Quantum Computing: Keio University launches IBM Q Network Hub
Source: Keio University Research Highlights
30 July 2018 Keio University is the only host in Asia of the IBM Q Hub for quantum computing.
On 17 May 2018 Keio University announced the launch of the IBM Q Network Hub at its Yagami Campus in Yokohama. "This is the first IBM Q Hub in Asia configured and authorized to access the IBMQ cloud computing system," says Naoki Yamamoto, an associate professor and the chair of the Keio University Quantum Computing Center. "We are building on Keio University's 20 years of expertise in quantum computing to work with specialists at IBM to support academic and industrial organizations to discover and harness the power of quantum computing for both scientific and business applications." The first four industrial partners in Japan to join the IBM Q Hub are JSR Corporation, MUFG Bank, Mizuho Financial Group, and Mitsubishi Chemical Corporation.
To date IBM has offered free access to its IBM Q 5 qubit system, enabling more than 50,000 users from over 150 academic institutes worldwide to undertake over 1.5 million experiments and produce more than 25 research publications.
Meanwhile, members of the Keio University IBM Q Network Hub are able to access IBM Q's commercial 20 qubit cloud system, and will in future also be able to access a 50-qubit IBM Q system.
The Keio University IBM Q Hub is part of a network of six IBM Q Hubs across the world. The others are located at IBM Research (USA), Oak Ridge National Laboratory (USA), The University of Oxford (UK), North Carolina State University (USA), and The University of Melbourne (Australia). The hubs provide access to IBM Q systems, technical support, educational resources, and networking for collaborative research.
Members of the Keio hub have multidisciplinary backgrounds and include researchers from private industry, specialists hired to work at the hub, and Keio University students and researchers, including overseas invited researchers.
"Education and nurturing the next generation of experts in quantum computing, or 'Quantum Natives' is a major goal for us," says Yamamoto. "We are organizing programs for both our domestic and international students to use the IBM Q Hub for writing algorithms. We have high expectations."
Entrance to the common room at the IBM Q Network Hub at Keio University's Yagami Campus in Yokohama.
Kanazawa University research: High-precision on-site analysis of precious metals in metallurgical waste spills
Source: Kanazawa University
(Kanazawa, 27 July 2018) Researchers from Kanazawa University report in Sensors and Actuators B: Chemical the application of a portable and efficient method for the on-site analysis of wastewaters for the quantitative analysis of their gold, platinum and palladium content.
Precious metals come in limited supply but are in high demand. They are mainly sourced through mining, but the possibility of recycling them from metallurgical waste leachates (waters that have passed through the treated materials during mineral processing and thus contain some of the compounds present in the minerals) is attracting growing attention. To this end, compact and portable instruments to perform the analysis of wastewaters in on-field rapid analysis are highly desirable to improve the efficiency of the recovery of precious metals.
Liquid-electrode plasma–optical emission spectrometry (LEP–OES) has emerged as a tool to implement on-site analysis of elements in aqueous matrices, as it is portable and much less costly than traditional methods. However, when the concentration of noble metals is very low, as is the case for precious metals in waste spills, the sensitivity of the technique become insufficient to produce accurate analysis — one of the problems is that in metallurgical waste leachates there are several ions that interfere with the analysis. In this case, analyte separation and enrichment steps (that is, steps that remove other substances and increase the concentration of the analyte to make detection easier) have to be included in the analysis of the samples for accurate detection of the precious metals.
This is what Suman Barua, Ismail M.M. Rahman, Hiroshi Hasegawa and colleagues from Kanazawa University and Fukushima University did, reporting the first application of LEP-OES in combination with a solid-phase extraction (SPE) system (which is used as the pre-treatment step to eliminate the competing ions and to enrich the noble metals) for the rapid on-site simultaneous analysis of the precious metals gold, palladium and platinum. The SPE parameters were optimized to maximize retention and recovery of the precious metals; the LEP-OES parameters to maximize the emission peaks for the individual elements.
The method was tested both on certified reference material for wastewater and on real aqueous waste samples, from which more than 95% of the precious metals were recovered. The high-precision on-site measurements could be performed in less than 15 minutes, opening the way to practical analysis of the precious metal content of wastewaters.
Suman Barua, Ismail M.M. Rahman, Maho Miyaguchi, Asami S. Mashio, Teruya Maki, Hiroshi Hasegawa, On-site analysis of gold, palladium, or platinum in acidic aqueous matrix using liquid electrode plasma-optical emission spectrometry combined with ion-selective preconcentration. Sensors and Actuators B: Chemical, 272, 91−99 (2018)
Okayama University research: Role of commensal microbiota in bone remodeling
Source: Okayama University
(Okayama, 26 December) Researchers at Okayama University report in the journal Molecules that commensal microbiota — microorganisms present in the human body — may play a key role in human-bone remodeling by enhancing the activity of both cells breaking down bone tissue and cells synthesizing bone.
Humans are host to several types of microorganisms like bacteria, fungi and viruses. Those residing in the human body without harming it are collectively called commensal microbiota. While it has been established that commensal microbiota play an important role in the body’s energy management and the development of its immune system, recent findings have suggested that they affect the regulation of human bone formation too. Now, by performing comparative experiments on mice, Professor Manabu Morita, Yoko Uchida (D.D.S.) and colleagues from Okayama University confirmed the link between commensal microbiota and bone cell regulation. Specifically, they found that the presence of the microorganisms enhances the activity of both osteoclasts (cells that break down bone tissue) and osteoblasts (cells that synthesize bone).
Professor Morita and colleagues worked with two types of mouse: germ-free (GF) mice, free of any microorganisms, and specific-pathogen-free (SPF) mice, which are guaranteed to be free of certain pathogens but at the same time host to commensal microbiota.
The researchers investigated the activity of osteoclasts and osteoblasts in 8-week-old GF and SPF mice. They first looked at body weight and size. The SPF mice were found to have larger body size but lower bone mineral density in alveolar bones (the bones that contain the tooth sockets on the jaw bones), an observation attributed to the presence of commensal microbiota. In addition, by analyzing blood serum of the mice for substances that are associated with osteoclast activity, Professor Morita and colleagues were able to conclude that commensal microbiota cause greater development and activity of osteoclasts.
The scientists also discovered that the expression of osteocalcin messenger RNA— a maker of bone mineralization — is significantly higher in SPF mice, providing a further link between commensal microbiota and bone-remodeling processes.
While the precise mechanism of commensal microbiota affecting the expression of osteo-blast-specific genes such as osteocalcin needs to be further investigated in order to be completely understood, quoting Professor Morita and colleagues, “[these results] suggest that the commensal microbiota prevents excessive mineralization possibly by stimulating osteocalcin expression in osteoblasts, and enhances both osteoblast and osteoclast activity by regulating specific transcription factors.”
Reference
Yoko Uchida, Koichiro Irie, Daiki Fukuhara, Kota Kataoka, Takako Hattori, Mitsuaki Ono, Daisuke Ekuni, Satoshi Kubota, Manabu Morita. Commensal microbiota enhance both osteoclast and osteoblast activities. Molecules, 2018 Jun 23;23(7). pii: E1517.
DOI: 10.3390/molecules23071517.
https://www.mdpi.com/1420-3049/23/7/1517
Microtomography images of a part of the alveolar bone in germ-free (GF) and specific-pathogen-free (SPF) mice.
The latest issue of Juntendo Medical Journal is now available
Source: Juntendo Medical Society
Juntendo Medical Journal Vol. 64 (2018) No. 2 Published in April 2018
Juntendo Medical Journal (JMJ) is the official open access journal of the Juntendo Medical Society. JMJ aims to introduce achievements in the fields of Basic and Clinical medicine, Sportology (Sports Medicine), Nursing, Preventive Medicine and Public Health.
JMJ has the richest histories among Japanese medical journals, with our first issues published in the 8th year of the Meiji Era (1875) under the Japanese name Juntendo Iji Zasshi. This name continues to appear on each issue’s cover in smaller kanji characters under our English designation “Juntendo Medical Journal,” which dates back to 1955. To increase dissemination to the international medical community, in 2014 English became the required language for all articles published in JMJ.
To further drive the internationalization of JMJ and raise the quality of the articles we publish, the Juntendo Medical Journal accepts manuscripts over a wide area of medical topics from members of the Juntendo Medical Society as well as other researchers in Japan and around the world involved in medical science.
Discover more about JMJ at: https://www.jstage.jst.go.jp/browse/jmj
The latest issue of Juntendo Medical Journal is now available
Source: Juntendo Medical Society
Juntendo Medical Journal Vol. 64 (2018) No. 2 Published on 16 April 2018
Juntendo Medical Journal (JMJ) is the official open access journal of the Juntendo Medical Society. JMJ aims to introduce achievements in the fields of Basic and Clinical medicine, Sportology (Sports Medicine), Nursing, Preventive Medicine and Public Health.
JMJ has the richest histories among Japanese medical journals, with our first issues published in the 8th year of the Meiji Era (1875) under the Japanese name Juntendo Iji Zasshi. This name continues to appear on each issue’s cover in smaller kanji characters under our English designation “Juntendo Medical Journal,” which dates back to 1955. To increase dissemination to the international medical community, in 2014 English became the required language for all articles published in JMJ.
To further drive the internationalization of JMJ and raise the quality of the articles we publish, the Juntendo Medical Journal accepts manuscripts over a wide area of medical topics from members of the Juntendo Medical Society as well as other researchers in Japan and around the world involved in medical science.
Discover more about JMJ at: https://www.jstage.jst.go.jp/browse/jmj
Kanazawa University research: Gaining insight into the molecular mechanisms behind squamous cell cancer
Source: Kanazawa University
(Kanazawa, 13 December 2017) Researchers at Kanazawa University report in EMBO Reports, 7 December 2017, new molecular mechanisms regulating cellular fate of squamous cell carcinomas.
Squamous cell carcinoma (SCC) is a lethal cancer arising from the stratified epithelia of skin, esophagus, cervix, as well as the head and neck tissues. Genomic analysis of SCCs identified genomic amplification of TP63 in up to 30% of tumors, with overexpression of its mRNA in the majority of SCCs.
ΔNp63α, one of the proteins encoded by TP63, has an important role in the epithelial development and maintenance. In SCCs, DNp63a functions as a key transcriptional regulator of different gene subsets in order to maintain or enhance malignant phenotypes. However, the mechanism controlling the nuclear transport of this protein, were, up to now, unclear.
Nucleoporins (NUPs) are a family of proteins building nuclear pore complexes (NPC) and mediating nuclear transport across the nuclear envelope. Recent evidence suggests a cell-type-specific function for certain NUPs; however, the significance of NUPs in SCC biology remains unknown.
In the present study, Hazawa et al. show that one particular nucleoporin, nucleoporin 62 (NUP62), is highly expressed in stratified squamous epithelia, and is further elevated in SCCs.
They further demonstrate that depletion of NUP62 inhibits proliferation and augments differentiation of SCC cells, suggesting NUP62 is required for preventing epidermal differentiation of SCCs. The impaired ability to maintain the undifferentiated status is associated with defects in ΔNp63α nuclear transport. Finally, they unmasked the detailed traffic machinery where the pro-differentiation Rho kinase (an enzyme that catalyzes the transfer of phosphate groups) inhibits the nuclear transport of ΔNp63α by reducing the interaction between NUP62 and ΔNp63α.
This study demonstrates the role of NUP62 regulating cellular fate of SCCs through ΔNp63α nuclear transport. However, whether these NUPs regulates cell identity in different tissues (or in other types of cancer cells) is still an open question. As the authors comment in the paper: “Our finding of convertible trafficking activity of NUP62 highlights the potential for therapeutic targeting of nuclear transport of this oncogene.”
Notes
Squamous cell carcinoma (SCC): SCC is the cancerous growth of cells in the squamous cells, which include the cells in the upper layers of the skin (the epidermis). SCC is mainly caused by excessive exposure to ultraviolet light over the course of many years. SCCs may affect different part of the body, including the skin, the esophagus and the cervix, and is particularly common in the head and neck.
Nuclear pore complex: the nucleus of eukaryotic cells is surrounded by a double membrane separating it from the cytoplasm, the thick solution that fills cells. Nuclear pore complexes are large protein complexes that cross this membrane, allowing the transport of molecules. The proteins that make up the nuclear pore complex are called nucleoporins.
Rho-associated protein kinase (ROCK): a kinase (that is, an enzyme that catalyzes the transfer of phosphate groups) involved in regulating the shape and movement of cells by acting on the cytoskeleton.
Reference
Masaharu Hazawa, De-Chen Lin, Akiko Kobayashi, Yan-Yi Jiang, Liang Xu, Firli Rahmah Primula Dewi, Mahmoud Shaaban Mohamed, Hartono, Mitsutoshi Nakada, Makiko Meguro-Horike, Shin-ichi Horike, H. Phillip Koeffler, Richard W. Wong.
ROCK-dependent phosphorylation of NUP62 regulates p63 nuclear transport and squamous cell carcinoma proliferation, EMBO reports (2017) e201744523
Published online 7 December 2017
DOI: 10.15252/embr.201744523
Figure. Hypothetical model of NUP62 action in regulating cell fate.
This work was supported by Japan Society for the Promotion of Science (JSPS) the Grants-in-Aid for Scientific Research, World Premier International Research Center Initiative (WPI), MEXT, Japan, and Institute for Frontier Science Initiative, Kanazawa University.
(Tokyo, 15 February) Researchers at Juntendo University report in Neurology the potential use of blood levels of caffeine and its byproducts as biomarkers for Parkinson’s disease. The finding is promising for the development of a method enabling early identification of the disease.
Parkinson’s disease is a degenerative disorder of the central nervous system, affecting the latter’s motor system — the part controlling bodily motion. Its symptoms include shaking, rigidity and difficulty with walking. There is evidence that daily caffeine consumption reduces the risk of developing Parkinson’s. Now, a team of researchers led by Nobutaka Hattori from Juntendo University School of Medicine have studied how traces of caffeine in the blood, after drinking coffee, can be indicative of Parkinson’s disease. The researchers found that caffeine levels are significantly lower in patients with the disease; caffeine concentrations could therefore be used as an indicator of Parkinson’s, particularly in its early stages.
The researchers studied a group of 139 people, both men and women, with and without Parkinson’s disease. Each person drank between 0 and 5 cups of coffee per day (except for one participant who drank more than six). Then, they checked the participants’ blood serum for traces of caffeine and its 11 so-called downstream metabolites — small molecules produced during caffeine-induced metabolic processes in the human body.
The scientists found that the serum levels of caffeine and of almost all metabolites, including theophylline, theobromine and paraxanthine — caffeine’s main byproducts — were lower in patients with Parkinson’s disease. Although the data obtained by Hattori’s team show that there is a clear relation between a person’s caffeine (metabolite) serum levels and having Parkinson’s disease, there was no significant association between the severity of the disease and the concentration of any of the caffeine-related substances. Also, there was no significant difference in serum levels between male and female patients (males are known to suffer more often from Parkinson’s disease).
The findings of Hattori and colleagues suggest that caffeine and caffeine metabolite levels in the blood can be, quoting the researchers, “early diagnostic biomarkers for the [Parkinson’s] disease”; moreover, the results “further indicated the neuroprotective effects of caffeine”.
Background
Parkinson’s disease
In patients suffering from Parkinson’s disease, progressive loss of the function or structure of neurons (brain cells) leads to a disorder of the central nervous system, affecting its motor system. Tremor, slowness of movement and difficulties with walking are among the main symptoms in the early stages of Parkinson’s, with dementia being common at more advanced stages.
The cause of Parkinson’s disease is unclear, but it is believed that genetic and environmental factors play a role. Men are more affected than women, and people who drink tea or coffee have a reduced risk. The latter inspired Nobutaka Hattori and colleagues from Juntendo University School of Medicine to check whether caffeine levels in the blood, and levels of the byproducts (metabolites) that caffeine intake causes, can be used as biomarkers for the diagnosis of Parkinson’s disease. They found that this is indeed the case.
Caffeine
Caffeine is an organic molecule that, when consumed through e.g. coffee or tea, stimulates the central nervous system. Its best-known effect is the prevention of (the onset of) drowsiness. Daily caffeine consumption has been shown to reduce the risk of developing Parkinson’s disease in men, and in women not taking hormone replacement therapy — caffeine’s neuroprotective effect.
The team of Nobutaka Hattori has now demonstrated that, following caffeine intake, the levels of caffeine and its metabolites in the blood serum are lower for people with Parkinson’s, independent of the stage of the disease, implying that these levels could be used as biomarkers for the disease in the early stage.
Reference
Motoki Fujimaki, Shinji Saiki, Yuanzhe Li, Naoko Kaga, Hikari Taka, Taku Hatano, Kei-Ichi Ishikawa, Yutaka Oji, Akio Mori, Ayami Okuzumi, Takahiro Koinuma, Shin-Ichi Ueno, Yoko Imamichi, Takashi Ueno, Yoshiki Miura, Manabu Funayama & Nobutaka Hattori. Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease. Neurology, January 3, 2018.
DOI: 10.1212/WNL.0000000000004888
http://n.neurology.org/content/90/5/e404
Figure 1. [From the Supplementary Information (page 7)]
Caffeine and its byproducts (metabolites) after intake in the human body. Levels of these molecules in the blood are lower for patients with Parkinson’s and can hence serve as biomarkers for the disease.
Health economics offers unique insights into modern Japanese society
Fusing expertise in medicine and health economics sheds new light on healthcare and gambling in Japan
“My family are all medical practitioners, so I followed in the tradition and studied medicine at Kyoto University,” says Rei Goto, an associate professor at the Graduate School of Business Administration, Keio University. “But ever since my schooldays, when healthcare was free for the elderly, I have been interested in government policy and management of Japan’s healthcare system.”
During his final year at medical school Goto went to Newcastle, England, for a short course in clinical training and “discovered the field of health economics” that was at the heart of healthcare management in the UK. “My visit to the UK reignited my interest in healthcare management,” says Goto. “So after completing my two year hospital residency, I started on a doctoral course in health economics at Kyoto University to study social issues in Japan, including healthcare costs and gambling.”
Rationalizing costs of outpatient treatment for children with hospital admissions
In this study Goto and colleagues analyzed the effect of reducing medical care subsidies given to children receiving outpatient treatment on inpatient admissions in Japanese hospitals. “We obtained inpatient data for 366,566 children in 1,390 municipalities in Japan from 2012 to 2013 using the Japanese Diagnostic Procedure Combination (DPC) database,” explains Goto. “Our aim was to elucidate the effects of increasing subsidies for outpatient care on hospital admissions.”
The survey showed that in general decreasing cost sharing for outpatient care did not significantly affect admissions to hospital. However, hospitals in low income regions showed a decrease in admissions, and those high income areas, an increase. “These results are important because prior to our study we did not know the effect of income on hospital admissions,” says Goto. “In low income areas, the increase in outpatient medical expenses may be offset by decreases in hospital medical expenses due to admissions.
Gambling on the future
Gambling in Japan is undergoing unprecedented changes as exemplified by recent government proposals to allow the construction of regulated casino resorts. “In this research we wanted to clarify the actual level of pathological gambling in Japan and verify whether easy access to gaming facilities is a risk factor for pathological gambling,” says Goto.
The researchers conducted an internet-survey on ‘lifestyle and leisure’ covering the whole of Japan (excluding minors) from 17 to 22 November 2014, with responses from 6,576 people, and used the South Oaks Gambling Screen to determine signs of gambling dependence.
Generally, the survey showed that gambling dependence was not related to the ease of access to pachinko parlors. However, accessibility was a significant factor in gambling dependence for men, and people living in low income areas. Also, accessibility of pachinko parlors was not a factor for women and people living in high income areas.
“I hope that our research on health and social issues in Japan, which has the world’s fastest aging population, will be a useful reference for scientists and policy makers in other countries,” says Goto. “We will continue to publish and disseminate information about this research for a global audience.”
Fig. 1 Rei Goto is combining his expertise in medicine and health economics to analyze social issues in Japan such as healthcare and gambling.
"STAM MI-Forum" provides up to date and wide ranging information for both newcomers and specialists on Materials Informatics (MI) related papers published in materials science journals world-wide. Furthermore, we also include commentary and information about papers published as Communications articles in the journal STAM.
For more information, please visit the official webpage: https://e-materials.net/stam/mi-forum/
Kanazawa University research: Genetic engineering mechanism visualized
Source: Kanazawa University
(Kanazawa, 10 November 2017) Researchers at Kanazawa University and the University of Tokyo report in Nature Communications the visualization of the dynamics of ‘molecular scissors’ — the main mechanism of the CRISPR-Cas9 genetic-engineering technique.
One of the techniques used in genetic engineering — the process of artificially modifying the genome of a living organism — involves the so-called CRISPR-Cas9 nuclease system. Using this system, a cell’s DNA can be cut at a desired site, where genes can be deleted or added. Selection of the site to be cut is done by a ‘guide RNA’ molecule bound to the Cas9 protein. Now, a team of researchers led by Mikihiro Shibata from Kanazawa University and Osamu Nureki from the University of Tokyo has visualized the dynamics of the CRISPR-Cas9 complex, in particular how it cuts DNA, providing valuable insights into the CRISPR-Cas9-mediated DNA cleavage mechanism.
For their visualization studies, the scientists used high-speed atomic-force microscopy (HS-AFM), a method for imaging surfaces. A surface is probed by moving a tiny cantilever over it; the force experienced by the probe can be converted into a height measure. A scan of the whole surface then results in a height map of the sample. The high-speed experimental set-up of Shibata and colleagues enabled extremely fast, repeated scans — convertible into movies — of the biomolecules taking part in the molecular scissoring action.
First, the scientists compared Cas9 without and with RNA attached (Cas9–RNA). They found that the former was able to flexibly adopt various conformations, while the latter has a fixed, two-lobe structure, highlighting the conformational-stabilization ability of the guide RNA. Then, Shibata and colleagues looked at how the stabilized Cas9–RNA complex targets DNA. They confirmed that it binds to a pre-selected protospacer adjacent motif (PAM) site in the DNA. A PAM is a short nucleotide sequence located next to the DNA’s target site, which is complementary to the guide RNA.
The research team’s high-speed movies further revealed that targeting (‘DNA interrogation’) is achieved through 3D diffusion of the Cas9–RNA complex. Finally, the researchers managed to visualize the dynamics of the cleavage process itself: they observed how the region of ‘molecular scissors’ undergoes conformational fluctuations after Cas9–RNA locally unwinds the double-stranded DNA .
The work of Shibata advances our understanding of the CRISPR-Cas9 genome-editing mechanism. In the words of the researchers: “… this study provides unprecedented details about the functional dynamics of CRISPR-Cas9, and highlights the potential of HS-AFM to elucidate the action mechanisms of RNA-guided effector nucleases from distinct CRISPR-Cas systems.”
Background
CRISPR-Cas9
CRISPR, short for “clustered regularly interspaced short palindromic repeats”, refers to a set of bacterial DNA sequences containing fragments of the DNA of viruses having earlier attacked the bacteria. These fragments are used by the bacteria to prevent further attacks by the same viruses. “Cas” refers to CRISPR-associated genes; “Cas9” is a CRISPR-associated protein with two nuclease domains (A nuclease is an enzyme capable of cleaving nucleic acids, organic molecules present in DNA and RNA).
In recent years, a genetic-engineering technique where a CRISPR-Cas9 complex acts as ‘molecular scissors’ has been developed; the Cas9 nuclease binds to a guide RNA molecule that contains information about the DNA site to target. Using high-speed atomic force microscopy, Mikihiro Shibata from Kanazawa University and colleagues have now studied the dynamics of the CRISPR-Cas9 complex in great detail.
Atomic force microscopy
Atomic force microscopy (AFM) is an imaging technique in which the image is formed by scanning a surface with a very small tip. Horizontal scanning motion of the tip is controlled via piezoelectric elements, while vertical motion is converted into a height profile, resulting in a height distribution of the sample’s surface. As the technique does not involve lenses, its resolution is not restricted by the so-called diffraction limit. In a high-speed setup, AFM can be used to produce movies of a sample’s evolution in real time. High-speed AFM has been used successfully to study protein dynamics, for example myosin V walking on an actin filament, the photo-induced conformational change of bacteriorhodopsin, and the degradation of cellulose. Shibata and colleagues have now applied the high-speed AFM technique for visualizing the dynamics of DNA cleavage by CRISPR-Cas9.
Reference
Mikihiro Shibata, Hiroshi Nishimasu, Noriyuki Kodera, Seiichi Hirano, Toshio Ando, Takayuki Uchihashi & Osamu Nureki. Real-space and real-time dynamics of CRISPR-Cas9 visualized by high-speed atomic force microscopy. Nature Communications, 10th November 2017.
Structures of Cas9. From left to right: Cas9 alone (apo-Cas9), Cas9 bound to RNA (Cas9–RNA), Cas9–RNA bound to its single-stranded DNA target (Cas9–RNA–DNA), Cas9–RNA bound to a partial DNA duplex (Cas9–RNA–DNA) and Cas9–RNA bound to its double-stranded DNA target (Cas9–RNA–DNA).
Movie 1. [Supplementary Movie 5 of the paper]
HS-AFM movies of DNA cleavage by Cas9–RNA. Fluctuations of the nuclease domain are indicated by magenta arrows. The cleavage products released from Cas9–RNA are indicated by blue arrows.
Keio University Research: Innovative touch sensitive avatar-robotic arm based on real time haptics
Source: Keio University
(Tokyo, 7 November 2017) Researchers at Keio University’s Haptics Research Center have developed a ‘real-time-avatar-robotic arm’ that transmits sound, vision, and highly sensitive feelings of touch to remotely located users. This innovative touch sensitive robotic technology was reported in the October 2017 issue of IEEE Transactions on Industrial Electronics and demonstrated at CEATEC (October 2017, Tokyo). The technology is expected to find applications in areas such as industrial manufacturing, harvesting farm produce, and nursing care.
Keio Research Highlights
https://research-highlights.keio.ac.jp/
Video showing the movement of the avatar robotic arm.
There is demand for robotic technology to overcome the daunting challenges of the 21st century such as providing care for the elderly in rapidly aging industrialized nations, supporting labor intensive agriculture, and responding to extreme emergencies where humans cannot intervene directly, such as nuclear power station disasters.
With this background, a growing number of researchers are focussing on the potential of ‘haptics’— man-machine communication based on touch—to solve these and related problems. In its simplest form, haptics enables users to feel the sense of touch via vibrations of forced motion. Such technology employs touch sensors that can be difficult to calibrate and often malfunction in extreme environments such as heat and radiation. Furthermore, conventional haptics technology is based on vibrations and is pseudo-tactile. So, although it can be used for games and entertainment, its range of industrial applications is very limited.
Takahiro Nozaki and colleagues of the Faculty of Science and Technology and Haptics Research Center at Keio University developed a haptic-based avatar-robot with a General Purpose Arm (GPA) that transmits sound, vision, movement, and importantly, highly sensitive sense of touch (force tactile transmission), to a remotely located user in real time. “This ‘real-haptics’ is an integral part of the Internet of Actions (IoA) technology, having applications in manufacturing, agriculture, medicine, and nursing care,” says Nozaki.
This is the world’s first high precision tactile force transmission technology that remembers human movements, edits them, and reproduces them. Also, this arm does not employ conventional touch sensors, thereby making it cheaper, more compact, and robust with respect to malfunction and noise.
The core technology behind this avatar-robot is based on high precision motors integrated in the avatar arm and algorithms to drive them. High precision control of force and position is critical for transmitting a sense of touch without using touch sensors.
Nozaki and colleagues have launched ‘Motion Lib’ to commercialize their ‘real-haptics technology’. The main product is an integrated chip called the ‘ABC-CORE’ IC force/tactile controller. This IC chip controls the force adjustment of DC/AC servomotors and forces tactile transmission with two motors synchronized in motion. Importantly, since the load force applied to the motor is calculated by an algorithm in the chip, it is not necessary to install force or torque sensors.
Background
High precision robotic arms are widely used in industry, for repetitive actions in automobile assembly lines, for example. However, such robotic arms only repeat a preprogramed series of commands, grabbing well-defined, solid components used for constructing cars.
The challenge is to be able to recognize the shape, material composition—soft or hard— and position of an object, and manipulate it according to real-time instructions from a user located at a distance from the arm, where the arm acts as a real-time avatar.
The critical technical breakthroughs in motor control and robotics for the robotic-avatar developed by Nozaki and co-workers were first reported by Keio University’s Kouhei Ohnishi, in 1983 in a paper titled, “Torque –speed regulation of DC motor based on load torque estimation method” (lPEC― Tokyo'83, page 1209).
Ohnishi continued to develop his ideas in his 1993 paper on ‘sensorless torque control’ (IEEE Transactions on Industrial Electronics, 40, 259, (1993)).
This report was followed by his proposals for ‘motion control in mechatronics’ (IEEE Transactions on Mechatronics, 1, 56, (1996)).
Then, in 2004, Ohnishi addressed the issue of ‘good sense of remote objects’ in AMC 2004– Kawasaki, Japan.
Future work
Nozaki has set up a consortium with 30 companies to undertake proof of concept projects for the commercialization of this technology as an integral part of the Internet of Actions (IoA). The assist-avatar robotic GPA is being tested for use in supporting farmers to pick fruit and other agricultural applications.
Touch sensitive avatar-robotic arm based on real-time haptics developed by Takahiro Nozaki and colleagues at the Keio University Haptics Research Center.
Reference
1. Satoshi Fukushima, Hiromu Sekiguchi, Yuki Saito, Wataru Iida, Takahiro Nozaki, and Kouhei Ohnishi. Artificial Replacement of Human Sensation Using Haptic Transplant Technology.
IEEE Transactions on Industrial Electronics, Online 2 October 2017. DOI: 10.1109/TIE.2017.2758757
Related information
1. Motion Lib, Inc.
http://motionlib.com/ (Japanese）
2. Haptics Research Center, Keio University
http://haptics-c.keio.ac.jp/ (Japanese)
Correspondence to
Takahiro Nozaki, Faculty of Science and Technology, Keio University
Okayama University research: Link between biological-clock disturbance and brain dysfunction uncovered
Source: Okayama University
Researchers at Okayama University describe in the Journal of Neuroscience that a certain protein known to play a major role in circadian rhythmicity — humans’ intrinsic 24-hour biological cycle — is also key to proper brain functioning. The findings may increase our understanding of neurological diseases and guide the development of future treatments.
Patients suffering from psychiatric or neurological diseases often have irregular sleep patterns. In fact, neurodegenerative diseases, such as Alzheimer’s, are believed to be caused by a disturbed biological response to the day/night cycle (a.k.a. circadian rhythm). A team of researchers led by Takeshi Takarada from Okayama University has now identified a link between circadian rhythm disturbance and brain dysfunction. The scientists showed that a protein called Bmal1, known to play an important role in circadian rhythmicity, also regulates the stability of the blood–brain barrier (BBB), a semipermeable membrane in the brain that separates blood from other, extracellular fluid.
Takarada and colleagues made their discovery by studying the function of Bmal1 in transgenic green-fluorescent-protein (GFP) mice. The introduction of GFP is a commonly used biomedical technique for obtaining fluorescence microscopy images — in this case, of the brains of mice. First, the researchers found that deletion of Bmal1 molecules results in an increased activity of astrocytes, a type of cell in the brain that provide biochemical support to the BBB. They then observed that Bmal1 deficiency leads to higher-than-normal permeability of the BBB due to pericyte dysfunction. Pericytes are cells needed to sustain proper BBB function; they regulate capillary blood flow.
As to the origin of the pericyte dysfunction causing reduced integrity of the BBB, the scientists were able to show that Bmal1 deletion affects the expression of platelet-derived growth factor receptor β (PDGFRβ) proteins in pericytes, which leads to a decrease in pericyte coverage of blood vessels in the brain. This reduced coverage was found to be age-dependent.
The work of Takarada and colleagues clearly establishes a connection between circadian rhythms and the physiological stability of the BBB: Bmal1 is involved in both. The scientists therefore concluded that “… Bmal1 may represent a novel target for the discovery and development of therapies for many neurodegenerative and/or psychiatric disorders related to abnormal BBB integrity.”
Background
Circadian rhythms and Bmal1
A biological process showing a natural periodic cycle of 24 hours — an Earthly day — is called a circadian rhythm. The mechanism behind such processes, seen in plants, animals, fungi and certain types of bacteria, is called a circadian clock. In humans, circadian rhythm disturbances are associated with psychiatric diseases such as bipolar disorder and neurodegenerative diseases such as Alzheimer’s disease.
An important molecular component of the circadian-clock mechanism is brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1); it regulates certain biochemical processes in the 24-hour cycle.
Takeshi Takarada and colleagues have now examined the role of Bmal1 in brain function, and found that reduced levels of Bmal1 affected the proper functioning of the blood–brain barrier (BBB), establishing a link between circadian rhythm disorders and neurological pathologies.
BBB
The blood–brain barrier (BBB) is a semipermeable membrane, separating blood circulating in the brain from other fluid in the central nervous system. It regulates the transit of water, certain gases and molecules like glucose and amino acids required for neural function. A properly functioning BBB features three particular types of cells: astrocytes, endothelial cells and pericytes. By looking at mice with a reduced Bmal1 content, Takarada and colleagues discovered astrocyte hyperactivity and pericyte dysfunction, with the latter compromising the integrity of the BBB.
Reference
Ryota Nakazato, Kenji Kawabe, Daisuke Yamada, Shinsuke Ikeno, Michihiro Mieda, Shigeki Shimba, Eiichi Hinoi, Yukio Yoneda & Takeshi Takarada. Disruption of Bmal1 impairs blood—brain barrier integrity via pericyte dysfunction. Journal of Neuroscience, September 14, 2017.
Confocal microscopy images showing the evolution of astrocyte activity (GFAP; increasing with age) and pericyte marker expression (Desmin, CD13, PDGFRβ; decreasing with age) in mice with Bmal1 deficit.
A class of drugs can harness the power of the body’s immune system to fight diverse tumors
By stimulating a patient’s immune system, a drug already in use to treat a blood disorder can thwart the growth of a variety of solid tumors, find a team at Keio University1.
The drug 5-aza-CdR is currently approved for treating a blood disorder that can lead to leukemia. It inhibits the methylation of DNA, preventing enzymes from chemically modifying genomic DNA. Such modifications can greatly alter the expression of genes that control a variety of critical cellular functions, including cell growth and survival.
Some studies have shown that methylation inhibitors such as 5-aza-CdR could be used to treat other cancers. These effects have generally been attributed to the drugs reactivating tumor-suppressor genes, but the actual mechanism remains poorly understood.
Yoshimasa Saito and his co-workers at Keio University set about figuring out how the drugs work. They began by assessing the effects of 5-aza-CdR on a mouse model of intestinal cancer. The team found that the drug cut the number of tumors that formed by roughly a third and that animals that received the drug tended to have smaller tumors than those that did not.
Having demonstrated that 5-aza-CdR can act on such cancers, the researchers then cultured cells derived from mouse intestinal tumors under conditions that promote the formation of three-dimensional ‘organoids’.
“Organoids are budding, cyst-like structures that closely recapitulate the properties of the original tumors,” explains Saito, “This makes them a powerful tool for studying how cancers respond to treatment.”
The researchers found that 5-aza-CdR strongly inhibited the growth of tumor-derived organoids and were minimally toxic to healthy intestinal cells.
Delving deeper, Saito’s team looked at which genes were turned off and on by this treatment and noticed a striking pattern. “Our findings indicated that DNA demethylation suppresses the proliferation of intestinal tumor organoids by inducing an anti-viral response,” says Saito. He and his colleagues suggest that the methylation inhibitors are somehow reactivating endogenous retroviruses — ancient viral DNA sequences that have accumulated over evolutionary history and now lie dormant throughout the genome. This initial antiviral response leads to immune activation and the shutting down of tumor proliferation.
“These findings represent a major shift in our understanding of the anti-tumor mechanisms of DNA demethylating agents,” says Saito.
The team believes the strategy could be effective for treating other cancers, and it has already obtained promising results with organoids derived from challenging tumors such as cholangiosarcoma and pancreatic cancer. “We are trying to develop a personalized therapy for refractory cancers,” says Saito.
Reference
Saito, Y., Nakaoka, T., Sakai, K., Muramatsu, T., Toshimitsu, K., Kimura, M., Kanai, T., Sato, T. & Saito, H. Inhibition of DNA methylation suppresses intestinal tumor organoids by inducing an anti-viral response. Scientific Reports 6, 25311 (2016). | article
Three-dimensional organoids derived from human cholangiosarcoma tumor cells.
Innovative 3D-printed ‘caring-tools’ to enhance the quality of life of elderly people
3D printing technology has important medical applications, such as manufacturing prosthetic parts, implants, and models of human organs. Here, researchers at Keio University in Tokyo, describe the potentially important role of 3D printing in nursing and long-term care for the elderly. Given Japan’s rapidly ageing society, demand for terminal care in hospitals or care facilities will exceed capacity in the near future. Furthermore, there are insufficient visiting nurses to provide in-house care. Therefore, strengthening in-house care is an urgent task for healthcare of the elderly. The introduction of information technology (IT) is an essential strategy from both aspects of work efficiency and providing high quality care.
Specifically, Shoko Miyagawa and colleagues at Keio University noticed the increased availability of 3D printers in self-help community centers throughout Japan. Based on interactions with nurses, medical practitioners, engineers and material designers, Miyagawa and her collaborators established a benchmark for specific digitally fabricated objects needed by patients and classified them into three types.
Firstly, are self-help devices enabling individuals to carry out specific tasks. For example, someone with paralyzed fingers who is unable to pinch, is assisted by a customized 3D-printed penholder for signing important documents.
Second, ‘caring tools’ facilitate interaction between care-givers and care-receivers. For instance, cutting out plasters in fun shapes — such as animals — with a laser cutter helps patients overcome negative perception of surgical tape.
Third, Miyagawa and colleagues identified educational objects as tools to learn how to perform therapy actions. For example, a 3D-printed semi-transparent cranial model can be used for practicing the insertion of a tube for vacuuming phlegm from a patient’s throat with light-emitting diodes acting as guides to follow its position inside the model. The researchers also addressed the question of safety, as the proposed 3D-printed objects must be washable and not produce skin irritation. Another important aspect of the research project of the Keio scientists is an assessment of the usage level of the objects. To this end, the researchers are currently developing an ‘internet-of-things’ sensing system: a data logger that can collect information about an object’s use for one month.
Having established the relevance of 3D printing techniques for improving the quality of life and the independence of elderly people, Miyagawa and colleagues conclude that, “in order to make digital fabrication more useful it is necessary to further reduce the cost of introduction and operation and to develop technologies to do so.”
A 3D printer used by Keio researchers to digitally fabricate objects such as a pen holder and cranial model for nursing and healthcare.
Reference
Asano, Y., Tanaka, H., Miyagawa, S. & Yoshioka, J. 3D printing and IoT for personalized everyday objects in nursing and healthcare. Proceedings SPIE 10167, Nanosensors, Biosensors, Info-Tech Sensors and 3D Systems advance online publication, 17 April 2017 | article
Simple biomechanical test could aid implant success
Provided by: Science and Technology of Advanced Materials
Opportunity to gain deeper insight into potential interaction between implants and body tissues through high-output benchtop screening.
The quality of the tissue-implant interface is key to the success of implant integration. High-output benchtop screening can help developers in assessing the complex interplay between biomaterials and the body to better prepare for clinical trials, highlights a review in the journal Science and Technology of Advanced Materials.
High-output screening aims to maximize the amount of consistent data and information from the minimum number of tests or specimens. One way to achieve this is to simulate the implant environment in more detail during benchtop tests. By enhancing the clinical relevance of in vitro results, medical device makers will gain deeper insight into the performance of their designs, making it more straightforward to select leading candidates. Identifying poor performers earlier in the pipeline could help bring down development costs and speed up the introduction of promising designs.
“This drastically reduces the time and effort required for clinical tests,” writes review author Michael Gasik, a researcher based at Aalto University Foundation in Finland.
To illustrate the concept, Gasik considers a dental implant, one of the most common types of implants worldwide, and advocates a simple biomechanical test for analyzing tissue implant quality.
A dental implant test sample comprises a titanium post surrounded by cultured tissue. The supply of media to the sample is controlled to enable changes in temperature, acidity, and bacterial conditions. The post can be vibrated to mimic chewing, and mechanical measurements assess how firmly the implant is bound to the tissue.
For implants, study objectives include the identification of improved tissue-biomaterial adherence and resistance to bacterial contamination and biofilm formation. Gasik notes that test platforms can also be tailored for more complex scenarios such as articular cartilage repair.
Figure: Benchtop test setup for the high-output screening of dental implants (DO = dissolved oxygen, T = temperature, pCO2 = partial pressure of CO2, DAQ = data acquisition, POST = post-processing data treatment, MCDA = multi-criteria decision aiding).
Article information:
Michael Gasik “Understanding biomaterial-tissue interface quality: combined in vitro evaluation” Science and Technology of Advanced Materials, 2017; 18:1, 550-562. http://doi.org/10.1080/14686996.2017.1348872
Provided by: Science and Technology of Advanced Materials
