Tag Archives: Japan Science and Technology Agency

May 28, 2018 release date for inorganic material database ‘AtomWork-Adv’

Announced in a May 23, 2018 news item on Nanowerk,

[Japan National Institute for Materials Science] NIMS will make its inorganic materials database, AtomWork-Adv (pronounced “atom work advanced”), available to the general public as a fee-based service starting Monday, May 28, 2018. This service will be provided by the Data Platform from the Center for Materials Research by Information Integration (CMI2), Research and Services Division of the Materials Data and Integrated System (MaDIS), NIMS.

A May 23, 2018 NIMS press release, which originated the news item, fills out the details (Note: Paragraph 1 is largely repetitive but there is contact information in there),

  1. NIMS will make its inorganic materials database, “AtomWork-Adv” (pronounced “atom work advanced”), available to the general public as a fee-based service starting Monday, May 28, 2018. This service will be provided by the Data Platform (Yibin Xu, Director) from the Center for Materials Research by Information Integration (CMI2), Research and Services Division of the Materials Data and Integrated System (MaDIS), NIMS. AtomWork-Adv markedly improves upon the amount of data available and the usability of the current web-based “AtomWork” database. We hope that this service will promote data-driven materials development using AI and machine learning.
  2. The increasingly popular use of AI and machine learning in materials development requires a high-quality materials database. NIMS publicized the AtomWork inorganic materials database—constructed using literature published up to 2002—on its MatNavi webpage (http://mits.nims.go.jp/index.html). While AtomWork is available free of charge, the data it contains is not updated and its functions, such as allowing users to copy, download and search data, are limited.
  3. The AtomWork-Adv database compiles crystal structure data (approx. 274,000 datasets), X-ray diffraction data (approx. 496,000 datasets), material properties data (approx. 298,000 datasets) and phase diagram data (approx. 40,000 datasets) collected from literature published up to 2014. The number of datasets in these categories are about three to five times greater than those in the Atom Work database. In addition, AtomWork-Adv is equipped with user-friendly functions, such as a versatile search tool which enables searches by element, composition, crystal structure and material property, a matrix function which identifies the number of datasets available for a specific binary material combination and an automatic charting function which allows the plotting of a graph between two material property variables and which displays material names in relation to these variables. Users can download data for use in data science-driven materials research and development (the number of downloads is restricted).
  4. Data will be continuously added to and updated in the fee-based AtomWork-Adv database. We are planning to add new data collected from literature between 2015 and 2016 to the database during FY2018.
  5. This database project was supported by the “Materials Research by Information Integration” Initiative (MI2I) sponsored by the Japan Science and Technology Agency (JST)’s Support Program for Starting up Innovation Hub.

Happy atom hunting!

CRISPR-CAS9 and gold

As so often happens in the sciences, now that the initial euphoria has expended itself problems (and solutions) with CRISPR ((clustered regularly interspaced short palindromic repeats))-CAAS9 are being disclosed to those of us who are not experts. From an Oct. 3, 2017 article by Bob Yirka for phys.org,

A team of researchers from the University of California and the University of Tokyo has found a way to use the CRISPR gene editing technique that does not rely on a virus for delivery. In their paper published in the journal Nature Biomedical Engineering, the group describes the new technique, how well it works and improvements that need to be made to make it a viable gene editing tool.

CRISPR-Cas9 has been in the news a lot lately because it allows researchers to directly edit genes—either disabling unwanted parts or replacing them altogether. But despite many success stories, the technique still suffers from a major deficit that prevents it from being used as a true medical tool—it sometimes makes mistakes. Those mistakes can cause small or big problems for a host depending on what goes wrong. Prior research has suggested that the majority of mistakes are due to delivery problems, which means that a replacement for the virus part of the technique is required. In this new effort, the researchers report that they have discovered just a such a replacement, and it worked so well that it was able to repair a gene mutation in a Duchenne muscular dystrophy mouse model. The team has named the new technique CRISPR-Gold, because a gold nanoparticle was used to deliver the gene editing molecules instead of a virus.

An Oct. 2, 2017 article by Abby Olena for The Scientist lays out the CRISPR-CAS9 problems the scientists are trying to solve (Note: Links have been removed),

While promising, applications of CRISPR-Cas9 gene editing have so far been limited by the challenges of delivery—namely, how to get all the CRISPR parts to every cell that needs them. In a study published today (October 2) in Nature Biomedical Engineering, researchers have successfully repaired a mutation in the gene for dystrophin in a mouse model of Duchenne muscular dystrophy by injecting a vehicle they call CRISPR-Gold, which contains the Cas9 protein, guide RNA, and donor DNA, all wrapped around a tiny gold ball.

The authors have made “great progress in the gene editing area,” says Tufts University biomedical engineer Qiaobing Xu, who did not participate in the work but penned an accompanying commentary. Because their approach is nonviral, Xu explains, it will minimize the potential off-target effects that result from constant Cas9 activity, which occurs when users deliver the Cas9 template with a viral vector.

Duchenne muscular dystrophy is a degenerative disease of the muscles caused by a lack of the protein dystrophin. In about a third of patients, the gene for dystrophin has small deletions or single base mutations that render it nonfunctional, which makes this gene an excellent candidate for gene editing. Researchers have previously used viral delivery of CRISPR-Cas9 components to delete the mutated exon and achieve clinical improvements in mouse models of the disease.

“In this paper, we were actually able to correct [the gene for] dystrophin back to the wild-type sequence” via homology-directed repair (HDR), coauthor Niren Murthy, a drug delivery researcher at the University of California, Berkeley, tells The Scientist. “The other way of treating this is to do something called exon skipping, which is where you delete some of the exons and you can get dystrophin to be produced, but it’s not [as functional as] the wild-type protein.”

The research team created CRISPR-Gold by covering a central gold nanoparticle with DNA that they modified so it would stick to the particle. This gold-conjugated DNA bound the donor DNA needed for HDR, which the Cas9 protein and guide RNA bound to in turn. They coated the entire complex with a polymer that seems to trigger endocytosis and then facilitate escape of the Cas9 protein, guide RNA, and template DNA from endosomes within cells.

In order to do HDR, “you have to provide the cell [with] the Cas9 enzyme, guide RNA by which you target Cas9 to a particular part of the genome, and a big chunk of DNA, which will be used as a template to edit the mutant sequence to wild-type,” explains coauthor Irina Conboy, who studies tissue repair at the University of California, Berkeley. “They all have to be present at the same time and at the same place, so in our system you have a nanoparticle which simultaneously delivers all of those three key components in their active state.”

Olena’s article carries on to describe how the team created CRISPR-Gold and more.

Additional technical details are available in an Oct. 3, 2017 University of California at Berkeley news release by Brett Israel (also on EurekAlert), which originated the news item (Note: A link has been removed) ,

Scientists at the University of California, Berkeley, have engineered a new way to deliver CRISPR-Cas9 gene-editing technology inside cells and have demonstrated in mice that the technology can repair the mutation that causes Duchenne muscular dystrophy, a severe muscle-wasting disease. A new study shows that a single injection of CRISPR-Gold, as the new delivery system is called, into mice with Duchenne muscular dystrophy led to an 18-times-higher correction rate and a two-fold increase in a strength and agility test compared to control groups.

Diagram of CRISPR-Gold

CRISPR–Gold is composed of 15 nanometer gold nanoparticles that are conjugated to thiol-modified oligonucleotides (DNA-Thiol), which are hybridized with single-stranded donor DNA and subsequently complexed with Cas9 and encapsulated by a polymer that disrupts the endosome of the cell.

Since 2012, when study co-author Jennifer Doudna, a professor of molecular and cell biology and of chemistry at UC Berkeley, and colleague Emmanuelle Charpentier, of the Max Planck Institute for Infection Biology, repurposed the Cas9 protein to create a cheap, precise and easy-to-use gene editor, researchers have hoped that therapies based on CRISPR-Cas9 would one day revolutionize the treatment of genetic diseases. Yet developing treatments for genetic diseases remains a big challenge in medicine. This is because most genetic diseases can be cured only if the disease-causing gene mutation is corrected back to the normal sequence, and this is impossible to do with conventional therapeutics.

CRISPR/Cas9, however, can correct gene mutations by cutting the mutated DNA and triggering homology-directed DNA repair. However, strategies for safely delivering the necessary components (Cas9, guide RNA that directs Cas9 to a specific gene, and donor DNA) into cells need to be developed before the potential of CRISPR-Cas9-based therapeutics can be realized. A common technique to deliver CRISPR-Cas9 into cells employs viruses, but that technique has a number of complications. CRISPR-Gold does not need viruses.

In the new study, research lead by the laboratories of Berkeley bioengineering professors Niren Murthy and Irina Conboy demonstrated that their novel approach, called CRISPR-Gold because gold nanoparticles are a key component, can deliver Cas9 – the protein that binds and cuts DNA – along with guide RNA and donor DNA into the cells of a living organism to fix a gene mutation.

“CRISPR-Gold is the first example of a delivery vehicle that can deliver all of the CRISPR components needed to correct gene mutations, without the use of viruses,” Murthy said.

The study was published October 2 [2017] in the journal Nature Biomedical Engineering.

CRISPR-Gold repairs DNA mutations through a process called homology-directed repair. Scientists have struggled to develop homology-directed repair-based therapeutics because they require activity at the same place and time as Cas9 protein, an RNA guide that recognizes the mutation and donor DNA to correct the mutation.

To overcome these challenges, the Berkeley scientists invented a delivery vessel that binds all of these components together, and then releases them when the vessel is inside a wide variety of cell types, triggering homology directed repair. CRISPR-Gold’s gold nanoparticles coat the donor DNA and also bind Cas9. When injected into mice, their cells recognize a marker in CRISPR-Gold and then import the delivery vessel. Then, through a series of cellular mechanisms, CRISPR-Gold is released into the cells’ cytoplasm and breaks apart, rapidly releasing Cas9 and donor DNA.

Schematic of CRISPR-Gold's method of action

CRISPR-Gold’s method of action (Click to enlarge).

A single injection of CRISPR-Gold into muscle tissue of mice that model Duchenne muscular dystrophy restored 5.4 percent of the dystrophin gene, which causes the disease, to the wild- type, or normal, sequence. This correction rate was approximately 18 times higher than in mice treated with Cas9 and donor DNA by themselves, which experienced only a 0.3 percent correction rate.

Importantly, the study authors note, CRISPR-Gold faithfully restored the normal sequence of dystrophin, which is a significant improvement over previously published approaches that only removed the faulty part of the gene, making it shorter and converting one disease into another, milder disease.

CRISPR-Gold was also able to reduce tissue fibrosis – the hallmark of diseases where muscles do not function properly – and enhanced strength and agility in mice with Duchenne muscular dystrophy. CRISPR-Gold-treated mice showed a two-fold increase in hanging time in a common test for mouse strength and agility, compared to mice injected with a control.

“These experiments suggest that it will be possible to develop non-viral CRISPR therapeutics that can safely correct gene mutations, via the process of homology-directed repair, by simply developing nanoparticles that can simultaneously encapsulate all of the CRISPR components,” Murthy said.

CRISPR-Cas9

CRISPR in action: A model of the Cas9 protein cutting a double-stranded piece of DNA

The study found that CRISPR-Gold’s approach to Cas9 protein delivery is safer than viral delivery of CRISPR, which, in addition to toxicity, amplifies the side effects of Cas9 through continuous expression of this DNA-cutting enzyme. When the research team tested CRISPR-Gold’s gene-editing capability in mice, they found that CRISPR-Gold efficiently corrected the DNA mutation that causes Duchenne muscular dystrophy, with minimal collateral DNA damage.

The researchers quantified CRISPR-Gold’s off-target DNA damage and found damage levels similar to the that of a typical DNA sequencing error in a typical cell that was not exposed to CRISPR (0.005 – 0.2 percent). To test for possible immunogenicity, the blood stream cytokine profiles of mice were analyzed at 24 hours and two weeks after the CRISPR-Gold injection. CRISPR-Gold did not cause an acute up-regulation of inflammatory cytokines in plasma, after multiple injections, or weight loss, suggesting that CRISPR-Gold can be used multiple times safely, and that it has a high therapeutic window for gene editing in muscle tissue.

“CRISPR-Gold and, more broadly, CRISPR-nanoparticles open a new way for safer, accurately controlled delivery of gene-editing tools,” Conboy said. “Ultimately, these techniques could be developed into a new medicine for Duchenne muscular dystrophy and a number of other genetic diseases.”

A clinical trial will be needed to discern whether CRISPR-Gold is an effective treatment for genetic diseases in humans. Study co-authors Kunwoo Lee and Hyo Min Park have formed a start-up company, GenEdit (Murthy has an ownership stake in GenEdit), which is focused on translating the CRISPR-Gold technology into humans. The labs of Murthy and Conboy are also working on the next generation of particles that can deliver CRISPR into tissues from the blood stream and would preferentially target adult stem cells, which are considered the best targets for gene correction because stem and progenitor cells are capable of gene editing, self-renewal and differentiation.

“Genetic diseases cause devastating levels of mortality and morbidity, and new strategies for treating them are greatly needed,” Murthy said. “CRISPR-Gold was able to correct disease-causing gene mutations in vivo, via the non-viral delivery of Cas9 protein, guide RNA and donor DNA, and therefore has the potential to develop into a therapeutic for treating genetic diseases.”

The study was funded by the National Institutes of Health, the W.M. Keck Foundation, the Moore Foundation, the Li Ka Shing Foundation, Calico, Packer, Roger’s and SENS, and the Center of Innovation (COI) Program of the Japan Science and Technology Agency.

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

Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair by Kunwoo Lee, Michael Conboy, Hyo Min Park, Fuguo Jiang, Hyun Jin Kim, Mark A. Dewitt, Vanessa A. Mackley, Kevin Chang, Anirudh Rao, Colin Skinner, Tamanna Shobha, Melod Mehdipour, Hui Liu, Wen-chin Huang, Freeman Lan, Nicolas L. Bray, Song Li, Jacob E. Corn, Kazunori Kataoka, Jennifer A. Doudna, Irina Conboy, & Niren Murthy. Nature Biomedical Engineering (2017) doi:10.1038/s41551-017-0137-2 Published online: 02 October 2017

This paper is behind a paywall.

Smectic liquid crystals

From an April 10, 2015 news release from the Tokyo Institute of Technology,

Researchers at Tokyo Institute of Technology have designed a smectic liquid crystal that overcomes many of the challenges posed by organic field effect transistor materials.

Crystalline organic semiconductors have attracted a lot of interest for convenient low-cost fabrication by printed electronics. However progress has been stymied by the low thermal durability and reproducibility of these materials. Now researchers at Tokyo Institute of Technology and the Japan Science and Technology Agency have designed a liquid crystal molecule that produces high-performance organic field effect transistors (FETs) with good temperature resilience and relatively low device variability in addition to high mobility.

Hiroaki Iino, Takayuki Usui and Jun-ichi Hanna designed a molecule that would incorporate a number of desirable liquid crystal qualities, in particular the smectic E phase. Low ordered liquid crystal phases form droplets at their melting temperature, but the smectic E phase has the advantage of retaining the thin-film shape.

They then fabricated organic FETs by spin coating a solution of their material at 110 °C before allowing it to cool. Comparison of the FET characteristics before and after mild annealing revealed a phase transition. Using atomic force microscopy the researchers identified that at around 120°C in the crystal formed a bilayer crystal phase.

The mobility of a bottom gated FET made from the material was around 12 cm2V-1s-1 comparable to single-crystal devices. “Considering that it could potentially be necessary to fabricate millions of FETs for display applications, polycrystalline OFETs may have an advantage over single-crystal OFETs,” point out the researchers in a report of the work. The devices also exhibited a minimal variability of just 1.2 cm2V-1s-1, which is likely an advantage from the smoothness of the obtained film.

The researchers conclude, “The discovery of a dramatic enhancement of FET mobility up to 13.9cm2V-1s-1, resulting from the phase transition from a monolayer to a bilayer crystal structure in mono-alkylated liquid crystalline molecules may lead to the possibility of designing new materials for the burgeoning field of printed electronics.”

Background

Small-molecule versus polymer FETs

The main issues around organic semiconductor FETs with small molecules are the low thermal durability. The same bonding that makes the molecules soluble for printing fabrication processes also leaves them prone to low melting points, which greatly inhibits the methods available for processing the materials. They also tend to form rough surfaces, which makes it difficult to reproducibly fabricate the devices that have the desired characteristics.

Attempts to use polymers with benzene-like delocalised electron bonding alleviated issues around the thermal durability to a certain extent. However, it exacerbated others, such as reproducible synthesis and purification of the polymers, as well as control of crystallinity and the molecular orientations towards both the substrate surface and the electrodes.

The design of the molecule

The researchers identified specific characteristics to enrol in the design of their molecule. They used a fused ring system of molecules with benzene-like delocalised electron bonding so that the material would readily crystallise. They then added a phenyl group to introduce the kind of disorder required for smectic E phase liquid crystals. A long flexible carbon chain was also added to encourage formation of a liquid crystal.

The molecule was also designed to have a single side chain so that crystallisation on cooling would be lower than that on heating. This is more convenient for fabrication processes with the material.

The phase transition

Studies of the field effect transistors before and after mild annealing revealed an improvement in carrier mobility by over an order of magnitude. The researchers concluded that the material underwent a phase transition between 70 °C and 120 °C. Improvements in device performance plateaued above 120 °C.

Atomic force microscope studies of the materials identified a step structure that changed from monolayer 2.8 nm steps to bilayer 5.7 nm steps following the phase transition. In the absence of a change in grain size or contact resistance, the researchers concluded that  crystal-to-crystal phase change from a monolayer to a bilayer structure was responsible for the improved transistor performance in annealed devices.

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

Liquid crystals for organic thin-film transistors by Hiroaki Iino, Takayuki Usui & Jun-ichi Hanna. Nature Communications 6, Article number: 6828 doi:10.1038/ncomms7828 Published 10 April 2015

This is an open access paper.

Nestling a two-element atomic chain inside a carbon nanotube

While there doesn’t seem to be a short-term application for this research from Japan, the idea of nestling a chain of two elements inside a carbon nanotube is intriguing, from an Oct. 16, 2014 news item on Nanowerk,

Kazutomo Suenaga of the Nanotube Research Center (NTRC) of the National Institute of Advanced Industrial Science and Technology (AIST) and Ryosuke Senga of the Nano-carbon Characterization Team, NTRC, AIST, have synthesized an atomic chain in which two elements are aligned alternately and have evaluated its physical properties on an atomic level.

An ionic crystalline atomic chain of cesium iodine (CsI) has been synthesized by aligning a cesium ion (Cs+), a cation and an iodine ion (I-), an anion, alternately by encapsulating CsI in the microscopic space inside a carbon nanotube. Furthermore, by using an advanced aberration-corrected electron microscope, the physical phenomena unique to the CsI atomic chain, such as the difference in dynamic behavior of its cations and anions, have been discovered. In addition, from theoretical calculation using density functional theory (DFT), this CsI atomic chain has been found to indicate different optical properties from a three-dimensional CsI crystal, and applications to new optical devices are anticipated.

An Oct. 16, 2014 National Institute of Advanced Industrial Science and Technology (AIST) press release, which originated the news item, situates the research within a social and historical context,

Social Background of Research

In the accelerating and ballooning information society, electronic devices used in computers and smartphones has constantly demanded higher performance and efficiency. The materials currently drawing expectations are low-dimensional materials with a single to few-atom width and thickness. Two-dimensional materials, typified by graphene, indicate unique physical characteristics not found in three-dimensional materials, such as its excellent electrical transport properties, and are being extensively researched.

An atomic chain, which has an even finer structure with a width of only one atom, has been predicted to display excellent electrical transport properties, like two-dimensional materials. Although expectations were higher than for two-dimensional materials from the viewpoint of integration, it had attracted little attention until now. This is because of the technological difficulties faced by the various processes of academic research from synthesis to analysis of atomic chains, and academic understanding has not progressed far (Fig. 1).

Figure 1
Figure 1 : Transition of target materials in material research

History of Research

AIST has been developing element analysis methods on a single-atom level to detect certain special structures including impurities, dopants and defects, that affect the properties of low-dimensional materials such as carbon nanotubes and graphene (AIST press releases on July 6, 2009, January 12, 2010, December 16, 2010 and July 9, 2012). In this research, efforts were made for the synthesis and analysis of the atomic chain, a low-dimensional material, using the accumulated technological expertise. This research has been supported by both the Strategic Basic Research Program of the Japan Science and Technology Agency (FY2012 to FY2016), and the Grants-in-aid for Scientific Research of the Japan Society for the Promotion of Science, “Development of elemental technology for the atomic-scale evaluation and application of low-dimensional materials using nano-space” (FY2014 to FY2016).

The press release also offers more details about the research and future applications,

Details of Research

The developed technology is the technology to expose carbon nanotubes, with a diameter of 1 nm or smaller, to CsI vapor to encapsulate CsI in the microscopic space inside the carbon nanotubes, to synthesize an atomic chain in which two elements, Cs and I, are aligned alternately. Furthermore, by combining aberration-corrected electron microscopy and an electronic spectroscopic technique known as electron energy-loss spectroscopy (EELS) detailed structural analysis of this atomic chain was conducted. In order to identify each atom aligned at a distance of 1 nm or less without destroying them, the accelerating voltage of the electron microscope was significantly lowered to 60 kV to reduce damage to the sample by electron beams, while maintaining sufficient spatial resolution of around 1 nm. Figure 2 indicates the smallest CsI crystal confirmed so far, and the CsI atomic chain synthesized in this research.

Figure 2
Figure 2 : Comparison of CsI atomic chain and CsI crystal
(Top: Actual annular dark-field images, Bottom: Corresponding models)

Figure 3 shows the annular dark-field (ADF) image of the CsI atomic chain and the element mapping for Cs and I, respectively, obtained by EELS. It can be seen that the two elements are aligned alternately. There has not been any report of this simple and ideal structure actually being produced and observed, and it can be said to be a fundamental, important finding in material science.

Normally, in an ADF image, those with larger atomic numbers appear brighter. However, in this CsI atomic chain, I (atomic number 53) appears brighter than Cs (atomic number 55). This is because Cs, being a cation, moves more actively (more accurately, the total amount of electrons scattered by the Cs atom is not very different from those of the I atom, but the electrons scattered by the moving Cs atom generate spatial expansion), indicating a difference in dynamic behavior of the cation and the anion that cannot occur in a large three-dimensional crystal. Locations where single Cs atom or I atom is absent, namely vacancies, were also found (Fig. 3, right).

The unique behavior and structure influence various physical properties. When optical absorption spectra were calculated using DFT, the response of the CsI atomic chain to light differed with the direction of incidence. Furthermore, it was found that in a CsI atomic chain with vacancies, the electron state of vacancy sites where the I atom is absent possess a donor level at which electrons were easily released, while vacancy sites where the Cs atom is absent possess a receptor level at which electrons were easily received. By making use of these physical properties, applications to new electro-optical devices, such as a micro-light source and an optical switch using light emission from a single vacancy in the CsI atomic chain, are conceivable. In addition, further research into combinations of other elements triggered by the present results may lead to the development of new materials and device applications. There are expectations for atomic chains to be the next-generation materials for devices in search of further miniaturization and integration.

Figure 3
Figure 3 : Synthesized CsI atomic chain, encapsulated in double-walled carbon nanotube
(From left: ADF image, element maps for Cs and I, model, ADF image of CsI atomic chains with vacancies)

Future Plans

Since the CsI atomic chain displays optical properties significantly different from large crystals that can be seen by the human eye, there are expectations for its application for new electro-optical devices such as a micro-light source and an optical switch using light emission from a single vacancy in the CsI atomic chain. The researchers will conduct experimental research in its application, focused on detailed study of its various physical properties, starting with its optical properties. In addition to CsI, efforts will also be made in the development of new materials that combine various elements, by applying this technology to other materials.

Furthermore, the mechanism of all adsorbents of radioactive substances (carbon nanotubes, zeolite, Prussian blue, etc.) currently being developed for commercial use are methods of encapsulating radioactive atoms inside microscopic space in the material. The researchers hope to utilize the knowledge of the behavior of the Cs atom in a microscopic space obtained in this research, to improve adsorption performance.

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

Atomic structure and dynamic behaviour of truly one-dimensional ionic chains inside ​carbon nanotubes by Ryosuke Senga, Hannu-Pekka Komsa, Zheng Liu, Kaori Hirose-Takai, Arkady V. Krasheninnikov, & Kazu Suenaga. Nature Materials (2014) doi:10.1038/nmat4069 Published online 14 September 2014

This paper is behind a paywall.