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Showing posts with label Nanotechnology. Show all posts
Showing posts with label Nanotechnology. Show all posts

Monday, 11 May 2020

Chemistry breakthrough could speed up drug development

Scientists have successfully developed a new technique to reliably grow crystals of organic soluble molecules from nanoscale droplets, unlocking the potential of accelerated new drug development.

Chemistry experts from Newcastle and Durham universities, working in collaboration with SPT Labtech, have grown the small crystals from nanoscale encapsulated droplets. Their innovative method, involving the use of inert oils to control evaporative solvent loss, has the potential to enhance the drug development pipeline.

Whilst crystallization of organic soluble molecules is a technique used by scientists all over the world, the ability to do so with such small quantities of analyte is ground-breaking.

Through the use of this new method, called Encapsulated Nanodroplet Crystallisation (ENaCt), the researchers have shown that hundreds of crystallisation experiments can be set up within a few minutes. Each experiment involves a few micrograms of molecular analyte dissolved in a few nanolitres of organic solvent and is automated, allowing for rapid set up of hundreds of unique experiments with ease. Concentration of these nanodroplet experiments results in the growth of the desired high quality single crystals that are suitable for modern X-ray diffraction analysis.

Publishing their findings in the journal Chem, the team, led by Drs Hall and Probert, of Newcastle University, UK, successfully developed a new approach to molecular crystallisation which allows access, within a few days, to high quality single crystals, whilst requiring only few milligrams of analyte.

Dr Hall, Senior Lecturer in Chemistry, Newcastle University, said: "We have developed a nanoscale crystallisation technique for organic-soluble small molecules, using high-throughput liquid-handling robotics to undertake multiple crystallisation experiments simultaneously with minimal sample requirements and high success rates.

"This new method has the potential to have far-reaching impact within the molecular sciences and beyond. Fundamental research will benefit from highly detailed characterisation of new molecules, such as natural products or complex synthetic molecules, by X-ray crystallography, whilst the development of new drugs by the pharmaceutical industry will be accelerated, through rapid access to characterised crystalline forms of new active pharmaceutical ingredients."

Understanding these new crystalline forms, known as polymorphs, is essential to the successful generation of new pharmaceutical agents and drugs. The ability to investigate these forms quickly and on a vast scale, whilst minimising the amount of analyte required, could be a key

Breakthrough enabled by the new ENaCT protocol.

Dr Paul Thaw from SPT Labtech, added: "Enabling this work to develop a novel high-throughput method for single crystal X-ray diffraction on mosquito® with the Newcastle team has been a pleasure. Having the ability to quickly screen organic soluble small molecules on the microgram scale will deliver valuable insight for both academic research and pharmaceutical drug design and validation."

Dr Probert, Senior Lecturer in Inorganic Chemistry and Head of Crystallography, Newcastle University, commented ." ..this new approach to crystallisation has the ability to transform the scientific landscape for the analysis of small molecules, not only in the drug discovery and delivery areas but also in the more general understanding of the crystalline solid state ..."

The whole team believe that the ENaCt methodology has the potential rewrite some of the preconceptions within the molecular sciences and beyond.


Andrew R. Tyler, Ronnie Ragbirsingh, Charles J. McMonagle, Paul G. Waddell, Sarah E. Heaps, Jonathan W. Steed, Paul Thaw, Michael J. Hall, Michael R. Probert.

Encapsulated Nanodroplet Crystallization of Organic-Soluble Small Molecules. 

Chem, 2020;

DOI: 10.1016/j.chempr.2020.04.009

Wednesday, 22 April 2020

World-first Memristor Devices Could Operate Like Brain Synapses

Only 10 years ago, scientists working on what they hoped would open a new frontier of neuromorphic computing could only dream of a device using miniature tools called memristors that would function/operate like real brain synapses.

But now a team at the University of Massachusetts Amherst has discovered, while on their way to better understanding protein nanowires, how to use these biological, electricity conducting filaments to make a neuromorphic memristor, or "memory transistor," device. It runs extremely efficiently on very low power, as brains do, to carry signals between neurons. Details are in Nature Communications.

As first author Tianda Fu, a Ph.D. candidate in electrical and computer engineering, explains, one of the biggest hurdles to neuromorphic computing, and one that made it seem unreachable, is that most conventional computers operate at over 1 volt, while the brain sends signals called action potentials between neurons at around 80 millivolts - many times lower. Today, a decade after early experiments, memristor voltage has been achieved in the range similar to conventional computer, but getting below that seemed improbable, he adds.

Fu reports that using protein nanowires developed at UMass Amherst from the bacterium Geobacter by microbiologist and co-author Derek Lovely, he has now conducted experiments where memristors have reached neurological voltages. Those tests were carried out in the lab of electrical and computer engineering researcher and co-author Jun Yao.

Yao says, "This is the first time that a device can function at the same voltage level as the brain. People probably didn't even dare to hope that we could create a device that is as power-efficient as the biological counterparts in a brain, but now we have realistic evidence of ultra-low power computing capabilities. It's a concept breakthrough and we think it's going to cause a lot of exploration in electronics that work in the biological voltage regime."

Lovely points out that Geobacter's electrically conductive protein nanowires offer many advantages over expensive silicon nanowires, which require toxic chemicals and high-energy processes to produce. Protein nanowires also are more stable in water or bodily fluids, an important feature for biomedical applications. For this work, the researchers shear nanowires off the bacteria so only the conductive protein is used, he adds.

Fu says that he and Yao had set out to put the purified nanowires through their paces, to see what they are capable of at different voltages, for example. They experimented with a pulsing on-off pattern of positive-negative charge sent through a tiny metal thread in a memristor, which creates an electrical switch.

They used a metal thread because protein nanowires facilitate metal reduction, changing metal ion reactivity and electron transfer properties. Lovely says this microbial ability is not surprising, because wild bacterial nanowires breathe and chemically reduce metals to get their energy the way we breathe oxygen.

As the on-off pulses create changes in the metal filaments, new branching and connections are created in the tiny device, which is 100 times smaller than the diameter of a human hair, Yao explains. It creates an effect similar to learning - new connections - in a real brain. He adds, "You can modulate the conductivity, or the plasticity of the nanowire-memristor synapse so it can emulate biological components for brain-inspired computing. Compared to a conventional computer, this device has a learning capability that is not software-based."

Fu recalls, "In the first experiments we did, the nanowire performance was not satisfying, but it was enough for us to keep going." Over two years, he saw improvement until one fateful day when his and Yao's eyes were riveted by voltage measurements appearing on a computer screen.

"I remember the day we saw this great performance. We watched the computer as current voltage sweep was being measured. It kept doing down and down and we said to each other, 'Wow, it's working.' It was very surprising and very encouraging."

Fu, Yao, Lovely and colleagues plan to follow up this discovery with more research on mechanisms, and to "fully explore the chemistry, biology and electronics" of protein nanowires in memristors, Fu says, plus possible applications, which might include a device to monitor heart rate, for example. Yao adds, "This offers hope in the feasibility that one day this device can talk to actual neurons in biological systems."


Fu, T., Liu, X., Gao, H., Ward, J. E., Liu, X., Yin, B., Wang, Z., Zhuo, Y., Walker, D. J. F., Joshua Yang, J., Chen, J., Lovley, D. R., & Yao, J. (2020).

Bioinspired bio-voltage memristors.

Nature Communications, 11(1), 1–10.

Friday, 17 April 2020

Making Big Data Processing More Energy Efficient Using Magnetic Circuits

The rapid progression of technology has led to a huge increase in energy usage to process the massive troves of data generated by devices. But researchers in the Cockrell School of Engineering at The University of Texas at Austin have found a way to make the new generation of smart computers more energy efficient.

Traditionally, silicon chips have formed the building blocks of the infrastructure that powers computers. But this research uses magnetic components instead of silicon and discovers new information about how the physics of the magnetic components can cut energy costs and requirements of training algorithms — neural networks that can think like humans and do things like recognize images and patterns.

"Right now, the methods for training your neural networks are very energy-intensive," said Jean Anne Incorvia, an assistant professor in the Cockrell School's Department of Electrical and Computer Engineering. "What our work can do is help reduce the training effort and energy costs."

The researchers' findings were published this week in IOP Nanotechnology. Incorvia led the study with first author and second-year graduate student Can Cui. Incorvia and Cui discovered that spacing magnetic nanowires, acting as artificial neurons, in certain ways naturally increases the ability for the artificial neurons to compete against each other, with the most activated ones winning out. Achieving this effect, known as “lateral inhibition,” traditionally requires extra circuitry within computers, which increases costs and takes more energy and space.

Incorvia said their method provides an energy reduction of 20 to 30 times the amount used by a standard back-propagation algorithm when performing the same learning tasks.

The same way human brains contain neurons, new-era computers have artificial versions of these integral nerve cells. Lateral inhibition occurs when the neurons firing the fastest are able to prevent slower neurons from firing. In computing, this cuts down on energy use in processing data.

Incorvia explains that the way computers operate is fundamentally changing. A major trend is the concept of neuromorphic computing, which is essentially designing computers to think like human brains. Instead of processing tasks one at a time, these smarter devices are meant to analyze huge amounts of data simultaneously. These innovations have powered the revolution in machine learning and artificial intelligence that has dominated the technology landscape in recent years.

This research focused on interactions between two magnetic neurons and initial results on interactions of multiple neurons. The next step involves applying the findings to larger sets of multiple neurons as well as experimental verification of their findings.


Can Cui, Otitoaleke Gideon Akinola, Naimul Hassan, Christopher Bennett, Matthew Marinella, Joseph Friedman, Jean Anne Currivan Incorvia.

Maximized Lateral Inhibition in Paired Magnetic Domain Wall Racetracks for Neuromorphic Computing.

Nanotechnology, 2020;

DOI: 10.1088/1361-6528/ab86e8

Friday, 3 April 2020

New Nanosensors could offer early detection of lung tumors

People who are at high risk of developing lung cancer, such as heavy smokers, are routinely screened with computed tomography (CT), which can detect tumors in the lungs. However, this test has an extremely high rate of false positives, as it also picks up benign nodules in the lungs.

Researchers at Massachusetts Institute of Technology (MIT) have developed a nanoparticle-based approach that allows the early diagnosis of lung cancer through a simple urine test. The strategy detects biomarkers resulting from the interaction of peptide-coated nanoparticles with disease-associated proteases in the tumor microenvironment.

Experiments in two different mouse models of lung cancer showed that the urine test could detect tumors as small as 2.8 mm3. The researchers hope that this type of noninvasive diagnosis could reduce the number of false positives associated with an existing test method, and help to detect more tumors in the early stages of the disease.

“If you look at the field of cancer diagnostics and therapeutics, there’s a renewed recognition of the importance of early cancer detection and prevention,” said study lead Sangeeta Bhatia, PhD, who is the John and Dorothy Wilson professor of health sciences and technology and electrical engineering and computer science, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science. “We really need new technologies that are going to give us the capability to see cancer when we can intercept it and intervene early.” Bhatia and colleagues report on development of the test in Science Translational Medicine Journal.

MIT engineers have developed nanoparticles that can be delivered to the lungs, where tumor-associated proteases cut peptides on the surface of the particles, releasing reporter molecules. Those reporters can be detected by a urine test.

Lung cancer is the most common cause of cancer-related death (25.3%) in the United States the authors wrote, and has a “dismal” five-year survival rate of 18.6%. Early detection is key, as the five-year survival rates are 6- to 13-fold higher in patients whose tumors are detected before they spread to distal sites in the body. People in the United States who are at high risk of developing lung cancer, such as heavy smokers, are routinely screened using low-dose computed tomography (LDCT), which can detect tumors in the lungs.

However, this test has an extremely high rate of false positives, as it also picks up benign nodules in the lungs. There is then a “considerable burden of complications incurred during unnecessary follow-up procedures,” the investigators stated, and the method isn’t routinely used in other countries. “As a result of these complications, screening by LDCT has not been widely adopted outside of the United States, and there is “an urgent need to develop diagnostic tests that increase the effectiveness of lung cancer screening.”

The approach taken by the MIT researchers is based on the use of what they call “activity-based sensors” that monitor for disease and intensify disease-associated signals, which can then be detected in urine. “Activity-based nanosensors leverage dysregulated protease activity to overcome the insensitivity of previous biomarker assays, amplifying disease-associated signals generated in the tumor microenvironment and providing a concentrated urine-based readout,” the team explained.

Bhatia’s lab has for several years been developing such nanoparticles that can detect cancer by interacting with proteases. These enzymes help tumor cells to escape their original locations by cutting through proteins of the extracellular matrix. To find the cancer-associated proteases Bhatia created nanoparticles coated with peptides that are targeted by the cancer-related proteases. The particles accumulate at tumor sites, where the peptides are cleaved, releasing biomarkers that can then be detected in a urine sample.

The Bhatia lab has previously developed sensors for colon and ovarian cancer, and in their new study, the researchers applied the technology to lung cancer, which kills about 150,000 people in the United States every year. They project that the test could be applied to confirm cancer in patients who have had a positive CT scan. These patients would commonly undergo a biopsy or other invasive test to search for lung cancer, but in some cases, this procedure can cause complications, so a noninvasive follow-up test could be useful to determine which patients actually need a biopsy, Bhatia said.

“The CT scan is a good tool that can see a lot of things,” she said. “The problem with it is that 95% of what it finds is not cancer, and right now you have to biopsy too many patients who test positive.”

To customize their sensors for lung cancer, the researchers analyzed data in The Cancer Genome Atlas, and identified proteases that are abundant in lung cancer. They created a panel of 14 peptide-coated nanoparticles that could interact with these enzymes.

The researchers then tested the sensors in two different genetic mouse models, “driven by either Kras/Trp53 (KP) mutations, or Eml4-Alk (EA) fusion,” that spontaneously develop lung cancer. To help prevent background noise that could come from other organs or the bloodstream, the researchers injected the particles directly into the animals’ airways. The researchers carried out their diagnostic test using the sensors at 5 weeks, 7.5 weeks, and 10.5 weeks after tumor growth began. To make the diagnoses more accurate, they used machine learning to train an algorithm to distinguish between data from mice that had tumors and from mice that did not.

Using this approach, the researchers found that they could accurately detect tumors in one of the mouse models as early as 7.5 weeks, when the tumors were only 2.8 mm3, on average. In the other strain of mice, tumors could be detected at 5 weeks. The sensors’ success rate was also comparable to or better than the success rate of CT scans performed at the same time points.

“Intrapulmonary administration of the nanosensors to a Kras- and Trp53-mutant lung adenocarcinoma mouse model confirmed the role of metalloproteases in lung cancer and enabled accurate detection of localized disease, with 100% specificity and 81% sensitivity,” they reported. “Furthermore, this approach generalized to an alternative autochthonous model of lung adenocarcinoma, where it detected cancer with 100% specificity and 95% sensitivity and was not confounded by lipopolysaccharide-driven lung inflammation.”

Importantly, the sensors could distinguish between early-stage cancer and noncancerous inflammation of the lungs, a common condition in smokers, and one of the reasons that CT scans produce so many false positives. “Activity-based nanosensors may have clinical utility as a rapid, safe, and cost-effective follow-up to LDCT, reducing the number of patients referred for invasive testing,” the authors concluded. “With further optimization and validation studies, activity-based nanosensors may one day provide an accurate, noninvasive, and radiation-free strategy for lung cancer testing.”

The authors acknowledged that their study was carried out in mouse models, which do not fully recapitulate human disease, and there were other study limitations that will need to be addressed. Clinical trials will be needed to fully validate the use of activity-based nanosensors for detecting lung cancer and distinguishing malignant from benign and extrapulmonary disease, they pointed out.

Bhatia envisions that the nanoparticle sensors could be used as a noninvasive diagnostic for people who get a positive result on a screening test, potentially eliminating the need for a biopsy. For use in humans, her team is working on a form of the particles that could be inhaled as a dry powder or through a nebulizer. Another possible application is using the sensors to monitor how well lung tumors respond to treatment, such as drugs or immunotherapies. “A great next step would be to take this into patients who have known cancer, and are being treated, to see if they’re on the right medicine,” Bhatia said.


Urinary detection of lung cancer in mice via noninvasive pulmonary protease profiling

Jesse D. Kirkpatrick, Andrew D. Warren, Ava P. Soleimany, Peter M. K. Westcott1, Justin C. Voog, Carmen Martin-Alonso, Heather E. Fleming, Tuomas Tammela, Tyler Jacks and Sangeeta N. Bhatia.

Science Translational Medicine  01 Apr 2020:
Vol. 12, Issue 537, eaaw0262

DOI: 10.1126/scitranslmed.aaw0262

Friday, 31 January 2020

Researchers have developed a nanoparticle to eat away plaque in the arteries

A new nanoparticle acting as a “Trojan Horse” makes it possible to target and literally gnaw at portions of arterial plaques of atheroma often responsible for heart attacks. This discovery may well be a potential future treatment for atherosclerosis, a disease that kills many people around the world.

How does it work? The nanoparticle is housed on the atherosclerotic plate because of its high selectivity for a specific type of immune cell: monocytes and macrophages.

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The team designed these nano particles that could specifically target the atherosclerotic plaques clogging up the heart arteries. The nano particles are microscopic carbon tubules, the team explained. These tubules contain a special drug called the SHP1 inhibitor.

These plaques normally are made up of platelets and cholesterol deposits and are teeming with immune cells. These nano particles are taught to target monocytes and macrophages, which are immune cells commonly found in the plaques. These smart particles then reach within the plaques and take with them the drug agent SPH1 inhibitor. This agent then stimulates the immune cells so that they break down and engulf the broken pieces of the plaques. Thus, the arteries are cleared of the plaques with the nanocarriers carrying in the plaque busting drugs. The plaque size could be reduced remarkably say the researchers and this could reduce the risk of heart attacks that is one of the leading killers around the world.

Within the macrophases inside the plaques, there is a signalling pathway called the SHP1 pathway/ This pathway normally prevents the cells from eating up dead cells or debris or apoptosis. These debris are created within the cores of the plaques, wrote the researchers. If the signalling pathway is blocked, the macrophages go on a killing and engulfing spree and thus clear the debris left by the broken plaques.

A typical feature of an atherosclerotic plaque, wrote the researchers is accumulation of the dead cells and debris within the core of the plaque. This becomes then the “necrotic core”. If the necrotic core is not cleared, the plaque rupture can clog the arteries and lead to the heart attack says the researchers. At present there are therapies that could clear the apoptotic cells. However these therapies could also harm the healthy cells around the plaque. This novel method of nanoparticle carrier delivery of the drugs with the core thus could help protect the surrounding healthy cells and work specifically within the core.

The white dotted line describes the atherosclerotic artery and the green areas represent the nanoparticles found in the plate. Red indicates macrophages (the type of cells that nanoparticles stimulate). Credit: Michigan State

Previous studies had already made it possible to act on the surface of cells, but this new approach works intracellularly and has proven effective in stimulating macrophages.

"We have discovered that we can stimulate macrophages to selectively kill dead and dying cells (these inflammatory cells are precursors to atherosclerosis) which are common causes of heart attack," says Smith. "We could deliver a small molecule inside the macrophages to 'order' them to start eliminating said cells again," he adds.

According to Smith, this approach would also have applications beyond atherosclerosis: “We were able to marry a revolutionary discovery concerning atherosclerosis, with the cutting edge selectivity and delivery capabilities of our advanced nanomaterials platform. We have shown that nanomaterials are able to selectively search and send a message to the necessary cells ,” he said. “This gives particular energy to our future work, which will include clinical trials with these nanomaterials, using large animal models and human tissue tests. We think it will be more beneficial than the previous methods,” he added.


Article: Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis

Alyssa M. Flores, Niloufar Hosseini-Nassab, Kai-Uwe Jarr, Jianqin Ye, Xingjun Zhu, Robert Wirka, Ai Leen Koh, Pavlos Tsantilas, Ying Wang, Vivek Nanda, Yoko Kojima, Yitian Zeng, Mozhgan Lotfi, Robert Sinclair, Irving L. Weissman, Erik Ingelsson, Bryan Ronain Smith & Nicholas J. Leeper

Nature Nanotechnology (2020)

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