Tag Archives: Alzheimer’s Disease

Brainy and brainy: a novel synaptic architecture and a neuromorphic computing platform called SpiNNaker

I have two items about brainlike computing. The first item hearkens back to memristors, a topic I have been following since 2008. (If you’re curious about the various twists and turns just enter  the term ‘memristor’ in this blog’s search engine.) The latest on memristors is from a team than includes IBM (US), École Politechnique Fédérale de Lausanne (EPFL; Swizterland), and the New Jersey Institute of Technology (NJIT; US). The second bit comes from a Jülich Research Centre team in Germany and concerns an approach to brain-like computing that does not include memristors.

Multi-memristive synapses

In the inexorable march to make computers function more like human brains (neuromorphic engineering/computing), an international team has announced its latest results in a July 10, 2018 news item on Nanowerk,

Two New Jersey Institute of Technology (NJIT) researchers, working with collaborators from the IBM Research Zurich Laboratory and the École Polytechnique Fédérale de Lausanne, have demonstrated a novel synaptic architecture that could lead to a new class of information processing systems inspired by the brain.

The findings are an important step toward building more energy-efficient computing systems that also are capable of learning and adaptation in the real world. …

A July 10, 2018 NJIT news release (also on EurekAlert) by Tracey Regan, which originated by the news item, adds more details,

The researchers, Bipin Rajendran, an associate professor of electrical and computer engineering, and S. R. Nandakumar, a graduate student in electrical engineering, have been developing brain-inspired computing systems that could be used for a wide range of big data applications.

Over the past few years, deep learning algorithms have proven to be highly successful in solving complex cognitive tasks such as controlling self-driving cars and language understanding. At the heart of these algorithms are artificial neural networks – mathematical models of the neurons and synapses of the brain – that are fed huge amounts of data so that the synaptic strengths are autonomously adjusted to learn the intrinsic features and hidden correlations in these data streams.

However, the implementation of these brain-inspired algorithms on conventional computers is highly inefficient, consuming huge amounts of power and time. This has prompted engineers to search for new materials and devices to build special-purpose computers that can incorporate the algorithms. Nanoscale memristive devices, electrical components whose conductivity depends approximately on prior signaling activity, can be used to represent the synaptic strength between the neurons in artificial neural networks.

While memristive devices could potentially lead to faster and more power-efficient computing systems, they are also plagued by several reliability issues that are common to nanoscale devices. Their efficiency stems from their ability to be programmed in an analog manner to store multiple bits of information; however, their electrical conductivities vary in a non-deterministic and non-linear fashion.

In the experiment, the team showed how multiple nanoscale memristive devices exhibiting these characteristics could nonetheless be configured to efficiently implement artificial intelligence algorithms such as deep learning. Prototype chips from IBM containing more than one million nanoscale phase-change memristive devices were used to implement a neural network for the detection of hidden patterns and correlations in time-varying signals.

“In this work, we proposed and experimentally demonstrated a scheme to obtain high learning efficiencies with nanoscale memristive devices for implementing learning algorithms,” Nandakumar says. “The central idea in our demonstration was to use several memristive devices in parallel to represent the strength of a synapse of a neural network, but only chose one of them to be updated at each step based on the neuronal activity.”

Here’s a link to and a citation for the paper,

Neuromorphic computing with multi-memristive synapses by Irem Boybat, Manuel Le Gallo, S. R. Nandakumar, Timoleon Moraitis, Thomas Parnell, Tomas Tuma, Bipin Rajendran, Yusuf Leblebici, Abu Sebastian, & Evangelos Eleftheriou. Nature Communications volume 9, Article number: 2514 (2018) DOI: https://doi.org/10.1038/s41467-018-04933-y Published 28 June 2018

This is an open access paper.

Also they’ve got a couple of very nice introductory paragraphs which I’m including here, (from the June 28, 2018 paper in Nature Communications; Note: Links have been removed),

The human brain with less than 20 W of power consumption offers a processing capability that exceeds the petaflops mark, and thus outperforms state-of-the-art supercomputers by several orders of magnitude in terms of energy efficiency and volume. Building ultra-low-power cognitive computing systems inspired by the operating principles of the brain is a promising avenue towards achieving such efficiency. Recently, deep learning has revolutionized the field of machine learning by providing human-like performance in areas, such as computer vision, speech recognition, and complex strategic games1. However, current hardware implementations of deep neural networks are still far from competing with biological neural systems in terms of real-time information-processing capabilities with comparable energy consumption.

One of the reasons for this inefficiency is that most neural networks are implemented on computing systems based on the conventional von Neumann architecture with separate memory and processing units. There are a few attempts to build custom neuromorphic hardware that is optimized to implement neural algorithms2,3,4,5. However, as these custom systems are typically based on conventional silicon complementary metal oxide semiconductor (CMOS) circuitry, the area efficiency of such hardware implementations will remain relatively low, especially if in situ learning and non-volatile synaptic behavior have to be incorporated. Recently, a new class of nanoscale devices has shown promise for realizing the synaptic dynamics in a compact and power-efficient manner. These memristive devices store information in their resistance/conductance states and exhibit conductivity modulation based on the programming history6,7,8,9. The central idea in building cognitive hardware based on memristive devices is to store the synaptic weights as their conductance states and to perform the associated computational tasks in place.

The two essential synaptic attributes that need to be emulated by memristive devices are the synaptic efficacy and plasticity. …

It gets more complicated from there.

Now onto the next bit.

SpiNNaker

At a guess, those capitalized N’s are meant to indicate ‘neural networks’. As best I can determine, SpiNNaker is not based on the memristor. Moving on, a July 11, 2018 news item on phys.org announces work from a team examining how neuromorphic hardware and neuromorphic software work together,

A computer built to mimic the brain’s neural networks produces similar results to that of the best brain-simulation supercomputer software currently used for neural-signaling research, finds a new study published in the open-access journal Frontiers in Neuroscience. Tested for accuracy, speed and energy efficiency, this custom-built computer named SpiNNaker, has the potential to overcome the speed and power consumption problems of conventional supercomputers. The aim is to advance our knowledge of neural processing in the brain, to include learning and disorders such as epilepsy and Alzheimer’s disease.

A July 11, 2018 Frontiers Publishing news release on EurekAlert, which originated the news item, expands on the latest work,

“SpiNNaker can support detailed biological models of the cortex–the outer layer of the brain that receives and processes information from the senses–delivering results very similar to those from an equivalent supercomputer software simulation,” says Dr. Sacha van Albada, lead author of this study and leader of the Theoretical Neuroanatomy group at the Jülich Research Centre, Germany. “The ability to run large-scale detailed neural networks quickly and at low power consumption will advance robotics research and facilitate studies on learning and brain disorders.”

The human brain is extremely complex, comprising 100 billion interconnected brain cells. We understand how individual neurons and their components behave and communicate with each other and on the larger scale, which areas of the brain are used for sensory perception, action and cognition. However, we know less about the translation of neural activity into behavior, such as turning thought into muscle movement.

Supercomputer software has helped by simulating the exchange of signals between neurons, but even the best software run on the fastest supercomputers to date can only simulate 1% of the human brain.

“It is presently unclear which computer architecture is best suited to study whole-brain networks efficiently. The European Human Brain Project and Jülich Research Centre have performed extensive research to identify the best strategy for this highly complex problem. Today’s supercomputers require several minutes to simulate one second of real time, so studies on processes like learning, which take hours and days in real time are currently out of reach.” explains Professor Markus Diesmann, co-author, head of the Computational and Systems Neuroscience department at the Jülich Research Centre.

He continues, “There is a huge gap between the energy consumption of the brain and today’s supercomputers. Neuromorphic (brain-inspired) computing allows us to investigate how close we can get to the energy efficiency of the brain using electronics.”

Developed over the past 15 years and based on the structure and function of the human brain, SpiNNaker — part of the Neuromorphic Computing Platform of the Human Brain Project — is a custom-built computer composed of half a million of simple computing elements controlled by its own software. The researchers compared the accuracy, speed and energy efficiency of SpiNNaker with that of NEST–a specialist supercomputer software currently in use for brain neuron-signaling research.

“The simulations run on NEST and SpiNNaker showed very similar results,” reports Steve Furber, co-author and Professor of Computer Engineering at the University of Manchester, UK. “This is the first time such a detailed simulation of the cortex has been run on SpiNNaker, or on any neuromorphic platform. SpiNNaker comprises 600 circuit boards incorporating over 500,000 small processors in total. The simulation described in this study used just six boards–1% of the total capability of the machine. The findings from our research will improve the software to reduce this to a single board.”

Van Albada shares her future aspirations for SpiNNaker, “We hope for increasingly large real-time simulations with these neuromorphic computing systems. In the Human Brain Project, we already work with neuroroboticists who hope to use them for robotic control.”

Before getting to the link and citation for the paper, here’s a description of SpiNNaker’s hardware from the ‘Spiking neural netowrk’ Wikipedia entry, Note: Links have been removed,

Neurogrid, built at Stanford University, is a board that can simulate spiking neural networks directly in hardware. SpiNNaker (Spiking Neural Network Architecture) [emphasis mine], designed at the University of Manchester, uses ARM processors as the building blocks of a massively parallel computing platform based on a six-layer thalamocortical model.[5]

Now for the link and citation,

Performance Comparison of the Digital Neuromorphic Hardware SpiNNaker and the Neural Network Simulation Software NEST for a Full-Scale Cortical Microcircuit Model by
Sacha J. van Albada, Andrew G. Rowley, Johanna Senk, Michael Hopkins, Maximilian Schmidt, Alan B. Stokes, David R. Lester, Markus Diesmann, and Steve B. Furber. Neurosci. 12:291. doi: 10.3389/fnins.2018.00291 Published: 23 May 2018

As noted earlier, this is an open access paper.

Hallucinogenic molecules and the brain

Psychedelic drugs seems to be enjoying a ‘moment’. After decades of being vilified and  declared illegal (in many jurisdictions), psychedelic (or hallucinogenic) drugs are once again being tested for use in therapy. A Sept. 1, 2017 article by Diana Kwon for The Scientist describes some of the latest research (I’ve excerpted the section on molecules; Note: Links have been removed),

Mind-bending molecules

© SEAN MCCABE

All the classic psychedelic drugs—psilocybin, LSD, and N,N-dimethyltryptamine (DMT), the active component in ayahuasca—activate serotonin 2A (5-HT2A) receptors, which are distributed throughout the brain. In all likelihood, this receptor plays a key role in the drugs’ effects. Krähenmann [Rainer Krähenmann, a psychiatrist and researcher at the University of Zurich]] and his colleagues in Zurich have discovered that ketanserin, a 5-HT2A receptor antagonist, blocks LSD’s hallucinogenic properties and prevents individuals from entering a dreamlike state or attributing personal relevance to the experience.12,13

Other research groups have found that, in rodent brains, 2,5-dimethoxy-4-iodoamphetamine (DOI), a highly potent and selective 5-HT2A receptor agonist, can modify the expression of brain-derived neurotrophic factor (BDNF)—a protein that, among other things, regulates neuronal survival, differentiation, and synaptic plasticity. This has led some scientists to hypothesize that, through this pathway, psychedelics may enhance neuroplasticity, the ability to form new neuronal connections in the brain.14 “We’re still working on that and trying to figure out what is so special about the receptor and where it is involved,” says Katrin Preller, a postdoc studying psychedelics at the University of Zurich. “But it seems like this combination of serotonin 2A receptors and BDNF leads to a kind of different organizational state in the brain that leads to what people experience under the influence of psychedelics.”

This serotonin receptor isn’t limited to the central nervous system. Work by Charles Nichols, a pharmacology professor at Louisiana State University, has revealed that 5-HT2A receptor agonists can reduce inflammation throughout the body. Nichols and his former postdoc Bangning Yu stumbled upon this discovery by accident, while testing the effects of DOI on smooth muscle cells from rat aortas. When they added this drug to the rodent cells in culture, it blocked the effects of tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine.

“It was completely unexpected,” Nichols recalls. The effects were so bewildering, he says, that they repeated the experiment twice to convince themselves that the results were correct. Before publishing the findings in 2008,15 they tested a few other 5-HT2A receptor agonists, including LSD, and found consistent anti-inflammatory effects, though none of the drugs’ effects were as strong as DOI’s. “Most of the psychedelics I have tested are about as potent as a corticosteroid at their target, but there’s something very unique about DOI that makes it much more potent,” Nichols says. “That’s one of the mysteries I’m trying to solve.”

After seeing the effect these drugs could have in cells, Nichols and his team moved on to whole animals. When they treated mouse models of system-wide inflammation with DOI, they found potent anti-inflammatory effects throughout the rodents’ bodies, with the strongest effects in the small intestine and a section of the main cardiac artery known as the aortic arch.16 “I think that’s really when it felt that we were onto something big, when we saw it in the whole animal,” Nichols says.

The group is now focused on testing DOI as a potential therapeutic for inflammatory diseases. In a 2015 study, they reported that DOI could block the development of asthma in a mouse model of the condition,17 and last December, the team received a patent to use DOI for four indications: asthma, Crohn’s disease, rheumatoid arthritis, and irritable bowel syndrome. They are now working to move the treatment into clinical trials. The benefit of using DOI for these conditions, Nichols says, is that because of its potency, only small amounts will be required—far below the amounts required to produce hallucinogenic effects.

In addition to opening the door to a new class of diseases that could benefit from psychedelics-inspired therapy, Nichols’s work suggests “that there may be some enduring changes that are mediated through anti-inflammatory effects,” Griffiths [Roland Griffiths, a psychiatry professor at Johns Hopkins University] says. Recent studies suggest that inflammation may play a role in a number of psychological disorders, including depression18 and addiction.19

“If somebody has neuroinflammation and that’s causing depression, and something like psilocybin makes it better through the subjective experience but the brain is still inflamed, it’s going to fall back into the depressed rut,” Nichols says. But if psilocybin is also treating the inflammation, he adds, “it won’t have that rut to fall back into.”

If it turns out that psychedelics do have anti-inflammatory effects in the brain, the drugs’ therapeutic uses could be even broader than scientists now envision. “In terms of neurodegenerative disease, every one of these disorders is mediated by inflammatory cytokines,” says Juan Sanchez-Ramos, a neuroscientist at the University of South Florida who in 2013 reported that small doses of psilocybin could promote neurogenesis in the mouse hippocampus.20 “That’s why I think, with Alzheimer’s, for example, if you attenuate the inflammation, it could help slow the progression of the disease.”

For anyone who was never exposed to the anti-hallucinogenic drug campaigns, this turn of events is mindboggling. There was a great deal of concern especially with LSD in the 1960s and it was not entirely unfounded. In my own family, a distant cousin, while under the influence of the drug, jumped off a building believing he could fly.  So, Kwon’s story opening with a story about someone being treated successfully for depression with a psychedelic drug was surprising to me . Why these drugs are being used successfully for psychiatric conditions when so much damage was apparently done under the influence in decades past may have something to do with taking the drugs in a controlled environment and, possibly, smaller dosages.

Curcumin: a scientific literature review concludes health benefits may be overstated

Given the number of times I’ve featured ‘curcumin research’, it seems only right to include this latest work. A Jan. 11, 2017 American Chemical Society (ACS) news release (also on EurekAlert) describes the results of a review of the scientific literature on curcumin’s (a constituent of turmeric) medicinal effectiveness,

Curcumin, a compound in turmeric, continues to be hailed as a natural treatment for a wide range of health conditions, including cancer and Alzheimer’s disease. But a new review of the scientific literature on curcumin has found it’s probably not all it’s ground up to be. The report in ACS’ Journal of Medicinal Chemistry instead cites evidence that, contrary to numerous reports, the compound has limited — if any — therapeutic benefit.

Turmeric, a spice often added to curries and mustards because of its distinct flavor and color, has been used for centuries in traditional medicine. Since the early 1990’s, scientists have zeroed in on curcumin, which makes up about 3 to 5 percent of turmeric, as the potential constituent that might give turmeric its health-boosting properties. More than 120 clinical trials to test these claims have been or are in the process of being run by clinical investigators. To get to the root of curcumin’s essential medicinal chemistry, the research groups of Michael A. Walters and Guido F. Pauli teamed up to extract key findings from thousands of scientific articles on the topic.

The researchers’ review of the vast curcumin literature provides evidence that curcumin is unstable under physiological conditions and not readily absorbed by the body, properties that make it a poor therapeutic candidate. Additionally, they could find no evidence of a double-blind, placebo-controlled clinical trial on curcumin to support its status as a potential cure-all. But, the authors say, this doesn’t necessarily mean research on turmeric should halt [emphasis mine]. Turmeric extracts and preparations could have health benefits, although probably not for the number of conditions currently touted. The researchers suggest that future studies should take a more holistic approach to account for the spice’s chemically diverse constituents that may synergistically contribute to its potential benefits.

Here’s a link to and citation for the paper,

The Essential Medicinal Chemistry of Curcumin by Kathryn M. Nelson, Jayme L. Dahlin, Jonathan Bisson, James Graham, Guido F. Pauli, and Michael A. Walters. J. Med. Chem., Article ASAP DOI: 10.1021/acs.jmedchem.6b00975 Publication Date (Web): January 11, 2017

Copyright © 2017 American Chemical Society

This paper is open access.

The character of water: both types

This is to use an old term, ‘mindblowing’. Apparently, there are two types of the liquid we call water according to a Nov. 10, 2016 news item on phys.org,

There are two types of liquid water, according to research carried out by an international scientific collaboration. This new peculiarity adds to the growing list of strange phenomena in what we imagine is a simple substance. The discovery could have implications for making and using nanoparticles as well as in understanding how proteins fold into their working shape in the body or misfold to cause diseases such as Alzheimer’s or CJD [Creutzfeldt-Jakob Disease].

A Nov. 10, 2016 Inderscience Publishers news release, which originated the news item, expands on the theme,

Writing in the International Journal of Nanotechnology, Oxford University’s Laura Maestro and her colleagues in Italy, Mexico, Spain and the USA, explain how the physical and chemical properties of water have been studied for more than a century and revealed some odd behavior not seen in other substances. For instance, when water freezes it expands. By contrast, almost every other known substance contracts when it is cooled. Water also exists as solid, liquid and gas within a very small temperature range (100 degrees Celsius) whereas the melting and boiling points of most other compounds span a much greater range.

Many of water’s bizarre properties are due to the molecule’s ability to form short-lived connections with each other known as hydrogen bonds. There is a residual positive charge on the hydrogen atoms in the V-shaped water molecule either or both of which can form such bonds with the negative electrons on the oxygen atom at the point of the V. This makes fleeting networks in water possible that are frozen in place when the liquid solidifies. They bonds are so short-lived that they do not endow the liquid with any structure or memory, of course.

The team has looked closely at several physical properties of water like its dielectric constant (how well an electric field can permeate a substance) or the proton-spin lattice relaxation (the process by which the magnetic moments of the hydrogen atoms in water can lose energy having been excited to a higher level). They have found that these phenomena seem to flip between two particular characters at around 50 degrees Celsius, give or take 10 degrees, i.e. from 40 to 60 degrees Celsius. The effect is that thermal expansion, speed of sound and other phenomena switch between two different states at this crossover temperature.

These two states could have important implications for studying and using nanoparticles where the character of water at the molecule level becomes important for the thermal and optical properties of such particles. Gold and silver nanoparticles are used in nanomedicine for diagnostics and as antibacterial agents, for instance. Moreover, the preliminary findings suggest that the structure of liquid water can strongly influence the stability of proteins and how they are denatured at the crossover temperature, which may well have implications for understanding protein processing in the food industry but also in understanding how disease arises when proteins misfold.

Here’s a link to and a citation for the paper,

On the existence of two states in liquid water: impact on biological and nanoscopic systems
by L.M. Maestro, M.I. Marqués, E. Camarillo, D. Jaque, J. García Solé, J.A. Gonzalo, F. Jaque, Juan C. Del Valle, F. Mallamace, H.E. Stanley.
International Journal of Nanotechnology (IJNT), Vol. 13, No. 8/9, 2016 DOI: 10.1504/IJNT.2016.079670

This paper is behind a paywall.

Breathing nanoparticles into your brain

Thanks to Dexter Johnson and his Sept. 8, 2016 posting (on the Nanoclast blog on the IEEE [Institute for Electrical and Electronics Engineers]) for bringing this news about nanoparticles in the brain to my attention (Note: Links have been removed),

An international team of researchers, led by Barbara Maher, a professor at Lancaster University, in England, has found evidence that suggests that the nanoparticles that were first detected in the human brain over 20 years ago may have an external rather an internal source.

These magnetite nanoparticles are an airborne particulate that are abundant in urban environments and formed by combustion or friction-derived heating. In other words, they have been part of the pollution in the air of our cities since the dawn of the Industrial Revolution.

However, according to Andrew Maynard, a professor at Arizona State University, and a noted expert on the risks associated with nanomaterials,  the research indicates that this finding extends beyond magnetite to any airborne nanoscale particles—including those deliberately manufactured.

“The findings further support the possibility of these particles entering the brain via the olfactory nerve if inhaled.  In this respect, they are certainly relevant to our understanding of the possible risks presented by engineered nanomaterials—especially those that are iron-based and have magnetic properties,” said Maynard in an e-mail interview with IEEE Spectrum. “However, ambient exposures to airborne nanoparticles will typically be much higher than those associated with engineered nanoparticles, simply because engineered nanoparticles will usually be manufactured and handled under conditions designed to avoid release and exposure.”

A Sept. 5, 2016 University of Lancaster press release made the research announcement,

Researchers at Lancaster University found abundant magnetite nanoparticles in the brain tissue from 37 individuals aged three to 92-years-old who lived in Mexico City and Manchester. This strongly magnetic mineral is toxic and has been implicated in the production of reactive oxygen species (free radicals) in the human brain, which are associated with neurodegenerative diseases including Alzheimer’s disease.

Professor Barbara Maher, from Lancaster Environment Centre, and colleagues (from Oxford, Glasgow, Manchester and Mexico City) used spectroscopic analysis to identify the particles as magnetite. Unlike angular magnetite particles that are believed to form naturally within the brain, most of the observed particles were spherical, with diameters up to 150 nm, some with fused surfaces, all characteristic of high-temperature formation – such as from vehicle (particularly diesel) engines or open fires.

The spherical particles are often accompanied by nanoparticles containing other metals, such as platinum, nickel, and cobalt.

Professor Maher said: “The particles we found are strikingly similar to the magnetite nanospheres that are abundant in the airborne pollution found in urban settings, especially next to busy roads, and which are formed by combustion or frictional heating from vehicle engines or brakes.”

Other sources of magnetite nanoparticles include open fires and poorly sealed stoves within homes. Particles smaller than 200 nm are small enough to enter the brain directly through the olfactory nerve after breathing air pollution through the nose.

“Our results indicate that magnetite nanoparticles in the atmosphere can enter the human brain, where they might pose a risk to human health, including conditions such as Alzheimer’s disease,” added Professor Maher.

Leading Alzheimer’s researcher Professor David Allsop, of Lancaster University’s Faculty of Health and Medicine, said: “This finding opens up a whole new avenue for research into a possible environmental risk factor for a range of different brain diseases.”

Damian Carrington’s Sept. 5, 2016 article for the Guardian provides a few more details,

“They [the troubling magnetite particles] are abundant,” she [Maher] said. “For every one of [the crystal shaped particles] we saw about 100 of the pollution particles. The thing about magnetite is it is everywhere.” An analysis of roadside air in Lancaster found 200m magnetite particles per cubic metre.

Other scientists told the Guardian the new work provided strong evidence that most of the magnetite in the brain samples come from air pollution but that the link to Alzheimer’s disease remained speculative.

For anyone who might be concerned about health risks, there’s this from Andrew Maynard’s comments in Dexter Johnson’s Sept. 8, 2016 posting,

“In most workplaces, exposure to intentionally made nanoparticles is likely be small compared to ambient nanoparticles, and so it’s reasonable to assume—at least without further data—that this isn’t a priority concern for engineered nanomaterial production,” said Maynard.

While deliberate nanoscale manufacturing may not carry much risk, Maynard does believe that the research raises serious questions about other manufacturing processes where exposure to high concentrations of airborne nanoscale iron particles is common—such as welding, gouging, or working with molten ore and steel.

It seems everyone is agreed that the findings are concerning but I think it might be good to remember that the percentage of people who develop Alzheimer’s Disease is much smaller than the population of people who have crystals in their brains. In other words, these crystals might (they don’t know) be a factor and likely there would have to be one or more factors to create the condition for developing Alzheimer’s.

Here’s a link to and a citation for the paper,

Magnetite pollution nanoparticles in the human brain by Barbara A. Maher, Imad A. M. Ahmed, Vassil Karloukovski, Donald A. MacLaren, Penelope G. Fouldsd, David Allsop, David M. A. Mann, Ricardo Torres-Jardón, and Lilian Calderon-Garciduenas. PNAS [Proceedings of the National Academy of Sciences] doi: 10.1073/pnas.1605941113

This paper is behind a paywall but Dexter’s posting offers more detail for those who are still curious.

Cornell University researchers breach blood-brain barrier

There are other teams working on ways to breach the blood-brain barrier (my March 26, 2015 post highlights work from a team at the University of Montréal) but this team from  Cornell is working with a drug that has already been approved by the US Food and Drug Administration (FDA) according to an April 8, 2016 news item on ScienceDaily,

Cornell researchers have discovered a way to penetrate the blood brain barrier (BBB) that may soon permit delivery of drugs directly into the brain to treat disorders such as Alzheimer’s disease and chemotherapy-resistant cancers.

The BBB is a layer of endothelial cells that selectively allow entry of molecules needed for brain function, such as amino acids, oxygen, glucose and water, while keeping others out.

Cornell researchers report that an FDA-approved drug called Lexiscan activates receptors — called adenosine receptors — that are expressed on these BBB cells.

An April 4, 2016 Cornell University news release by Krishna Ramanujan, which originated the news item, expands on the theme,

“We can open the BBB for a brief window of time, long enough to deliver therapies to the brain, but not too long so as to harm the brain. We hope in the future, this will be used to treat many types of neurological disorders,” said Margaret Bynoe, associate professor in the Department of Microbiology and Immunology in Cornell’s College of Veterinary Medicine. …

The researchers were able to deliver chemotherapy drugs into the brains of mice, as well as large molecules, like an antibody that binds to Alzheimer’s disease plaques, according to the paper.

To test whether this drug delivery system has application to the human BBB, the lab engineered a BBB model using human primary brain endothelial cells. They observed that Lexiscan opened the engineered BBB in a manner similar to its actions in mice.

Bynoe and Kim discovered that a protein called P-glycoprotein is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Lexiscan acts on one of the adenosine receptors expressed on BBB endothelial cells specifically activating them. They showed that Lexiscan down-regulates P-glycoprotein expression and function on the BBB endothelial cells. It acts like a switch that can be turned on and off in a time dependent manner, which provides a measure of safety for the patient.

“We demonstrated that down-modulation of P-glycoprotein function coincides exquisitely with chemotherapeutic drug accumulation” in the brains of mice and across an engineered BBB using human endothelial cells, Bynoe said. “The amount of chemotherapeutic drugs that accumulated in the brain was significant.”

In addition to P-glycoprotein’s role in inhibiting foreign substances from penetrating the BBB, the protein is also expressed by many different types of cancers and makes these cancers resistant to chemotherapy.

“This finding has significant implications beyond modulation of the BBB,” Bynoe said. “It suggests that in the future, we may be able to modulate adenosine receptors to regulate P-glycoprotein in the treatment of cancer cells resistant to chemotherapy.”

Because Lexiscan is an FDA-approved drug, ”the potential for a breakthrough in drug delivery systems for diseases such as Alzheimer’s disease, Parkinson’s disease, autism, brain tumors and chemotherapy-resistant cancers is not far off,” Bynoe said.

Another advantage is that these molecules (adenosine receptors  and P-glycoprotein are naturally expressed in mammals. “We don’t have to knock out a gene or insert one for a therapy to work,” Bynoe said.

The study was funded by the National Institutes of Health and the Kwanjung Educational Foundation.

Here’s a link to and a citation for the paper,

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier by Do-Geun Kim and Margaret S. Bynoe. J Clin Invest. doi:10.1172/JCI76207 First published April 4, 2016

Copyright © 2016, The American Society for Clinical Investigation.

This paper appears to be open access.

Nanotechnology delivery system for skin disease therapies

A Feb. 29, 2016 news item on ScienceDaily announces a new development concerning free radicals that may be helpful with skin diseases and pathologies,

Researchers at The Hebrew University of Jerusalem have developed a nanotechnology-based delivery system containing a protective cellular pathway inducer that activates the body’s natural defense against free radicals efficiently, a development that could control a variety of skin pathologies and disorders.

A Feb. 29, 2016 Hebrew University of Jerusalem press release on EurekAlert, which originated the news item, expands on the theme,

The human skin is constantly exposed to various pollutants, UV rays, radiation and other stressors that exist in our day-to-day environment. When they filter into the body they can create Reactive Oxygen Species (ROS) – oxygen molecules known as Free Radicals, which are able to damage and destroy cells, including lipids, proteins and DNA.

In the skin – the largest organ of the body – an excess of ROS can lead to various skin conditions, including inflammatory diseases, pigmenting disorders, wrinkles and some types of skin cancer, and can also affect internal organs. This damage is known as Oxidative Stress.

The body is naturally equipped with defense mechanisms to counter oxidative stress. It has anti-oxidants and, more importantly, anti-oxidant enzymes that attack the ROS before they cause damage.

In a review article published in the journal Cosmetics, a PhD student from The Hebrew University of Jerusalem, working in collaboration with researchers at the Technion – Israel Institute of Technology, suggested an innovative way to invigorate the body to produce antioxidant enzymes, while maintaining skin cell redox balance – a gentle equilibrium between Reactive Oxygen Species and their detoxification.

“The approach of using the body’s own defense system is very effective. We showed that activation of the body’s defense system with the aid of a unique delivery system is feasible, and may leverage dermal cure,” said Hebrew University researcher Maya Ben-Yehuda Greenwald.

Ben-Yehuda Greenwald showed that applying nano-size droplets of microemulsion liquids containing a cellular protective pathway inducer into the skin activates the natural skin defense systems.

“Currently, there are many scientific studies supporting the activation of the body’s defense mechanisms. However, none of these studies has demonstrated the use of a nanotechnology-based delivery system to do so,” Ben-Yehuda Greenwald said.

Production of antioxidant enzymes in the body is signaled in the DNA by activation of Nrf2 – a powerful protein that exists in every cell in our body. This Nrf2 cellular-protective signaling pathway is a major intersection of many other signaling pathways affecting each other and determining cell functionality and fate. Nrf2 is capable of coordinating the cellular response to internal as well as external stressors by tight regulation of phase-II protective enzymes, such as the antioxidant enzymes.

Ben-Yehuda Greenwald has also discovered a new family of compounds capable of activating the Nrf2 pathway. Moreover, by incorporating them into the unique delivery system she has developed, she managed to efficiently stimulate the activation of the Nrf2 pathway and mimic the activity of the body’s’ natural way of coping with a variety of stress conditions.

“The formula we have created could be used in topical medication for treating skin conditions. Our formula could be used both as preventive means and for treatment of various skin conditions, such as infections, over-exposure to UV irradiation, inflammatory conditions, and also internal disease,” she said.

While the researchers focused on the skin, the formulation could prove to be effective in enhancing the body’s natural protection against the damaging effects of ROS in other parts of the body, such as inflammation in cardiovascular diseases, heart attack, cancer, multiple sclerosis and Alzheimer’s.

Here’s an image provided by Ben-Yehuda Greenwald illustrating the team’s work,

Caption: These are the consequences of skin exposure to stressors. Credit: Maya Ben-Yehuda Greenwald

Caption: These are the consequences of skin exposure to stressors. Credit: Maya Ben-Yehuda Greenwald

Here’s a link to and a citation for the paper,

Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System by Maya Ben-Yehuda Greenwald, Shmuel Ben-Sasson, Havazelet Bianco-Peled, and Ron Kohen. Cosmetics 2016, 3(1), 1; doi:10.3390/cosmetics3010001 Published: 15 January 2016

This paper appears to be open access.

Proteins which cause Alzheimer’s disease can be used to grow functionalized nanowires

This is the first time I’ve ever heard of anything good resulting from Alzheimer’s Disease (even if it’s tangential). From the May 24, 2013 news item on ScienceDaily,

Prof. Sakaguchi and his team in Graduate School of Science, Hokkaido University,jointly with MANA PI Prof. Kohei Uosaki and a research group from the University of California, Santa Barbara, have successfully developed a new technique for efficiently creating functionalized nanowires for the first time ever.

The group focused on the natural propensity of amyloid peptides, molecules which are thought to cause Alzheimer’s disease, to self-assemble into nanowires in an aqueous solution and controlled this molecular property to achieve their feat.

The May 23, 2013 National Institute for Materials press release, which originated the news item, offers insight into why functionalized nanowires are devoutly desired,

Functionalized nanowires are extremely important in the construction of nanodevices because they hold promise for use as integrated circuits and for the generation of novel properties, such as conductivity, catalysts and optical properties which are derived from their fine structure. However, some have remarked on the technical and financial limitations of the microfabrication technology required to create these structures. Meanwhile, molecular self-organization and functionalization have attracted attention in the field of next-generation nanotechnology development. Amyloid peptides, which are thought to cause Alzheimer’s disease, possess the ability to self-assemble into highly stable nanowires in an aqueous solution. Focusing on this, the research team became the first to successfully develop a new method for efficiently creating a multifunctional nanowire by controlling this molecular property.

The team designed a new peptide called SCAP, or structure-controllable amyloid peptide, terminated with a three-amino-acid-residue cap. By combining multiple SCAPs with different caps, the team found that self-organization is highly controlled at the molecular level. Using this new control method, the team formed a molecular nanowire with the largest aspect ratio ever achieved. In addition, they made modifications using various functional molecules including metals, semiconductors and biomolecules that successfully produced an extremely high quality functionalized nanowire. Going forward, this method is expected to contribute significantly to the development of new nanodevices through its application to a wide range of functional nanomaterials with self-organizing properties.

You can find the published paper here,

Formation of Functionalized Nanowires by Control of Self-Assembly Using Multiple Modified Amyloid Peptides by Hiroki Sakai, Ken Watanabe, Yuya Asanomi, Yumiko Kobayashi, Yoshiro Chuman, Lihong Shi, Takuya Masuda, Thomas Wyttenbach, Michael T. Bowers, Kohei Uosaki, & Kazuyasu Sakaguchi1. Advanced Functional Materials. doi: 10.1002/adfm.201300577 Article first published online: 23 APR 2013

The study is behind a paywall.

I have written about nanowires before and, in keeping with today’s theme of peculiar relationships  (Alzheimer’s disease), prior to this, the most unusual nanowire item I’ve come across had to do with growing them to the sounds  of music. From the Nanotech Mysteries (wiki), Scientists get musical page (Note: Footnotes have been removed),

After testing Deep Purple’s ‘Smoke on the Water‘, Chopin’s ‘Nocturne Opus 9 no. 1‘, Josh Abraham’s ‘Addicted to Bass‘, Rammstein’s ‘Das Model‘, and Abba’s ‘Dancing Queen‘, David Parlevliet found that music can be used to grow nanowires but they will be kinky.

Scientists want to grow straight nanowires and one of the popular methods is to “[blast] a voltage through silane gas to produce a plasma that pulses on and off at 1000 times a second. Over time the process enables molecules from the gas to deposit on a glass slide in the form of a mesh of crystalline silicon nanowires.”

Parlevliet, a PhD student at Murdoch University in Perth, Australia, plugged in a music player instead of a pulse generator usually used for this purpose and observed the results. While there are no current applications for kinky nanowires, the Deep Purple music created the densest mesh. Rammstein’s music grew nanowires the least successfully. In his presentation to the Australian Research Council Nanotechnology Network Symposium in March 2008, Parlevliet concluded that music could become more important for growing nanowires if applications can be found for the kinky ones.

Self-assembling protein inspires University of Montreal’s researchers to smaller efforts

Protein folding doesn’t seem all that exciting to me and the notion that it might lead to self-assembled, living machines isn’t all that new (see my May 31, 2012 posting about a Living Foundries project). So the June 10, 2012 news item on Nanowerk left me with a flat feeling, initially,

Enabling bioengineers to design new molecular machines for nanotechnology applications is one of the possible outcomes of a study by University of Montreal researchers that was published in Nature Structural and Molecular Biology today (“Visualizing transient protein folding intermediates by tryptophan scanning mutagenesis” [behind a paywall]). The scientists have developed a new approach to visualize how proteins assemble, which may also significantly aid our understanding of diseases such as Alzheimer’s and Parkinson’s, which are caused by errors in assembly.

“In order to survive, all creatures, from bacteria to humans, monitor and transform their environments using small protein nanomachines made of thousands of atoms,” explained the senior author of the study, Prof. Stephen Michnick of the university’s department of biochemistry. “For example, in our sinuses, there are complex receptor proteins that are activated in the presence of different odor molecules. Some of those scents warn us of danger; others tell us that food is nearby.” Proteins are made of long linear chains of amino acids, which have evolved over millions of years to self-assemble extremely rapidly – often within thousandths of a split second – into a working nanomachine.

My ears pricked up when the talk turned to capturing images of action, which occurs in a “fleetingly short time,”

“To understand how a protein goes from a linear chain to a unique assembled structure, we need to capture snapshots of its shape at each stage of assembly said Dr. Alexis Vallée-Bélisle, first author of the study. “The problem is that each step exists for a fleetingly short time and no available technique enables us to obtain precise structural information on these states within such a small time frame. We developed a strategy to monitor protein assembly by integrating fluorescent probes throughout the linear protein chain so that we could detect the structure of each stage of protein assembly, step by step to its final structure.” The protein assembly process is not the end of its journey, as a protein can change, through chemical modifications or with age, to take on different forms and functions. “Understanding how a protein goes from being one thing to becoming another is the first step towards understanding and designing protein nanomachines for biotechnologies such as medical and environmental diagnostic sensors, drug synthesis or delivery,” Vallée-Bélisle said.

Here’s an image of protein self-assembly from the University of Montreal (Université de Montréal) website (Montréal, Québec, Canada),

Vallée-Bélisle and Michnick have developed a new approach to visualize how proteins assemble, which may also significantly aid our understanding of diseases such as Alzheimer's and Parkinson's, which are caused by errors in assembly. Here shown are two different assembly stages (purple and red) of the protein ubiquitin and the fluorescent probe used to visualize these stage (tryptophan: see yellow). Credit: Peter Allen

I would have liked a little more detail (e.g. how little time is there to capture the images?) but there isn’t always time either for the people who write these news releases or for me to follow up with questions. Given the huge political unrest amongst students over the proposed tuition fees and the Québec government’s attempts (sometimes described as draconian) to impose order, I’m impressed this news release was pulled together.