinical trials in men."
Using a novel mouse model that develops cancer within the prostate over a period of six to nine months, Aronson and his team were able to study cancer incidence and cell growth. The mice were assigned to a dietary fat group at three weeks of age, when they first started ingesting food. The prostates and prostate cells were studied at seven months.
During the growth phase when the precancerous lesions develop, called PIN or prostate intraepithelial neoplasia, Aronson found that mice on the low-fat diet had higher levels of a protein in their bloodstreams that binds to insulin like growth factor, which spurs prostate cancer growth. Aronson believes that lowering dietary fat and increasing levels of the binding protein slows prostate cancer development by cutting off the growth factor that allows prostate cancer to thrive.
"A low-fat, high-fiber diet combined with weight loss and exercise is well known to be healthy in terms of heart disease and is known to reduce the risk of heart attacks and strokes, so that would be a healthy choice to make," Aronson said. "Whether or not it will prevent prostate cancer in humans remains to be seen."
Aronson is now conducting a short term study in men who are randomly assigned to a Western diet higher in polyunsaturated fat or a low-fat diet with fish oil supplements. The next step is to see how these diets affect malignant and benign human prostate tissue, Aronson said.
"We're looking at specific markers and growth factors in human tissue known to be important for development and progression of prostate cancer," he said. "It's this work we hope will lead to longer term prevention strategies incorporating dietary changes."
UCLA's Jonsson Comprehensive Cancer Center comprises about 235 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2007, the Jonsson Cancer Center was named the best cancer center in California by U.S. News & World Report, a ranking it has held for eight consecutive years. For more information on the Jonsson Cancer Center, visit our Web site at cancer.ucla/.
Source: Kim Irwin
University of California - Los Angeles
воскресенье, 15 мая 2011 г.
New Lab Manual Focuses On Essential Methods For Purifying And Characterizing Proteins
A new, user-friendly laboratory manual for protein purification and analysis has just been released by Cold Spring Harbor Laboratory Press. Designed for routine, day-to-day use in the laboratory, it includes essential step-wise protocols as well as background information, recommended experimental strategies, and troubleshooting advice on the most fundamental protein-related methods used by scientists at all levels.
Understanding how proteins function is an essential part of many biological research endeavors. The complexity and sheer number of proteins in a cell are impediments to identifying proteins of interest or purifying proteins for function and structure analysis. Thus, reducing the complexity of a protein sample or in some cases purifying a protein to homogeneity is necessary.
The convenient new manual, Basic Methods in Protein Purification and Analysis, integrates established in vitro and in vivo molecular techniques with more modern in silico methods. It takes the user from the initial steps of obtaining cellular and subcellular extracts, through the purification and isolation steps appropriate for the protein of interest, and, finally, to the steps involved in characterizing and identifying proteins, protein complexes, and protein-protein interactions. Rounding out the manual is an extensive appendix of essential methods for quantifying protein concentration, stabilizing and storing proteins, concentrating proteins, and immunoblotting.
Basic Methods in Protein Purification and Analysis was derived in large part from the popular laboratory manuals Proteins and Proteomics, Purifying Proteins for Proteomics (both by Richard Simpson), and Protein-Protein Interactions (edited by Erica Golemis and Peter Adams), which have proven to be both very successful and highly regarded.
This is the second volume in the Basic Methods series; the first, Basic Methods in Microscopy focused on essential techniques for imaging cells and tissues, including sample preparation, microscope use, and image interpretation.
About the book
Basic Methods in Protein Purification and Analysis: A Laboratory Manual (© 2009, Cold Spring Harbor Laboratory Press) was edited by Richard J. Simpson (Joint ProteomicS Laboratory [JPSL] of the Ludwig Institute for Cancer Research and the Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia), Peter D. Adams (Fox Chase Cancer Center, Philadelphia), and Erica A. Golemis (Fox Chase Cancer Center, Philadelphia). It is available in hardcover (ISBN 978-087969868-3) and paperback (ISBN 978-087969867-6) and is 436 pp. in length (illus., appendices, index). For additional information, please see here.
About Cold Spring Harbor Laboratory Press
Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media, located on Long Island, New York. Since 1933, it has furthered the advance and spread of scientific knowledge in all areas of genetics and molecular biology, including cancer biology, plant science, bioinformatics, and neurobiology. It is a division of Cold Spring Harbor Laboratory, an innovator in life science research and the education of scientists, students, and the public.
Cold Spring Harbor Laboratory Press
Understanding how proteins function is an essential part of many biological research endeavors. The complexity and sheer number of proteins in a cell are impediments to identifying proteins of interest or purifying proteins for function and structure analysis. Thus, reducing the complexity of a protein sample or in some cases purifying a protein to homogeneity is necessary.
The convenient new manual, Basic Methods in Protein Purification and Analysis, integrates established in vitro and in vivo molecular techniques with more modern in silico methods. It takes the user from the initial steps of obtaining cellular and subcellular extracts, through the purification and isolation steps appropriate for the protein of interest, and, finally, to the steps involved in characterizing and identifying proteins, protein complexes, and protein-protein interactions. Rounding out the manual is an extensive appendix of essential methods for quantifying protein concentration, stabilizing and storing proteins, concentrating proteins, and immunoblotting.
Basic Methods in Protein Purification and Analysis was derived in large part from the popular laboratory manuals Proteins and Proteomics, Purifying Proteins for Proteomics (both by Richard Simpson), and Protein-Protein Interactions (edited by Erica Golemis and Peter Adams), which have proven to be both very successful and highly regarded.
This is the second volume in the Basic Methods series; the first, Basic Methods in Microscopy focused on essential techniques for imaging cells and tissues, including sample preparation, microscope use, and image interpretation.
About the book
Basic Methods in Protein Purification and Analysis: A Laboratory Manual (© 2009, Cold Spring Harbor Laboratory Press) was edited by Richard J. Simpson (Joint ProteomicS Laboratory [JPSL] of the Ludwig Institute for Cancer Research and the Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia), Peter D. Adams (Fox Chase Cancer Center, Philadelphia), and Erica A. Golemis (Fox Chase Cancer Center, Philadelphia). It is available in hardcover (ISBN 978-087969868-3) and paperback (ISBN 978-087969867-6) and is 436 pp. in length (illus., appendices, index). For additional information, please see here.
About Cold Spring Harbor Laboratory Press
Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media, located on Long Island, New York. Since 1933, it has furthered the advance and spread of scientific knowledge in all areas of genetics and molecular biology, including cancer biology, plant science, bioinformatics, and neurobiology. It is a division of Cold Spring Harbor Laboratory, an innovator in life science research and the education of scientists, students, and the public.
Cold Spring Harbor Laboratory Press
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