Scientists have answered a long-standing molecular stumper regarding DNA: How can parts of such a rigid molecule bend and coil without requiring large amounts of force? According to a team of researchers from the United States and the Netherlands, led by a physicist from the University of Pennsylvania, DNA is much more flexible than previously believed when examined over extremely small lengths. They used a technique called atomic force microscopy to determine the amount of energy necessary to bend DNA over nano-size lengths (about a million times smaller than a printed letter).
The findings, which appear in the November issue of the journal Nature Nanotechnology, illustrate how molecular properties often appear different when viewed at different degrees of magnification.
"DNA is not a passive molecule. It constantly needs to bend, forming loops and kinks, as other molecules interact with it," said Philip Nelson, a professor in Penn's Department of Physics and Astronomy in the School of Arts and Sciences. "But when people looked at long chunks of DNA, it always seemed to behave like a stiff elastic rod."
For example, DNA must wrap itself around proteins, forming tiny molecular structures called nucleosomes, which help regulate how genes are read. The formation of tight DNA loops also plays a key role in switching some genes off. According to Nelson, such processes were considered a minor mystery of nature, in part because researchers didn't have the tools of nanotechnology to examine molecules in such fine detail.
"Common sense and physics seemed to tell us that DNA just shouldn't spontaneously bend into such tight structures, yet it does," Nelson said. "In the conventional view of a DNA molecule, wrapping DNA into a nucleosome would be like bending a yardstick around a baseball."
To study DNA on the needed short length scales, Nelson and his colleagues used a technique called high-resolution atomic force microscopy to obtain a direct measurement of the energy it would take to bend lengths of DNA just a few nanometers long. The technique involves dragging an extremely sharp tip across the contours of the molecule in order to create a picture of its structure.
With this tool, Nelson and his colleagues measured the energies required to make various bends in DNA at lengths of five to 50 nanometers --- about a thousand times smaller than the diameter of a typical human cell.
''We found that DNA has different apparent properties when probed at short lengths than the entire molecule does when taken as a whole," Nelson said. ''Its resistance to large-angle bends at this scale is much smaller than previously suspected."
Nelson is also a member of Penn's Nano--Bio Interface Center, which explores how the fields of nanotechnology, biology and medicine all intersect.
"The nanoscale just happens to also be the scale at which cell biology operates," Nelson said. "We're entering an era when we are able to use the tools of nanotechnology to answer fundamental puzzles of biology."
Nelson's collaborators include Paul A. Wiggins from the Whitehead Institute at MIT, Rob Phillips from Caltech, Jonathan Widom from Northwestern University and Thijn van der Heijden, Fernando Moreno--Herrero and Cees Dekker from Delft University.
Contact: Greg Lester
University of Pennsylvania
понедельник, 30 мая 2011 г.
FSU Researchers Examine How Bacteria Become Resistant To Antibiotics
A study by two Florida State University biochemists makes an important contribution to science's understanding of a serious problem causing concern worldwide: the growing resistance of some harmful bacteria to the drugs that were intended to kill them.
Investigating exactly how bacteria learn to fend off antibiotics prescribed to treat infections is the subject of new research by Assistant Professor Brian G. Miller of FSU's Department of Chemistry and Biochemistry and one of his graduate research assistants, Kevin K. Desai. They have found that bacteria are remarkably resilient to toxic substances, such as antibiotics, because bacteria have the innate ability to produce a large variety of proteins. Those proteins then are able to do things such as pump toxins out or alter toxins so that they can no longer kill the bacteria.
"Most of us take antibiotics to eliminate infections without considering what would happen if they failed to work," said Kevin Desai, a graduate research assistant in Florida State's Department of Chemistry and Biochemistry. "While treating bacterial infections has typically been as easy as swallowing a pill, researchers are apprehensive about the increasing frequency of infections that are resistant to antibiotics, and are searching for ways to regain the upper hand."
In their study, Miller and Desai learned that about 2 percent of all the proteins produced by the model bacterium E. coli can be linked to enabling resistance to a single toxin called bromoacetate. Their research also has implications in elucidating the function of specific proteins and understanding how bacteria in the environment can survive in the presence of toxic manmade chemicals such as pesticides.
A paper describing Desai and Miller's work was published this week in the prestigious journal Proceedings of the National Academy of Sciences. That paper is titled "Recruitment of Genes and Enzymes Conferring Resistance to the Nonnatural Toxin Bromoacetate."
"The recent rise of antibiotic resistance demonstrates that bacteria are capable of rapidly evolving evasive strategies," they wrote. "It also has exposed our lack of knowledge about the evolutionary processes leading to resistance."
Understanding the mechanisms by which bacteria evade environmental threats has direct relevance for understanding and combating the rise of antibiotic resistance, Desai and Miller added.
The techniques described in the paper will be highly useful for other researchers in the field because it will allow them to predict the resistance to specific antibiotics. Any resistance mechanisms identified could then be inhibited so that the antibiotics will retain their effectiveness.
Their research was funded, in part, by grants from the James and Ester King Biomedical Research Program and from the National Institute of Diabetes and Digestive and Kidney Diseases.
Source:
FSU
Investigating exactly how bacteria learn to fend off antibiotics prescribed to treat infections is the subject of new research by Assistant Professor Brian G. Miller of FSU's Department of Chemistry and Biochemistry and one of his graduate research assistants, Kevin K. Desai. They have found that bacteria are remarkably resilient to toxic substances, such as antibiotics, because bacteria have the innate ability to produce a large variety of proteins. Those proteins then are able to do things such as pump toxins out or alter toxins so that they can no longer kill the bacteria.
"Most of us take antibiotics to eliminate infections without considering what would happen if they failed to work," said Kevin Desai, a graduate research assistant in Florida State's Department of Chemistry and Biochemistry. "While treating bacterial infections has typically been as easy as swallowing a pill, researchers are apprehensive about the increasing frequency of infections that are resistant to antibiotics, and are searching for ways to regain the upper hand."
In their study, Miller and Desai learned that about 2 percent of all the proteins produced by the model bacterium E. coli can be linked to enabling resistance to a single toxin called bromoacetate. Their research also has implications in elucidating the function of specific proteins and understanding how bacteria in the environment can survive in the presence of toxic manmade chemicals such as pesticides.
A paper describing Desai and Miller's work was published this week in the prestigious journal Proceedings of the National Academy of Sciences. That paper is titled "Recruitment of Genes and Enzymes Conferring Resistance to the Nonnatural Toxin Bromoacetate."
"The recent rise of antibiotic resistance demonstrates that bacteria are capable of rapidly evolving evasive strategies," they wrote. "It also has exposed our lack of knowledge about the evolutionary processes leading to resistance."
Understanding the mechanisms by which bacteria evade environmental threats has direct relevance for understanding and combating the rise of antibiotic resistance, Desai and Miller added.
The techniques described in the paper will be highly useful for other researchers in the field because it will allow them to predict the resistance to specific antibiotics. Any resistance mechanisms identified could then be inhibited so that the antibiotics will retain their effectiveness.
Their research was funded, in part, by grants from the James and Ester King Biomedical Research Program and from the National Institute of Diabetes and Digestive and Kidney Diseases.
Source:
FSU
ETH Zurich Professor Wins European Science Award
The Korber Prize, one of the most prestigious German awards in science, recognizes European scientists for applied and pioneering research. This year's award honors chemist Peter Seeberger for his groundbreaking research in the synthesis of complex sugars. The Korber Foundation, located in Hamburg, Germany, decided to honor Professor Seeberger for the development of an instrument that automatically synthesizes carbohydrates, thereby facilitating the production of novel synthetic sugar-based vaccines.
Professor Seeberger sees the award as confirmation of "the excellent work carried out by my team members. It is also an incentive to [other] researchers at the university to work on the very real problems of developing countries, to help deal with the most important health issues concerning the poor around the world."
The sugar specialist
Working at the crossroads of chemistry and biology, Professor Seeberger focuses on the so-called oligosaccharides. Each cell in the body is surrounded by an extra-cellular matrix, the glycans, made up of polysaccharide chains and branched sugars. Cells use the glycans to recognize one another and to exchange signalling molecules. As well, bacteria, viruses and fungi use the glycans to locate specific cells in the body in order to attack them: cancer-producing helicobacter bacteria attach themselves to the glycans in the gastric mucous membrane; flu viruses bind to the glycans on the lungs.
Vaccine to come
In order to develop a carbohydrate-based vaccine, researchers must first determine which glycans are typical for the disease of interest. These glycans are extracted, or produced chemically, then connected to a harmless protein. This conjugate vaccine is injected into the recipient. The immune system develops antibodies to these glycans, which will provide protection when a natural pathogen later enters the body.
Using the automated oligosaccharide synthesizer, known as the 'sugar ma-chine', that he developed, Professor Seeberger and his colleagues have succeeded not only in chemically producing glycans of pathogens, but also in developing vaccine candidates against malaria, leishmaniasis, aids, anthrax and tuberculosis.
In the past, producing a single complex sugar meant months or years of laboratory work. With the 'sugar machine', production time is reduced to less than one day, thus significantly speeding up basic research, and the development of new diagnostic tools and drugs. The malaria vaccine candidate is most advanced of the vaccines currently being tested. Animals tests have demonstrated the vac-ine's effectiveness. First tests on humans will be carried out in 2008.
Contact: Roman Klingler
Swiss Federal Institute of Technology
Professor Seeberger sees the award as confirmation of "the excellent work carried out by my team members. It is also an incentive to [other] researchers at the university to work on the very real problems of developing countries, to help deal with the most important health issues concerning the poor around the world."
The sugar specialist
Working at the crossroads of chemistry and biology, Professor Seeberger focuses on the so-called oligosaccharides. Each cell in the body is surrounded by an extra-cellular matrix, the glycans, made up of polysaccharide chains and branched sugars. Cells use the glycans to recognize one another and to exchange signalling molecules. As well, bacteria, viruses and fungi use the glycans to locate specific cells in the body in order to attack them: cancer-producing helicobacter bacteria attach themselves to the glycans in the gastric mucous membrane; flu viruses bind to the glycans on the lungs.
Vaccine to come
In order to develop a carbohydrate-based vaccine, researchers must first determine which glycans are typical for the disease of interest. These glycans are extracted, or produced chemically, then connected to a harmless protein. This conjugate vaccine is injected into the recipient. The immune system develops antibodies to these glycans, which will provide protection when a natural pathogen later enters the body.
Using the automated oligosaccharide synthesizer, known as the 'sugar ma-chine', that he developed, Professor Seeberger and his colleagues have succeeded not only in chemically producing glycans of pathogens, but also in developing vaccine candidates against malaria, leishmaniasis, aids, anthrax and tuberculosis.
In the past, producing a single complex sugar meant months or years of laboratory work. With the 'sugar machine', production time is reduced to less than one day, thus significantly speeding up basic research, and the development of new diagnostic tools and drugs. The malaria vaccine candidate is most advanced of the vaccines currently being tested. Animals tests have demonstrated the vac-ine's effectiveness. First tests on humans will be carried out in 2008.
Contact: Roman Klingler
Swiss Federal Institute of Technology
Dynamic Visualization Of Simplest Circadian Clock Provided By New Research
Scientists have acquired a more dynamic picture of events that underlie the functions of a bacterial biological clock. New research published online March 13th by Cell Press in the journal Molecular Cell, shows how the simplest organism known to have a circadian clock keeps time and may enhance our understanding of how other organisms establish and govern chronological rhythms.
A variety of organisms have evolved endogenous timing systems called a circadian clock that allows them to regulate metabolic activities in a day/night cycle. The simplest organisms known to possess a circadian oscillator are the cyanobacteria, better known as blue-green algae. The essential components of the circadian oscillator in cyanobacteria are the three clock proteins KaiA, KaiB and KaiC, all of which are expressed in the cyanobacterium S. elongatus.
Considerable research has implicated the phosphorylation cycle of KaiC as the central pacemaker in cyanobacteria and has demonstrated that the Kai proteins are repeatedly assembled and disassembled into heteromultimeric complexes, termed periodosomes. The crystal structure of each clock protein has also been determined and analyzed.
"Despite the substantial progress in structural characterization, the relationship between the assembly/disassembly dynamics and the circadian phosphorylation of KaiC is still poorly understood, mainly because of the difficulty in unraveling the underlying mechanisms solely from the static molecular pictures of individual clock components," explains Dr. Akiyama from the Japan Science and Technology Agency.
To obtain a more complete visualization of the cyanobacterial circadian oscillator, Dr. Akiyama and colleagues used small-angle X-ray scattering (SAXS) to follow the assembly/disassembly dynamics of the S. elongatus heteromultimeric Kai complexes in real time. The researchers found that the assembly/disassembly processes are crucial for phase entrainment in the early synchronizing stage but are passively driven by the phosphorylation status of KaiC in the late oscillatory stage. Further, KaiA and KaiB are recruited to KaiC in a phosphorylation-dependent manner.
"Our findings demonstrate that the initial phase of the cyanobacterial oscillator is determined predominantly by the assembly/disassembly communication of the clock components, and that the period is essentially resistant to intracellular noise such as collisions, cytoplasmic viscosity and crowding. These resistances are achieved in the binary and ternary complexes by recruiting KaiA homodimers, KaiB homotetramers and KaiC homohexamers in a phosphorylation-dependent manner," concludes Dr. Akiyama.
The researchers include Shuji Akiyama, PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, Japan; RIKEN SPring-8 Center, Harima Institute; Atsushi Nohara, Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan; Kazuki Ito, RIKEN SPring-8 Center, Harima Institute; and Yuichiro Maeda, ERATO Actin Filament Dynamics Project, Japan Science and Technology Agency, c/o RIKEN, Harima SPring-8 Center, Structural Biology Research Center, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan.
Source: Cathleen Genova
Cell Press
A variety of organisms have evolved endogenous timing systems called a circadian clock that allows them to regulate metabolic activities in a day/night cycle. The simplest organisms known to possess a circadian oscillator are the cyanobacteria, better known as blue-green algae. The essential components of the circadian oscillator in cyanobacteria are the three clock proteins KaiA, KaiB and KaiC, all of which are expressed in the cyanobacterium S. elongatus.
Considerable research has implicated the phosphorylation cycle of KaiC as the central pacemaker in cyanobacteria and has demonstrated that the Kai proteins are repeatedly assembled and disassembled into heteromultimeric complexes, termed periodosomes. The crystal structure of each clock protein has also been determined and analyzed.
"Despite the substantial progress in structural characterization, the relationship between the assembly/disassembly dynamics and the circadian phosphorylation of KaiC is still poorly understood, mainly because of the difficulty in unraveling the underlying mechanisms solely from the static molecular pictures of individual clock components," explains Dr. Akiyama from the Japan Science and Technology Agency.
To obtain a more complete visualization of the cyanobacterial circadian oscillator, Dr. Akiyama and colleagues used small-angle X-ray scattering (SAXS) to follow the assembly/disassembly dynamics of the S. elongatus heteromultimeric Kai complexes in real time. The researchers found that the assembly/disassembly processes are crucial for phase entrainment in the early synchronizing stage but are passively driven by the phosphorylation status of KaiC in the late oscillatory stage. Further, KaiA and KaiB are recruited to KaiC in a phosphorylation-dependent manner.
"Our findings demonstrate that the initial phase of the cyanobacterial oscillator is determined predominantly by the assembly/disassembly communication of the clock components, and that the period is essentially resistant to intracellular noise such as collisions, cytoplasmic viscosity and crowding. These resistances are achieved in the binary and ternary complexes by recruiting KaiA homodimers, KaiB homotetramers and KaiC homohexamers in a phosphorylation-dependent manner," concludes Dr. Akiyama.
The researchers include Shuji Akiyama, PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, Japan; RIKEN SPring-8 Center, Harima Institute; Atsushi Nohara, Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan; Kazuki Ito, RIKEN SPring-8 Center, Harima Institute; and Yuichiro Maeda, ERATO Actin Filament Dynamics Project, Japan Science and Technology Agency, c/o RIKEN, Harima SPring-8 Center, Structural Biology Research Center, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan.
Source: Cathleen Genova
Cell Press
Shedding Light On Evolution Of Human Complexity
A painstaking analysis of thousands of genes and the proteins they encode shows that human beings are biologically complex, at least in part, because of the way humans evolved to cope with redundancies arising from duplicate genes.
"We have found a specific evolutionary mechanism to account for a portion of the intricate biological complexity of our species," said Ariel Fernandez, professor of bioengineering at Rice University. "It is a coping mechanism, a process that enables us to deal with the fitness consequences of inefficient selection. It enables some of our proteins to become more specialized over time, and in turn makes us more complex."
Fernandez is the lead author of a paper slated to appear in the December issue of the journal Genome Research. The research is available online now.
Fernandez said the study drew from previous findings by his own research group and from seminal work of Michael Lynch, Distinguished Professor of Biology at Indiana University and a recently elected a fellow of the National Academy of Science. Lynch's work has shown that natural selection is less efficient in humans as compared with simpler creatures like bacteria. This "selection inefficiency" arises from the smaller population size of humans as compared with unicellular organisms.
"In all organisms, genes get duplicated every so often, for reasons we don't fully understand," Fernandez said. "When working efficiently, natural selection eliminates many of these duplicates, which are called 'paralogs.' In our earlier work, we saw that an unusual number of gene duplicates had survived in the human genome, which makes sense given selection inefficiency in humans."
In prior research on protein structure, Fernandez's team found that some proteins are packaged more poorly than others. Moreover, they found that the least-efficiently packed proteins are structurally stable only when they bind with partner proteins to form complexes.
"These poorly packed proteins are potential troublemakers when gene duplication occurs," Fernandez said. "The paralog encodes more copies of the protein than the body needs. This is called a 'dosage imbalance,' and it can make us sick. For instance, dosage imbalance has been implicated in Alzheimer's and other diseases."
Given selection inefficiency, Fernandez knew that paralogs encoding poorly packed proteins could remain in the human genome for quite a while. So he and graduate student Jianpeng Chen decided to examine whether gene duplicates had remained in the genome long enough for random genetic mutations to affect the paralogs dissimilarly. Fernandez and Chen, now a senior researcher in Beijing, China, cross-analyzed databases on genomics, protein structure, microRNA regulation and protein expression in such troublesome paralogs.
"The longer these duplicate genes stick around due to inefficient selection, the more likely they are to suffer a random mutation," Fernandez said. "Portions of every gene act to regulate protein expression -- by binding with microRNA, for example. We found numerous instances where random mutations had caused paralogs to be expressed dissimilarly, in ways that removed detrimental dosage imbalances."
Lynch said one aspect of Fernandez's research that is potentially groundbreaking is the observed tendency of proteins to evolve a more open structure in complex organisms.
"This observation fits with the general theory that large organisms with relatively small population sizes -- compared to microbes -- are subject to the vagaries of random genetic drift and hence the accumulation of very mildly deleterious mutations," Lynch said.
In principle, he said, the accumulation of such mutations may encourage a slight breakdown in protein stability. This, in turn, opens the door to interactions with other proteins that can return a measure of that lost stability.
"These are the potential roots for the emergence of novel protein-protein interactions, which are the hallmark of evolution in complex, multicellular species," Lynch said. "In other words, the origins of some key aspects of the evolution of complexity may have their origins in completely nonadaptive processes."
Fernandez said the research reveals how increasingly specialized proteins can evolve. He drew an analogy to a business that hires two delivery drivers that initially cover the same parts of town but eventually specialize to deliver only to specific neighborhoods.
"Eventually, even if times become tough, you cannot lay off either of them because they each became so specialized that your company needs them both," he said.
The more simple a creature is, the fewer specialized proteins it possesses. Humans and other higher-order mammals need many specialized proteins to build the specialized tissues in their skin, skeleton and organs. Even more specialized proteins are needed to maintain and regulate them. This complexity requires that the duplicates of the original jack-of-all-trades gene be retained, but this does not happen unless selection is inefficient. This is frequently a point of contention between proponents of evolution and intelligent design.
Fernandez and Chen looked at duplicate genes across the human genome and found that the more poorly packed a protein was, the more likely it was to be distinguished through paralog specialization.
"This supports the case for evolution because it shows that you can drive complexity with random mutations in duplicate genes," Fernandez said. "But this also implies that random drift must prevail over Darwinian selection. In other words, if Darwinian selection were ruthlessly efficient in humans -- as it is in bacteria and unicellular eukaryotes -- then our level of complexity would not be possible."
The research is supported by the National Institutes of Health.
Source: Jade Boyd
Rice University
"We have found a specific evolutionary mechanism to account for a portion of the intricate biological complexity of our species," said Ariel Fernandez, professor of bioengineering at Rice University. "It is a coping mechanism, a process that enables us to deal with the fitness consequences of inefficient selection. It enables some of our proteins to become more specialized over time, and in turn makes us more complex."
Fernandez is the lead author of a paper slated to appear in the December issue of the journal Genome Research. The research is available online now.
Fernandez said the study drew from previous findings by his own research group and from seminal work of Michael Lynch, Distinguished Professor of Biology at Indiana University and a recently elected a fellow of the National Academy of Science. Lynch's work has shown that natural selection is less efficient in humans as compared with simpler creatures like bacteria. This "selection inefficiency" arises from the smaller population size of humans as compared with unicellular organisms.
"In all organisms, genes get duplicated every so often, for reasons we don't fully understand," Fernandez said. "When working efficiently, natural selection eliminates many of these duplicates, which are called 'paralogs.' In our earlier work, we saw that an unusual number of gene duplicates had survived in the human genome, which makes sense given selection inefficiency in humans."
In prior research on protein structure, Fernandez's team found that some proteins are packaged more poorly than others. Moreover, they found that the least-efficiently packed proteins are structurally stable only when they bind with partner proteins to form complexes.
"These poorly packed proteins are potential troublemakers when gene duplication occurs," Fernandez said. "The paralog encodes more copies of the protein than the body needs. This is called a 'dosage imbalance,' and it can make us sick. For instance, dosage imbalance has been implicated in Alzheimer's and other diseases."
Given selection inefficiency, Fernandez knew that paralogs encoding poorly packed proteins could remain in the human genome for quite a while. So he and graduate student Jianpeng Chen decided to examine whether gene duplicates had remained in the genome long enough for random genetic mutations to affect the paralogs dissimilarly. Fernandez and Chen, now a senior researcher in Beijing, China, cross-analyzed databases on genomics, protein structure, microRNA regulation and protein expression in such troublesome paralogs.
"The longer these duplicate genes stick around due to inefficient selection, the more likely they are to suffer a random mutation," Fernandez said. "Portions of every gene act to regulate protein expression -- by binding with microRNA, for example. We found numerous instances where random mutations had caused paralogs to be expressed dissimilarly, in ways that removed detrimental dosage imbalances."
Lynch said one aspect of Fernandez's research that is potentially groundbreaking is the observed tendency of proteins to evolve a more open structure in complex organisms.
"This observation fits with the general theory that large organisms with relatively small population sizes -- compared to microbes -- are subject to the vagaries of random genetic drift and hence the accumulation of very mildly deleterious mutations," Lynch said.
In principle, he said, the accumulation of such mutations may encourage a slight breakdown in protein stability. This, in turn, opens the door to interactions with other proteins that can return a measure of that lost stability.
"These are the potential roots for the emergence of novel protein-protein interactions, which are the hallmark of evolution in complex, multicellular species," Lynch said. "In other words, the origins of some key aspects of the evolution of complexity may have their origins in completely nonadaptive processes."
Fernandez said the research reveals how increasingly specialized proteins can evolve. He drew an analogy to a business that hires two delivery drivers that initially cover the same parts of town but eventually specialize to deliver only to specific neighborhoods.
"Eventually, even if times become tough, you cannot lay off either of them because they each became so specialized that your company needs them both," he said.
The more simple a creature is, the fewer specialized proteins it possesses. Humans and other higher-order mammals need many specialized proteins to build the specialized tissues in their skin, skeleton and organs. Even more specialized proteins are needed to maintain and regulate them. This complexity requires that the duplicates of the original jack-of-all-trades gene be retained, but this does not happen unless selection is inefficient. This is frequently a point of contention between proponents of evolution and intelligent design.
Fernandez and Chen looked at duplicate genes across the human genome and found that the more poorly packed a protein was, the more likely it was to be distinguished through paralog specialization.
"This supports the case for evolution because it shows that you can drive complexity with random mutations in duplicate genes," Fernandez said. "But this also implies that random drift must prevail over Darwinian selection. In other words, if Darwinian selection were ruthlessly efficient in humans -- as it is in bacteria and unicellular eukaryotes -- then our level of complexity would not be possible."
The research is supported by the National Institutes of Health.
Source: Jade Boyd
Rice University
How Does Aspirin Crystallize? - Two Different Crystalline Forms Of Aspirin In Intergrown Domains
When you get a headache, you probably reach for aspirin. What is giving researchers a headache is the question of the crystal structure of aspirin. Is there another form on top of the long-known one? A team of scientists from Denmark, Germany, and India seems to have solved this controversial puzzle: yes, there is a second structure-but it does not exist as a pure form. “The two crystalline forms of aspirin are so closely related,” explains the research team of Andrew D. Bond, Roland Boese and Gautam R. Desiraju in Angewandte Chemie, “that they form structures containing domains of both crystal types.”
In 2004, computer calculations had indicated that while the long-known crystal structure of aspirin (form I) is definitely one of the most stable forms, another version might exist that is just as stable, though it had not yet been discovered-a clear challenge to researchers in the field. The difference between the proposed structures is slight: both have identical layers containing molecules grouped into pairs, but these layers are arranged differently in the two different structures. In 2005, researchers in the USA announced the discovery of the predicted structure (form II). But was this merely an artifact?
“We can now clear this matter up,” say Bond, Boese and Desiraju, after very careful examination of aspirin crystals. “Aspirin has a tendency to crystallize with an unusual intergrown structure. The same single crystal contains domains with both arrangements lying side by side.” The distribution and ratio of the domains are variable but limited. Whereas a pure form I exists, it has so far only been possible to obtain crystals containing a maximum of 85 % form II. The ratio of the two domains within crystals produced under identical conditions seems to be roughly constant.
This discovery upends fundamental principles and requires new concepts: chemists previously understood “polymorphism” to mean that a molecule can take on one or another packing arrangement in the crystalline state; a single crystal of a specific chemical substance is either one polymorph or the other. Aspirin is the first case in which two different “polymorphic” structures exist in one single crystal. So is aspirin polymorphic or not? Should the definition of polymorphism be updated? Such questions are not just philosophical in nature, but could have tangible implications in patent law, because each polymorph of a compound is viewed as a separate patentable substance.
Author: Roland Boese, Universität Duisburg-Essen (Germany)
Link
”On the Polymorphism of Aspirin”
Angewandte Chemie International Edition 2007, 46, No. 4, 615вЂ"617, doi: 10.1002/anie.200602378
Author: Gautam Desiraju, University of Hyderabad (India)
Link
” On the Polymorphism of Aspirin: Crystalline Aspirin as Intergrowths of Two "Polymorphic" Domains”
Angewandte Chemie International Edition 2007, 46, No. 4, 618вЂ"622, doi: 10.1002/anie.200603373
www3.interscience.wiley
In 2004, computer calculations had indicated that while the long-known crystal structure of aspirin (form I) is definitely one of the most stable forms, another version might exist that is just as stable, though it had not yet been discovered-a clear challenge to researchers in the field. The difference between the proposed structures is slight: both have identical layers containing molecules grouped into pairs, but these layers are arranged differently in the two different structures. In 2005, researchers in the USA announced the discovery of the predicted structure (form II). But was this merely an artifact?
“We can now clear this matter up,” say Bond, Boese and Desiraju, after very careful examination of aspirin crystals. “Aspirin has a tendency to crystallize with an unusual intergrown structure. The same single crystal contains domains with both arrangements lying side by side.” The distribution and ratio of the domains are variable but limited. Whereas a pure form I exists, it has so far only been possible to obtain crystals containing a maximum of 85 % form II. The ratio of the two domains within crystals produced under identical conditions seems to be roughly constant.
This discovery upends fundamental principles and requires new concepts: chemists previously understood “polymorphism” to mean that a molecule can take on one or another packing arrangement in the crystalline state; a single crystal of a specific chemical substance is either one polymorph or the other. Aspirin is the first case in which two different “polymorphic” structures exist in one single crystal. So is aspirin polymorphic or not? Should the definition of polymorphism be updated? Such questions are not just philosophical in nature, but could have tangible implications in patent law, because each polymorph of a compound is viewed as a separate patentable substance.
Author: Roland Boese, Universität Duisburg-Essen (Germany)
Link
”On the Polymorphism of Aspirin”
Angewandte Chemie International Edition 2007, 46, No. 4, 615вЂ"617, doi: 10.1002/anie.200602378
Author: Gautam Desiraju, University of Hyderabad (India)
Link
” On the Polymorphism of Aspirin: Crystalline Aspirin as Intergrowths of Two "Polymorphic" Domains”
Angewandte Chemie International Edition 2007, 46, No. 4, 618вЂ"622, doi: 10.1002/anie.200603373
www3.interscience.wiley
Yale University's Strobel Recognized For Work On RNA
Yale University's Scott A. Strobel, professor of Molecular Biophysics and Biochemistry, has been awarded the prestigious Schering-Plough Research Institute Award.
The award is given by the American Society of Biochemistry and Molecular Biology to recognize outstanding scientific contributions made by young researchers early in their careers.
Strobel will give the award lecture, titled "Three Views of RNA Catalysis: Ribozymes, Ribosomes, and Riboswitches,"'" at the society's annual meeting in San Diego on April 6.
Strobel is a leader at the interface between chemical and structural biology and is an expert on the function of RNA. His lab uses insights from several disciplines, including biochemistry and molecular biology, and employs such technologies as organic synthesis and X-ray crystallography to study reactions catalyzed by RNA. Many scientists now use techniques that he developed to study RNA activity.
"Scott Strobel has made seminal contributions to our understanding of the structure and functions of RNA in nature," said Yale Provost Andrew D. Hamilton. "He has provided not only detailed mechanistic insights into the chemistry of RNA but has revealed the beauty in the complexity of its catalytic role."
Strobel has been at Yale for the past 12 years and has served as chair of the Department of Molecular Biophysics and Biochemistry for the past two years. Prior to coming to Yale, Strobel did his postdoctoral work with Nobel Prize winner Thomas R. Cech at the University of Colorado. With the support of a $1 million grant from the Howard Hughes Medical Institute, Strobel has designed an innovative new course to engage students in science and to "give them control of scientific decisions and inspire them to see science as something they can do." As part of the course, students travel to the rainforest to search for plants and analyze endophytes for novel biological chemicals.
Strobel said the support of organizations such as the American Society of Biochemistry and Molecular Biology is crucial for the development of professional scientists.
yale
The award is given by the American Society of Biochemistry and Molecular Biology to recognize outstanding scientific contributions made by young researchers early in their careers.
Strobel will give the award lecture, titled "Three Views of RNA Catalysis: Ribozymes, Ribosomes, and Riboswitches,"'" at the society's annual meeting in San Diego on April 6.
Strobel is a leader at the interface between chemical and structural biology and is an expert on the function of RNA. His lab uses insights from several disciplines, including biochemistry and molecular biology, and employs such technologies as organic synthesis and X-ray crystallography to study reactions catalyzed by RNA. Many scientists now use techniques that he developed to study RNA activity.
"Scott Strobel has made seminal contributions to our understanding of the structure and functions of RNA in nature," said Yale Provost Andrew D. Hamilton. "He has provided not only detailed mechanistic insights into the chemistry of RNA but has revealed the beauty in the complexity of its catalytic role."
Strobel has been at Yale for the past 12 years and has served as chair of the Department of Molecular Biophysics and Biochemistry for the past two years. Prior to coming to Yale, Strobel did his postdoctoral work with Nobel Prize winner Thomas R. Cech at the University of Colorado. With the support of a $1 million grant from the Howard Hughes Medical Institute, Strobel has designed an innovative new course to engage students in science and to "give them control of scientific decisions and inspire them to see science as something they can do." As part of the course, students travel to the rainforest to search for plants and analyze endophytes for novel biological chemicals.
Strobel said the support of organizations such as the American Society of Biochemistry and Molecular Biology is crucial for the development of professional scientists.
yale
Oncogene Inhibits Tumor Suppressor To Promote Cancer: Study Links B-RAF And LKB1
Scientists have uncovered an interesting connection between two important protein kinase signaling pathways that are associated with cancer. The research, published by Cell Press in the January 30th issue of the journal Molecular Cell, may direct new therapeutic strategies for multiple types of cancer.
The protein kinase LKB1 is a known tumor suppressor and the LKB1-AMPK signaling pathway couples energy metabolism with cell growth, proliferation and survival. "Mutations in LKB1 are not frequent in human cancers and it is not clear how tumor cells suppress the signaling pathway to gain growth advantage under conditions of energy stress (common in cancer cells)," explains senior study author Dr. Lewis C. Cantley from Beth Israel Deaconess Medical Center and Harvard Medical School.
Dr. Cantley and colleagues, including Dr. Bin Zheng, designed a study to investigate the molecular mechanisms associated with suppression of the LKB1-AMPK pathway in tumor cells. The researchers used malignant melanoma cells that often have a mutation called "V600E" in the RAF protein B-RAF. The RAF-MEK-ERK pathway is well established as a key regulator of cell growth, proliferation, differentiation and survival.
Mutations in the RAF kinase B-RAF have been found in many types of human cancer but, while oncogenic B-RAF V600E has been linked with tumor induction, growth, maintenance and progression, the specific molecular mechanisms have not been identified. Dr. Cantley's group found that melanoma cells with the B-RAF V600E mutation had impaired AMPK activation and that inhibition of B-RAF signaling activated AMPK.
The researchers went on to show that LKB1 was phosphorylated by two kinases that are downstream of B-RAF, ERK and Rsk. The phosphorylation of LKB1 interfered with the ability of LKB1 to bind and activate AMPK. Importantly, expression of mutant LKB1 that could not be phosphorylated resulted in activation of AMPK and an inhibition of melanoma cell proliferation.
"Taken together, our results provide a molecular linkage between the LKLB1-AMPK and the RAF-MEK-ERK pathways and suggest that suppression of LKB1 function by B-RAF V600E plays an important role in B-RAF V600E-driven tumorigenesis," says Dr. Zheng. "It's conceivable that tumor cells must turn off the LKB1-AMPK signaling pathway to gain a growth advantage under conditions of energy stress."
Given that B-RAF mutation and loss of LKB1 are associated with multiple types of cancer, the work is likely to have a significant clinical impact. "Further understanding of how the intriguing molecular linkage between LKB1-AMPK and RAF-MEK-ERK functions in tumorigenesis could potentially provide great therapeutic opportunities for cancer treatment," offers Dr. Cantley.
The researchers include Bin Zheng, Harvard Medical School, Boston, MA; Joseph H. Jeong, Dana-Farber Cancer Institute, Boston, MA; John M. Asara, Harvard Medical School, Boston, MA; Yuan-Ying Yuan, Harvard Medical School, Boston, MA; Scott R. Granter, Brigham and Women's Hospital, Boston, MA; Lynda Chin, Dana-Farber Cancer Institute; and Lewis C. Cantley, Harvard Medical School, Boston, MA.
Source: Cathleen Genova
Cell Press
The protein kinase LKB1 is a known tumor suppressor and the LKB1-AMPK signaling pathway couples energy metabolism with cell growth, proliferation and survival. "Mutations in LKB1 are not frequent in human cancers and it is not clear how tumor cells suppress the signaling pathway to gain growth advantage under conditions of energy stress (common in cancer cells)," explains senior study author Dr. Lewis C. Cantley from Beth Israel Deaconess Medical Center and Harvard Medical School.
Dr. Cantley and colleagues, including Dr. Bin Zheng, designed a study to investigate the molecular mechanisms associated with suppression of the LKB1-AMPK pathway in tumor cells. The researchers used malignant melanoma cells that often have a mutation called "V600E" in the RAF protein B-RAF. The RAF-MEK-ERK pathway is well established as a key regulator of cell growth, proliferation, differentiation and survival.
Mutations in the RAF kinase B-RAF have been found in many types of human cancer but, while oncogenic B-RAF V600E has been linked with tumor induction, growth, maintenance and progression, the specific molecular mechanisms have not been identified. Dr. Cantley's group found that melanoma cells with the B-RAF V600E mutation had impaired AMPK activation and that inhibition of B-RAF signaling activated AMPK.
The researchers went on to show that LKB1 was phosphorylated by two kinases that are downstream of B-RAF, ERK and Rsk. The phosphorylation of LKB1 interfered with the ability of LKB1 to bind and activate AMPK. Importantly, expression of mutant LKB1 that could not be phosphorylated resulted in activation of AMPK and an inhibition of melanoma cell proliferation.
"Taken together, our results provide a molecular linkage between the LKLB1-AMPK and the RAF-MEK-ERK pathways and suggest that suppression of LKB1 function by B-RAF V600E plays an important role in B-RAF V600E-driven tumorigenesis," says Dr. Zheng. "It's conceivable that tumor cells must turn off the LKB1-AMPK signaling pathway to gain a growth advantage under conditions of energy stress."
Given that B-RAF mutation and loss of LKB1 are associated with multiple types of cancer, the work is likely to have a significant clinical impact. "Further understanding of how the intriguing molecular linkage between LKB1-AMPK and RAF-MEK-ERK functions in tumorigenesis could potentially provide great therapeutic opportunities for cancer treatment," offers Dr. Cantley.
The researchers include Bin Zheng, Harvard Medical School, Boston, MA; Joseph H. Jeong, Dana-Farber Cancer Institute, Boston, MA; John M. Asara, Harvard Medical School, Boston, MA; Yuan-Ying Yuan, Harvard Medical School, Boston, MA; Scott R. Granter, Brigham and Women's Hospital, Boston, MA; Lynda Chin, Dana-Farber Cancer Institute; and Lewis C. Cantley, Harvard Medical School, Boston, MA.
Source: Cathleen Genova
Cell Press
Potential Target For Treatment Of Mixed Lineage Leukemia Identified By Shilatifard And Colleagues
Ali Shilatifard, Ph.D., Investigator, has identified a cellular factor that can reverse histone trimethylation caused by the trithorax gene, the Drosophila homologue of the human mixed lineage leukemia gene, MLL. MLL, which is found in translocations in a variety of hematological malignancies, is a histone H3K4 methyltransferase.
The paper, "The trithorax-group gene little imaginal discs in Drosophila encodes a histone H3 trimethyl-Lys4 demethylase," was posted in the Advanced Online Publication section of Nature Structural & Molecular Biology. The publication identified a cellular factor that can reverse histone trimethylation associated with mixed lineage leukemia. This, in turn, may allow for the identification of new targets for the treatment of leukemia caused by MLL translocations.
"This work demonstrates that a Drosophila gene product, little imaginal discs (Lid), removes methyl groups from histone H3K4," explains Dr. Shilatifard. "A reduction of Lid results in a specific genome-wide increase in H3K4 trimethylation levels with no effect on other patterns of histone trimethylations. Animals with reduced Lid levels have higher levels of H3K4 trimethylation, resulting in altered distribution of the chromo-helicase protein, the CHD1."
"Dr. Shilatifard's first publication since joining the Institute earlier this year is a fascinating one," said Robb Krumlauf, Ph.D., Scientific Director. "The role of MLL in a variety of blood-related cancers has been well-established. These findings give us a promising option for developing targeted treatments to combat these types of leukemia."
Additional contributing authors to the paper include co-equal first authors Joel Eissenberg, Saint Louis University School of Medicine, and Min Gyu Lee, The Wistar Institute; Jessica Schneider and Anne Ilvarsonn at Saint Louis University School of Medicine; and Ramin Shiekhattar, The Wistar Institute.
Dr. Shilatifard conducted some of this research prior to joining the Stowers Institute while serving as a faculty member of the Saint Louis University School of Medicine and the Saint Louis University Cancer Center.
About the Stowers Institute
Housed in a 600,000 square-foot state-of-the-art facility on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts basic research on fundamental processes of cellular life. Through its commitment to collaborative research and the use of cutting-edge technology, the Institute seeks more effective means of preventing and curing disease. The Institute was founded by Jim and Virginia Stowers, two cancer survivors who have created combined endowments of $2 billion in support of basic research of the highest quality.
Contact: Marie Jennings
Stowers Institute for Medical Research
The paper, "The trithorax-group gene little imaginal discs in Drosophila encodes a histone H3 trimethyl-Lys4 demethylase," was posted in the Advanced Online Publication section of Nature Structural & Molecular Biology. The publication identified a cellular factor that can reverse histone trimethylation associated with mixed lineage leukemia. This, in turn, may allow for the identification of new targets for the treatment of leukemia caused by MLL translocations.
"This work demonstrates that a Drosophila gene product, little imaginal discs (Lid), removes methyl groups from histone H3K4," explains Dr. Shilatifard. "A reduction of Lid results in a specific genome-wide increase in H3K4 trimethylation levels with no effect on other patterns of histone trimethylations. Animals with reduced Lid levels have higher levels of H3K4 trimethylation, resulting in altered distribution of the chromo-helicase protein, the CHD1."
"Dr. Shilatifard's first publication since joining the Institute earlier this year is a fascinating one," said Robb Krumlauf, Ph.D., Scientific Director. "The role of MLL in a variety of blood-related cancers has been well-established. These findings give us a promising option for developing targeted treatments to combat these types of leukemia."
Additional contributing authors to the paper include co-equal first authors Joel Eissenberg, Saint Louis University School of Medicine, and Min Gyu Lee, The Wistar Institute; Jessica Schneider and Anne Ilvarsonn at Saint Louis University School of Medicine; and Ramin Shiekhattar, The Wistar Institute.
Dr. Shilatifard conducted some of this research prior to joining the Stowers Institute while serving as a faculty member of the Saint Louis University School of Medicine and the Saint Louis University Cancer Center.
About the Stowers Institute
Housed in a 600,000 square-foot state-of-the-art facility on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts basic research on fundamental processes of cellular life. Through its commitment to collaborative research and the use of cutting-edge technology, the Institute seeks more effective means of preventing and curing disease. The Institute was founded by Jim and Virginia Stowers, two cancer survivors who have created combined endowments of $2 billion in support of basic research of the highest quality.
Contact: Marie Jennings
Stowers Institute for Medical Research
Federal Guidance Helps Protect Against Misuse Of Synthetic DNA
Federal guidance issued aims to reduce the risk that synthetic DNA will be misused deliberately to create dangerous organisms. Screening Framework Guidance for Providers of Synthetic Double-Stranded DNA, issued by the U.S. Department of Health and Human Services, supports national biosecurity goals and balances the promise of synthetic DNA with its potential biosecurity risks.
Synthetic DNA is becoming a key material used in life sciences and biotechnology, including the emerging scientific field of synthetic biology. Among other applications, synthetic DNA is being used to develop new ways or improve existing ways to fight disease.
While there are significant potential benefits, synthetic DNA could potentially be used to recreate dangerous organisms that are covered under existing regulations. As such, development of technologies utilizing synthetic DNA must be encouraged in a safe and secure manner.
"This guidance is an important step in ensuring that synthetic DNA is used to promote, not threaten, public health," said HHS Assistant Secretary for Preparedness and Response Dr. Nicole Lurie, whose office led the broad interagency effort to develop the guidance. "The guidance also recognizes the steps industry has taken proactively to address potential biosecurity risks and seeks to minimize negative impacts on research and business."
Screening synthetic DNA orders may help to reduce the risk that an individual with malicious intent could access and use synthetic double-stranded DNA products to create a dangerous organism that is currently regulated. The guidance recommends baseline standards for use by companies to screen orders for synthetic double-stranded DNA products.
These recommendations include screening customers as well as DNA sequences, and follow-up screening as necessary. The guidance also recommends consulting with U.S. government contacts as needed, clarifies how to report suspicious orders, and encourages the industry to develop best practices in addressing potential biosecurity concerns.
In developing the guidance, the White House Office of Science and Technology Policy and the National Security Council staff convened a federal interagency working group which met with relevant stakeholders, including members of industry, academia, and federal agencies involved in synthetic DNA policy, and incorporated public input.
Because the technology, the industry, and the nature of the biosecurity risks are changing rapidly, the guidance will be reviewed by the federal interagency working group on a regular basis and revised as necessary.
Source:
HHS
Synthetic DNA is becoming a key material used in life sciences and biotechnology, including the emerging scientific field of synthetic biology. Among other applications, synthetic DNA is being used to develop new ways or improve existing ways to fight disease.
While there are significant potential benefits, synthetic DNA could potentially be used to recreate dangerous organisms that are covered under existing regulations. As such, development of technologies utilizing synthetic DNA must be encouraged in a safe and secure manner.
"This guidance is an important step in ensuring that synthetic DNA is used to promote, not threaten, public health," said HHS Assistant Secretary for Preparedness and Response Dr. Nicole Lurie, whose office led the broad interagency effort to develop the guidance. "The guidance also recognizes the steps industry has taken proactively to address potential biosecurity risks and seeks to minimize negative impacts on research and business."
Screening synthetic DNA orders may help to reduce the risk that an individual with malicious intent could access and use synthetic double-stranded DNA products to create a dangerous organism that is currently regulated. The guidance recommends baseline standards for use by companies to screen orders for synthetic double-stranded DNA products.
These recommendations include screening customers as well as DNA sequences, and follow-up screening as necessary. The guidance also recommends consulting with U.S. government contacts as needed, clarifies how to report suspicious orders, and encourages the industry to develop best practices in addressing potential biosecurity concerns.
In developing the guidance, the White House Office of Science and Technology Policy and the National Security Council staff convened a federal interagency working group which met with relevant stakeholders, including members of industry, academia, and federal agencies involved in synthetic DNA policy, and incorporated public input.
Because the technology, the industry, and the nature of the biosecurity risks are changing rapidly, the guidance will be reviewed by the federal interagency working group on a regular basis and revised as necessary.
Source:
HHS
Using Honeybee Venom Toxin To Develop A New Tool For Studying Hypertension
Researchers at the University of Pennsylvania School of Medicine have modified a honeybee venom toxin so that it can be used as a tool to study the inner workings of ion channels that control heart rate and the recycling of salt in kidneys. In general, ion channels selectively allow the passage of small ions such as sodium, potassium, or calcium into and out of the cell.
The study, published in the Proceedings of the National Academy of Sciences, is from the laboratory of Zhe Lu, M.D, Ph.D., Professor of Physiology and a Howard Hughes Medical Institute Investigator, who looked at the action of a natural bee toxin on inward-rectifier potassium channels, Kir channels for short, to identify new approaches to treat cardiovascular disease.
The honeybee venom toxin, called tertiapin, or TPN, stops the flow of potassium ions across cell membranes by plugging up the opening of Kir channels on the outside of cells. Kir channels in kidneys are potential new targets for treating hypertension. "The clue comes from patients with genetic defects in these channels who lose a lot of sodium because it cannot be effectively reabsorbed and thus have low blood pressure," notes Lu. "An inhibitor specifically against these kidney channels will allow this idea to be tested."
Developing a specific inhibitor for one type of Kir channel has been challenging because the target site is very similar among different types of Kir channels. For example, while TPN inhibits Kir type 1 channels in kidney cells, it also inhibits other types of Kir channels in heart cells. After more than a decade, Lu and his colleagues succeeded in bioengineering a TPN that selectively inhibits Kir channels important for salt recycling in kidneys.
By introducing two mutations into TPN, they engineered a variant, called TPNLQ, which stems the flow of potassium ions in renal Kir type 1 channels at low concentrations, and with a 250-fold sensitivity over six other types of Kir channels.
The development of TPNLQ demonstrates that a highly specific inhibitor of potassium channels can be engineered. TPNLQ can now be used as a tool to prove the concept, in animal studies, that reducing salt reabsorption by plugging up renal Kir type 1 potassium channels is a potential new way to treat hypertension.
Yajamana Ramu and Yanping Xu of Penn conducted this study with Dr. Lu. The research was supported by the National Institutes of General Medical Sciences and the University of Pennsylvania Research Foundation.
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals - its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top 10 "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center - a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
Source: Karen Kreeger
University of Pennsylvania School of Medicine
The study, published in the Proceedings of the National Academy of Sciences, is from the laboratory of Zhe Lu, M.D, Ph.D., Professor of Physiology and a Howard Hughes Medical Institute Investigator, who looked at the action of a natural bee toxin on inward-rectifier potassium channels, Kir channels for short, to identify new approaches to treat cardiovascular disease.
The honeybee venom toxin, called tertiapin, or TPN, stops the flow of potassium ions across cell membranes by plugging up the opening of Kir channels on the outside of cells. Kir channels in kidneys are potential new targets for treating hypertension. "The clue comes from patients with genetic defects in these channels who lose a lot of sodium because it cannot be effectively reabsorbed and thus have low blood pressure," notes Lu. "An inhibitor specifically against these kidney channels will allow this idea to be tested."
Developing a specific inhibitor for one type of Kir channel has been challenging because the target site is very similar among different types of Kir channels. For example, while TPN inhibits Kir type 1 channels in kidney cells, it also inhibits other types of Kir channels in heart cells. After more than a decade, Lu and his colleagues succeeded in bioengineering a TPN that selectively inhibits Kir channels important for salt recycling in kidneys.
By introducing two mutations into TPN, they engineered a variant, called TPNLQ, which stems the flow of potassium ions in renal Kir type 1 channels at low concentrations, and with a 250-fold sensitivity over six other types of Kir channels.
The development of TPNLQ demonstrates that a highly specific inhibitor of potassium channels can be engineered. TPNLQ can now be used as a tool to prove the concept, in animal studies, that reducing salt reabsorption by plugging up renal Kir type 1 potassium channels is a potential new way to treat hypertension.
Yajamana Ramu and Yanping Xu of Penn conducted this study with Dr. Lu. The research was supported by the National Institutes of General Medical Sciences and the University of Pennsylvania Research Foundation.
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals - its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's top 10 "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center - a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
Source: Karen Kreeger
University of Pennsylvania School of Medicine
How Life-Threatening Blood Clots Take Hold
When plaques coating blood vessel walls rupture and expose collagen, platelets spring into action to form a blood clot at the damaged site. Now, a new report in the April 17th issue of the journal Cell, a Cell Press publication, reveals how those life-threatening clots - a leading cause of death in the United States, Europe and other industrialized countries - get an early grip. The discovery might offer a new way to fight clot formation before it can even begin, according to the researchers.
"Compared to other diseases, blood clotting has been very well understood," said Athan Kuliopulos of Tufts Medical Center and Tufts University School of Medicine. Nevertheless, he continued, many people still suffer from heart attacks, ischemic stroke and death as a result of clot formation.
"Drugs designed to inhibit clots through known pathways are widely used by millions. They work well, but not perfectly. There is still an unmet need." Those drugs include aspirin and the so-called thienopyridines, including Clopidogrel (trade name Plavix).
Scientists have known that a protein called thrombin plays an important role in clot formation as a potent activator of platelets. It also cuts fibrinogen into fibrin, a fibrous protein that works together with platelets to form a clot.
But thrombin isn't the whole story. Enzymes known as matrix metalloproteases have recently emerged as important players in platelet function and the biology of blood vessels. Two of those enzymes, MMP-1 and MMP-2 can actually encourage platelet activation, according to earlier studies, although the means were unknown. In cancer cells too, MMP-1 activates a receptor known as PAR1 - the same receptor that is also responsible for receiving the thrombin signal on human platelets.
"There is abundant proMMP-1 coating platelets," Kuliopulos said. "We thought maybe it was on the outside waiting to be activated by something. Maybe it could be involved in an early event in blood clotting, before thrombin is around."
Indeed, Kuliopulos' team has now connected those dots. They show that exposure of platelets to collagen activates MMP-1, which in turn directly cut PAR1 on the surface of platelets. Collagen is the first thing a platelet "sees" when a blood vessel ruptures or is cut.
The MMP-1-PAR1 pathway activates another set of molecular players known to be involved in early clot formation, he said. Those activated platelets change their shape, sending out spikes and membrane sheets. "Within seconds, they become more sticky," adhering to the vessel surface and then other platelets.
Moreover, they show that treatments that block the MMP1-PAR1 pathway prevent blood clots from forming in the presence of collagen, suggesting that drugs targeting this metalloprotease-receptor system could offer a new way to treat patients with acute coronary syndromes.
According to the new results, PAR1 inhibitors already being tested in clinical trials might have an added benefit, Kuliopulos said. It's also possible they might work a little too well, since there is a careful balance between the risk of dangerous blood clots and the risk of bleeding. "An MMP-1 inhibitor might be better tolerated," he said.
The researchers include Vishal Trivedi, Adrienne Boire, Boris Tchernychev, Nicole C. Kaneider, Andrew J. Leger, Katie O'Callaghan, Lidija Covic, and Athan Kuliopulos, of Tufts University School of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA.
Source:
Cathleen Genova
Cell Press
View drug information on PLAVIX.
"Compared to other diseases, blood clotting has been very well understood," said Athan Kuliopulos of Tufts Medical Center and Tufts University School of Medicine. Nevertheless, he continued, many people still suffer from heart attacks, ischemic stroke and death as a result of clot formation.
"Drugs designed to inhibit clots through known pathways are widely used by millions. They work well, but not perfectly. There is still an unmet need." Those drugs include aspirin and the so-called thienopyridines, including Clopidogrel (trade name Plavix).
Scientists have known that a protein called thrombin plays an important role in clot formation as a potent activator of platelets. It also cuts fibrinogen into fibrin, a fibrous protein that works together with platelets to form a clot.
But thrombin isn't the whole story. Enzymes known as matrix metalloproteases have recently emerged as important players in platelet function and the biology of blood vessels. Two of those enzymes, MMP-1 and MMP-2 can actually encourage platelet activation, according to earlier studies, although the means were unknown. In cancer cells too, MMP-1 activates a receptor known as PAR1 - the same receptor that is also responsible for receiving the thrombin signal on human platelets.
"There is abundant proMMP-1 coating platelets," Kuliopulos said. "We thought maybe it was on the outside waiting to be activated by something. Maybe it could be involved in an early event in blood clotting, before thrombin is around."
Indeed, Kuliopulos' team has now connected those dots. They show that exposure of platelets to collagen activates MMP-1, which in turn directly cut PAR1 on the surface of platelets. Collagen is the first thing a platelet "sees" when a blood vessel ruptures or is cut.
The MMP-1-PAR1 pathway activates another set of molecular players known to be involved in early clot formation, he said. Those activated platelets change their shape, sending out spikes and membrane sheets. "Within seconds, they become more sticky," adhering to the vessel surface and then other platelets.
Moreover, they show that treatments that block the MMP1-PAR1 pathway prevent blood clots from forming in the presence of collagen, suggesting that drugs targeting this metalloprotease-receptor system could offer a new way to treat patients with acute coronary syndromes.
According to the new results, PAR1 inhibitors already being tested in clinical trials might have an added benefit, Kuliopulos said. It's also possible they might work a little too well, since there is a careful balance between the risk of dangerous blood clots and the risk of bleeding. "An MMP-1 inhibitor might be better tolerated," he said.
The researchers include Vishal Trivedi, Adrienne Boire, Boris Tchernychev, Nicole C. Kaneider, Andrew J. Leger, Katie O'Callaghan, Lidija Covic, and Athan Kuliopulos, of Tufts University School of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA.
Source:
Cathleen Genova
Cell Press
View drug information on PLAVIX.
When Less Is More; How Mitochondrial Signals Extend Lifespan
In making your pro-longevity resolutions, like drinking more red wine and maintaining a vibrant social network, here's one you likely forgot: dialing down your mitochondria. It turns out that slowing the engines of these tiny cellular factories could extend your life-an observation relevant not only to aging research but to our understanding of how cells communicate with each another.
So report researchers at the Salk Institute for Biological Studies in the Jan. 7, 2011, issue of Cell. Howard Hughes Medical Institute investigator Andrew Dillin, Ph.D., and his colleagues used the roundworm Ceanorhabditis elegans to show that perturbing mitochondrial function in subsets of worm cells sent global signals governing longevity of the entire organism.
"In this study we show how signals sent from distressed mitochondria are communicated to distant tissues to promote survival and enhance longevity," says Dillin, an associate professor in the Molecular and Cell Biology Laboratory.
The identity of the signal sent from mitochondrially-distressed cells-a hypothetical factor Dillin calls a "mitokine" -remains unknown. Nonetheless, he speculates that mitokines could one day be lobbed as messengers from healthy to unhealthy tissues to treat degenerative conditions.
"Imagine if we could perturb mitochondria in the liver, and make them send a mitokine to degenerating neurons," he says. "Instead of trying to get a drug into the brain, we could exploit the body's ability to send out a natural rescue signal."
It may seem paradoxical that reducing mitochondrial activity increases longevity because mitochondria, particles classically described as energy-producing "powerhouses", seem like good guys. How could keeping powerhouses humming along briskly be anything but a plus?
But it turns out that many investigators, Dillin included, have observed puzzling relationships between mitochondria, energy generation and longevity-interactions that suggest that living long does not necessarily require prospering at the subcellular level.
"As a postdoctoral fellow I did a screen looking for worm genes that increased longevity," says Dillin citing a 2002 Science study that inspired the current work. "Many genes were related to mitochondrial function. If you disabled them, worms lived longer, although their respiration or metabolism was reduced. We wondered whether this is why animals lived longer."
The current Cell study shows it's not that simple. Dillin and graduate students Jenni Durieux, Ph.D., first author, and Suzanne Wolff, Ph.D., engineered "transgenic" worms in which a gene named cco-1 was disabled. cco-1 encodes a protein essential for biochemical reactions known collectively as the Electron Transport Chain (ETC), which are required for mitochondria to generate energy-and thus, for cells to live.
A key finding was that worms with ETC selectively impaired by cco-1 loss in either intestine or nerve cells lived longer than normal worms, while worms with ETC perturbed in muscle, skin or the germline did not, suggesting that a unique signal emanating from damaged mitochondria in nerve or gut, and communicated at a distance, extended lifespan.
"Curiously, ETC manipulation had to occur within a critical time window in a worm's lifespan to get the maximal effect," says Dillin, noting that effects were long-lasting. "It was like you could manipulate mitochondria in a 30-year-old human and get an extra 15 years, while in an 80-year-old, you might only gain two or three years."
To determine how cells respond to the pro-longevity cue, the group monitored a cellular emergency plan called the Unfolded Protein Response (UPR). Cells mount it when proteins accumulate excessively and begin to unravel-or "misfold"-which is toxic to cells. To avert cell death, the UPR mobilizes a team of helpers who, like sales clerks at a Gap sweater table, refold accumulating misfolded proteins piling up inside a cell.
When Dillin and colleagues fed worms reagents blocking the UPR, they found that disruption of cco-1 in neurons or intestine no longer had a lifespan-enhancing effect. This dramatic finding illustrates that initiating refolding of proteins, in this case in response to faraway mitochondrial stress, is in fact the very activity that enhances longevity.
Before 2000, biology textbooks defined mitochondria solely in terms of energy production. "We were caught up in mitochondrial metabolic function," says Dillin, remarking that pro-longevity signals characterized in the current study aren't strictly metabolic. "But we now recognize numerous other critical activities performed by mitochondria."
For example, a "metabolic" explanation for enhanced longevity, known as the "rate of living" theory, goes like this: revved up mitochondria burn cells' energy candle at both ends, leading to (your) premature demise. Conversely, cells that parsimoniously spend energy-possibly due to compromised mitochondrial output-live longer.
Dillin's study refutes this scenario. "We show that it all comes down to protein folding," says Dillin. "That's become the unifying theme in my lab."
This study was funded by grants from the Glenn Foundation for Medical Research, the NIH and by the Howard Hughes Medical Institute.
Source: Salk Institute for Biological Studies
So report researchers at the Salk Institute for Biological Studies in the Jan. 7, 2011, issue of Cell. Howard Hughes Medical Institute investigator Andrew Dillin, Ph.D., and his colleagues used the roundworm Ceanorhabditis elegans to show that perturbing mitochondrial function in subsets of worm cells sent global signals governing longevity of the entire organism.
"In this study we show how signals sent from distressed mitochondria are communicated to distant tissues to promote survival and enhance longevity," says Dillin, an associate professor in the Molecular and Cell Biology Laboratory.
The identity of the signal sent from mitochondrially-distressed cells-a hypothetical factor Dillin calls a "mitokine" -remains unknown. Nonetheless, he speculates that mitokines could one day be lobbed as messengers from healthy to unhealthy tissues to treat degenerative conditions.
"Imagine if we could perturb mitochondria in the liver, and make them send a mitokine to degenerating neurons," he says. "Instead of trying to get a drug into the brain, we could exploit the body's ability to send out a natural rescue signal."
It may seem paradoxical that reducing mitochondrial activity increases longevity because mitochondria, particles classically described as energy-producing "powerhouses", seem like good guys. How could keeping powerhouses humming along briskly be anything but a plus?
But it turns out that many investigators, Dillin included, have observed puzzling relationships between mitochondria, energy generation and longevity-interactions that suggest that living long does not necessarily require prospering at the subcellular level.
"As a postdoctoral fellow I did a screen looking for worm genes that increased longevity," says Dillin citing a 2002 Science study that inspired the current work. "Many genes were related to mitochondrial function. If you disabled them, worms lived longer, although their respiration or metabolism was reduced. We wondered whether this is why animals lived longer."
The current Cell study shows it's not that simple. Dillin and graduate students Jenni Durieux, Ph.D., first author, and Suzanne Wolff, Ph.D., engineered "transgenic" worms in which a gene named cco-1 was disabled. cco-1 encodes a protein essential for biochemical reactions known collectively as the Electron Transport Chain (ETC), which are required for mitochondria to generate energy-and thus, for cells to live.
A key finding was that worms with ETC selectively impaired by cco-1 loss in either intestine or nerve cells lived longer than normal worms, while worms with ETC perturbed in muscle, skin or the germline did not, suggesting that a unique signal emanating from damaged mitochondria in nerve or gut, and communicated at a distance, extended lifespan.
"Curiously, ETC manipulation had to occur within a critical time window in a worm's lifespan to get the maximal effect," says Dillin, noting that effects were long-lasting. "It was like you could manipulate mitochondria in a 30-year-old human and get an extra 15 years, while in an 80-year-old, you might only gain two or three years."
To determine how cells respond to the pro-longevity cue, the group monitored a cellular emergency plan called the Unfolded Protein Response (UPR). Cells mount it when proteins accumulate excessively and begin to unravel-or "misfold"-which is toxic to cells. To avert cell death, the UPR mobilizes a team of helpers who, like sales clerks at a Gap sweater table, refold accumulating misfolded proteins piling up inside a cell.
When Dillin and colleagues fed worms reagents blocking the UPR, they found that disruption of cco-1 in neurons or intestine no longer had a lifespan-enhancing effect. This dramatic finding illustrates that initiating refolding of proteins, in this case in response to faraway mitochondrial stress, is in fact the very activity that enhances longevity.
Before 2000, biology textbooks defined mitochondria solely in terms of energy production. "We were caught up in mitochondrial metabolic function," says Dillin, remarking that pro-longevity signals characterized in the current study aren't strictly metabolic. "But we now recognize numerous other critical activities performed by mitochondria."
For example, a "metabolic" explanation for enhanced longevity, known as the "rate of living" theory, goes like this: revved up mitochondria burn cells' energy candle at both ends, leading to (your) premature demise. Conversely, cells that parsimoniously spend energy-possibly due to compromised mitochondrial output-live longer.
Dillin's study refutes this scenario. "We show that it all comes down to protein folding," says Dillin. "That's become the unifying theme in my lab."
This study was funded by grants from the Glenn Foundation for Medical Research, the NIH and by the Howard Hughes Medical Institute.
Source: Salk Institute for Biological Studies
Protein Complementarity May Offer New Insights Into Autoimmune Diseases
The discovery of "complementary" antibodies against plasminogen in patients with blood vessel inflammation caused by anti-neutrophil cytoplasmic autoantibodies (ANCAs) may lead to new approaches to research, testing, and treatment of ANCA vasculitis and other autoimmune diseases, suggests a paper in the December Journal of the American Society of Nephrology (JASN).
"This research is especially important because it opens new avenues for exploration of autoimmune disease that embrace the concepts of protein complementarity," comments Ronald J. Falk, MD, of UNC Kidney Center, University of North Carolina, Chapel Hill, one of the authors of the study. "The power of this approach has gone unappreciated, even though the basic ideas of protein complementarity have been proven in other settings over the years."
The researchers looked for complementary proteins in a group of patients with a rare autoimmune disease called ANCA vasculitis. People with autoimmune diseases have abnormal "autoantibodies" that cause the immune system to attack the body's own cells and tissues. In patients with ANCA vasculitis, the ANCAs attack a type of white blood cells called neutrophils, which in turn attack the blood vessel walls. The resulting blood vessel inflammation (vasculitis) can lead to kidney damage (glomerulonephritis) and other complications.
The patients in the study had a particularly aggressive form of vasculitis caused by ANCAs against a protein called PR3. They were being treated with a procedure called plasma exchange therapy (or plasmapheresis), which removes the PR3 ANCAs from the blood. "Using an antibody reactive with complementary PR3 protein, produced in the laboratory, we analyzed protein pools removed from the patients' plasma during plasma exchange therapy to identify any existing proteins that were reactive with the anti-complementary PR3 antibody," Dr. Falk explains. Previous studies have suggested that antibodies to complementary proteins may play an important role in the initiation of autoimmune diseases.
The results showed autoantibodies to a complementary protein that, to the researchers' surprise, turned out to be plasminogen a protein that plays a key role in blood clotting. 22% of the patients with PR3 ANCA vasculitis had anti-plasminogen antibodies, including 56% of those who had serious blood-clotting problems as a complication of their disease. "Identification of potentially pathogenic [disease-causing] anti-plasminogen antibodies provides an explanation of why patients with PR3-ANCA disease have a high incidence of blood clots," says Dr. Falk.
The results may have important implications for the care of patients with ANCA vasculitis most immediately, in identifying those at high risk of developing blood clots. However, the assay used in the study was inadequate for clinical use. "What is needed is a clinical test that is specific and precise enough to measure anti-plasminogen antibody levels," adds Dr. Falk. Further studies will be needed to establish the clinical value of such a test, including the correlation between complementary antibody levels and the risk of blood clots.
In addition, the study suggests that complementary antibodies may play a more important role in autoimmune diseases than scientists have previously realized. The methods used may lead to the discovery of autoantibodies to complementary proteins in other autoimmune diseases for example, rheumatoid arthritis or multiple sclerosis. "Hopefully, our discoveries will entice scientists to consider the potential implications of protein complementarity," says Dr. Falk.
This research was supported by National Institutes of Health grant 2P01 DK058335.
The article, entitled "Antibodies with Dual Reactivity to Plasminogen and Complementary PR3 in PR3-ANCA Vasculitis," will appear online at jasn.asnjournals on Wednesday, August 13, 2008, and in the December 2008 print issue of JASN.
ASN is a not-for-profit organization of 11,000 physicians and scientists dedicated to the study of nephrology and committed to providing a forum for the promulgation of information regarding the latest research and clinical findings on kidney diseases. ASN publishes JASN, the Clinical Journal of the American Society of Nephrology (CJASN), and the Nephrology Self-Assessment Program (NephSAP). In January 2009, the Society will launch ASN Kidney News, a newsmagazine for nephrologists, scientists, allied health professionals, and staff.
American Society of Nephrology (ASN)
1725 I St. NW, Ste. 510
Washington, DC 20006
United States
asn-online
"This research is especially important because it opens new avenues for exploration of autoimmune disease that embrace the concepts of protein complementarity," comments Ronald J. Falk, MD, of UNC Kidney Center, University of North Carolina, Chapel Hill, one of the authors of the study. "The power of this approach has gone unappreciated, even though the basic ideas of protein complementarity have been proven in other settings over the years."
The researchers looked for complementary proteins in a group of patients with a rare autoimmune disease called ANCA vasculitis. People with autoimmune diseases have abnormal "autoantibodies" that cause the immune system to attack the body's own cells and tissues. In patients with ANCA vasculitis, the ANCAs attack a type of white blood cells called neutrophils, which in turn attack the blood vessel walls. The resulting blood vessel inflammation (vasculitis) can lead to kidney damage (glomerulonephritis) and other complications.
The patients in the study had a particularly aggressive form of vasculitis caused by ANCAs against a protein called PR3. They were being treated with a procedure called plasma exchange therapy (or plasmapheresis), which removes the PR3 ANCAs from the blood. "Using an antibody reactive with complementary PR3 protein, produced in the laboratory, we analyzed protein pools removed from the patients' plasma during plasma exchange therapy to identify any existing proteins that were reactive with the anti-complementary PR3 antibody," Dr. Falk explains. Previous studies have suggested that antibodies to complementary proteins may play an important role in the initiation of autoimmune diseases.
The results showed autoantibodies to a complementary protein that, to the researchers' surprise, turned out to be plasminogen a protein that plays a key role in blood clotting. 22% of the patients with PR3 ANCA vasculitis had anti-plasminogen antibodies, including 56% of those who had serious blood-clotting problems as a complication of their disease. "Identification of potentially pathogenic [disease-causing] anti-plasminogen antibodies provides an explanation of why patients with PR3-ANCA disease have a high incidence of blood clots," says Dr. Falk.
The results may have important implications for the care of patients with ANCA vasculitis most immediately, in identifying those at high risk of developing blood clots. However, the assay used in the study was inadequate for clinical use. "What is needed is a clinical test that is specific and precise enough to measure anti-plasminogen antibody levels," adds Dr. Falk. Further studies will be needed to establish the clinical value of such a test, including the correlation between complementary antibody levels and the risk of blood clots.
In addition, the study suggests that complementary antibodies may play a more important role in autoimmune diseases than scientists have previously realized. The methods used may lead to the discovery of autoantibodies to complementary proteins in other autoimmune diseases for example, rheumatoid arthritis or multiple sclerosis. "Hopefully, our discoveries will entice scientists to consider the potential implications of protein complementarity," says Dr. Falk.
This research was supported by National Institutes of Health grant 2P01 DK058335.
The article, entitled "Antibodies with Dual Reactivity to Plasminogen and Complementary PR3 in PR3-ANCA Vasculitis," will appear online at jasn.asnjournals on Wednesday, August 13, 2008, and in the December 2008 print issue of JASN.
ASN is a not-for-profit organization of 11,000 physicians and scientists dedicated to the study of nephrology and committed to providing a forum for the promulgation of information regarding the latest research and clinical findings on kidney diseases. ASN publishes JASN, the Clinical Journal of the American Society of Nephrology (CJASN), and the Nephrology Self-Assessment Program (NephSAP). In January 2009, the Society will launch ASN Kidney News, a newsmagazine for nephrologists, scientists, allied health professionals, and staff.
American Society of Nephrology (ASN)
1725 I St. NW, Ste. 510
Washington, DC 20006
United States
asn-online
CLC Bio And Beijing Genomics Institute Challenge Vast Volumes Of Bioinformatics Data
CLC bio, Beijing Genomics Institute (BGI), and SD Genomics (SDG) announce:
A global leader within bioinformatics and genomics, Beijing Genomics Institute, has joined forces with the world's leading bioinformatics solution provider, CLC bio, and genomics solutions experts, SD Genomics, to resolve one of the major barriers within the life science community today: To compute and understand the massive amounts of data created in academic research institutions as well as biotech and pharmaceutical companies.
Chief Executive Officer at Beijing Genomics Institute, Wang Jian, states
"All indications point to very high growth rates in the global genomics and bioinformatics markets - but we also know that nearly all researchers are facing large problems working efficiently with the tools available today. They simply don't have the proper solutions to help analyze and provide an overall understanding of the massive amounts of biological data produced. This collaboration brings together a group of companies with the capability and strength to break down these barriers and provide global solutions to our customers all over the world."
The vast volume of data created by the new sequence technologies such as the massively parallel ultra-high-throughput sequencing systems presented by ABI, Helicos, 454, and Illumina (formerly known as Solexa), create an urgent need for new and innovative IT solutions for handling and interpreting such data in an efficient and value adding way. CLC bio and Beijing Genomics Institute aim to remove these barriers by collaborating in various fields, such as development of innovative and competitive plug-ins for use with CLC bio's workbench platform, as well as implementation of some of BGI's well-known genomics tools to be used through CLC bio's very popular and globally widespread software solutions.
Chief Executive Officer of SD Genomics, Jens Sundbye, states
"This collaboration will not only be an advantage for existing key customers like Merck and Novo Nordisk; any global customer - small, medium or large - will have new, intriguing possibilities to get better results in less time, and remove essential barriers in their workflow."
About CLC bio
CLC bio is the world's leading bioinformatics solution provider, solely focusing on the development of bioinformatics: software, hardware, data analysis, and custom-designed bioinformatics algorithms. CLC bio is an Apple solution provider and value added reseller.
CLC bio's mission is to be among the most innovative bioinformatics companies in the 21st century. This is realized through:
-- Development of bioinformatics software and hardware based on the latest scientific findings
-- User-friendly, integrated and intuitive software solutions
-- Continuous focus on customer needs and superior customer service
-- Frequent product updates including the latest IT technologies and bioinformatics algorithms
-- A flexible IT architecture, enabling customers to buy or develop individualized solutions at a reasonable price
clcbio
About Beijing Genomics Institute
Beijing Genomics Institute, part of Hua Da Group, is a leading global Genomics Institute and commercial partner established in July 1999. Since then BGI has grown rapidly through international cooperation and increasing support from the Chinese government. BGI now has two campuses, one in Beijing and the other in Hangzhou.
With world class demonstrated capabilities in research and capacity building in genomics and bioinformatics, BGI aims to realize ambitious growth plans in order to consolidate its position as a leading global supplier together with strong European partners, SD Genomics and Hua Holding.
genomics.cn
About SD Genomics
SD Genomics is a superior full-service solution provider within biotechnological and biomedical products and services including oligonucleotides, sequencing services, bioinformatics services, and microarrays to our customers focusing on value added solutions.
Based on competitive global competences SD Genomics' mission is to provide one stop value added quality solutions for the global Life Sciences Industry and Research.
As innovators in their markets SD Genomics create customer satisfaction and build long-term relationships.
SD Genomics also participates in collaborations where customers can concentrate on core value added projects by outsourcing tasks.
sdgenomics.dk
A global leader within bioinformatics and genomics, Beijing Genomics Institute, has joined forces with the world's leading bioinformatics solution provider, CLC bio, and genomics solutions experts, SD Genomics, to resolve one of the major barriers within the life science community today: To compute and understand the massive amounts of data created in academic research institutions as well as biotech and pharmaceutical companies.
Chief Executive Officer at Beijing Genomics Institute, Wang Jian, states
"All indications point to very high growth rates in the global genomics and bioinformatics markets - but we also know that nearly all researchers are facing large problems working efficiently with the tools available today. They simply don't have the proper solutions to help analyze and provide an overall understanding of the massive amounts of biological data produced. This collaboration brings together a group of companies with the capability and strength to break down these barriers and provide global solutions to our customers all over the world."
The vast volume of data created by the new sequence technologies such as the massively parallel ultra-high-throughput sequencing systems presented by ABI, Helicos, 454, and Illumina (formerly known as Solexa), create an urgent need for new and innovative IT solutions for handling and interpreting such data in an efficient and value adding way. CLC bio and Beijing Genomics Institute aim to remove these barriers by collaborating in various fields, such as development of innovative and competitive plug-ins for use with CLC bio's workbench platform, as well as implementation of some of BGI's well-known genomics tools to be used through CLC bio's very popular and globally widespread software solutions.
Chief Executive Officer of SD Genomics, Jens Sundbye, states
"This collaboration will not only be an advantage for existing key customers like Merck and Novo Nordisk; any global customer - small, medium or large - will have new, intriguing possibilities to get better results in less time, and remove essential barriers in their workflow."
About CLC bio
CLC bio is the world's leading bioinformatics solution provider, solely focusing on the development of bioinformatics: software, hardware, data analysis, and custom-designed bioinformatics algorithms. CLC bio is an Apple solution provider and value added reseller.
CLC bio's mission is to be among the most innovative bioinformatics companies in the 21st century. This is realized through:
-- Development of bioinformatics software and hardware based on the latest scientific findings
-- User-friendly, integrated and intuitive software solutions
-- Continuous focus on customer needs and superior customer service
-- Frequent product updates including the latest IT technologies and bioinformatics algorithms
-- A flexible IT architecture, enabling customers to buy or develop individualized solutions at a reasonable price
clcbio
About Beijing Genomics Institute
Beijing Genomics Institute, part of Hua Da Group, is a leading global Genomics Institute and commercial partner established in July 1999. Since then BGI has grown rapidly through international cooperation and increasing support from the Chinese government. BGI now has two campuses, one in Beijing and the other in Hangzhou.
With world class demonstrated capabilities in research and capacity building in genomics and bioinformatics, BGI aims to realize ambitious growth plans in order to consolidate its position as a leading global supplier together with strong European partners, SD Genomics and Hua Holding.
genomics.cn
About SD Genomics
SD Genomics is a superior full-service solution provider within biotechnological and biomedical products and services including oligonucleotides, sequencing services, bioinformatics services, and microarrays to our customers focusing on value added solutions.
Based on competitive global competences SD Genomics' mission is to provide one stop value added quality solutions for the global Life Sciences Industry and Research.
As innovators in their markets SD Genomics create customer satisfaction and build long-term relationships.
SD Genomics also participates in collaborations where customers can concentrate on core value added projects by outsourcing tasks.
sdgenomics.dk
Complexity Of Crohn's Disease Revealed As 'gene' Count Tops 30
New research has trebled the number of genetic regions known to be implicated in Crohn's disease, a form of inflammatory bowel disease, to over thirty. The research, published in the journal Nature Genetics, has identified a number of potential new targets for drug development as well as providing surprising new links between the condition and other common diseases including asthma.
Crohn's disease affects between 1 in 500 and 1 in 1000 people within the UK, causing inflammation of gastrointestinal tract and leading to pain, ulcers and diarrhoea. The disease can strike at any age, but onset is typically between 15 and 40 years old. As many as 80% of people suffering from the disease will require surgery at some point.
Previous studies have already identified 11 genes and loci (regions of the genome typically including one or more genes) that increase susceptibility to the disease. Now an international collaboration of researchers has identified a further 21 new genes and loci. The team of scientists and clinicians involved used DNA samples from almost 12,000 people. Many were from UK patient collections and analysed originally in the Wellcome Trust Case Control Consortium - the largest study ever undertaken into the genetics underlying common diseases - with others coming from European and North American collections.
"We now know of more than thirty genetic regions that affect susceptibility to Crohn's disease," says Dr Jeffrey Barrett from the Wellcome Trust Centre for Human Genetics at the University of Oxford, lead author of the study. "These explain only about a fifth of the genetic risk, which implies that there may be hundreds of genes implicated in the disease, each increasing susceptibility by a small amount.
"Whilst this study shows the power of genome wide association studies to reveal the genetics behind common diseases, it also highlights the complexity of diseases such as Crohn's."
Genome wide association studies have led to an explosion in the number of genes known to be implicated in complex diseases such as diabetes, heart disease and Crohn's disease. The first two Crohn's disease susceptibility genes were discovered in 2001, followed by a third in 2006. The Wellcome Trust Case Control Consortium and parallel studies took that number above ten the following year using genome wide association studies. This number has now almost trebled to thirty-two.
Amongst the findings are loci containing genes known to be implicated in a number of other common diseases including diabetes, rheumatoid arthritis and psoriasis. However, the genetic relationship between Crohn's and these other diseases is not always straightforward. For example, the genetic variant PTPN2 appears to increase susceptibility to both Crohn's disease and type 1 diabetes. But the similarly named PTPN22 increases the risk of developing type 1 diabetes, yet appears to offer protection from Crohn's.
Although some of the disease connections were unsurprising - there is already a known epidemiological correlation between Crohn's disease and psoriasis, for example - the ORMDL3 gene on chromosome 17 provided the most unexpected link. ORMDL3 was already known to be a genetic risk factor for childhood asthma, but until now, no epidemiological link had ever been seen between asthma and Crohn's disease.
"It's too early for us to say how Crohn's disease and many of these other diseases, including asthma, are linked at a biological level," says Dr Miles Parkes, Consultant Gastroenterologist at Addenbrooke's Hospital and the University of Cambridge, who also worked on the study. "However, we are building up a picture of the biology underlying Crohn's disease, and the more we understand about the underlying biology of these diseases, the better equipped we will be to treat them.
"Studies such as this are not about developing diagnostic tests, but about identifying targets for new drugs therapies. Crohn's disease can be a very serious condition, often requiring surgery, and the sooner we can understand the underlying causes, the sooner we will be able to devise new treatments to help our patients."
Some of the most likely candidates for so-called "druggable" targets include the CCR6 gene, which is thought to be part of the signalling machinery that causes white blood cells in the gut to become over-active, leading to inflammation. These particular white blood cells, known as Th17 cells, are also present in inflamed joints, implying that CCR6 may also be relevant to rheumatoid arthritis, and therefore of added interest to the pharmaceutical industry.
"Genetics, and particularly the large scale approach of genome wide association studies, offers much hope for understanding the biological causes of complex diseases," says Dr Mark Walport, Director of the Wellcome Trust. "Studies such as this also highlight the important relationships between different diseases and, as such, may offer valuable insights into the pathways that lead to common symptoms such as inflammation."
The collection of samples was supported by the National Association for Colitis and Crohn's Disease.
Source: Craig Brierley
Wellcome Trust
Crohn's disease affects between 1 in 500 and 1 in 1000 people within the UK, causing inflammation of gastrointestinal tract and leading to pain, ulcers and diarrhoea. The disease can strike at any age, but onset is typically between 15 and 40 years old. As many as 80% of people suffering from the disease will require surgery at some point.
Previous studies have already identified 11 genes and loci (regions of the genome typically including one or more genes) that increase susceptibility to the disease. Now an international collaboration of researchers has identified a further 21 new genes and loci. The team of scientists and clinicians involved used DNA samples from almost 12,000 people. Many were from UK patient collections and analysed originally in the Wellcome Trust Case Control Consortium - the largest study ever undertaken into the genetics underlying common diseases - with others coming from European and North American collections.
"We now know of more than thirty genetic regions that affect susceptibility to Crohn's disease," says Dr Jeffrey Barrett from the Wellcome Trust Centre for Human Genetics at the University of Oxford, lead author of the study. "These explain only about a fifth of the genetic risk, which implies that there may be hundreds of genes implicated in the disease, each increasing susceptibility by a small amount.
"Whilst this study shows the power of genome wide association studies to reveal the genetics behind common diseases, it also highlights the complexity of diseases such as Crohn's."
Genome wide association studies have led to an explosion in the number of genes known to be implicated in complex diseases such as diabetes, heart disease and Crohn's disease. The first two Crohn's disease susceptibility genes were discovered in 2001, followed by a third in 2006. The Wellcome Trust Case Control Consortium and parallel studies took that number above ten the following year using genome wide association studies. This number has now almost trebled to thirty-two.
Amongst the findings are loci containing genes known to be implicated in a number of other common diseases including diabetes, rheumatoid arthritis and psoriasis. However, the genetic relationship between Crohn's and these other diseases is not always straightforward. For example, the genetic variant PTPN2 appears to increase susceptibility to both Crohn's disease and type 1 diabetes. But the similarly named PTPN22 increases the risk of developing type 1 diabetes, yet appears to offer protection from Crohn's.
Although some of the disease connections were unsurprising - there is already a known epidemiological correlation between Crohn's disease and psoriasis, for example - the ORMDL3 gene on chromosome 17 provided the most unexpected link. ORMDL3 was already known to be a genetic risk factor for childhood asthma, but until now, no epidemiological link had ever been seen between asthma and Crohn's disease.
"It's too early for us to say how Crohn's disease and many of these other diseases, including asthma, are linked at a biological level," says Dr Miles Parkes, Consultant Gastroenterologist at Addenbrooke's Hospital and the University of Cambridge, who also worked on the study. "However, we are building up a picture of the biology underlying Crohn's disease, and the more we understand about the underlying biology of these diseases, the better equipped we will be to treat them.
"Studies such as this are not about developing diagnostic tests, but about identifying targets for new drugs therapies. Crohn's disease can be a very serious condition, often requiring surgery, and the sooner we can understand the underlying causes, the sooner we will be able to devise new treatments to help our patients."
Some of the most likely candidates for so-called "druggable" targets include the CCR6 gene, which is thought to be part of the signalling machinery that causes white blood cells in the gut to become over-active, leading to inflammation. These particular white blood cells, known as Th17 cells, are also present in inflamed joints, implying that CCR6 may also be relevant to rheumatoid arthritis, and therefore of added interest to the pharmaceutical industry.
"Genetics, and particularly the large scale approach of genome wide association studies, offers much hope for understanding the biological causes of complex diseases," says Dr Mark Walport, Director of the Wellcome Trust. "Studies such as this also highlight the important relationships between different diseases and, as such, may offer valuable insights into the pathways that lead to common symptoms such as inflammation."
The collection of samples was supported by the National Association for Colitis and Crohn's Disease.
Source: Craig Brierley
Wellcome Trust
Nanotubes Sniff Out Cancer Agents In Living Cells - Carbon Nanotubes Used To Monitor Chemotherapy, Detect Toxins At The Single-Molecule Level
MIT engineers have developed carbon nanotubes into sensors for cancer drugs and other DNA-damaging agents inside living cells.
The sensors, made of carbon nanotubes wrapped in DNA, can detect chemotherapy drugs such as cisplatin as well as environmental toxins and free radicals that damage DNA.
"We've made a sensor that can be placed in living cells, healthy or malignant, and actually detect several different classes of molecules that damage DNA," said Michael Strano, associate professor of chemical engineering and senior author of a paper on the work appearing in the Dec. 14 online edition of Nature Nanotechnology.
Such sensors could be used to monitor chemotherapy patients to ensure the drugs are effectively battling tumors. Many chemotherapy drugs are very powerful DNA disruptors and can cause serious side effects, so it is important to make sure that the drugs are reaching their intended targets.
"You could figure out not only where the drugs are, but whether a drug is active or not," said Daniel Heller, a graduate student in chemical engineering and lead author of the paper.
The sensor can detect DNA-alkylating agents, a class that includes cisplatin, and oxidizing agents such as hydrogen peroxide and hydroxyl radicals.
Using the sensors, researchers can monitor living cells over an extended period of time. The sensor can pinpoint the exact location of molecules inside cells, and for one agent, hydrogen peroxide, it can detect a single molecule.
The new technology takes advantage of the fact that carbon nanotubes fluoresce in near-infrared light. Human tissue does not, which makes it easier to see the nanotubes light up.
Each nanotube is coated with DNA, which binds to DNA-damaging agents present in the cell. That interaction between the DNA and DNA disruptor changes the intensity and/or wavelength of the fluorescent light emitted by the nanotube. The agents produce different signatures that can be used to identify them.
"We can differentiate between different types of molecules depending on how they interact," Strano said.
Because they are coated in DNA, these nanotube sensors are safe for injection in living cells. (Nanotubes can come in many different lengths and can be coated with different materials, which influences whether they are safe or toxic, Strano said.)
In future studies, the researchers plan to use the sensors to study the effects of various antioxidants, such as the compounds in green tea, and learn how to more effectively use toxic chemotherapy drugs.
Other authors of the paper include MIT graduate student Hong Jin of the Department of Chemical Engineering. Researchers from the University of Illinois at Urbana-Champaign also contributed to the work, which was funded by the National Science Foundation.
Written by Anne Trafton, MIT News Office
MIT
The sensors, made of carbon nanotubes wrapped in DNA, can detect chemotherapy drugs such as cisplatin as well as environmental toxins and free radicals that damage DNA.
"We've made a sensor that can be placed in living cells, healthy or malignant, and actually detect several different classes of molecules that damage DNA," said Michael Strano, associate professor of chemical engineering and senior author of a paper on the work appearing in the Dec. 14 online edition of Nature Nanotechnology.
Such sensors could be used to monitor chemotherapy patients to ensure the drugs are effectively battling tumors. Many chemotherapy drugs are very powerful DNA disruptors and can cause serious side effects, so it is important to make sure that the drugs are reaching their intended targets.
"You could figure out not only where the drugs are, but whether a drug is active or not," said Daniel Heller, a graduate student in chemical engineering and lead author of the paper.
The sensor can detect DNA-alkylating agents, a class that includes cisplatin, and oxidizing agents such as hydrogen peroxide and hydroxyl radicals.
Using the sensors, researchers can monitor living cells over an extended period of time. The sensor can pinpoint the exact location of molecules inside cells, and for one agent, hydrogen peroxide, it can detect a single molecule.
The new technology takes advantage of the fact that carbon nanotubes fluoresce in near-infrared light. Human tissue does not, which makes it easier to see the nanotubes light up.
Each nanotube is coated with DNA, which binds to DNA-damaging agents present in the cell. That interaction between the DNA and DNA disruptor changes the intensity and/or wavelength of the fluorescent light emitted by the nanotube. The agents produce different signatures that can be used to identify them.
"We can differentiate between different types of molecules depending on how they interact," Strano said.
Because they are coated in DNA, these nanotube sensors are safe for injection in living cells. (Nanotubes can come in many different lengths and can be coated with different materials, which influences whether they are safe or toxic, Strano said.)
In future studies, the researchers plan to use the sensors to study the effects of various antioxidants, such as the compounds in green tea, and learn how to more effectively use toxic chemotherapy drugs.
Other authors of the paper include MIT graduate student Hong Jin of the Department of Chemical Engineering. Researchers from the University of Illinois at Urbana-Champaign also contributed to the work, which was funded by the National Science Foundation.
Written by Anne Trafton, MIT News Office
MIT
A New Way To Study How Breast Cancer Spreads Developed By Einstein Researchers
In a breakthrough study appearing in advance online publication of Nature Methods, researchers at Albert Einstein College of Medicine of Yeshiva University describe for the first time a method of viewing individual breast cancer cells for several days at a time. The study, by scientists in Einstein's Gruss Lipper Biophotonics Center, provides detail on how cancer cells invade surrounding tissue and reach blood vessels. These movements are the first steps of the potentially deadly stage of cancer known as metastasis.
The new method of viewing cancer cells over several days in their natural environment is considered significant because prior methods of study only allowed cells to be viewed clearly for several hours at one time. Having a longer and clearer window into how cancer cells move during the early stages of metastasis may help scientists develop more effective cancer therapies. For 2007, the American Cancer Society reported that a woman with metastatic breast cancer had an average survival rate of two years.
Using intravital imaging, the researchers developed a "photoswitch" to mark cancer cells of their choosing within a tumor and observe how these tumor cells in mice move in their surrounding tissue. The technique allowed researchers to see individually labeled tumor cells move in real time and in living mice.
"One focus of our laboratories has been developing methods to see what cancer cells are doing when followed over time in the most realistic setting," explained Jeffrey Segall, Ph.D., professor of anatomy and structural biology. "Mapping the fate of tumor cells in different regions of a tumor was not possible before the development of the photoswitching technology," explained John Condeelis, Ph.D., co-chair and professor of anatomy and structural biology and co-director of the Gruss Lipper Biophotonics Center.
The new method involves the placement of a frame containing a small glass window onto the breast tumor of a mouse formed from cancerous cells that have a specific tag. Through the glass, individual breast tumor cells are targeted with a laser that 'marks' the cancer cells red. By viewing the cells through the window using a microscope, researchers can follow the cells as they spread. The mouse can move around and live normally with the glass plate and then be anesthetized briefly for observance under the microscope. The marked cancer cells are followed over a period of days until they lose their brightness.
Using this technique, investigators found that breast cancer cells closer to blood vessels were more aggressive and directed in their invasiveness than cancer cells farther from blood vessels. The cancer cells near blood vessels also appeared in the lung indicating that they are disseminated throughout the body.
As co-lead author, Bojana Gligorijevic Ph.D., explained, "Our work showed how important the microenvironment of a tumor is to the behavior of a cancer cell and the metastatic outcome of the tumor itself. We can now look at the early steps of metastasis in high resolution and specific regions of the tumor."
This finding marks the first time a direct link was shown between the presence of blood vessels and the invasive ability of a cancer cell, which strengthens the growing theory that blood supply is crucial to effective metastasis. It also suggests that many cancer therapies currently in development, which are directed at cutting off blood supply to tumors, may be on the right track.
The research was conducted by Dmitriy Kedrin, Bojana Gligorijevic, Ph.D. and team leader Jacco van Rheenen, Ph.D. under the direction of Drs. Segall and Condeelis. Vladislav Verkhusha, Ph.D., associate professor of anatomy and structural biology, and Jeffrey Wyckoff, M.F.A., B.S., senior associate of anatomy and structural biology, both members of the Biophotonics Center, contributed novel photo-switching protein, and expertise in intravital imaging, respectively. This study required this broad multidisciplinary team and the resources of the Center to make the technical leap needed to achieve this new result. The Center has been supported by the generous contributions of Evelyn Lipper.
Each year, cancer kills 553,000 people in the U.S. Most cancer deaths are caused by complications from metastasis, the spread of cancer cells to distant tissues and organs through the blood, rather than from the primary tumor itself. This research provides a powerful tool for studying cancer metastasis and is part of a growing body of Einstein cancer research that sheds light on how cancer spreads.
The study has been chosen for highlight at the 48th Annual Meeting of The American Society of Cell Biology in San Francisco on December 15, 2008 to be presented by Dr. Gligorijevic.
Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. It is the home to some 2,000 faculty members, 750 M.D. students, 350 Ph.D. students (including 125 in combined M.D./Ph.D. programs) and 380 postdoctoral investigators. Today, Einstein receives more than $150 million annually in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Through its extensive affiliation network involving five hospital centers in the Bronx, Manhattan and Long Island - which includes Montefiore Medical Center, Einstein's officially designated University Hospital - the College runs one of the largest post-graduate medical training program in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training. For more information, please visit aecom.yu.
Source: Michael Heller
Albert Einstein College of Medicine
The new method of viewing cancer cells over several days in their natural environment is considered significant because prior methods of study only allowed cells to be viewed clearly for several hours at one time. Having a longer and clearer window into how cancer cells move during the early stages of metastasis may help scientists develop more effective cancer therapies. For 2007, the American Cancer Society reported that a woman with metastatic breast cancer had an average survival rate of two years.
Using intravital imaging, the researchers developed a "photoswitch" to mark cancer cells of their choosing within a tumor and observe how these tumor cells in mice move in their surrounding tissue. The technique allowed researchers to see individually labeled tumor cells move in real time and in living mice.
"One focus of our laboratories has been developing methods to see what cancer cells are doing when followed over time in the most realistic setting," explained Jeffrey Segall, Ph.D., professor of anatomy and structural biology. "Mapping the fate of tumor cells in different regions of a tumor was not possible before the development of the photoswitching technology," explained John Condeelis, Ph.D., co-chair and professor of anatomy and structural biology and co-director of the Gruss Lipper Biophotonics Center.
The new method involves the placement of a frame containing a small glass window onto the breast tumor of a mouse formed from cancerous cells that have a specific tag. Through the glass, individual breast tumor cells are targeted with a laser that 'marks' the cancer cells red. By viewing the cells through the window using a microscope, researchers can follow the cells as they spread. The mouse can move around and live normally with the glass plate and then be anesthetized briefly for observance under the microscope. The marked cancer cells are followed over a period of days until they lose their brightness.
Using this technique, investigators found that breast cancer cells closer to blood vessels were more aggressive and directed in their invasiveness than cancer cells farther from blood vessels. The cancer cells near blood vessels also appeared in the lung indicating that they are disseminated throughout the body.
As co-lead author, Bojana Gligorijevic Ph.D., explained, "Our work showed how important the microenvironment of a tumor is to the behavior of a cancer cell and the metastatic outcome of the tumor itself. We can now look at the early steps of metastasis in high resolution and specific regions of the tumor."
This finding marks the first time a direct link was shown between the presence of blood vessels and the invasive ability of a cancer cell, which strengthens the growing theory that blood supply is crucial to effective metastasis. It also suggests that many cancer therapies currently in development, which are directed at cutting off blood supply to tumors, may be on the right track.
The research was conducted by Dmitriy Kedrin, Bojana Gligorijevic, Ph.D. and team leader Jacco van Rheenen, Ph.D. under the direction of Drs. Segall and Condeelis. Vladislav Verkhusha, Ph.D., associate professor of anatomy and structural biology, and Jeffrey Wyckoff, M.F.A., B.S., senior associate of anatomy and structural biology, both members of the Biophotonics Center, contributed novel photo-switching protein, and expertise in intravital imaging, respectively. This study required this broad multidisciplinary team and the resources of the Center to make the technical leap needed to achieve this new result. The Center has been supported by the generous contributions of Evelyn Lipper.
Each year, cancer kills 553,000 people in the U.S. Most cancer deaths are caused by complications from metastasis, the spread of cancer cells to distant tissues and organs through the blood, rather than from the primary tumor itself. This research provides a powerful tool for studying cancer metastasis and is part of a growing body of Einstein cancer research that sheds light on how cancer spreads.
The study has been chosen for highlight at the 48th Annual Meeting of The American Society of Cell Biology in San Francisco on December 15, 2008 to be presented by Dr. Gligorijevic.
Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. It is the home to some 2,000 faculty members, 750 M.D. students, 350 Ph.D. students (including 125 in combined M.D./Ph.D. programs) and 380 postdoctoral investigators. Today, Einstein receives more than $150 million annually in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Through its extensive affiliation network involving five hospital centers in the Bronx, Manhattan and Long Island - which includes Montefiore Medical Center, Einstein's officially designated University Hospital - the College runs one of the largest post-graduate medical training program in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training. For more information, please visit aecom.yu.
Source: Michael Heller
Albert Einstein College of Medicine
The Journal Of Experimental Biology 2009 Symposium: Survival In A Changing World:
Each year, The Company of Biologists (biologists/) organises and supports a themed conference as the basis of a special review issue of The Journal of Experimental Biology. The main aim of this annual Symposium is to unite outstanding biologists and bring together their varied expertise on one particular subject. It is a leisurely meeting with enough time to talk and to discuss. The social side of science is also catered for - an academic meeting in the traditional sense. As the journal is primarily associated with coverage of comparative aspects of biology, with this Symposium we would like to stress our interest in exploring the phenomena of life at all levels of biological organization in a physiological and evolutionary context.
The Summary of the 2007 Intergovernmental Panel on Climate Change (IPCC) Report concludes that 'Warming of the climate system is unequivocal, as is now evident from observations of increases in global average air and ocean temperatures, widespread melting of snow and ice, and rising global average sea level'. These environmental changes have already significantly impacted the habitats and living conditions of many species, including our own. Anthropogenic pollution and myriad releases of biologically active substances into the environment have further changed the world for living organisms. The aim of this Symposium is to assess the impacts many of these changes have had on animal biodiversity and ecology, emphasizing adaptation and resilience in physiological systems.
The Symposium is a satellite to the International Union of Physiological Sciences (IUPS) 36th World Congress and will be held in the beautiful setting of Awaji Island, the largest island in Japan's Inland Sea, at the Awaji Yumebutai International Conference Center, with accommodation in the adjoining Western Awaji Island Hotel. Within 90 minutes travel of Kansai International Airport or Kyoto, Awaji Yumebutai provides a relaxed atmosphere that lends itself to work, dialogue and recreation.
The Symposium will comprise presentations by a list of 18 distinguished invited speakers and will also include open registration for a maximum of 30 additional delegates. There will be a poster session for registered delegates to present their work and plenty of scope for informal discussion. All invited oral presentations will be published as a special issue of The Journal of Experimental Biology in early 2010.
Session topics include:
Climate change and arctic ecological responses вЂ" past, present and future
Climate change and its influence on terrestrial animals
Climate change and its influence on aquatic animals
Emerging zoonosis and human diseases
Animal resilience and adaptation in coping with changes
Population and ecosystem responses to land use change and contaminants
Awaji Island, Japan : 2-6 August 2009
For further information and to register, go to: sicw09.biologists/
Source: Dr. Michaela Handel
The Company of Biologists
The Summary of the 2007 Intergovernmental Panel on Climate Change (IPCC) Report concludes that 'Warming of the climate system is unequivocal, as is now evident from observations of increases in global average air and ocean temperatures, widespread melting of snow and ice, and rising global average sea level'. These environmental changes have already significantly impacted the habitats and living conditions of many species, including our own. Anthropogenic pollution and myriad releases of biologically active substances into the environment have further changed the world for living organisms. The aim of this Symposium is to assess the impacts many of these changes have had on animal biodiversity and ecology, emphasizing adaptation and resilience in physiological systems.
The Symposium is a satellite to the International Union of Physiological Sciences (IUPS) 36th World Congress and will be held in the beautiful setting of Awaji Island, the largest island in Japan's Inland Sea, at the Awaji Yumebutai International Conference Center, with accommodation in the adjoining Western Awaji Island Hotel. Within 90 minutes travel of Kansai International Airport or Kyoto, Awaji Yumebutai provides a relaxed atmosphere that lends itself to work, dialogue and recreation.
The Symposium will comprise presentations by a list of 18 distinguished invited speakers and will also include open registration for a maximum of 30 additional delegates. There will be a poster session for registered delegates to present their work and plenty of scope for informal discussion. All invited oral presentations will be published as a special issue of The Journal of Experimental Biology in early 2010.
Session topics include:
Climate change and arctic ecological responses вЂ" past, present and future
Climate change and its influence on terrestrial animals
Climate change and its influence on aquatic animals
Emerging zoonosis and human diseases
Animal resilience and adaptation in coping with changes
Population and ecosystem responses to land use change and contaminants
Awaji Island, Japan : 2-6 August 2009
For further information and to register, go to: sicw09.biologists/
Source: Dr. Michaela Handel
The Company of Biologists
Chemotherapy's Damage To The Brain Detailed By Researchers
A commonly used chemotherapy drug causes healthy brain cells to die off long after treatment has ended and may be one of the underlying biological causes of the cognitive side effects - or "chemo brain" - that many cancer patients experience. That is the conclusion of a study published in the Journal of Biology.
A team of researchers at the University of Rochester Medical Center (URMC) and Harvard Medical School have linked the widely used chemotherapy drug 5-fluorouracil (5-FU) to a progressing collapse of populations of stem cells and their progeny in the central nervous system.
"This study is the first model of a delayed degeneration syndrome that involves a global disruption of the myelin-forming cells that are essential for normal neuronal function," said Mark Noble, Ph.D., director of the University of Rochester Stem Cell and Regenerative Medicine Institute and senior author of the study. "Because of our growing knowledge of stem cells and their biology, we can now begin to understand and define the molecular mechanisms behind the cognitive difficulties that linger and worsen in a significant number of cancer patients."
Cancer patients have long complained of neurological side effects such as short-term memory loss and, in extreme cases, seizures, vision loss, and even dementia. Until very recently, these cognitive side effects were often dismissed as the byproduct of fatigue, depression, and anxiety related to cancer diagnosis and treatment. Now a growing body of evidence has documented the scope of these conditions, collectively referred to as chemo brain. And while it is increasingly acknowledged by the scientific community that many chemotherapy agents may have a negative impact on brain function in a subset of cancer patients, the precise mechanisms that underlie this dysfunction have not been identified.
Virtually all cancer survivors experience short-term memory loss and difficulty concentrating during and shortly after treatment. A study two years ago by researchers with the James P. Wilmot Cancer Center at the University of Rochester showed that upwards of 82% of breast cancer patients reported that they suffer from some form of cognitive impairment.
While these effects tend to wear off over time, a subset of patients, particularly those who have been administered high doses of chemotherapy, begin to experience these cognitive side effects months or longer after treatment has ceased and the drugs have long since departed their systems. For example, a recent study estimates that somewhere between 15 and 20 percent of the nation's 2.4 million female breast cancer survivors have lingering cognitive problems years after treatment. Another study showed that 50 percent of women had not recovered their previous level of cognitive function one year after treatment.
Two years ago, Noble and his team showed that three common chemotherapy drugs used to treat a wide range of cancers were more toxic to healthy brain cells than the cancer cells they were intended to treat. While these experiments were among the first to establish a biological basis for the acute onset of chemo brain, they did not explain the lingering impact that many patients experience.
The scientists conducted a similar series of experiments in which they exposed both individual cell populations and mice to doses of 5-fluorouracil (5-FU) in amounts comparable to those used in cancer patients. 5-FU is among a class of drugs called antimetabolites that block cell division and has been used in cancer treatment for more than 40 years. The drug, which is often administered in a "cocktail" with other chemotherapy drugs, is currently used to treat breast, ovarian, stomach, colon, pancreatic and other forms of cancer.
The researchers discovered that months after exposure, specific populations of cells in the central nervous - oligodendrocytes and dividing precursor cells from which they are generated - underwent such extensive damage that, after 6 months, these cells had all but disappeared in the mice.
Oligodendrocytes play an important role in the central nervous system and are responsible for producing myelin, the fatty substance that, like insulation on electrical wires, coats nerve cells and enables signals between cells to be transmitted rapidly and efficiently. The myelin membranes are constantly being turned over, and without a healthy population of oligodendrocytes, the membranes cannot be renewed and eventually break down, resulting in a disruption of normal impulse transmission between nerve cells.
These findings parallel observations in studies of cancer survivors with cognitive difficulties. MRI scans of these patients' brains revealed a condition similar to leukoencephalopathy. This demyelination - or the loss of white matter - can be associated with multiple neurological problems.
"It is clear that, in some patients, chemotherapy appears to trigger a degenerative condition in the central nervous system," said Noble. "Because these treatments will clearly remain the standard of care for many years to come, it is critical that we understand their precise impact on the central nervous system, and then use this knowledge as the basis for discovering means of preventing such side effects."
Noble points out that not all cancer patients experience these cognitive difficulties, and determining why some patients are more vulnerable may be an important step in developing new ways to prevent these side effects. Because of this study, researchers now have a model which, for the first time, allows scientists to begin to examine this condition in a systematic manner.
Other investigators participating in the study include Ruolan Han, Ph.D., Yin M. Yang, M.D., Anne Luebke, Ph.D., Margot Mayer-Proschel, Ph.D., all with URMC, and Joerg Dietrich, M.D., Ph.D., formerly with URMC and now with Harvard Medical School. The study was funded by the National Institutes of Neurological Disorders and Stroke, the Komen Foundation for the Cure, and the Wilmot Cancer Center.
Source: Mark Michaud
University of Rochester Medical Center
A team of researchers at the University of Rochester Medical Center (URMC) and Harvard Medical School have linked the widely used chemotherapy drug 5-fluorouracil (5-FU) to a progressing collapse of populations of stem cells and their progeny in the central nervous system.
"This study is the first model of a delayed degeneration syndrome that involves a global disruption of the myelin-forming cells that are essential for normal neuronal function," said Mark Noble, Ph.D., director of the University of Rochester Stem Cell and Regenerative Medicine Institute and senior author of the study. "Because of our growing knowledge of stem cells and their biology, we can now begin to understand and define the molecular mechanisms behind the cognitive difficulties that linger and worsen in a significant number of cancer patients."
Cancer patients have long complained of neurological side effects such as short-term memory loss and, in extreme cases, seizures, vision loss, and even dementia. Until very recently, these cognitive side effects were often dismissed as the byproduct of fatigue, depression, and anxiety related to cancer diagnosis and treatment. Now a growing body of evidence has documented the scope of these conditions, collectively referred to as chemo brain. And while it is increasingly acknowledged by the scientific community that many chemotherapy agents may have a negative impact on brain function in a subset of cancer patients, the precise mechanisms that underlie this dysfunction have not been identified.
Virtually all cancer survivors experience short-term memory loss and difficulty concentrating during and shortly after treatment. A study two years ago by researchers with the James P. Wilmot Cancer Center at the University of Rochester showed that upwards of 82% of breast cancer patients reported that they suffer from some form of cognitive impairment.
While these effects tend to wear off over time, a subset of patients, particularly those who have been administered high doses of chemotherapy, begin to experience these cognitive side effects months or longer after treatment has ceased and the drugs have long since departed their systems. For example, a recent study estimates that somewhere between 15 and 20 percent of the nation's 2.4 million female breast cancer survivors have lingering cognitive problems years after treatment. Another study showed that 50 percent of women had not recovered their previous level of cognitive function one year after treatment.
Two years ago, Noble and his team showed that three common chemotherapy drugs used to treat a wide range of cancers were more toxic to healthy brain cells than the cancer cells they were intended to treat. While these experiments were among the first to establish a biological basis for the acute onset of chemo brain, they did not explain the lingering impact that many patients experience.
The scientists conducted a similar series of experiments in which they exposed both individual cell populations and mice to doses of 5-fluorouracil (5-FU) in amounts comparable to those used in cancer patients. 5-FU is among a class of drugs called antimetabolites that block cell division and has been used in cancer treatment for more than 40 years. The drug, which is often administered in a "cocktail" with other chemotherapy drugs, is currently used to treat breast, ovarian, stomach, colon, pancreatic and other forms of cancer.
The researchers discovered that months after exposure, specific populations of cells in the central nervous - oligodendrocytes and dividing precursor cells from which they are generated - underwent such extensive damage that, after 6 months, these cells had all but disappeared in the mice.
Oligodendrocytes play an important role in the central nervous system and are responsible for producing myelin, the fatty substance that, like insulation on electrical wires, coats nerve cells and enables signals between cells to be transmitted rapidly and efficiently. The myelin membranes are constantly being turned over, and without a healthy population of oligodendrocytes, the membranes cannot be renewed and eventually break down, resulting in a disruption of normal impulse transmission between nerve cells.
These findings parallel observations in studies of cancer survivors with cognitive difficulties. MRI scans of these patients' brains revealed a condition similar to leukoencephalopathy. This demyelination - or the loss of white matter - can be associated with multiple neurological problems.
"It is clear that, in some patients, chemotherapy appears to trigger a degenerative condition in the central nervous system," said Noble. "Because these treatments will clearly remain the standard of care for many years to come, it is critical that we understand their precise impact on the central nervous system, and then use this knowledge as the basis for discovering means of preventing such side effects."
Noble points out that not all cancer patients experience these cognitive difficulties, and determining why some patients are more vulnerable may be an important step in developing new ways to prevent these side effects. Because of this study, researchers now have a model which, for the first time, allows scientists to begin to examine this condition in a systematic manner.
Other investigators participating in the study include Ruolan Han, Ph.D., Yin M. Yang, M.D., Anne Luebke, Ph.D., Margot Mayer-Proschel, Ph.D., all with URMC, and Joerg Dietrich, M.D., Ph.D., formerly with URMC and now with Harvard Medical School. The study was funded by the National Institutes of Neurological Disorders and Stroke, the Komen Foundation for the Cure, and the Wilmot Cancer Center.
Source: Mark Michaud
University of Rochester Medical Center
Researchers Investigate Next Generation Medical And Robotic Devices Inspired By Lyfish
To the causal aquarium visitor, the jellyfish doesn't seem to be a particularly powerful swimmer; compared to a fish, it glides slowly and peacefully.
But for Janna Nawroth, a graduate student at the California Institute of Technology in Pasadena, the undulations of this simple invertebrate hold secrets that may make possible a new generation of tiny pumps for medical applications and soft robotics -- work she described at the American Physical Society Division of Fluid Dynamics (DFD) meeting in Long Beach, CA
"Most pumps are made of rigid materials," says Nawroth. "For medical pumps inside the human body, we need flexible pumps because they move fluids in a much gentler way that does not destroy tissues and cells."
Nawroth is working with Caltech engineer John Dabiri, an expert on jellyfish propulsion. His research has shown these cnidarians tend to fall into two categories -- those that produce faster, harder strokes and those that create weaker but more efficient strokes. He has also studied the flows and eddies created by the strokes, which can be characterized by a dimensionless quantity called a Reynolds number.
"We're really lucky," says Nawroth. "The Reynolds numbers we see in the movement of jellyfish of different sizes and ages are in the right range as what we need for medical applications."
As a step towards creating flexible pumps, Nawroth is studying how jellyfish shape and tissue composition adapt to the demands imposed by flow conditions at different Reynolds numbers. Jellyfish at millimeter scales, for example, exploit the small layer of water that adheres to their surface as they move and use it as additional paddle at no extra cost. Further, a clever arrangement of multiple pacemakers within the jellyfish body allow for a reliable yet tunable pumping mechanism.
In the future, Nawroth plans to use this practical understanding to help design a whole spectrum of flexible pumps that are optimized for different tasks and conditions.
The presentation: Learning from jellyfish: Fluid transport in muscular pumps at intermediate Reynolds numbers
Source:
Jason Socrates Bardi
American Institute of Physics
But for Janna Nawroth, a graduate student at the California Institute of Technology in Pasadena, the undulations of this simple invertebrate hold secrets that may make possible a new generation of tiny pumps for medical applications and soft robotics -- work she described at the American Physical Society Division of Fluid Dynamics (DFD) meeting in Long Beach, CA
"Most pumps are made of rigid materials," says Nawroth. "For medical pumps inside the human body, we need flexible pumps because they move fluids in a much gentler way that does not destroy tissues and cells."
Nawroth is working with Caltech engineer John Dabiri, an expert on jellyfish propulsion. His research has shown these cnidarians tend to fall into two categories -- those that produce faster, harder strokes and those that create weaker but more efficient strokes. He has also studied the flows and eddies created by the strokes, which can be characterized by a dimensionless quantity called a Reynolds number.
"We're really lucky," says Nawroth. "The Reynolds numbers we see in the movement of jellyfish of different sizes and ages are in the right range as what we need for medical applications."
As a step towards creating flexible pumps, Nawroth is studying how jellyfish shape and tissue composition adapt to the demands imposed by flow conditions at different Reynolds numbers. Jellyfish at millimeter scales, for example, exploit the small layer of water that adheres to their surface as they move and use it as additional paddle at no extra cost. Further, a clever arrangement of multiple pacemakers within the jellyfish body allow for a reliable yet tunable pumping mechanism.
In the future, Nawroth plans to use this practical understanding to help design a whole spectrum of flexible pumps that are optimized for different tasks and conditions.
The presentation: Learning from jellyfish: Fluid transport in muscular pumps at intermediate Reynolds numbers
Source:
Jason Socrates Bardi
American Institute of Physics
PAZAR Offers Free Shopping In A Virtual Bazaar Of Gene Regulation Data
An international team has opened a virtual bazaar, called PAZAR, which allows biologists to share information about gene regulation through individually managed 'boutiques' (data collections). According to research published in the online open access journal, Genome Biology, customers can access data without any charge from any boutique or extract information from the 'superstores' that aggregate data of similar types.
In deciphering the human genome sequence, researchers hope to understand the when and where of gene expression because this could speed development of novel cancer therapies or stem cell treatments for degenerative disease, and explain complex diseases such as diabetes.
Much of the information gathered in costly studies of gene regulation is poorly accessible if available at all. Individual research teams often generate databases or post files on the internet, but these data are fragmented and can be lost over time. The research team, led by Wyeth Wasserman at the University of British Columbia and Child & Family Research Institute, Vancouver, Canada, and colleagues from Bulgaria, Canada, France, and the USA, describe a novel approach to managing this information by bringing it together for the first time using PAZAR.
PAZAR is, explain the researchers, "an open-access and open-source database of transcription factor and regulatory sequence annotation". As such, it fulfils a longstanding need for a large data collection of regulatory sequences unrestricted by commercial concerns. Its novel shopping-mall-like structure (pazar is Bulgarian for shopping mall) will allow researchers to share data collections and computational predictions in an organized and accessible manner.
In order to demonstrate the advantages and features of PAZAR and its depth of annotation, the researchers used the Pleiades Promoter Project collection of brain-linked regulatory sequences as a show case. They have been working internationally with boutique operators and are currently expanding the data represented, and improving the curation tools. By bringing small data collections together Wasserman and colleagues are aiming to bring the data to international scientific customers and are encouraging other researchers to open new boutiques in this genomic mall.
Article:
Software PAZAR: a framework for collection and dissemination of cis-regulatory sequence annotation
Elodie Portales-Casamar, Stefan Kirov, Jonathan Lim, Stuart Lithwick, Magdalena I Swanson, Amy Ticoll, Jay Snoddy and Wyeth W Wasserman
Genome Biology (in press)
All articles are available free of charge, according to BioMed Central's Open Access policy.
Author contact:
Jennifer Kohm (Press Office, Child & Family Research Institute)
BioMed Central is an independent online publishing house committed to providing open access to peer-reviewed biological and medical research. This commitment is based on the view that immediate free access to research and the ability to freely archive and reuse published information is essential to the rapid and efficient communication of science.
BioMed Central currently publishes over 160 journals across biology and medicine. In addition to open-access original research, BioMed Central also publishes reviews, commentaries and other non-original-research content. Depending on the policies of the individual journal, this content may be open access or provided only to subscribers.
Source: Charlotte Webber
BioMed Central
In deciphering the human genome sequence, researchers hope to understand the when and where of gene expression because this could speed development of novel cancer therapies or stem cell treatments for degenerative disease, and explain complex diseases such as diabetes.
Much of the information gathered in costly studies of gene regulation is poorly accessible if available at all. Individual research teams often generate databases or post files on the internet, but these data are fragmented and can be lost over time. The research team, led by Wyeth Wasserman at the University of British Columbia and Child & Family Research Institute, Vancouver, Canada, and colleagues from Bulgaria, Canada, France, and the USA, describe a novel approach to managing this information by bringing it together for the first time using PAZAR.
PAZAR is, explain the researchers, "an open-access and open-source database of transcription factor and regulatory sequence annotation". As such, it fulfils a longstanding need for a large data collection of regulatory sequences unrestricted by commercial concerns. Its novel shopping-mall-like structure (pazar is Bulgarian for shopping mall) will allow researchers to share data collections and computational predictions in an organized and accessible manner.
In order to demonstrate the advantages and features of PAZAR and its depth of annotation, the researchers used the Pleiades Promoter Project collection of brain-linked regulatory sequences as a show case. They have been working internationally with boutique operators and are currently expanding the data represented, and improving the curation tools. By bringing small data collections together Wasserman and colleagues are aiming to bring the data to international scientific customers and are encouraging other researchers to open new boutiques in this genomic mall.
Article:
Software PAZAR: a framework for collection and dissemination of cis-regulatory sequence annotation
Elodie Portales-Casamar, Stefan Kirov, Jonathan Lim, Stuart Lithwick, Magdalena I Swanson, Amy Ticoll, Jay Snoddy and Wyeth W Wasserman
Genome Biology (in press)
All articles are available free of charge, according to BioMed Central's Open Access policy.
Author contact:
Jennifer Kohm (Press Office, Child & Family Research Institute)
BioMed Central is an independent online publishing house committed to providing open access to peer-reviewed biological and medical research. This commitment is based on the view that immediate free access to research and the ability to freely archive and reuse published information is essential to the rapid and efficient communication of science.
BioMed Central currently publishes over 160 journals across biology and medicine. In addition to open-access original research, BioMed Central also publishes reviews, commentaries and other non-original-research content. Depending on the policies of the individual journal, this content may be open access or provided only to subscribers.
Source: Charlotte Webber
BioMed Central
E-Learning Opportunity To Specifically Focus On Trials Of Biologics
WHO:
The American Association of Pharmaceutical Scientists (AAPS) is a professional, scientific society of approximately 12,000 members employed in industry, academia, government and other research institutes worldwide. Founded in 1986, AAPS provides a dynamic international forum for the exchange of knowledge among scientists to enhance their contributions to public health. AAPS offers timely scientific programs, on-going education, information resources, opportunities for networking, and professional development.
WHAT:
AAPS is pleased to present the complimentary eLearning Webinar on Use of PKPD Modeling for Starting Dose Selection in First-in-Human Trials of Biologics. This module is organized by the AAPS Clinical Pharmacology and Translational Research Section. This Webinar will be conducted by Balaji Agoram, Ph.D.
WHY:
The purpose of this free Webinar is to illustrate the use of pharmacokinetic/pharmacodynamic models to select rational starting doses in clinical trials within the Minimum Anticipated Biological Effect Level (MABEL) principle using literature data and through simulations. Participants will gain understanding of the complex biologic drug-receptor interaction dynamics and the multiple factors affecting the dose-receptor occupancy relationship.
WHEN:
October 29, 2009
12:30 PM to 2:00 PM EDT
For additional information about the workshop, and to register, visit aapspharmaceutica/webinars/PKPD.
Source:
Joseph Catapano
American Association of Pharmaceutical Scientists
The American Association of Pharmaceutical Scientists (AAPS) is a professional, scientific society of approximately 12,000 members employed in industry, academia, government and other research institutes worldwide. Founded in 1986, AAPS provides a dynamic international forum for the exchange of knowledge among scientists to enhance their contributions to public health. AAPS offers timely scientific programs, on-going education, information resources, opportunities for networking, and professional development.
WHAT:
AAPS is pleased to present the complimentary eLearning Webinar on Use of PKPD Modeling for Starting Dose Selection in First-in-Human Trials of Biologics. This module is organized by the AAPS Clinical Pharmacology and Translational Research Section. This Webinar will be conducted by Balaji Agoram, Ph.D.
WHY:
The purpose of this free Webinar is to illustrate the use of pharmacokinetic/pharmacodynamic models to select rational starting doses in clinical trials within the Minimum Anticipated Biological Effect Level (MABEL) principle using literature data and through simulations. Participants will gain understanding of the complex biologic drug-receptor interaction dynamics and the multiple factors affecting the dose-receptor occupancy relationship.
WHEN:
October 29, 2009
12:30 PM to 2:00 PM EDT
For additional information about the workshop, and to register, visit aapspharmaceutica/webinars/PKPD.
Source:
Joseph Catapano
American Association of Pharmaceutical Scientists
Brain And Reproductive Development Affected By Compounds From Soy, New Study Shows
Two hormone-like compounds linked to the consumption of soy-based foods can cause irreversible changes in the structure of the brain, resulting in early-onset puberty and symptoms of advanced menopause in research animals, according to a new study by researchers at North Carolina State University. The study is a breakthrough in determining how these compounds can cause reproductive health problems, as well as in providing a key building block for how to treat these problems.
The study is the first to show that the actual physical organization of a region of the brain that is important for female reproduction can be significantly altered by exposure to phytoestrogens - or plant-produced chemicals that mimic hormones - during development. Specifically, the study finds that the compounds alter the sex-specific organization of the hypothalamus - a brain region that is essential to the regulation of puberty and ovulation. The study also shows that the phytoestrogens could cause long-term effects on the female reproductive system.
While the study examined the impact of these compounds on laboratory rats, neurotoxicologist Dr. Heather Patisaul - who co-authored the study - says the affected "circuitry" of the brain is similar in both rats and humans. Patisaul is an assistant professor in NC State's Department of Zoology. Her co-author is Heather Bateman, a doctoral student in the department.
Patisaul says this finding is extremely important because, while the changes in brain structure cannot be reversed, "if you understand what is broken, you may be able to treat it." Patisaul says she is in the process of evaluating the effects of these compounds on the ovaries themselves.
Patisaul says that this study is also "a step towards ascertaining the effects of phytoestrogens on developing fetuses and newborns." Patisaul adds that these phytoestrogenic compounds cross the placental barrier in humans and that, while many people are concerned about the effects of man-made compounds on human health, it is important to note that some naturally occurring substances can have similar effects.
In the study, which will be published in an upcoming issue of Neurotoxicology, the researchers exposed newborn rats to physiologically relevant doses of the phytoestrogens genistein and equol, and then looked at reproductive health markers in the rats throughout their adulthood. The neonatal stage of development in rats is comparable to the latter stages of pregnancy for humans, Patisaul says. Genistein is a phytoestrogen that is found in various plants, including soybeans and soy-based foods. Equol is a hormone-like compound that is formed when bacteria found in the digestive system metabolize another phytoestrogen. However, only approximately a third of humans have the necessary bacteria to produce equol.
The study shows that both genistein and equol result in the early disruption of the rats' estrus cycle - which would be corollary to early onset of menopause in a human. The study also showed that genistein caused the early onset of puberty. The disruption of the estrus cycle could stem from problems with the brain or the ovaries, so the researchers decided to determine if the compounds had any effect on brain development or function.
Patisaul explains that the brains of both female rats and female humans have a region that regulates ovulation. "That part of the brain," Patisaul says, "is organized by hormones during development - which is the neonatal stage for rats and during gestation for humans." Patisaul says the new study shows that the female brain is "critically sensitive" to genistein and equol during this crucial stage of development - and that this may indicate that the brain is also especially sensitive during this period to all phytoestrogens and possibly other man-made chemicals, such as bisphenol-A.
Abstract:
"Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased GnRH activation and kisspeptin fiber density in the hypothalamus"
Authors: Dr. Heather B. Patisaul, Heather L. Bateman, North Carolina State University
Published: July 2008, online by Neurotoxicology
It is well established that estrogen administration during neonatal development can advance pubertal onset and prevent the maintenance of regular estrous cycles in female rats. This treatment paradigm also eliminates the preovulatory rise of gonadotropin releasing hormone (GnRH). It remains unclear, however, through which of the two primary forms of the estrogen receptor (ERО± or ERОІ) this effect is mediated. It is also unclear whether endocrine disrupting compounds (EDCs) can produce similar effects. Here we compared the effect of neonatal exposure to estradiol benzoate (EB), the ERО± specific agonist 1,3,5-tris(4-Hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), the ERОІ specific agonist diarylpropionitrile (DPN) and the naturally occurring EDCs genistein (GEN) and equol (EQ) on pubertal onset, estrous cyclicity, GnRH activation, and kisspeptin content in the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei. Vaginal opening was significantly advanced by EB and GEN. By ten weeks postpuberty, irregular estrous cycles were observed in all groups except the control group. GnRH activation, as measured by the percentage of immunopositive GnRH neurons that were also immunopositive for Fos, was significantly lower in all treatment groups except the DPN group compared to the control group. GnRH activation was absent in the PPT group. These data suggest that neonatal exposure to EDCs can suppress GnRH activity in adulthood, and that ERО± plays a pivotal role in this process. Kisspeptins (KISS) have recently been characterized to be potent stimulators of GnRH secretion. Therefore we quantified the density of KISS immunolabeled fibers in the AVPV and ARC. In the AVPV, KISS fiber density was significantly lower in the EB and GEN groups compared to the control group but only in the EB and PPT groups in the ARC. The data suggest that decreased stimulation of GnRH neurons by KISS could be a mechanism by which EDCs can impair female reproductive function.
Source: Matt Shipman
North Carolina State University
View drug information on Estradiol Transdermal System.
The study is the first to show that the actual physical organization of a region of the brain that is important for female reproduction can be significantly altered by exposure to phytoestrogens - or plant-produced chemicals that mimic hormones - during development. Specifically, the study finds that the compounds alter the sex-specific organization of the hypothalamus - a brain region that is essential to the regulation of puberty and ovulation. The study also shows that the phytoestrogens could cause long-term effects on the female reproductive system.
While the study examined the impact of these compounds on laboratory rats, neurotoxicologist Dr. Heather Patisaul - who co-authored the study - says the affected "circuitry" of the brain is similar in both rats and humans. Patisaul is an assistant professor in NC State's Department of Zoology. Her co-author is Heather Bateman, a doctoral student in the department.
Patisaul says this finding is extremely important because, while the changes in brain structure cannot be reversed, "if you understand what is broken, you may be able to treat it." Patisaul says she is in the process of evaluating the effects of these compounds on the ovaries themselves.
Patisaul says that this study is also "a step towards ascertaining the effects of phytoestrogens on developing fetuses and newborns." Patisaul adds that these phytoestrogenic compounds cross the placental barrier in humans and that, while many people are concerned about the effects of man-made compounds on human health, it is important to note that some naturally occurring substances can have similar effects.
In the study, which will be published in an upcoming issue of Neurotoxicology, the researchers exposed newborn rats to physiologically relevant doses of the phytoestrogens genistein and equol, and then looked at reproductive health markers in the rats throughout their adulthood. The neonatal stage of development in rats is comparable to the latter stages of pregnancy for humans, Patisaul says. Genistein is a phytoestrogen that is found in various plants, including soybeans and soy-based foods. Equol is a hormone-like compound that is formed when bacteria found in the digestive system metabolize another phytoestrogen. However, only approximately a third of humans have the necessary bacteria to produce equol.
The study shows that both genistein and equol result in the early disruption of the rats' estrus cycle - which would be corollary to early onset of menopause in a human. The study also showed that genistein caused the early onset of puberty. The disruption of the estrus cycle could stem from problems with the brain or the ovaries, so the researchers decided to determine if the compounds had any effect on brain development or function.
Patisaul explains that the brains of both female rats and female humans have a region that regulates ovulation. "That part of the brain," Patisaul says, "is organized by hormones during development - which is the neonatal stage for rats and during gestation for humans." Patisaul says the new study shows that the female brain is "critically sensitive" to genistein and equol during this crucial stage of development - and that this may indicate that the brain is also especially sensitive during this period to all phytoestrogens and possibly other man-made chemicals, such as bisphenol-A.
Abstract:
"Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased GnRH activation and kisspeptin fiber density in the hypothalamus"
Authors: Dr. Heather B. Patisaul, Heather L. Bateman, North Carolina State University
Published: July 2008, online by Neurotoxicology
It is well established that estrogen administration during neonatal development can advance pubertal onset and prevent the maintenance of regular estrous cycles in female rats. This treatment paradigm also eliminates the preovulatory rise of gonadotropin releasing hormone (GnRH). It remains unclear, however, through which of the two primary forms of the estrogen receptor (ERО± or ERОІ) this effect is mediated. It is also unclear whether endocrine disrupting compounds (EDCs) can produce similar effects. Here we compared the effect of neonatal exposure to estradiol benzoate (EB), the ERО± specific agonist 1,3,5-tris(4-Hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), the ERОІ specific agonist diarylpropionitrile (DPN) and the naturally occurring EDCs genistein (GEN) and equol (EQ) on pubertal onset, estrous cyclicity, GnRH activation, and kisspeptin content in the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei. Vaginal opening was significantly advanced by EB and GEN. By ten weeks postpuberty, irregular estrous cycles were observed in all groups except the control group. GnRH activation, as measured by the percentage of immunopositive GnRH neurons that were also immunopositive for Fos, was significantly lower in all treatment groups except the DPN group compared to the control group. GnRH activation was absent in the PPT group. These data suggest that neonatal exposure to EDCs can suppress GnRH activity in adulthood, and that ERО± plays a pivotal role in this process. Kisspeptins (KISS) have recently been characterized to be potent stimulators of GnRH secretion. Therefore we quantified the density of KISS immunolabeled fibers in the AVPV and ARC. In the AVPV, KISS fiber density was significantly lower in the EB and GEN groups compared to the control group but only in the EB and PPT groups in the ARC. The data suggest that decreased stimulation of GnRH neurons by KISS could be a mechanism by which EDCs can impair female reproductive function.
Source: Matt Shipman
North Carolina State University
View drug information on Estradiol Transdermal System.
A Predator From East Africa That Chooses Malaria Vectors As Preferred Prey
In choice tests using live prey as well as dead prey mounted in a life-like posture on cork discs, we found an East African jumping spider, Evarcha culicivora, to choose blood-fed female mosquitoes in the genus Anopheles as its preferred prey. Mosquitoes in the genus Anopheles are best known as the vectors of malaria and E. culicivora is the first predator that has been found to single out Anopheles as prey. In a sated condition, E. culicivoraВґs preference held regardless of the sex or age of the spider. When fasted, larger spiders chose both mosquito choices (sympatric mosquitoes of different genera) in equal numbers, but the smaller E. culicivora maintained their preference for Anopheles.
Anopheles holds its body at a 45 degree angle relative to the substrate when resting, whereas other mosquitoes rest with their bodies parallel to the surface of the substrate. We investigated whether the characteristic resting posture of Anopheles was a cue E. culicivora uses to distinguish these mosquitoes from others. To do this we drew 3D virtual mosquitoes whose movement was based on frame-by-frame copying of digital video footage of grooming Anopheles. The use of virtual mosquitoes eliminated variables except the variable in question. We found the single most important visual cue used to distinguish Anopheles mosquitoes is its resting position. Finding a predator that chooses Anopheles as its preferred prey shows that we should not abandon efforts to search for avenues for the biological control of malaria.
plosone
Anopheles holds its body at a 45 degree angle relative to the substrate when resting, whereas other mosquitoes rest with their bodies parallel to the surface of the substrate. We investigated whether the characteristic resting posture of Anopheles was a cue E. culicivora uses to distinguish these mosquitoes from others. To do this we drew 3D virtual mosquitoes whose movement was based on frame-by-frame copying of digital video footage of grooming Anopheles. The use of virtual mosquitoes eliminated variables except the variable in question. We found the single most important visual cue used to distinguish Anopheles mosquitoes is its resting position. Finding a predator that chooses Anopheles as its preferred prey shows that we should not abandon efforts to search for avenues for the biological control of malaria.
plosone
Fungal Compound To Combat Prostate Cancer?
Can a substance from a fungus that grows on decaying trees provide a cure for aggressive prostate cancer? This is the hope of researchers at Lund University in Sweden. In an interdisciplinary collaborative effort involving urologists, molecular biologists and chemists in Malmö and Lund, scientists are trying to develop this compound into a means for combating certain forms of prostate cancer.
In 2006 in Europe, an estimated 345,900 prostate cancer cases were diagnosed. In Sweden with nearly 10,000 new cases of prostate cancer per year, this is the most common form of cancer among men in Sweden. The disease often develops slowly, but the proportion of more aggressive forms of prostate cancer is growing. The fungal compound galiellalactone could be used against tumors that cannot be treated with surgery or radiation and does not respond to hormone treatment.
"In our trials this compound has curbed the growth of prostate cancer cells both in animal experiments and in laboratory experiments," says the researcher Rebecka Hellsten. The research team she belongs to was recently granted SEK 1.3 million from the Holger K. Christiansen Foundation in Denmark. The team consists of Dr. Rebecka Hellsten and Professor Anders Bjartell from the Section for Urological Cancer Research at the University Hospital in Malmö and Professor Olov Sterner and Dr. Martin Johansson from the Section for Organic Chemistry at Lund University.
Olov Sterner and his associates do research on organic molecules from plants, fungi, and marine organisms, and how they can be used in the development of drugs or industrially useful substances. They have developed a synthetic method for producing the fungal compound and will now attempt to tweak the substance to make it even more effective against tumor cells.
The mushroom the substance originates from is called Galiella rufa, which grows in clusters on old wood in eastern North America. The fungi are bowl-shaped, dark on the outside, reddish yellow on the inside, and a few centimeters across. It was discovered that this particular mushroom can be used to fight prostate cancer in connection with a study run by a German research team, when they were testing extracts from various species of fungi to find substances that could disrupt a certain signaling pathway in human cells.
"The German scientists were not thinking about prostate cancer, but the signaling pathway the study targeted is also relevant to these particular tumor cells. If we can alter the fungal substance synthetically so it impacts the signaling in tumor cells even more effectively, we could have a drug for tumors that we can't deal with today," says Rebecka Hellsten.
VETENSKAPSRГ…DET (THE SWEDISH RESEARCH COUNCIL)
Regeringstgatan 56
103 78 Stockholm
vr.se
In 2006 in Europe, an estimated 345,900 prostate cancer cases were diagnosed. In Sweden with nearly 10,000 new cases of prostate cancer per year, this is the most common form of cancer among men in Sweden. The disease often develops slowly, but the proportion of more aggressive forms of prostate cancer is growing. The fungal compound galiellalactone could be used against tumors that cannot be treated with surgery or radiation and does not respond to hormone treatment.
"In our trials this compound has curbed the growth of prostate cancer cells both in animal experiments and in laboratory experiments," says the researcher Rebecka Hellsten. The research team she belongs to was recently granted SEK 1.3 million from the Holger K. Christiansen Foundation in Denmark. The team consists of Dr. Rebecka Hellsten and Professor Anders Bjartell from the Section for Urological Cancer Research at the University Hospital in Malmö and Professor Olov Sterner and Dr. Martin Johansson from the Section for Organic Chemistry at Lund University.
Olov Sterner and his associates do research on organic molecules from plants, fungi, and marine organisms, and how they can be used in the development of drugs or industrially useful substances. They have developed a synthetic method for producing the fungal compound and will now attempt to tweak the substance to make it even more effective against tumor cells.
The mushroom the substance originates from is called Galiella rufa, which grows in clusters on old wood in eastern North America. The fungi are bowl-shaped, dark on the outside, reddish yellow on the inside, and a few centimeters across. It was discovered that this particular mushroom can be used to fight prostate cancer in connection with a study run by a German research team, when they were testing extracts from various species of fungi to find substances that could disrupt a certain signaling pathway in human cells.
"The German scientists were not thinking about prostate cancer, but the signaling pathway the study targeted is also relevant to these particular tumor cells. If we can alter the fungal substance synthetically so it impacts the signaling in tumor cells even more effectively, we could have a drug for tumors that we can't deal with today," says Rebecka Hellsten.
VETENSKAPSRГ…DET (THE SWEDISH RESEARCH COUNCIL)
Regeringstgatan 56
103 78 Stockholm
vr.se
Подписаться на:
Сообщения (Atom)