Nanoparticle chomps away plaques that cause heart attacks

Illustration of atherosclerotic plaque in blood vessel (stock image).

Michigan State University and Stanford University scientists have invented a nanoparticle that eats away -- from the inside out -- portions of plaques that cause heart attacks.

Bryan Smith, associate professor of biomedical engineering at MSU, and a team of scientists created a "Trojan Horse" nanoparticle that can be directed to eat debris, reducing and stabilizing plaque. The discovery could be a potential treatment for atherosclerosis, a leading cause of death in the United States.

The results, published in the current issue of Nature Nanotechnology, showcases the nanoparticle that homes in on atherosclerotic plaque due to its high selectivity to a particular immune cell type -- monocytes and macrophages. Once inside the macrophages in those plaques, it delivers a drug agent that stimulates the cell to engulf and eat cellular debris. Basically, it removes the diseased/dead cells in the plaque core. By reinvigorating the macrophages, plaque size is reduced and stabilized.

Smith said that future clinical trials on the nanoparticle are expected to reduce the risk of most types of heart attacks, with minimal side effects due to the unprecedented selectivity of the nanodrug.

Smith's studies focus on intercepting the signaling of the receptors in the macrophages and sending a message via small molecules using nano-immunotherapeutic platforms. Previous studies have acted on the surface of the cells, but this new approach works intracellularly and has been effective in stimulating macrophages.

"We found we could stimulate the macrophages to selectively eat dead and dying cells -- these inflammatory cells are precursor cells to atherosclerosis -- that are part of the cause of heart attacks," Smith said. "We could deliver a small molecule inside the macrophages to tell them to begin eating again."

This approach also has applications beyond atherosclerosis, he added.

"We were able to marry a groundbreaking finding in atherosclerosis by our collaborators with the state-of-the-art selectivity and delivery capabilities of our advanced nanomaterial platform. We demonstrated the nanomaterials were able to selectively seek out and deliver a message to the very cells needed," Smith said. "It gives a particular energy to our future work, which will include clinical translation of these nanomaterials using large animal models and human tissue tests. We believe it is better than previous methods."

Smith has filed a provisional patent and will begin marketing it later this year.

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Materials provided by Michigan State University. Note: Content may be edited for style and length.

Pathways that extend lifespan by 500 percent identified

Caenorhabditis elegans (stock image).

Scientists at the MDI Biological Laboratory, in collaboration with scientists from the Buck Institute for Research on Aging in Novato, Calif., and Nanjing University in China, have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research.

The increase in lifespan would be the equivalent of a human living for 400 or 500 years, according to one of the scientists.

The research draws on the discovery of two major pathways governing aging in C. elegans, which is a popular model in aging research because it shares many of its genes with humans and because its short lifespan of only three to four weeks allows scientists to quickly assess the effects of genetic and environmental interventions to extend healthy lifespan.

Because these pathways are "conserved," meaning that they have been passed down to humans through evolution, they have been the subject of intensive research. A number of drugs that extend healthy lifespan by altering these pathways are now under development. The discovery of the synergistic effect opens the door to even more effective anti-aging therapies.

The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.

"Despite the discovery in C. elegans of cellular pathways that govern aging, it hasn't been clear how these pathways interact," said Hermann Haller, M.D., president of the MDI Biological Laboratory. "By helping to characterize these interactions, our scientists are paving the way for much-needed therapies to increase healthy lifespan for a rapidly aging population."

The elucidation of the cellular mechanisms controlling the synergistic response is the subject of a recent paper in the online journal Cell Reports entitled "Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity." The authors include Jarod A. Rollins, Ph.D., and Aric N. Rogers, Ph.D., of the MDI Biological Laboratory.

"The synergistic extension is really wild," said Rollins, who is the lead author with Jianfeng Lan, Ph.D., of Nanjing University. "The effect isn't one plus one equals two, it's one plus one equals five. Our findings demonstrate that nothing in nature exists in a vacuum; in order to develop the most effective anti-aging treatments we have to look at longevity networks rather than individual pathways."

The discovery of the synergistic interaction could lead to the use of combination therapies, each affecting a different pathway, to extend healthy human lifespan in the same way that combination therapies are used to treat cancer and HIV, Pankaj Kapahi, Ph.D., of the Buck Institute, has said. Kapahi is a corresponding author of the paper with Rogers and Di Chen, Ph.D., of Nanjing University.

The synergistic interaction may also may explain why scientists have been unable to identify a single gene responsible for the ability of some people to live to extraordinary old ages free of major age-related diseases until shortly before their deaths.

The paper focuses on how longevity is regulated in the mitochondria, which are the organelles in the cell responsible for energy homeostasis. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysregulation and aging. Rollins' future research will focus on the further elucidation of the role of mitochondria in aging, he said.

The research was conducted at the MDI Biological Laboratory and Nanjing University using information from double mutants developed by Kapahi. Rollins' and Rogers' work was supported by the National Institutes of Health (AG056743), the Morris Scientific Discovery Fund and the National Institute of General Medical Sciences (P20GM103423 and P20GM104318).

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Materials provided by Mount Desert Island Biological Laboratory. Note: Content may be edited for style and length.

Pathways that extend lifespan by 500 percent identified

Caenorhabditis elegans (stock image).

Scientists at the MDI Biological Laboratory, in collaboration with scientists from the Buck Institute for Research on Aging in Novato, Calif., and Nanjing University in China, have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research.

The increase in lifespan would be the equivalent of a human living for 400 or 500 years, according to one of the scientists.

The research draws on the discovery of two major pathways governing aging in C. elegans, which is a popular model in aging research because it shares many of its genes with humans and because its short lifespan of only three to four weeks allows scientists to quickly assess the effects of genetic and environmental interventions to extend healthy lifespan.

Because these pathways are "conserved," meaning that they have been passed down to humans through evolution, they have been the subject of intensive research. A number of drugs that extend healthy lifespan by altering these pathways are now under development. The discovery of the synergistic effect opens the door to even more effective anti-aging therapies.

The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.

"Despite the discovery in C. elegans of cellular pathways that govern aging, it hasn't been clear how these pathways interact," said Hermann Haller, M.D., president of the MDI Biological Laboratory. "By helping to characterize these interactions, our scientists are paving the way for much-needed therapies to increase healthy lifespan for a rapidly aging population."

The elucidation of the cellular mechanisms controlling the synergistic response is the subject of a recent paper in the online journal Cell Reports entitled "Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity." The authors include Jarod A. Rollins, Ph.D., and Aric N. Rogers, Ph.D., of the MDI Biological Laboratory.

"The synergistic extension is really wild," said Rollins, who is the lead author with Jianfeng Lan, Ph.D., of Nanjing University. "The effect isn't one plus one equals two, it's one plus one equals five. Our findings demonstrate that nothing in nature exists in a vacuum; in order to develop the most effective anti-aging treatments we have to look at longevity networks rather than individual pathways."

The discovery of the synergistic interaction could lead to the use of combination therapies, each affecting a different pathway, to extend healthy human lifespan in the same way that combination therapies are used to treat cancer and HIV, Pankaj Kapahi, Ph.D., of the Buck Institute, has said. Kapahi is a corresponding author of the paper with Rogers and Di Chen, Ph.D., of Nanjing University.

The synergistic interaction may also may explain why scientists have been unable to identify a single gene responsible for the ability of some people to live to extraordinary old ages free of major age-related diseases until shortly before their deaths.

The paper focuses on how longevity is regulated in the mitochondria, which are the organelles in the cell responsible for energy homeostasis. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysregulation and aging. Rollins' future research will focus on the further elucidation of the role of mitochondria in aging, he said.

The research was conducted at the MDI Biological Laboratory and Nanjing University using information from double mutants developed by Kapahi. Rollins' and Rogers' work was supported by the National Institutes of Health (AG056743), the Morris Scientific Discovery Fund and the National Institute of General Medical Sciences (P20GM103423 and P20GM104318).

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Materials provided by Mount Desert Island Biological Laboratory. Note: Content may be edited for style and length.

Researchers build a particle accelerator that fits on a chip

Subatomic particle collisions illustration (stock image).

On a hillside above Stanford University, the SLAC National Accelerator Laboratory operates a scientific instrument nearly 2 miles long. In this giant accelerator, a stream of electrons flows through a vacuum pipe, as bursts of microwave radiation nudge the particles ever-faster forward until their velocity approaches the speed of light, creating a powerful beam that scientists from around the world use to probe the atomic and molecular structures of inorganic and biological materials.

Now, for the first time, scientists at Stanford and SLAC have created a silicon chip that can accelerate electrons -- albeit at a fraction of the velocity of that massive instrument -- using an infrared laser to deliver, in less than a hair's width, the sort of energy boost that takes microwaves many feet.

Writing in the Jan. 3 issue of Science, a team led by electrical engineer Jelena Vuckovic explained how they carved a nanoscale channel out of silicon, sealed it in a vacuum and sent electrons through this cavity while pulses of infrared light -- to which silicon is as transparent as glass is to visible light -- were transmitted by the channel walls to speed the electrons along.

The accelerator-on-a-chip demonstrated in Science is just a prototype, but Vuckovic said its design and fabrication techniques can be scaled up to deliver particle beams accelerated enough to perform cutting-edge experiments in chemistry, materials science and biological discovery that don't require the power of a massive accelerator.

"The largest accelerators are like powerful telescopes. There are only a few in the world and scientists must come to places like SLAC to use them," Vuckovic said. "We want to miniaturize accelerator technology in a way that makes it a more accessible research tool."

Team members liken their approach to the way that computing evolved from the mainframe to the smaller but still useful PC. Accelerator-on-a-chip technology could also lead to new cancer radiation therapies, said physicist Robert Byer, a co-author of the Science paper. Again, it's a matter of size. Today, medical X-ray machines fill a room and deliver a beam of radiation that's tough to focus on tumors, requiring patients to wear lead shields to minimize collateral damage.

"In this paper we begin to show how it might be possible to deliver electron beam radiation directly to a tumor, leaving healthy tissue unaffected," said Byer, who leads the Accelerator on a Chip International Program, or ACHIP, a broader effort of which this current research is a part.

Inverse design

In their paper, Vuckovic and graduate student Neil Sapra, the first author, explain how the team built a chip that fires pulses of infrared light through silicon to hit electrons at just the right moment, and just the right angle, to move them forward just a bit faster than before.

To accomplish this, they turned the design process upside down. In a traditional accelerator, like the one at SLAC, engineers generally draft a basic design, then run simulations to physically arrange the microwave bursts to deliver the greatest possible acceleration. But microwaves measure 4 inches from peak to trough, while infrared light has a wavelength one-tenth the width of a human hair. That difference explains why infrared light can accelerate electrons in such short distances compared to microwaves. But this also means that the chip's physical features must be 100,000 times smaller than the copper structures in a traditional accelerator. This demands a new approach to engineering based on silicon integrated photonics and lithography.

Vuckovic's team solved the problem using inverse design algorithms that her lab has developed. These algorithms allowed the researchers to work backward, by specifying how much light energy they wanted the chip to deliver, and tasking the software with suggesting how to build the right nanoscale structures required to bring the photons into proper contact with the flow of electrons.

"Sometimes, inverse designs can produce solutions that a human engineer might not have thought of," said R. Joel England, a SLAC staff scientist and co-author on the Science paper.

The design algorithm came up with a chip layout that seems almost otherworldly. Imagine nanoscale mesas, separated by a channel, etched out of silicon. Electrons flowing through the channel run a gantlet of silicon wires, poking through the canyon wall at strategic locations. Each time the laser pulses -- which it does 100,000 times a second -- a burst of photons hits a bunch of electrons, accelerating them forward. All of this occurs in less than a hair's width, on the surface of a vacuum-sealed silicon chip, made by team members at Stanford.

The researchers want to accelerate electrons to 94 percent of the speed of light, or 1 million electron volts (1MeV), to create a particle flow powerful enough for research or medical purposes. This prototype chip provides only a single stage of acceleration, and the electron flow would have to pass through around 1,000 of these stages to achieve 1MeV. But that's not as daunting at it may seem, said Vuckovic, because this prototype accelerator-on-a-chip is a fully integrated circuit. That means all of the critical functions needed to create acceleration are built right into the chip, and increasing its capabilities should be reasonably straightforward.

The researchers plan to pack a thousand stages of acceleration into roughly an inch of chip space by the end of 2020 to reach their 1MeV target. Although that would be an important milestone, such a device would still pale in power alongside the capabilities of the SLAC research accelerator, which can generate energy levels 30,000 times greater than 1MeV. But Byer believes that, just as transistors eventually replaced vacuum tubes in electronics, light-based devices will one day challenge the capabilities of microwave-driven accelerators.

Meanwhile, in anticipation of developing a 1MeV accelerator on a chip, electrical engineer Olav Solgaard, a co-author on the paper, has already begun work on a possible cancer-fighting application. Today, highly energized electrons aren't used for radiation therapy because they would burn the skin. Solgaard is working on a way to channel high-energy electrons from a chip-sized accelerator through a catheter-like vacuum tube that could be inserted below the skin, right alongside a tumor, using the particle beam to administer radiation therapy surgically.

"We can derive medical benefits from the miniaturization of accelerator technology in addition to the research applications," Solgaard said.

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Materials provided by Stanford University. Original written by Tom Abate. Note: Content may be edited for style and length.

NASA’s Helical Engine Design that Uses Closed-Cycle Propellant; A Proposed Stardrive that May Enable Interstellar Travel

Twentieth Century technology has relied on the use of fuels and chemical propellants to propel our ships, planes, and cars. The propulsion technology of the future will not use chemical combustion to produce thrust, and the 21st century will see the emergence of propellant-less propulsion systems. Such technologies will provide the means to travel faster than ever before at a fraction of current costs and with no pollution by-products.

This becomes absolutely crucial for interplanetary and interstellar travel, as we have stated before in RSF commentary1 reporting on Resonance-based technology may provide inertial mass reduction—the future of space travel will not be performed with chemical propellants. As an example, to date the most viable proposal for an interstellar mission with current technological capabilities is the Breakthrough Starshot project which will use a fleet of light sail probes propelled to 20% percent the speed of light via laser pulses.

Considering the significant limitations of combustion-based propulsion (as well as the harmful environmental impacts), there is a strong drive to develop the next-generation propulsion systems that will move us into the next phase of technological advancement. Torus Tech, a research and development company founded by Nassim Haramein, the founder of the Resonance Science Foundation, is researching quantum vacuum engineering technologies that will enable gravitational control and zero-point energy production.

NASA is also moving forward with developing novel propulsion systems. NASA has been working on a number of small skunkworks projects, one of which—the EmDrive—has shown promise as a viable methodology for producing thrust with microwave resonance. In a new proposal, David Burns at NASA’s Marshall Space Flight Center has described a novel propellant-less propulsion system that, much like the EmDrive, utilizes relativistic effects to generate thrust in what he calls a Relativistic Momentum Transfer Model. David Burns describes his novel design in a research paper the Helical Engine. The drive derives its appellation from the core engine which is a helical particle accelerator. The core propels ions down a helical beam guide, which imparts both a z-axis velocity component and a rotational component—it is tantamount to an ionic vortex propelled (rotating in the X and Y axes) propelled along its Z-axis. The helical beam guide is tapered, so that the base has a smaller diameter than the top, in this way ions moving through the waveguide can be accelerated at one end while the radius of rotation increases, increasing the absolute velocity; and decelerated on the return with a decreasing radius of rotation, reducing the absolute velocity.

The end result is that the ions have more mass at one end of the core where they transfer their momentum to the ship, and less mass at the other end, resulting in a net-increase of momentum in the direction of travel. The core is a closed-loop helical beam guide, so no ions are required to be added or expelled, and because of the relativistic effects the drive essentially produces thrust by expelling the ions’ mass as “propellant”. The velocity change for an ion traveling through a single cycle is small, however the beam guide contains over 3×1012 ions that complete over a half million round trip cycles each second, in which each ion applies a force aligned with the direction of travel of the ship.

There are significant challenges before the Helical Engine can become a practical technology. It requires a lot of energy to control the electric and magnetic components of the particle accelerator and produces small amounts of thrust relative to the energy requirements. It will require solar panel power for satellite operations and nuclear power for interplanetary and interstellar travel. However, with a fission reactor the engine could produce thrust indefinitely without the need for significant refueling, enabling the craft to accelerate to extremely high speeds, and the engine will be reliable as the ions are the only moving part. Further critical thinking and design will undoubtedly bring the Helical Engine to a practical propulsion technology.

Read more: NASA engineer’s ‘helical engine’ may violate the laws of physics

RSF In-Perspective:
1We are not going to be able to travel to the stars using chemical combustion engines. In fact, interplanetary transit within our local solar system is impractical utilizing chemical combustion. Even the height of explosion-based “blow-it up” technology, external nuclear pulse propulsion, detailed in the Orion Project, would take 44 years traveling at its top speed (0.1c) to reach the nearest stellar system to our own. The reasons for becoming an interstellar civilization are myriad and a prerequisite to the long-term survivability of humanity. In addition, the same technology that would get us to the stars would enable us to travel on the surface of earth without producing pollutants that alter the atmosphere and environment, allow for the means to feasibly capture and sequester green-house gases, and the ability to deflect potentially devastating asteroids and meteoroids. As such, a technology with even the smallest potential to offer novel means of propulsion and energy production should be explored in earnest, even if current physics theory say it is “impossible”.

Resonance-based technology may provide inertial mass reduction. By: William Brown, Biophysicist with the Resonance Science Foundation.

Experts unlock key to photosynthesis, a find that could help us meet food security demands

Green leaf in sunlight

Scientists have solved the structure of one of the key components of photosynthesis, a discovery that could lead to photosynthesis being 'redesigned' to achieve higher yields and meet urgent food security needs.

The study, led by the University of Sheffield and published today in the journal Nature, reveals the structure of cytochrome b6f -- the protein complex that significantly influences plant growth via photosynthesis.

Photosynthesis is the foundation of life on Earth providing the food, oxygen and energy that sustains the biosphere and human civilisation.

Using a high-resolution structural model, the team found that the protein complex provides the electrical connection between the two light-powered chlorophyll-proteins (Photosystems I and II) found in the plant cell chloroplast that convert sunlight into chemical energy.

Lorna Malone, the first author of the study and a PhD student in the University of Sheffield's Department of Molecular Biology and Biotechnology, said: "Our study provides important new insights into how cytochrome b6f utilises the electrical current passing through it to power up a 'proton battery'. This stored energy can then be then used to make ATP, the energy currency of living cells. Ultimately this reaction provides the energy that plants need to turn carbon dioxide into the carbohydrates and biomass that sustain the global food chain."

The high-resolution structural model, determined using single-particle cryo-electron microscopy, reveals new details of the additional role of cytochrome b6f as a sensor to tune photosynthetic efficiency in response to ever-changing environmental conditions. This response mechanism protects the plant from damage during exposure to harsh conditions such as drought or excess light.

Dr Matt Johnson, reader in Biochemistry at the University of Sheffield and one of the supervisors of the study added: "Cytochrome b6f is the beating heart of photosynthesis which plays a crucial role in regulating photosynthetic efficiency.

"Previous studies have shown that by manipulating the levels of this complex we can grow bigger and better plants. With the new insights we have obtained from our structure we can hope to rationally redesign photosynthesis in crop plants to achieve the higher yields we urgently need to sustain a projected global population of 9-10 billion by 2050."

The research was conducted in collaboration with the Astbury Centre for Structural Molecular Biology at the University of Leeds.

Researchers now aim to establish how cytochrome b6f is controlled by a myriad of regulatory proteins and how these regulators affect the function of this complex.

Specific neurons that map memories now identified in the human brain

An important aspect of human memory is our ability to conjure specific moments from the vast array of experiences that have occurred in any given setting. For example, if asked to recommend a tourist itinerary for a city you have visited many times, your brain somehow enables you to selectively recall and distinguish specific memories from your different trips to provide an answer.

Studies have shown that declarative memory -- the kind of memory you can consciously recall like your home address or your mother's name -- relies on healthy medial temporal lobe structures in the brain, including the hippocampus and entorhinal cortex (EC). These regions are also important for spatial cognition, demonstrated? by the Nobel-Prize-winning discovery of "place cells" and "grid cells" in these regions -- neurons that activate to represent specific locations in the environment during navigation (akin to a GPS). However, it has not been clear if or how this "spatial map" in the brain relates to a person's memory of events at those locations, and how neuronal activity in these regions enables us to target a particular memory for retrieval among related experiences.

A team led by neuroengineers at Columbia Engineering has found the first evidence that individual neurons in the human brain target specific memories during recall. They studied recordings in neurosurgical patients who had electrodes implanted in their brains and examined how the patients' brain signals corresponded to their behavior while performing a virtual-reality (VR) object-location memory task. The researchers identified "memory-trace cells" whose activity was spatially tuned to the location where subjects remembered encountering specific objects. The study is published today in Nature Neuroscience.

"We found these memory-trace neurons primarily in the entorhinal cortex (EC), which is one of the first regions of the brain affected by the onset of Alzheimer 's disease," says Joshua Jacobs, associate professor of biomedical engineering, who directed the study. "Because the activity of these neurons is closely related to what a person is trying to remember, it is possible that their activity is disrupted by diseases like Alzheimer's, leading to memory deficits. Our findings should open up new lines of investigation into how neural activity in the entorhinal cortex and medial temporal lobe helps us target past events for recall, and more generally how space and memory overlap in the brain."

The team was able to measure the activity of single neurons by taking advantage of a rare opportunity: invasively recording from the brains of 19 neurosurgical patients at several hospitals, including the Columbia University Irving Medical Center. The patients had drug-resistant epilepsy and so had already had recording electrodes implanted in their brains for their clinical treatment. The researchers designed experiments as engaging and immersive VR computer games and the bedridden patients used laptops and handheld controllers to move through virtual environments. In performing the task, subjects first navigated through the environment to learn the locations of four unique objects. Then the researchers removed the objects and asked patients to move through the environment and mark the location of one specific object on each trial.

The team measured the activity of neurons as the patients moved through the environment and marked their memory targets. Initially, they identified purely spatially tuned neurons similar to "place cells" that always activated when patients moved through specific locations, regardless of the subjects' memory target. "These neurons seemed only to care about the person's spatial location, like a pure GPS," says Salman E. Qasim, Jacobs' PhD student and lead author of the study.

But the researchers also noticed that other neurons only activated in locations relevant to the memory the patient was recalling on that trial -- whenever patients were instructed to target a different memory for recall, these neurons changed their activity to match the new target's remembered location. What especially excited Jacobs and Qasim is that they could actually decode the specific memory a patient was targeting based on the activity of these neurons.

"Our study demonstrates that neurons in the human brain track the experiences we are willfully recalling, and can change their activity patterns to differentiate between memories. They're just like the pins on your Google map that mark the locations you remember for important events," Qasim says. "This discovery might provide a potential mechanism for our ability to selectively call upon different experiences from the past and highlights how these memories may influence our brain's spatial map."

Jacobs and Qasim plan next to look for evidence that these neurons represent memories in non-spatial contexts to better characterize their role in memory function. "We know now that neurons care about where our memories occur and now we want to see if these neurons care about other features of those memories, like when they occurred, what occurred, and so on," Qasim notes.

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Materials provided by Columbia University School of Engineering and Applied Science. Original written by Holly Evarts.