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Ozumi K.,University of Illinois at Chicago | Sudhahar V.,University of Illinois at Chicago | Kim H.W.,University of Illinois at Chicago | Chen G.-F.,University of Illinois at Chicago | And 10 more authors.
Hypertension | Year: 2012

Extracellular superoxide dismutase (SOD3) is a secretory copper enzyme involved in protecting angiotensin II (Ang II)-induced hypertension. We found previously that Ang II upregulates SOD3 expression and activity as a counterregulatory mechanism; however, underlying mechanisms are unclear. Antioxidant 1 (Atox1) is shown to act as a copper-dependent transcription factor, as well as a copper chaperone, for SOD3 in vitro, but its role in Ang II-induced hypertension in vivo is unknown. Here we show that Ang II infusion increases Atox1 expression, as well as SOD3 expression and activity, in aortas of wild-type mice, which are inhibited in mice lacking Atox1. Accordingly, Ang II increases vascular superoxide production, reduces endothelium-dependent vasodilation, and increases vasoconstriction in mesenteric arteries to a greater extent in Atox1 than in wild-type mice. This contributes to augmented hypertensive response to Ang II in Atox1 mice. In cultured vascular smooth muscle cells, Ang II promotes translocation of Atox1 to the nucleus, thereby increasing SOD3 transcription by binding to Atox1-responsive element in the SOD3 promoter. Furthermore, Ang II increases Atox1 binding to the copper exporter ATP7A, which obtains copper from Atox1, as well as translocation of ATP7A to plasma membranes, where it colocalizes with SOD3. As its consequence, Ang II decreases vascular copper levels, which is inhibited in Atox1 mice. In summary, Atox1 functions to prevent Ang II-induced endothelial dysfunction and hypercontraction in resistant vessels, as well as hypertension, in vivo by reducing extracellular superoxide levels via increasing vascular SOD3 expression and activity. © 2012 American Heart Association, Inc.


News Article | November 14, 2016
Site: www.eurekalert.org

Menlo Park, Calif. -- Scientists have used the powerful X-ray laser at the Department of Energy's SLAC National Accelerator Laboratory to make the first snapshots of a chemical interaction between two biomolecules - one that flips an RNA "switch" that regulates production of proteins, the workhorse molecules of life. The results, published today in Nature, show the game-changing potential of X-ray free-electron lasers, or XFELs, for studying RNA, which guides protein manufacturing in the cell, serves as the primary genetic material in retroviruses such as HIV and also plays a role in most forms of cancer. And because this particular type of RNA switch, known as a riboswitch, is found only in bacteria, a deeper understanding of its function may offer a way to turn off protein production and kill harmful germs without causing side effects in the humans they infect. "Previous experiments at SLAC's X-ray laser have studied biological reactions like photosynthesis that are triggered by light. But this is the first to observe one that is triggered by the chemical interaction of two biomolecules in real time and at the atomic scale," said Yun-Xing Wang, a structural biologist at the National Cancer Institute's Center for Cancer Research who led the international research team. "This really demonstrates the unique capability that X-ray free-electron lasers offer that no current technology, or any other technology on the horizon, can do. It's like you have a camera with a very fast shutter speed, so you can catch every move of the biomolecules in action." The experiments were carried out at SLAC's Linac Coherent Light Source (LCLS), a DOE Office of Science User Facility. They are the first to demonstrate how XFELs can take snapshots and potentially make movies of RNA and other biomolecules as they chemically interact - offering glimpses into fundamental workings of the cell that can't be obtained any other way. RNA is a key part of the genetic material in all living cells. It comes in several types that work together to guide the production of proteins by the cell's ribosomes, according to blueprints encoded in DNA. But both DNA and RNA also contain extensive regions that don't code for any protein - the so-called genetic "dark matter." Scientists thought for many years that these regions didn't do anything. Now they know that they play an important role in determining where and when genes turn on and off and otherwise fine-tuning their function. The vast majority of cancers are due to mutations in these non-coding regions, Wang said, so understanding how these regions work is important for cancer research as well as fundamental biology. However, figuring out what the RNA non-coding regions do is difficult. RNA molecules are wobbly and flexible, so it's hard to incorporate them into the large crystals typically needed to study their atomic structure at X-ray light sources. LCLS removes this barrier by allowing scientists to get structural information from much smaller, nanosized crystals, which are much easier to make. Its powerful X-ray laser pulses, a billion times brighter than any available before, are so short that they collect data from each crystal in a few millionths of a billionth of a second, before damage from the X-rays sets in. Wang's team studied a riboswitch from Vibrio vulnificus, a bacterium related to the one that causes cholera. The riboswitch sits in a long strand of messenger RNA (mRNA), which copies DNA's instructions for making a protein so they can be read and carried out by the ribosome. The switch acts like a thermostat that regulates protein production. In this case, the mRNA guides production of a protein that in turn helps to produce a small molecule called adenine. When there is too much adenine in the bacterial cell, adenine molecules enter pockets in the riboswitches and flip the riboswitches into a different shape, and this changes the pace of protein and adenine production. First Stills of an Elegant Film For the LCLS experiments, the researchers made nanocrystals that incorporated millions of copies of the riboswitch and mixed them with a solution containing adenine molecules. Each crystal was so small that adenine could quickly and uniformly penetrate into every corner of it, enter riboswitch pockets and flip them almost instantaneously, as if they were millions of synchronized swimmers executing a single flawless move. The scientists took snapshots of this interaction by hitting the crystals with X-ray laser pulses at carefully timed intervals after the mixing started. This gave them the first glimpse of a fleeting intermediate stage in the process, which occurred 10 seconds in. Separately, they obtained the first images of the riboswitch in its initial, empty-pocket state, and discovered that it existed in two slightly different configurations, only one of which participates in switching. The researchers were surprised to discover that the sudden change in the shape of the riboswitches was so dramatic that it changed the shape of the entire crystal, too. Normally a major change like this would crack the crystal and spoil the experiment. But because these crystals were so small they held together, so the X-ray laser could still get structural information from them. "To me it's still a mystery how the crystal managed to do that," said Soichi Wakatsuki, a professor at SLAC and at the Stanford School of Medicine and head of the lab's Biosciences Division, who was not part of the research team. "This actually opens up a lot of new possibilities and gives us a new way to look at how RNA and proteins interact with small molecules, so this is very exciting." In addition to the National Cancer Institute and SLAC's LCLS, scientists contributing to the research came from Arizona State University, Johns Hopkins University, the Center for Free-Electron Laser Science at Deutsches Elektronen-Synchrotron (DESY), University of Hamburg, Hauptmann-Woodward Medical Research Institute, the National Institutes of Health and the DOE's Argonne National Laboratory. Funding came from the National Science Foundation and the NIH Intramural Research Programs. SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the U.S. Department of Energy Office of Science. To learn more, please visit http://www. . SLAC National Accelerator Laboratory is supported by the Office of Science of the U.S. Department of Energy. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information, please visit science.energy.gov.


News Article | November 15, 2016
Site: www.sciencedaily.com

Scientists have used the powerful X-ray laser at the Department of Energy's SLAC National Accelerator Laboratory to make the first snapshots of a chemical interaction between two biomolecules -- one that flips an RNA "switch" that regulates production of proteins, the workhorse molecules of life. The results, published today in Nature, show the game-changing potential of X-ray free-electron lasers, or XFELs, for studying RNA, which guides protein manufacturing in the cell, serves as the primary genetic material in retroviruses such as HIV and also plays a role in most forms of cancer. And because this particular type of RNA switch, known as a riboswitch, is found only in bacteria, a deeper understanding of its function may offer a way to turn off protein production and kill harmful germs without causing side effects in the humans they infect. "Previous experiments at SLAC's X-ray laser have studied biological reactions like photosynthesis that are triggered by light. But this is the first to observe one that is triggered by the chemical interaction of two biomolecules in real time and at the atomic scale," said Yun-Xing Wang, a structural biologist at the National Cancer Institute's Center for Cancer Research who led the international research team. "This really demonstrates the unique capability that X-ray free-electron lasers offer that no current technology, or any other technology on the horizon, can do. It's like you have a camera with a very fast shutter speed, so you can catch every move of the biomolecules in action." The experiments were carried out at SLAC's Linac Coherent Light Source (LCLS), a DOE Office of Science User Facility. They are the first to demonstrate how XFELs can take snapshots and potentially make movies of RNA and other biomolecules as they chemically interact -- offering glimpses into fundamental workings of the cell that can't be obtained any other way. RNA is a key part of the genetic material in all living cells. It comes in several types that work together to guide the production of proteins by the cell's ribosomes, according to blueprints encoded in DNA. But both DNA and RNA also contain extensive regions that don't code for any protein -- the so-called genetic "dark matter." Scientists thought for many years that these regions didn't do anything. Now they know that they play an important role in determining where and when genes turn on and off and otherwise fine-tuning their function. The vast majority of cancers are due to mutations in these non-coding regions, Wang said, so understanding how these regions work is important for cancer research as well as fundamental biology. However, figuring out what the RNA non-coding regions do is difficult. RNA molecules are wobbly and flexible, so it's hard to incorporate them into the large crystals typically needed to study their atomic structure at X-ray light sources. LCLS removes this barrier by allowing scientists to get structural information from much smaller, nanosized crystals, which are much easier to make. Its powerful X-ray laser pulses, a billion times brighter than any available before, are so short that they collect data from each crystal in a few millionths of a billionth of a second, before damage from the X-rays sets in. Wang's team studied a riboswitch from Vibrio vulnificus, a bacterium related to the one that causes cholera. The riboswitch sits in a long strand of messenger RNA (mRNA), which copies DNA's instructions for making a protein so they can be read and carried out by the ribosome. The switch acts like a thermostat that regulates protein production. In this case, the mRNA guides production of a protein that in turn helps to produce a small molecule called adenine. When there is too much adenine in the bacterial cell, adenine molecules enter pockets in the riboswitches and flip the riboswitches into a different shape, and this changes the pace of protein and adenine production. First Stills of an Elegant Film For the LCLS experiments, the researchers made nanocrystals that incorporated millions of copies of the riboswitch and mixed them with a solution containing adenine molecules. Each crystal was so small that adenine could quickly and uniformly penetrate into every corner of it, enter riboswitch pockets and flip them almost instantaneously, as if they were millions of synchronized swimmers executing a single flawless move. The scientists took snapshots of this interaction by hitting the crystals with X-ray laser pulses at carefully timed intervals after the mixing started. This gave them the first glimpse of a fleeting intermediate stage in the process, which occurred 10 seconds in. Separately, they obtained the first images of the riboswitch in its initial, empty-pocket state, and discovered that it existed in two slightly different configurations, only one of which participates in switching. The researchers were surprised to discover that the sudden change in the shape of the riboswitches was so dramatic that it changed the shape of the entire crystal, too. Normally a major change like this would crack the crystal and spoil the experiment. But because these crystals were so small they held together, so the X-ray laser could still get structural information from them. "To me it's still a mystery how the crystal managed to do that," said Soichi Wakatsuki, a professor at SLAC and at the Stanford School of Medicine and head of the lab's Biosciences Division, who was not part of the research team. "This actually opens up a lot of new possibilities and gives us a new way to look at how RNA and proteins interact with small molecules, so this is very exciting."


The results, published today in Nature, show the game-changing potential of X-ray free-electron lasers, or XFELs, for studying RNA, which guides protein manufacturing in the cell, serves as the primary genetic material in retroviruses such as HIV and also plays a role in most forms of cancer. And because this particular type of RNA switch, known as a riboswitch, is found only in bacteria, a deeper understanding of its function may offer a way to turn off protein production and kill harmful germs without causing side effects in the humans they infect. "Previous experiments at SLAC's X-ray laser have studied biological reactions like photosynthesis that are triggered by light. But this is the first to observe one that is triggered by the chemical interaction of two biomolecules in real time and at the atomic scale," said Yun-Xing Wang, a structural biologist at the National Cancer Institute's Center for Cancer Research who led the international research team. "This really demonstrates the unique capability that X-ray free-electron lasers offer that no current technology, or any other technology on the horizon, can do. It's like you have a camera with a very fast shutter speed, so you can catch every move of the biomolecules in action." The experiments were carried out at SLAC's Linac Coherent Light Source (LCLS), a DOE Office of Science User Facility. They are the first to demonstrate how XFELs can take snapshots and potentially make movies of RNA and other biomolecules as they chemically interact - offering glimpses into fundamental workings of the cell that can't be obtained any other way. RNA is a key part of the genetic material in all living cells. It comes in several types that work together to guide the production of proteins by the cell's ribosomes, according to blueprints encoded in DNA. But both DNA and RNA also contain extensive regions that don't code for any protein - the so-called genetic "dark matter." Scientists thought for many years that these regions didn't do anything. Now they know that they play an important role in determining where and when genes turn on and off and otherwise fine-tuning their function. The vast majority of cancers are due to mutations in these non-coding regions, Wang said, so understanding how these regions work is important for cancer research as well as fundamental biology. However, figuring out what the RNA non-coding regions do is difficult. RNA molecules are wobbly and flexible, so it's hard to incorporate them into the large crystals typically needed to study their atomic structure at X-ray light sources. LCLS removes this barrier by allowing scientists to get structural information from much smaller, nanosized crystals, which are much easier to make. Its powerful X-ray laser pulses, a billion times brighter than any available before, are so short that they collect data from each crystal in a few millionths of a billionth of a second, before damage from the X-rays sets in. Wang's team studied a riboswitch from Vibrio vulnificus, a bacterium related to the one that causes cholera. The riboswitch sits in a long strand of messenger RNA (mRNA), which copies DNA's instructions for making a protein so they can be read and carried out by the ribosome. The switch acts like a thermostat that regulates protein production. In this case, the mRNA guides production of a protein that in turn helps to produce a small molecule called adenine. When there is too much adenine in the bacterial cell, adenine molecules enter pockets in the riboswitches and flip the riboswitches into a different shape, and this changes the pace of protein and adenine production. First Stills of an Elegant Film For the LCLS experiments, the researchers made nanocrystals that incorporated millions of copies of the riboswitch and mixed them with a solution containing adenine molecules. Each crystal was so small that adenine could quickly and uniformly penetrate into every corner of it, enter riboswitch pockets and flip them almost instantaneously, as if they were millions of synchronized swimmers executing a single flawless move. The scientists took snapshots of this interaction by hitting the crystals with X-ray laser pulses at carefully timed intervals after the mixing started. This gave them the first glimpse of a fleeting intermediate stage in the process, which occurred 10 seconds in. Separately, they obtained the first images of the riboswitch in its initial, empty-pocket state, and discovered that it existed in two slightly different configurations, only one of which participates in switching. The researchers were surprised to discover that the sudden change in the shape of the riboswitches was so dramatic that it changed the shape of the entire crystal, too. Normally a major change like this would crack the crystal and spoil the experiment. But because these crystals were so small they held together, so the X-ray laser could still get structural information from them. "To me it's still a mystery how the crystal managed to do that," said Soichi Wakatsuki, a professor at SLAC and at the Stanford School of Medicine and head of the lab's Biosciences Division, who was not part of the research team. "This actually opens up a lot of new possibilities and gives us a new way to look at how RNA and proteins interact with small molecules, so this is very exciting." Explore further: Scientists watch bacterial sensor respond to light in real time More information: J. R. Stagno et al, Structures of riboswitch RNA reaction states by mix-and-inject XFEL serial crystallography, Nature (2016). DOI: 10.1038/nature20599


Ashino T.,University of Illinois at Chicago | Sudhahar V.,University of Illinois at Chicago | Urao N.,Center for Lung and Vascular Biology | Oshikawa J.,Center for Lung and Vascular Biology | And 12 more authors.
Circulation Research | Year: 2010

Rationale: Copper, an essential nutrient, has been implicated in vascular remodeling and atherosclerosis with unknown mechanism. Bioavailability of intracellular copper is regulated not only by the copper importer CTR1 (copper transporter 1) but also by the copper exporter ATP7A (Menkes ATPase), whose function is achieved through copper-dependent translocation from trans-Golgi network (TGN). Platelet-derived growth factor (PDGF) promotes vascular smooth muscle cell (VSMC) migration, a key component of neointimal formation. Objective: To determine the role of copper transporter ATP7A in PDGF-induced VSMC migration. Methods and results: Depletion of ATP7A inhibited VSMC migration in response to PDGF or wound scratch in a CTR1/copper-dependent manner. PDGF stimulation promoted ATP7A translocation from the TGN to lipid rafts, which localized at the leading edge, where it colocalized with PDGF receptor and Rac1, in migrating VSMCs. Mechanistically, ATP7A small interfering RNA or CTR small interfering RNA prevented PDGF-induced Rac1 translocation to the leading edge, thereby inhibiting lamellipodia formation. In addition, ATP7A depletion prevented a PDGF-induced decrease in copper level and secretory copper enzyme precursor prolysyl oxidase (Pro-LOX) in lipid raft fraction, as well as PDGF-induced increase in LOX activity. In vivo, ATP7A expression was markedly increased and copper accumulation was observed by synchrotron-based X-ray fluorescence microscopy at neointimal VSMCs in wire injury model. Conclusions: These findings suggest that ATP7A plays an important role in copper-dependent PDGF-stimulated VSMC migration via recruiting Rac1 to lipid rafts at the leading edge, as well as regulating LOX activity. This may contribute to neointimal formation after vascular injury. Our findings provide insight into ATP7A as a novel therapeutic target for vascular remodeling and atherosclerosis. © 2010 American Heart Association, Inc.


Even if a guest walked into the kitchen and held their breath, they still would slough off 10 million bacterial cells in just 60 minutes through skin shed. While the idea may seem revolting, Jack A. Gilbert, UChicago associate professor in ecology & evolution and group leader for microbial ecology in the Biosciences Division at the U.S. Department of Energy's Argonne National Laboratory, assures us it's not. "Nearly all of the germs graciously donated by our friends and family are not disgusting," said Gilbert, who has made a career of exploring how microbial communities assemble themselves in natural and man-made environments. "They are probably good for us in many different ways." Gilbert said our over-sanitized environment may ultimately leave us weaker than our ancestors, who were agrarian and were constantly surrounded by a wide variety of plants and animals. Their bodies adapted to such changes—and so our bodies expect to encounter them, too, he said. "Our ancestors experienced many different types of bacteria on a regular basis," he said. "When you live with such rich biodiversity, the body expects to see it and when it doesn't, it freaks out, which is why we are seeing an explosion in allergies, asthma and hay fever. Our bodies are overreacting to the absence of these organisms." Our constant hand washing—though it might prevent a nasty flu—might also keep us from developing immunities. "We have done a really good job at keeping the bad bugs at bay," Gilbert said, "but we've failed at keeping in those that we need because we live an indoor, sedentary lifestyle." Inviting friends and family to come around on a regular basis may help stimulate our immune systems, he said. Likewise, having very young children interact with a wide variety of animals is only beneficial to their health and greatly outweighs the slim chance of exposure to something harmful, he said. In fact, Gilbert believes some of the social rituals we carry out today—hand shaking, hugging, kissing—may have evolved over millennia as a way to share, spread and develop immunities to bacteria. Kissing, for example, may promote healthy digestion, train the immune system and may even lead to better cognition, Gilbert said. Germs are so prevalent and impossible to eliminate, Gilbert said, there is no need to go overboard scrubbing the house after holiday gatherings. "I would say there is no real reason to increase cleanliness protocols in your property unless one of your guests is really sick, in which case you can isolate them—or tell them not to come over at all," he said.


Suresh A.K.,Biosciences Division | Pelletier D.A.,Biosciences Division | Wang W.,Environmental science Division | Morrell-Falvey J.L.,Biosciences Division | And 3 more authors.
Langmuir | Year: 2012

Due to their unique antimicrobial properties silver nanocrystallites have garnered substantial attention and are used extensively for biomedical applications as an additive to wound dressings, surgical instruments and bone substitute materials. They are also released into unintended locations such as the environment or biosphere. Therefore it is imperative to understand the potential interactions, fate and transport of nanoparticles with environmental biotic systems. Numerous factors including the composition, size, shape, surface charge, and capping molecule of nanoparticles are known to influence cell cytotoxicity. Our results demonstrate that the physical/chemical properties of the silver nanoparticles including surface charge, differential binding and aggregation potential, which are influenced by the surface coatings, are a major determining factor in eliciting cytotoxicity and in dictating potential cellular interactions. In the present investigation, silver nanocrystallites with nearly uniform size and shape distribution but with different surface coatings, imparting overall high negativity to high positivity, were synthesized. These nanoparticles included poly(diallyldimethylammonium) chloride-Ag, biogenic-Ag, colloidal-Ag (uncoated), and oleate-Ag with zeta potentials +45 ± 5, -12 ± 2, -42 ± 5, and -45 ± 5 mV, respectively; the particles were purified and thoroughly characterized so as to avoid false cytotoxicity interpretations. A systematic investigation on the cytotoxic effects, cellular response, and membrane damage caused by these four different silver nanoparticles was carried out using multiple toxicity measurements on mouse macrophage (RAW-264.7) and lung epithelial (C-10) cell lines. Our results clearly indicate that the cytotoxicity was dependent on various factors such as surface charge and coating materials used in the synthesis, particle aggregation, and the cell-type for the different silver nanoparticles that were investigated. Poly(diallyldimethylammonium)-coated Ag nanoparticles were found to be the most toxic, followed by biogenic-Ag and oleate-Ag nanoparticles, whereas uncoated or colloidal silver nanoparticles were found to be the least toxic to both macrophage and lung epithelial cells. Also, based on our cytotoxicity interpretations, lung epithelial cells were found to be more resistant to the silver nanoparticles than the macrophage cells, regardless of the surface coating. © 2012 American Chemical Society.


News Article | January 4, 2016
Site: www.rdmag.com

Lives of soldiers and others injured in remote locations could be saved with a cell-free protein synthesis system developed at the Department of Energy's Oak Ridge National Laboratory. The device, a creation of a team led by Andrea Timm and Scott Retterer of the lab's Biosciences Division, uses microfabricated bioreactors to facilitate the on-demand production of therapeutic proteins for medicines and biopharmaceuticals. Making these miniature factories cell-free, which eliminates the maintenance of a living system, simplifies the process and lowers cost. "With this approach, we can produce more protein faster, making our technology ideal for point-of-care use," Retterer said. "The fact it's cell-free reduces the infrastructure needed to produce the protein and opens the possibility of creating proteins when and where you need them, bypassing the challenge of keeping the proteins cold during shipment and storage." ORNL's bioreactor features elegance through a permeable nanoporous membrane and serpentine design fabricated using a combination of electron beam and photolithography and advanced material deposition processes. This design enables prolonged cell-free reactions for efficient production of proteins, making it easily adaptable for use in isolated locations and at disaster sites. From a functional perspective, the design uses long serpentine channels integrated in a way to allow the exchange of materials between parallel reactor and feeder channels. With this approach, the team can control the exchange of metabolites, energy and species that inhibit production of the desired protein. Through other design features, researchers extend reaction times and improve yields. "We show that the microscale bioreactor design produces higher protein yields than conventional tube-based batch formats and that product yields can be dramatically improved by facilitating small molecule exchange with the dual-channel bioreactor," the authors wrote in their paper, published in the journal Small. The researchers also note that on-demand biologic synthesis would aid the production of drugs that are costly to mass-produce, including orphan drugs and personalized medicines.


News Article | December 31, 2015
Site: www.biosciencetechnology.com

Lives of soldiers and others injured in remote locations could be saved with a cell-free protein synthesis system developed at the Department of Energy's Oak Ridge National Laboratory. The device, a creation of a team led by Andrea Timm and Scott Retterer of the lab's Biosciences Division, uses microfabricated bioreactors to facilitate the on-demand production of therapeutic proteins for medicines and biopharmaceuticals. Making these miniature factories cell-free, which eliminates the maintenance of a living system, simplifies the process and lowers cost. "With this approach, we can produce more protein faster, making our technology ideal for point-of-care use," Retterer said. "The fact it's cell-free reduces the infrastructure needed to produce the protein and opens the possibility of creating proteins when and where you need them, bypassing the challenge of keeping the proteins cold during shipment and storage." ORNL's bioreactor features elegance through a permeable nanoporous membrane and serpentine design fabricated using a combination of electron beam and photolithography and advanced material deposition processes. This design enables prolonged cell-free reactions for efficient production of proteins, making it easily adaptable for use in isolated locations and at disaster sites. From a functional perspective, the design uses long serpentine channels integrated in a way to allow the exchange of materials between parallel reactor and feeder channels. With this approach, the team can control the exchange of metabolites, energy and species that inhibit production of the desired protein. Through other design features, researchers extend reaction times and improve yields. "We show that the microscale bioreactor design produces higher protein yields than conventional tube-based batch formats and that product yields can be dramatically improved by facilitating small molecule exchange with the dual-channel bioreactor," the authors wrote in their paper, published in the journal Small. The researchers also note that on-demand biologic synthesis would aid the production of drugs that are costly to mass-produce, including orphan drugs and personalized medicines.


News Article | December 29, 2015
Site: phys.org

The device, a creation of a team led by Andrea Timm and Scott Retterer of the lab's Biosciences Division, uses microfabricated bioreactors to facilitate the on-demand production of therapeutic proteins for medicines and biopharmaceuticals. Making these miniature factories cell-free, which eliminates the maintenance of a living system, simplifies the process and lowers cost. "With this approach, we can produce more protein faster, making our technology ideal for point-of-care use," Retterer said. "The fact it's cell-free reduces the infrastructure needed to produce the protein and opens the possibility of creating proteins when and where you need them, bypassing the challenge of keeping the proteins cold during shipment and storage." ORNL's bioreactor features elegance through a permeable nanoporous membrane and serpentine design fabricated using a combination of electron beam and photolithography and advanced material deposition processes. This design enables prolonged cell-free reactions for efficient production of proteins, making it easily adaptable for use in isolated locations and at disaster sites. From a functional perspective, the design uses long serpentine channels integrated in a way to allow the exchange of materials between parallel reactor and feeder channels. With this approach, the team can control the exchange of metabolites, energy and species that inhibit production of the desired protein. Through other design features, researchers extend reaction times and improve yields. "We show that the microscale bioreactor design produces higher protein yields than conventional tube-based batch formats and that product yields can be dramatically improved by facilitating small molecule exchange with the dual-channel bioreactor," the authors wrote in their paper, published in the journal Small. The researchers also note that on-demand biologic synthesis would aid the production of drugs that are costly to mass-produce, including orphan drugs and personalized medicines. Explore further: Biomolecules for the production line More information: Towards Microfluidic Reactors for Cell-Free Protein Synthesis at the Point-of-Care, Small, 2015.

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