RESEARCH HIGHLIGHTS 2016
www.naist.jp/en

A NEW

VISION
Blurring the edges of possibility inaugmented reality p18

BUDDING IDEAS
Exploring a biological clockthat controls flower growth andunderpins our food supply p52

A CUT ABOVE?
Why diamonds and pencils are
created equal to one
atomic explorer p57

The history of NAIST
NAIST was founded in 1991 as a Japanese national university consisting solely of graduate schools in three
integrated areas: information science, biological sciences and materials science. At present, about 1,000
students — 19% from overseas — are supervised by roughly 200 NAIST faculty.
With its cutting-edge facilities and a 5 to 1 student-to-faculty ratio, NAIST’s world-leading education and research
are a direct result of its rich, global environment and supportive infrastructure. Moreover, the outstandingachievements of NAIST’s faculty and students are shared worldwide through patents, licenses, spin-off companies,
and active exchange with overseas partners.
NAIST has quickly established itself as a world-class education and research center where young science andtechnology researchers become tomorrow’s global leaders.
NAIST Research Highlights showcases the mostpromising and important research achievementsof each laboratory at NAIST and presents theircurrent research and core technologies to the
public. The publication distills highly technicalresearch papers into short, easy-to-understandarticles that appeal to a global audience of both specialists andnon-specialists. NAIST Research Highlights aims to inform readersof the latest developments in NAIST’s pioneering research, andto stimulate new and existing international collaborations. Digital
versions of each issue can be accessed online at:
http://ipw.naist.jp/iri/naura/en/highlight.html

Aims
&
Scope

NAURA (NAIST URA team)publishes NAIST Research Highlights
under the auspices of the “Program
NAURA
for Promoting the Enhancementof Research Universities”, which
is funded by Japan’s Ministry of
Education, Culture, Sports, Science and Technology(MEXT). Through this program, NAIST further supports
its cutting-edge research while expanding into newinterdisciplinary ﬁelds in science and technology
toward becoming a globally recognized education andresearch center.

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published in NAIST Research Highlights or toarrange an interview with a faculty,
please contact:

Contents
Editorial
03

NAIST Graduate Schools

Nurturing discovery

04

The three graduate schools that make up NAIST

Information Science

30

10

12

06

22

Impact06 A beacon of hope in an emergency

Research Highlight

10 Rolling forward to meet society’s needs

Impact12 Teaching human anatomy to intelligent machines

Research Highlight

16 A penetrating gaze

Feature & Highlight

18 Blurring the edges of reality
20 Keeping it real in the virtual world

Impact22 Statistics to remove language barriers

Research Highlights

26 Eyes open to online security
27 More to viewing art than meets the eye

Feature & Highlight

28 Embedded in life
30 Playing with urban sensing

Contents
Biological Sciences

36

48

Impact33 Search for a sense of self in immunity

Research Highlights

36 On the pathway to successful therapies
38 Brewing a heat-loving yeast species

52

Feature & Highlight

Feature & Highlight

40 Planting seeds of wisdom
42 Exploring the secrets of parasitic plants

50 Exploring the fundamentals of plant growth
52 The timer that controls flower size

Research Highlights

Research Highlights

44 Getting to the root of what lies beneath46 Inflammatory disease study yields knockout results
48 Decrypting plant defense signals

54 A creative flow finds the forces behind cell migration
55 Protein-secretion machinery

Materials Science64

70

Impact57 Making use of an ultra-small world

Feature & Highlight60
62

A scintillating career
Bright future for radiation detection

Research Highlight

64 Glucose monitor gets under your skin

66
67
68
70
72

Research Highlights

A gateway to splitting hydrogen
Bleeding-edge science to improve digital memory
Stacking the odds in graphene’s favour
The sweet lure of light to sugar
Feeding a growing need for shrinking devices

Feature & Highlight

74 Exploring cells with intense light
76 Test of strength sheds new light on plants

Research Highlight

78 Dissolving obstacles to a superior drug solution

62

RESEARCH HIGHLIGHTS 2016

Nurturing
discoveryWelc ome to NA IST Re s e a rch
Highlights 2016. This publication
prov ides an over v iew of t hework and people of one of Japan’s leading
research bodies, the Nara Institute of Scienceand Technology. In these pages we present aview of the institute’s achievements in threedifferent formats. Research Highlights areshort features that cover recent extraordinary
advances and brea kt hroughs: from t hedevelopment of an implantable continuous
glucose monitoring device with potential
for diabetics (p64); to the discovery of ascintillator with possible security and medical
applications (p62).
Five longer Impact profiles explore someof our research achieving significant applied
outcomes, such as the work of the Functional
Genomics and Medicine Laboratory (p33).
Under Yasumasa Ishida's leadership, this lab
is at the forefront of investigations of the PD-1

gene that controls aspects of the body’s T-cell
immune response.
Our Augmented Human Communication
Laboratory, headed by Satoshi Nakamura, isusing big data to develop software capable ofseamless speech translation (p22).
Of course, at the heart of such outcomesa re ou r resea rchers. E ach yea r NA IST
attracts more leaders in scientific fields.
And here, in a series of six longer Features,
we spotlight the careers of some of thelatest international stars to join our ranks.
They include Chistian Sandor, a leader inaugmented reality (p18), and parasitic plant
specialist, Satoko Yoshida (p40), who willlead our new Plant Symbiosis Laboratory.
We look for wa rd to nu r t u r i ng t hei r
important work and the careers of all our
researchers in the atmosphere of cutting-edge
discovery that will continue to be fosteredat NAIST.

On the cover

By coming up with a fast way
to calibrate actual and virtual
realities, NAIST researchers are
one step closer to their goal of
producing the ultimate display.
Page 20

NAIST Research Highlights 3

NAIST Graduate Schools

NAIST graduate education and research programs aim to be at the world-leading edge of research in scienceand technology, speciﬁcally in the core ﬁelds of information, biological and materials sciences. They actively
engage in cross-disciplinary studies to explore and seek solutions in the most challenging areas.

Information Science
The core focus of the Graduate School of Information Science is on communication between society, people and computers, as wellas the computing infrastructure for the big-data era that will support sustainable growth and societal development well into the
future. Our world-class faculty, staff and curriculum contribute to the cultivation of researchers and engineers who will be leaders intomorrow’s universally connected society.

Computer Science• Computing Architecture• Dependable System• Ubiquitous Computing Systems• Mobile Computing• Software Engineering• Software Design and Analysis• Internet Engineering• Internet Architecture and Systems

Media Informatics• Computational Linguistics• Augmented Human Communication• Network Systems• Vision and Media Computing• Interactive Media Design• Optical Media Interface• Ambient Intelligence• Social Computing

Applied Informatics• Robotics• Intelligent System Control• Large-scale Systems Management• Mathematical Informatics• Imaging-based Computational
Biomedicine• Computational Systems Biology• Robotics Vision

Biological Sciences
The ultimate goal of research in the Graduate School of Biological Sciences is to uncover various structures and functions of
microorganisms, plants and animals at the molecular and cellular levels, and to clarify principles of the basic phenomena of life andbiological diversity. Based on highly advanced basic research, we provide research and development that beneﬁts human well-being,
through which we train researchers to play active roles in the global community.

Plant Biology• Intercellular Communications• Plant Cell Function• Plant Developmental Signaling• Plant Metabolic Regulation• Plant Growth Regulation• Plant Morphological Dynamics• Plant Stem Cell Regulation and
Floral Patterning• Plant Immunity• Plant Symbiosis• Plant Developmental Biology

Biomedical Science• Molecular Signal Transduction• Functional Genomics and Medicine• Molecular and Cell Genetics• Tumor Cell Biology• Molecular Immunobiology• Applied Immunology• Molecular Medicine and Cell Biology• Developmental Biomedical Science

Systems Biology• Microbial Molecular Genetics• Systems Microbiology• Cell Signaling• Applied Stress Microbiology• Structural Biology• Membrane Molecular Biology• Gene Regulation Research• Systems Neurobiology and Medicine

Materials Science
The main research area in the Graduate School of Materials Science is photonic nanoscience, which seeks to understand themechanisms of materials on the electron, atomic and molecular levels from the perspective of ‘seeing with light’, ‘creating with light’and ‘transmitting with light’. Researchers aim to create new materials, structures and functions. We systematically educate students
to become excellent leaders in research and development ﬁelds in global society.

Organic Materials• Advanced Polymer Science• Synthetic Organic Chemistry• Photonic Molecular Science• Photofunctional Organic Chemistry• Nanomaterials and Polymer Chemistry• Functional Polymer Science• Ecomaterial Science• Advanced Functional Materials

Biological Materials• Biomimetic Materials Science• Supramolecular Science• Biocompatible Materials Science
4 NAIST Research Highlights

Device Materials• Photonic Device Science• Information Device Science• Sensing Device• Organic Electronics• Mesoscopic Materials Science• Intelligent Materials Science• Sensory Materials and Devices• Nanostructure Magnetism• Complex Molecular Systems• Green Nano Systems

Quantum Materials• Quantum Materials Science• Surface Materials Science• Bio-Process Engineering• Nanostructure Magnetism• Complex Molecular Systems• Green Nano Systems
As of April 1, 2016

Information
ScienceInformation Science
6 NAIST Research Highlights

Information Science

IMPACTInternet Architecture and Systems Laboratory & ITC | Professor Kazutoshi Fujikawa

A beacon of hope inan emergency© 2016 Kazutoshi Fujikawa

RESEARCHERS ARE
BUILDING A RELIABLE
COMMUNICATIONINFRASTRUCTURE USINGSATELLITE SYSTEMS FOR
USE IN DISASTERS

NAIST Research Highlights 7

Information ScienceAt 2:46 pm on 11 March 2011, a magnitude 9 earthquake hit
70 kilometres off Japan’s eastern shore, precipitating one of
the world’s most devastating and costly natural disasters.
Within minutes, the North Pacific Ocean had risen and was
threatening Japan’s eastern coastline. At 3:18, a swell of eight‑metre
waves struck the city of Ofunato. At 3:26, 8.5-metre waves wererecorded in the Port of Miyako, almost 100 kilometres to thenorth and at 3:51 waves taller than a three-storey building, higher
than 9.3 metres, inundated Soma city, more than 200 kilometres tothe south.
The hour and five minutes it took for the tsunami to reach its
maximum height was about the same amount of time it would havetaken emergency workers to set up a satellite communication system.
Kazutoshi Fujikawa and his team at NAIST’s Internet Architecture andSystems Laboratory, have since reduced that time to about 15 seconds,
in a project that looks certain to save many lives.
Fujikawa also leads the Information Initiative Center, which
manages and operates an advanced network infrastructure andcomputer system for students and researchers at NAIST, known as
Mandara. The system connects more than 4,000 terminals and is oneof the fastest campus networks in the world.
Unlike many researchers in Japan studying satellite communication, Fujikawa is more interested in its applications than in theoreticalanalysis. “We want to design useful communication infrastructure byusing satellite systems in the case of a disaster,” he explains. Natural
disasters can cause comprehensive breakdowns in existing mobile,

8 NAIST Research Highlights

landline and internet telecommunications infrastructure. These
failures can delay emergency responses and rescue efforts, leading topreventable losses of life.
Decentralized Wi-Fi routers can open up channels of communication during a disaster, but only within a radius of 100 metres. Some
researchers have even suggested using low-flying aircraft to serve as
emergency Wi-Fi access points, but they also have limited coverage.
Satellite communication networks cover a much wider range, fromentire countries or regions to the whole Earth. But, these systems cantake up to 3 hours to set up and require 1.3 seconds to transmit information between users, via space — a delay that is impossible to eliminate.
Fujikawa’s group has applied network management and operation
techniques to seamlessly switch, within seconds, from the regular telecommunication network to the satellite network. In their system, adish known as a very small aperture terminal (VSAT) is used to send
and receive information from an orbiting satellite.
The VSAT system weighs less than 60 kilograms, and fits in a box
about 1 cubic metre in size. In a recent trial, Fujikawa hitched the
VSAT system to a hybrid car to allow users to transmit information
while on the move, as would be required during a disaster response
operation. To realize the network, they partnered with satellite communications provider Japan Radio Company (JRC) and satellite
operator JSAT.
Fujikawa’s team has also since incorporated drones equipped with
Wi-Fi access points to their network for emergency reconnaissanceInformation Science© Jon Sheer/Moment/Getty

and rescue. People who are injured
or trapped can connect to the drone’s
Wi-Fi service using their mobile
phones, which then records theirposition. When the drone returns tothe car (see image, right), this information is sent via satellite for processing to
pinpoint the exact location of stricken
individuals.
Fujikawa’s team is now working to
implement various configurations of
the network so that it can be used inreal disaster situations. “Our aim is toprovide communications infrastructure
in an emergency, which can be used asordinary internet,” he says.
© 2016 Kazutoshi Fujikawa
The Japan Disaster Medical AssistanceTeam (DMAT) tested the system in a2015 training drill on 1 September, the anniversary of the Great Kanto
earthquake of 1923 that killed almost 150,000 people. This date is now
used each year to mark Japan’s Disaster Prevention Day, during which
nationwide safety drills are held. A VSAT system was fixed aboard the

Izumo-class helicopter destroyer ship in
Yokosuka, south of Tokyo, to transmit
messages between a stationary DMAT
team and the hybrid car.
Although the high cost of the system
might prove prohibitive to its adoption
by the government on a national scale,individual hospitals across Japan are
already using the system to prepare
themselves for the next big disaster.
VSAT transceivers have been set upon the rooftops of four hospitals:
Yonemuri Hospital, on Japan’s southwestern tip; Iwate Medical University,in the far north; and, in between, theNational Disaster Medical Center andOsaka National Hospital.
These systems will allow rescue
teams to get immediate assistance from doctors for treating criticalinjuries when the usual lines of communication have broken down.
Fujikawa plans to further test the satellite communication system
for transmission delays and to assess its geographic reach.

More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/cs-08-en.html
Researcher: Kazutoshi Fujikawa

NAIST Research Highlights 9© Thinkstockphoto.com

Intelligent System Control Laboratory | Professor Kenji Sugimoto

Robotics

Smart systems

Rolling forward to meetsociety’s needs

Elistibus eos qui doluptatur, occat pore, sum et late volo que odit autes elestiatur mos“

After a brief
training period, thewheelchair could
deduce the intended
destination, morethan 80% of
the time.

10 NAIST Research Highlights

Fully automated wheelchair navigation
systems have been in use for sometime and can easily transport users topredefined locations. But, what happens whena user decides to take a last-moment detour tothe kitchen for a midnight snack or navigate
a hallway where a pet has inconveniently
decided to take a nap? Existing systems falterin such instances.
Recognizing the gap between available
technologies and the needs of wheelchairusers, the Japan Society for the Promotion of
Science provided researchers at NAIST and
the University of Technology Sydney withan International Joint Research Grant for the“development of mobility assistance sharedcontrol strategies for increased autonomy.”
The collaborative project has resulted in asensor-laden wheelchair designed to guideusers’ movements through their surrounding
environments.
The wheelchair represents an amalgamof assistive inventions, including touchrecognition algorithms originally developed
for a robotic hand at NAIST, which allow
wheelchairs to ‘sense’ user intentions as
they navigate through complex real-world
environments.
Leading the Japanese side of theinternational collaboration has been
Takamitsu Matsubara, of NAIST’S Intelligent
System Control Laboratory. Matsubara’s© Eky Akmal/EyeEm/EyeEm/Getty

Robotic wheelchairs detect, adapt and immediately
respond to users’ intentions“

Information Science

R E S E A R C H H I G H L I G H TS

at the IEEE RO-MAN2015 conference1, where
it was recognized by the Robotics Society ofJapan and the Korea Robotics Society with theDistinguished Interdisciplinary Research Award.
The award recognizes, Matsubara says, that thetechnology the team is developing may allow
wheelchair users to express human desire andintent in the near future.
Reference
1. Matsubara, T., Miro, J. V., Tanaka, D., Poon, J. &Sugimoto, K. Sequential intention estimation of a mobility aid user for intelligent navigational assistance.
Proceedings of the 24th IEEE International Symposium
on Robot and Human Interactive Communication(RO-MAN2015) (2016).

The intelligent wheelchairdeveloped by NAIST and the
University of Technology Sydney.

More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/ai-02-en.html
Researcher: Takamitsu Matsubara

NAIST Research Highlights 11

Information Science

as desired, both to foster his or her sense ofcontrol over the environment and to maintainmental and motor skills.
Exerting a little control goes a long way. An
experimental trial showed that after a brief
training period, the wheelchair could deducethe intended destination more than 80% of
the time using only its knowledge of current
location and recent joystick movements. If thedirection seems wrong to the user — or if sometime on a sunny porch beckons instead of ashower — a simple movement of the joystick
can immediately alter the robot’s calculation of
intended destination.
A paper detailing the technologies used in
the project to allow assistive wheelchairs tosense user intentions as they navigate throughcomplex real-world environments was presented© 2016 Takamitsu Matsubara

other projects include the development ofseveral technologies in artificial intelligenceand motor control for humanoid robots, andthese have made significant contributions to
the wheelchair project. Just as an artificial
robot hand trying to use an unknown object
must examine its properties, the wheelchair’s
sensors continuously probe the proximityof nearby walls and furniture, providing asensitive rendering of its precise relationshipto surrounding objects and surfaces.
In a more recent development, Matsubara
has realized that while his robotic hand would
probably be fully operational all the time,
the wheelchair had to navigate only whenneeded. In response, the team has exploredthe development of algorithms that would
allow the user to stay in control for as long

Information Science

IMPACT
Imaging-based Computational Biomedicine Laboratory | Professor Yoshinobu Sato

Teaching humananatomy to intelligent
machines© PeopleImages/E+/Getty

12 NAIST Research Highlights

G

oogle has revolutionized the way we navigate ourworld by using raw satellite images to build powerful,interactive maps of almost every city and town. Now
computer scientists, Yoshinobu Sato and Yoshito Otake, aredoing much the same thing for the human body. Their team at
NAIST’s Imaging-based Computational Biomedicine laboratory
is using raw CT, MRI and X-ray images to develop some of themost advanced anatomical maps available of bones, muscles andabdominal organs. These could soon be used as tools to train
medical students, improve the accuracy of diagnosis and surgery
and speed up patient recovery.
“We want to harness the power of computers for real clinicalcare,” says Sato, the laboratory’s head, who has 20 years’
experience in this field. “The fun part about our job is developing
systems that will really help patients get better,” adds Otake, aspecialist in X-ray image analysis.

NAIST Research Highlights 13

Information Science

RESEARCHERS ARE
DEVELOPING MEDICALIMAGE ANALYSISSOFTWARE FOR
IMPROVED DIAGNOSIS,RECOVERY ANDREHABILITATIVE CARE

Information Science
Doctors often diagnose diseases by using machinery — such as CT
and MRI equipment — that creates images using electromagnetic radiation to scan internal structures that are hidden to the naked eye. To
make the most of these tools they need to spend years learning how toaccurately interpret the sliced, black-and-white representations of interconnecting tissues and organs that they produce. Sato and Otake are
now teaching computers to read these scanned images with similar oreven higher degrees of accuracy. “For computers to understand medical
images, they need to understand human anatomy,” Sato explains.
Current image analysis software requires a lot of manual input.
Imagine, for example, a doctor treating a patient suspected of having a

14 NAIST Research Highlights

diseased liver. They first have to draw the outline of the liver in a CT
scan for the system to calculate its characteristics. Sato and Otake want
to automate the entire process, and in the case of the liver, are usinglarge image databases — known as ‘medical big data’ — to train computers to recognize the shape of this and the rest of the body’s organs.
The artificial intelligence system then gradually learns to predict thelocation of the liver, as well as other features of interest such as mass,
tissue damage and any potentially cancerous growths.
To recognize multiple organs and tissues, the system employs a technique that would be familiar to lovers of jigsaw puzzles, Sato explains.
It begins by identifying the easier sections, such as the skin and bones,
before moving on to the more ambiguous regions of the muscles. “Basically our algorithm implements common sense,” Sato says. This strategy
creates a more accurate depiction of multiple organs as they appear in
the context of the body. Sato compared the strategy to current state-

Information Science© 2016 Yoshinobu Sato“of-art techniques and found that the pancreas,aorta and inferior vena cava were more accurately
defined using the hierarchical approach of thesystem developed by him and Otake.
The NAIST researchers’ technique is also
extremely versatile and can be used to describe
many different bodily organs using a wide rangeof image formats, including images enhancedwith contrast agents, such as dyes. By analysing
X-ray imagery in real-time, the system could
be brought into the operating room, and could
be used to observe muscles in motion. “We aretrying to combine image analysis with simulations to eventually be able
to predict biomechanical function,” Otake says.
The team plans to extend its application to the entire body and eventually to all diseased states and wants to improve the system’s robustness by using larger databases of thousands of images.
Sato and Otake hope to bring their systems to clinical practise within
the next five to 10 years. To achieve this, they are working closely withmedical practitioners in collaborating institutions in Japan, including
Osaka University, Kanazawa University and Nara Medical University,
and Johns Hopkins University in the United States.
“Medical doctors are very enthusiastic about our research,” Sato says.
The system being developed at NAIST could be used for applications
such as helping doctors to identify tumors and other diseases, surgeons
to develop more accurate surgical plans and technicians to design
implants more suited to a patient’s personal bone
shape and structure. The large database of knowledge embedded in the systems could also be used
to teach medical students. Sato and Otake havealready begun testing the technology for theconstruction and preoperative planning of knee,
hip and arm implants.
Prior to total hip replacement surgery, experienced surgeons have to develop preoperativeplans in which they identify the size, three-dimensional position and orientation of an implantusing CT scans of a patient. Sato fed these previously generated plans to an automated system,and then tested the system’s ability to generate pre-operative plans for
new patients. The system effectively reproduced the plans of experienced surgeons in 40 cases.
Ultimately, Sato and Otake’s research will lead to quicker andeasier recoveries for patients as well as saving lives. “Our research
will ultimately help to make surgery more accurate, precise and safe,”
Otake says. We are trying to
combine image
analysis withsimulations toeventually be able topredict biomechanicalfunction.

“

More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/ai-05-en.html
Researcher: Yoshinobu Sato

NAIST Research Highlights 15

Optical Media Interface Laboratory | Professor Yasuhiro Mukaigawa

Imaging technology

A penetrating gazeVizualization of hidden features in objects such as paintings is
improved by a sophisticated image processing technique“

Our method could
also be applied to
medical imaging tolook inside thehuman body.

“

Information Science

R E S E A R C H H I G H L I G H TS

16 NAIST Research Highlights

Information Science© 2016 Yasuhiro Mukaigawa© 2016 Yasuhiro Mukaigawa

Multi-frequency illumination can reveal hidden internal features of materials and objects, such as earlier artworks (right) that have been painted over (left).

R

ecently developed techniques such as
X-ray fluorescence (XRF) and infrared
reflectography (IRR) have given
researchers a previously unimagined ability
to look below the surface of paintings andother objects. They have, for example,
found lost, obscured art, forgotten artists’signatures and multiple layers of paintbeneath famous works of art such as the
Mona Lisa.
Now, NAIST researchers have developed a
non-contact method that allows them to see
through the surface of translucent objects
to visualize hidden layers1. Their techniquemakes it possible to sequentially unveil thehistory of objects such as paintings without
the potential damaging effect of XRF andwith more clarity than IRR. This nextevolution of depth-penetrating visualization
has been developed by Yasuhiro Mukaigawa,
who heads NAIST’s Optical Media Interface
Laboratory, Osaka University’s Kenichiro
Tanaka and colleagues.
“The structure inside a translucent object
is often invisible due to overlying material.

However, by removing the light-scattering
effect of the upper layers, we can visualize
a clear image of the internal structure,”
Mukaigawa explains. “The problem is,the appearance we normally observe isthe visual ‘sum’ of all internal layers, andseparating these layers as images is usually
impossible.”
The team began with a theoreticalanalysis of the problem. As light penetrates
a material, it is progressively scattered by
the matter until it can penetrate no deeper.
This scattered light can then re-emerge
from the surface, but is re-scattered on its
way back out.
The researchers modelled this process
as a series of depth-dependent ‘point
spread functions’, and in doing so realized
they could recover the deeper images
by illuminating the material with acheckerboard pattern and processing theobtained images.
“We project a checkerboard pattern on
to the material and scan the pattern pitchfrom small to large,” Mukaigawa says.

“We can then separate the internal layers
corresponding to each pitch using someslightly complicated, but straightforward,
computation.”
The researchers used their ‘multifrequency illumination’ technique to reveal
with remarkable clarity hidden paintingsand even the signed name of an artist whose
work had been painted over.
This imaging technique also forms thebasis for a document-scanning system thatcan filter out the appearance of the wrong
side when scanning double-sided prints.
Historical artwork and archiving, however,are not the only potential application ofthis technique. “Our method could also be
applied to medical imaging to look inside
the human body,” Mukaigawa says.
Reference
1. Tanaka, K., Mukaigawa, Y., Kubo, H., Matsushita,
Y. & Yagi, Y. Recovering inner slices of translucent
objects by multi-frequency illumination. Proceedings
28th IEEE Conference on Computer Vision and Pattern
Recognition 5464–5472 (2015).

More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/mi-06-en.html
Researcher: Yasuhiro Mukaigawa

NAIST Research Highlights 17

Interactive Media Design Laboratory | Professor Hirokazu Kato

Christian Sandor

Blurring
the edgesof reality
Science fiction and real family
hardship inspire this shining
star of augmented reality

A

sk Christian Sandor to summarise his
research in one sentence and he will tell you
he wants to build a holodeck. Star Trek fanswill know, of course, that he’s talking about
the fictional virtual reality simulator that first
appeared in the landmark sci-fi televisionseries during the 1980s!
Sandor is now a 40-year-old computerscience associate professor in NAIST’s Graduate School ofInformation Science. But at heart, he’s still a kid with a dreamand he believes his vision can best be served in his new Nara
laboratory base.
“There are really no limits to the research you can do at NAIST.
It’s the ultimate freedom,” Sandor explains. “If someone offered
me a place at Cambridge or Stanford University I wouldn’t go.
This is definitely the best place for my work.”
Sandor is a leading light internationally in augmented reality,
where technology aims to enhance our perceptions of real-world
experiences. Inspired as much by science fiction as his studies,
he’s determined to bring his childhood dreams to life.
“When I was growing up, I watched a lot of Star Trek,” Sandor
admits. “I loved the holodeck room where you can experience
anything you want, from a sandy beach to a historical setting, andeverything feels completely real.”
Sandor began his PhD in 2001 at the Technical Universityof Munich in Germany. As he began experiencing augmented
reality with leading scientists such as Professor Gudrun Klinker,
who is known for exploring links between augmented reality andwearable and ubiquitous computing, he realised his childhood
18 NAIST Research Highlights© TedX Adelaide

Information
Information
ScienceScien

F E AT U R E

Information
Information
ScienceScien© TedX Adelaide

ambitions were already coming to life. “Professor Gudrun Klinker
was actually making this idea happen, which was very inspiring
for me,” Sandor recalls. “It was a very important juncture in
my career.”
In 2004, Professor Steven Feiner, who directs the Computer
Graphics and User Interfaces Laboratory at Columbia University,
agreed to be Sandor’s associate PhD supervisor.
“Professor Feiner is a pioneer of this field,” Sandor says. “He’smentored me a lot since then. I discuss every job offer with him.”
After completing his PhD in the United States, Sandor went towork at the Tokyo research headquarters of Canon, the Japanesemultinational that specialises in imaging and optical technology.
“At that time, Canon were by far the industry leaders in this area
so I spent 2 years in Japan as a researcher,” Sandor says.
He then moved to the other side of the world, to Australia,
where he founded the Magic Vision Lab at the University of South
Australia in the city of Adelaide.
Industry collaborations on cutting-edge technology withmultinational giants, Samsung and Google, followed. Despite
substantial career success, however, Sandor still felt he could
achieve more in a different research environment and in 2014
accepted an opportunity to work alongside Hirokazu Kato,
heading up NAIST’s Interactive Media Design Laboratory. The
institute’s drawcards were reduced teaching obligations, strong
funding levels and atmosphere of intellectual freedom.
“When I was in Australia, I was teaching 12 hours a week. Now,
I teach 12 hours a year,” Sandor says, explaining the appeal of the
NAIST model. “This is fantastic because I have so much moretime to do research. No professor I talk to, whether from America,
Europe or China, can believe this.”
Sandor also appreciates NAIST’s financial resources. “I think in
my first year, I spent more than [I did] in 6 years in Australia,” hesays. “There is a continuous stream of funds from the university
so you’re not completely dependent on government grants, andindustry sponsorship.
“It means I could just sit in my office and have crazy ideas, if I
wanted to. Very few places offer that opportunity.”

Sandor heads a team working on ref ining the augmented
reality experience to make it indistinguishable from actual
reality. “The two most important senses to get right are
vision and touch,” he says. “A major problem for all augmented
reality products is establishing a realistic depth of f ield. All
the headset displays that are currently available suffer fromthis problem.”In the real world, when an eye refocuses beyond an object itwill become blurry, he explains. However, in the virtual world, allobjects remain in focus. “So just by refocusing your eye you can
immediately tell what is virtual and not virtual,” Sandor says. “Ourlab now has a prototype that means when a person refocuses,
the computer graphics will react accordingly. So I think we areleading in this area of research.” (See "Keeping it real in thevirtual world" on page 18.)
Sandor’s team is also making progress in touch, a sensory
area that offers even greater challenges when replicating thehuman experience. “We have a room-sized robot that we canuse to experiment with touching large-scale virtual objects in
a 3 × 3 × 2 metre workspace,” he says. “I don’t think any otherresearch group has achieved that yet.”
As a teacher, Sandor is ver y comfortable with NAIST’spedagogic model. “I do project work with my PhD and master’s
students, which I prefer to the classical classroom teachingstyle. I actually don’t think that [traditional] model works
very well,” he says. “Hands-on work is better than one-way
communication.”
Throughout his career, Sandor has been inspired by his father,
who escaped from communist Hungary in 1956, and created aprosperous life in Germany. “He had nothing,” Sandor explains.
“But within 10 years he was a millionaire in Germany. That was
inspiring for me. The idea that if you work hard you can achieve
anything.
“My ultimate goal is for people [to] experience a world likein the movie The Matrix; a world where digital information andreal things are blended together, so it’s not clear any more what’s
digital and reality.” More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/mi-05-en.html
Researcher: Christian Sandor

NAIST Research Highlights 19

Interactive Media Design Laboratory | Professor Hirokazu KatoAugmented reality

Keeping it real in thevirtual world
Tracking eye movements allows fast calibration ofaugmented reality displays

The eye-imaging camera automaticallykeeps the head-mounted display
calibrated.

20 NAIST Research Highlights© 2016 Kenneth R Moser

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R E S E A R C H H I G H L I G H TS

Information
Information
ScienceScien“

My mission in life
is to build theultimate display.

“To appreciate how computer-madevirtual realities are merging with
our real-world experiences, we canlook to pilots viewing heads-up displaysof flight-paths or Google Glass users
looking through web-based data at realscenes around them.
NAIST has much bigger ambitions
than these. Combining actual and virtual
realities, however, requires calibration
systems to match the movements of auser with their view of the virtual objects
with which they are interacting. Christian
Sandor and colleagues at NAIST’s Interactive Media Design Laboratory have helped
develop a greatly improved calibration technique that can be performed simply, quickly
and needs to be done only once1.
“My mission in life is to build the ultimate
display,” says Sandor, describing his work on
augmented reality systems in which virtual
objects merge with the real world around us.
He wants to build systems that allow users
to be able to manipulate and feel computer-generated objects that can be examined
and altered remotely. This could be useful for
designers, doctors, city planners and anyone
who needs to interact with objects andinformation not directly before them in thereal world.
“The applications are literally endless,”says Sandor, as he talks of concepts now
found only in science fiction. To advanceto more sophisticated options the current
calibration procedures need to be greatly
simplified. Many of the most advanced
systems require the virtual images to beviewed through a headset. Sandor explainsthat putting on a headset and moving yourhead around to calibrate before each use isacceptable for a laboratory environment but
not for general application.
His NAIST team, in collaboration withcolleagues in Japan, Germany and theUnited States, has integrated an eye-tracking system into their augmented reality
headset (see image). This means that after an
initial calibration, the system automaticallyrecalibrates each time it is put on.
Significant challenges remain before
the eye-tracking calibration process canbe incorporated into commercial applications. Some of these concern improving theaccuracy and resolution of the calibration.
Ironically, however, to make the user’s experience ever more lifelike some challenges
involve recreating the limitations of real life.
“For example, we want to make graphics
that get blurred like real objects do whenusers refocus their eyes,” explains Sandor. To
address such challenges, his work towards
the ultimate display continues.
Reference
1. Moser, K., Itoh, Y., Oshima, K., Swan, J. E.,
Klinker, G. & Sandor, C. Subjective evaluation of asemi-automatic optical see-through head-mounted
display calibration technique. IEEE Transactions on
Visualization and Computer Graphics, 21, 491-500,
March 2015

*To read more about the career ofChristian Sandor, one of NAIST’s
newest researchers, see Blurring
the edges of reality on page 18.

More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/mi-05-en.html
Researcher: Christian Sandor

NAIST Research Highlights 21

Information Science

IMPACT
Augmented Human Communication Laboratory | Professor Satoshi Nakamura© TarikVision/iStock/Getty Images Plus/Getty

Statistics to remove
language barriers

22 NAIST Research Highlights

NAIST Research Highlights 23

Information Science

BIG DATA AND
ALGORITHMS AREHELPING TO MAKE
SIMULTANEOUS
SPEECH-TO-SPEECH
TRANSLATION AREALITY

Information Science“

24 NAIST Research Highlights

Projects Agency (DARPA) has been investigating
speech-to-speech translation for use by defence
personnel, while the European Union has been
looking at it for use in its multilingual parliament.
Separately, Microsoft has been working at speech
and text translation for use as part of applications
such as Skype.
Nakamura has been at the forefront of the field
since he received his bachelor’s degree from the
Kyoto Institute of Technology in 1981 and joined
the Sharp Corporation to help create a voice-activated word processor. “I
was very much attracted to the study of the human perception or humanunderstanding by computer,” he explains. He was soon seconded from
Sharp to be part of Japan’s first national speech translation project, theAdvanced Telecommunications Research Institute International (ATR).
He received his PhD on that research from Kyoto University.
At the time, machine translation was largely a rules-based process,revolving around guidelines devised by linguists who set out whatshould happen when one language was translated into another. However,
Nakamura was among the global research leaders to drive the shift inthe early 21st century from the handcrafted rules-based model to themodern statistics-based model.
The statistical model has little need for linguistics and instead focuses
on a corpus — or huge databank — of parallel sentences in each language,
which is analysed to guide translations. “Once we collect a huge amountof data, the computer can determine the rules automatically,” Nakamura

We are working
on knowledge
acquisition from the
web and knowledge
acquisition from thehuman being.

“Researchers in NAIST’s Augmented
Human Communication (AHC) Laboratory are pushing technological and international boundaries to boost the speed and accuracy with which computers convert spoken words
from one language to another.
“We are aiming to beat the human interpreterwith our speech-to-speech simultaneoustranslation,” explains AHC Laboratory director,
Satoshi Nakamura, one of the world’s leading
speech recognition and translation technology developers. AHC isa NAIST Super Research Group; established in 2011 with the broad
agenda to ‘go beyond the communication barrier’ and examine ‘next
generation big data analytics’. The two areas are closely linked, says
Nakamura, with big data increasingly being incorporated into the mosteffective and accurate translation systems.
Speech-to-speech translation is a three-step process. The initialspeech recognition must first be performed as accurately as possible by
the computer. Then the computer must translate what has been said into
the target language, via a process known as machine translation. Finally,
the computer synthesises the translated words into speech recognisableby the end-user.
Nakamura says the prospect of being able to have one’s words translated
automatically into another person’s language has long been a dreamfor humankind. It’s an area of strong government and industry interest
across the world. In the United States, the Defense Advanced Research

Information Science© 2016 Satoshi Nakamura

CAPTIONxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxx

says. Putting this into practice in 2007, Nakamura and his colleagues
created the world’s first network-based speech-to-speech translation
service for 3G mobile phones — the NTT Docomo 905i — at ATR.
And in 2010, they created VoiceTra for the iPhone at Japan’s National
Institute of Information and Communications Technology (NICT).
Both are designed to cater for travel-related translation, relatively
short sentences of between two people at most, and have been accessed
many millions of times. These applications, however, are limited by
the need for translations to be done on a sentence-by-sentence basis
to prevent misunderstandings. This significantly slows the process, as
the translation of each sentence cannot begin until the previous one has
been completed.
At NAIST’s AHC Laboratory, researchers are now working to look forways of overcoming this delay. They’re looking to have the technology
break up the sentences it ‘hears’ and, using algorithms, determine theprobability of what the sentence will mean when complete, to come up
with the most accurate translation.
At the same time, the accuracy of any translation is dependent on thesize of the databanks of the original and target languages. To increase thesize and scope of the language data stored, the AHC lab has an ambitious
plan to be able to include information drawn from the internet. This isbeing done as part of the NAIST Big Data Project. “We are working on

knowledge acquisition from the web and knowledge acquisition fromthe human being,” Nakamura says. “And trying to determine how we
can generalise the knowledge in order to use this knowledge to improve
speech translation quality.”
Prior to Nakamura’s 2011 move to NAIST, he was a leader ininternational efforts to engineer compatible international networked
translation systems. This is to ensure that the massive language
databanks being created can be accessed internationally and enablemultilingual translation of as many as possible of the world’s morethan 6,000 languages. He has helped devise standardized international
communication protocols as part of the Universal Speech Translation
Advanced Research (U-STAR) Consortium.
“It is very important to extend the speech-to-speech technology tovarious countries and their languages,” Nakamura observes. This entails
ongoing work with NICT and equivalent organisations in countries
across Asia and the rest of the world.
Nakamura says he is now approaching one of his original researchgoals, to determine how human beings, and therefore computers, canunderstand speech.
“The interesting thing is that there are a lot of differences between
the cultures and languages,” he notes, “but all of these factors can beconsidered in speech-to-speech translation.”

More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/mi-02-en.html
Researcher: Satoshi Nakamura

NAIST Research Highlights 25

Internet Engineering Laboratory | Professor Suguru Yamaguchi

Cyber behaviour

Eyes open to
online security
An internet web user’s gaze is linked to their likelihood of fallingprey to online phishing scams

B

y tracking eye movements during
online activities, NAIST researchers
have identified the browsing habitsthat could be putting users at risk of online
fraud1. The findings have the potential toplug one of the largest gaps in web security— user behaviour.
Online businesses invest heavily insecuring websites for users. Financial
institutions, for example, rely on extremely

high levels of security for online banking.
Such systems are generally resistant tohacking attacks. But organizations remain
largely powerless to prevent users from being
deceived by so-called ‘phishing’ scams that
directly target their clients.
A typical phishing attack occurs whena user is directed to a bogus website thatis a carbon-copy of a legitimate site andduped into entering login details, which

can then be used by criminals. Althougha phishing attempt can be easily identified
by confirming the legitimacy of the web
address before entering any personal details,
it remains one of the most prevalent andsuccessful of online scamming methods.
Youki Kadobayashi from NAIST’s
Internet Engineering Laboratory andproject colleagues, Daisuke Miyamoto,from the University of Tokyo, andGregory Blanc from Telecom SudParisdrew on cognitive psychology insights
to explore whether users display tell-talesigns that they might be susceptible to suchattacks. Their investigation was conducted aspart of the international NECOMA project,a cyber-defense research collaboration
between the European Union (EU) andJapan. And, in a rare arrangement, it was
supported by the EU’s main instrument
for research funding, the Horizon 2020
program (formerly the FP7 — Seventh
Framework Programme for Research andTechnological Development).
“Even experienced users can be at risk,”Miyamoto explains. “When told that there
has been suspicious activity on an online
account, users’ primary focus is on logging
into the account to check for theft, notevaluating whether the notification itself is apotential phishing attack.”
The research team set up a series ofexperiments to investigate whether the
movement of a user’s gaze around a web
page could be used to flag browsing
behavior that was putting them at risk ofphishing. Using a software application thattracked eye movements via the computer’scamera, the researchers were able togenerate ‘heat maps’ of a user’s gaze (seeimage) that told much about their level of
security risk.
“We found that novices do not look at
the address bar and do not have rigorous
criteria for evaluating phishing,” Miyamoto
says. “This system could be used to warn
users when they are not being wary
enough, without being intrusive or blocking
potentially legitimate websites.”
The researchers are now developing abrowser extension that interacts with eyetracking devices to monitor user activity andphishing risk. 
Reference1.

Eye tracking shows that when presented with a web page, expert web users spend most of their timeevaluating the address bar. Novice users focus, instead, on page elements such as logos.

Miyamoto, D., Blanc, G. & Kadobayashi, Y. Eye cantell: On the correlation between eye movement andphishing identification. Proceedings of the 22nd International Conference on Neural Information Processing(ICONIP) 223–232 (2015).

More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/cs-07-en.html
Researcher: Youki Kadobayashi

26 NAIST Research Highlights© weerapatkiatdumrong/iStock/Getty Images Plus/Getty

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© PeopleImages/Digital Vision/Getty

Mathematical Informatics Laboratory | Professor Kazushi Ikeda

Where our gaze falls seems to reveal our expertise.

Informatics

More to viewing art
than meets the eye
Artists may extract visual information from different and deeper features in paintings than art novicesW

hat do our eyes do when we lookat a painting? Research suggests
the answer depends on the viewers’
expertise, a finding with surprisingly wideranging implications1. Differences in the way
people look at a work of art could hold clues
to the processes going on within a viewer’s
brain. The insights gained by NAIST scientists
studying this issue may be applied to manyother situations when the way we view a scene
is influenced by our expertise and experience.
Naoko Koide is now part of the researchteam in Kazushi Ikeda’s Mathematical
Informatics Laboratory at NAIST. But her
first degree was in fine art and she is intriguedby how people view art . . . literally. “Naoko
wondered why and how artists and art
novices were different,” Ikeda explains. “Shejoined my lab to study the differences using
neuroscientific methods.” The NAIST teamtackled the challenge along with co-workers

at the National Institute of Information andCommunications Technology, in Osaka, andKyushu Institute of Technology, in Fukuoka.
The researchers used a commercial eyetracking system based on infrared camerasthat record where a subject’s gaze is focused attime intervals of 100 milliseconds. The subjects
were six art students with a high level of artistic
ability and experience, and eight novices withno art expertise. To prevent any influence fromdepictions of obvious real-life objects, they
viewed a variety of abstract paintings. Digitizedversions of the paintings were used to classify
the most obvious and striking aspects of each.
The gaze of the art student ‘experts’ was foundto be more widely focused on the paintings asa whole, compared to the novices who focusedmore on the obvious features.
“Our results suggest artists may extract
visual information from paintings based onhigh-level features,” Ikeda says.

By this he means that the artists’ knowledge
and experience leads them to look beyond themost obvious visual stimuli in a painting andpay more attention to deeper details.
“Artists are an example of experts,” headds, and so they may reveal insights into the
behavior of many kinds of experts. Ikeda is
now investigating other activities in which
visual attention is crucial, such as driving
a vehicle.
It may eventually become feasible to detect
whether or not someone has specific expertiseor experience just by monitoring their gaze.
How we look at things, it seems, may reveal
secrets about what we know.
Reference
1. Koide, N., Kubo, T., Nishida, S., Shibata, T. & Ikeda,
K. Art expertise reduces influence of visual salienceon fixation in viewing abstract paintings. PLOS One
10, e0117696 (2015).

More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/ai-04-en.html
Researcher: Kazushi Ikeda

NAIST Research Highlights 27

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RESEARCH HIGHLIGHTS

Ubiquitous Computing Systems Laboratory | Professor Keiichi Yasumoto

Yutaka Arakawa

Embeddedin life
The iPhone changed everything forthis ambitious inventor who
is using information
to tweak humanbehaviourAs a child, computer scientist Yutaka Arakawa
spent a lot of time making things in a ”secretlab space”, where he tinkered with a soldering
iron creating electronic gadgets.
It was a portent of things to come. “In mymind, I’m not a true scientist,” he says of thedirection his professional life has taken. “Butan engineer with academic knowledge.”
Arakawa spent the first 12 years of his science career at Tokyo’s
Keio University, where he gained his PhD in engineering andmoved swiftly up the ranks to become an assistant professor.
“In the early part of my career, I was researching the highspeed broadband network, and how the network could work more
efficiently,” Arakawa recalls, describing it as an “interesting but
heavy” research field.
“It required a massive budget and lots of cooperation withcompanies. If you proposed an improved method, then the process
would need to be standardized before it could be distributed,”he says, explaining that because there were many researchers
working together, the contribution of each became diluted.
“I felt this kind of research was good for the company, but badfor young researchers.”
In his spare time, Arakawa was developing applications andwebsites for fun. And soon his desire to make an individual
contribution to the fast-developing digital communicationsindustry became overwhelming.
28 NAIST Research Highlights

During his PhD studies, the young scientist had been working
as a software engineer at a technology company. But after several
years, Arakawa realised that as fast as he could develop a newidea, his commercial competitors would catch up. “Technologies
evolved every year, so it was exciting, but I felt unstable,”he says. “Any small technical advantage was soon used byother companies.
“At this point I received some good advice. My PhD supervisor,
Naoaki Yamanaka, a professor at Keio University, encouraged
me to keep exploring novel technology in an academic position.
He told me to find a great technical advantage for establishing astrong commercial company,” Arakawa says.
He knew Yamanaka was right and in 2006 Arakawa accepted
an assistant professor position at Keio where he began exploring
new technology that could help him establish his own company
in the field of computer networks. “It was not easy. In two years I
couldn’t find an idea,” he says. “Then the iPhone came along, andI decided to change my research topic drastically from computer
networks to smartphone technology!”
Arakawa began exploring ubiquitous computing systems —where sensors and wireless networks are incorporated directly
into our lives via the world around us, and everyday items haveembedded microprocessing technology.
“This decision changed my life. I succeeded in getting a newposition with Kyushu University [in Fukuoka], in 2009,” he says.
“I found the new research topics interesting and had many

© 2016 Yutaka Arakawa

Information ScienceF E AT U R E

Information Science
good ideas. In 2011, I won an international
scholarship to study in France and Germany for
15 months.”
Soon after returning to Japan in 2013,
Arakawa joined the cutting-edge Ubiquitous
Computing Systems Laboratory at NAIST
and he’s become passionate about developing
sensors that allow people to increase theirself-awareness.
“To understand a human by using various
sensors is very interesting to me. And I love
wearables,” he explains. “It is so exciting tocreate a new service that can be installed into
any user’s smartphone or gadget to give them a
new experience.”
For scientists such as Arakawa, whose work
must keep pace with heavily resourced global
IT companies, f inding the right research
environment is key. “Creativity, implementationand speed are the important points. In our field,
Apple and Google are very powerful leaders.
They have lots of money, and stimulating work
environments,” Arakawa says. “Therefore, wemust propose novel and creative ideas to matchthem, and also create a productive workplacewith excellent facilities.
“ I n m y l a b a t N A I S T w e a r e l u c k y.
Researcher s have big budgets, and areencouraged to explore innovative research
topics. We have created a good, collaborative
atmosphere where students stay late, chatand forge friendships, while working on
breakthrough science.”
Arakawa’s team is made up of scientists
whose skills complement one another. “InJapan, one professor generally manages one

laboratory. But at NAIST, the professor teams
up with an associate professor and two assistantprofessors to manage one laboratory,” he says.
“All of them work together for one goal without
question. Only a few universities in Japan havethis style, and it’s one of the reasons I wanted
to work here.”
Arakawa says that this style of collaboration
helps move his research forward more quickly.
“For example, I’m not good at analysing thedata from my work. So in the past, my research
has stopped when I no longer have the skills
to take an idea further,” he says. “Now, I cancollaborate with my assistant professor who
is an expert in data mining. This leads to newknowledge that we can use to propose a newresearch application.”
Arakawa is now close to preparing his first
product for market, a small sensor board that hehas been developing for the past decade. And
his research focus is shifting towards the next
step for his field — computational intervention.
(See "Playing with urban sensing" on page 30.)“This is when our behaviour is changed byinformation,” he says explaining that a simple
example is a recently launched location-based
mobile game called Ingress. “Participants movein the real world based on the information fromthe internet. The game tells players to visit
places in order to get points, so it encourages
exploration and exercise.”
To Arakawa, such an intervention is the
beginning of a deeper conversation: “We startconsidering how we can evoke changes inhuman behaviour, and encourage behaviours
that are more sustainable for society.”

More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/cs-03-en.html
Researcher: Yutaka Arakawa

NAIST Research Highlights 29

Ubiquitous Computing Systems Laboratory | Professor Keiichi Yasumoto

Ubiquitous computing

Playing withurban sensing
Using crowds to collect data is an invaluable resource for planning andpublic health, and these researchers want to make it fun

Ranking system

Badge system

Badge level
User rank (highlighted)
Collected badge list

Badges and rankings from a smartphone app that ‘collects’ the brightness of street lamps.

30 NAIST Research HighlightsResearchers working on urban planning,
environmental monitoring and publichealth issues have turned to crowdsof people with smartphone, to collect andanalyze data on a scale beyond anything
previously possible.
It’s called ‘participatory sensing’ andbecause it relies on volunteers’ willingness
to submit accurate, up-to-date information,
incentives are needed to maintain continued
user involvement.
Money is one obvious lure, but withresearch budgets typically limited, two
NAIST information technology experts
have applied game play techniques tomotivate engagement. “I want to makesensing more fun by introducing gamification,” explains Yutaka Arakawa
from NAIST’s Ubiquitous Computing
Systems Laboratory.
In an invited commentary in the Journalof Information Processing, Arakawa and colleague Yuki Matsuda liken the problem of
encouraging participatory sensing to sailing1.
The yacht could be fitted with an engine, but
the gasoline to run it would be expensive.
Gamification, they argue, provides a natural

Reprinted from Ref 1, Copyright 2016, with permission from the Information Processing Society of Japan

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Information Science© Artur Debat/Moment/Getty

energy source — the wind in the sails, as
the metaphor goes — although the moving
yacht must continuously resist the “splashing waves” of disinterest and dissatisfaction
from users.
The authors discuss two gamification
experiences from their own participatory sensing research that deal with these“splashing waves”. In one study, Arakawa
and colleagues asked participants to reportvarious features of the surrounding environment with photographic or textual explanations; using points, titles and rankings tokeep people immersed in the task at hand.
The other, from Matsuda and a collaborator,
called for participants to collect informationon the brightness of street lamps, integrating
badges, rankings and maps to provide similar
incentives for involvement.
In these two instances, the gamification elements worked “so-so,” Arakawa
admits. “There are many issues that shouldbe improved.” But generating more funand value for participants is not easy. “Thebalance of game and sensing is a difficult
issue,” he says. But it’s not insurmountable.
Arakawa points to the community-based
traffic and navigation app Waze, which iswildly successful with more than 50 million
drivers worldwide uploading informationsuch as the price of gas or location of
accidents. He expects many more similar
platforms to trickle into our lives.
“Various human activities promoted
by gamification would be helpful for our
future,” Arakawa says. “If we successfully
introduce ‘fun’ into various social problems,
I expect that gamification will be one of themost important ingredients for a smart andsustainable society.”
Reference
1. Arakawa, Y. & Matsuda, Y. Gamification mechanism for enhancing a participatory urban sensing:survey and practical results. Journal of Information
Processing 24, 31–38 (2016).

*To read about the inspiration
behind the work of Yutaka
Arakawa, another of NAIST’s
newest researchers, see
Embedded in life p28.

More information about the group's research can be found at http://isw3.naist.jp/Contents/Research/cs-03-en.html
Researcher: Yutaka Arakawa

NAIST Research Highlights 31

Biological
SciencesBiological Sciences

IMPACT
Functional Genomics and Medicine Laboratory | Associate Professor Yasumasa Ishida

Search for a sense of
self in immunity© luismmolina/E+/Getty

NEW RESEARCH AIMSTO ANSWER ONE OF
MEDICINE’S BIGGESTQUESTIONS: HOW DO THE
BODY’S IMMUNE CELLS
DETERMINE WHAT IS SELF
AND WHAT IS NOT?

NAIST Research Highlights 33

Biological SciencesT

he immune system’s ability to identify what to tolerate and what
to attack is a puzzle that has gripped laboratories worldwide for
decades. At NAIST, the Functional Genomics and Medicine
Laboratory, led by Yasumasa Ishida, is at the forefront of this researchwith new investigations of the PD-1 gene that effectively switches parts ofthe body’s T-cell immune response on and off.
This work has the potential to transform
medicine, from transplants and the treatmentof autoimmune diseases and cancers, tovaccines and chronic disorders. “No one doubtsthat PD-1 plays some kind of pivotal roles in‘self–nonself ’ discrimination by T cells,” Ishida
explains. “We are trying to elucidate its real
physiological functions to better explain its rolein cancer and other diseases and so enable more
effective and less-damaging treatments.”
It was Ishida who first identified the PD-1
gene, in 1991 when he was an assistant professor
at Kyoto University, under the supervision of Tasuku Honjo. At the time,
there was a global race to find the genes that caused cells to undergo‘programmed cell death’ as part of normal development. This happens ona large scale to immature T cells in the thymus, as part of the body’s effort
to weed out ineffective or overaggressive immune cells.
Ishida’s interest in immune research was sparked during his medical“

training, when he became fascinated by the mechanisms behind graft
rejection in transplant patients. “I wondered why the same humantissues are rejected by our immune system and I strongly wished tounderstand the molecular mechanisms with which our T lymphocytes –the conductor of the immunity orchestra — could distinguish ‘self ’ from‘nonself ’,” Ishida says.
At Kyoto he used the then relatively new
genetic analysis technique, subtractive
hybridization, to try to determine what geneor genes in T cells were being expressed when
the cell deaths occurred. His work identified
the single gene that he labelled the PD-1 gene,for programmed death. However, not longafterwards it was found that the expression ofthis gene, also called PDCD1, did not induce
cell death but instead stopped the immune
response of T cells.
Expression of the gene creates the signalling
protein, PD-1, that forms a receptor on the surface of the T cell. When
this receptor is linked with one of its ligands — PD-L1 or PD-L2 — ittriggers inactivation of the cell’s immune response, stopping it fromdestroying cells it would otherwise attack.
In the case of melanoma, renal, lung and blood cancers, and potentiallymany others, the tumours appear to use PD-1 signalling to stop thePD-1 appears to beprotecting cancer
cells from attack by
the immune system.
Is PD-1 on our side,or on the side ofcancer cells?

“

34 NAIST Research Highlights

Biological Sciences© MedicalRF.com/Getty

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immune system attacking them. Recent breakthrough immunotherapies
block the PD-1 signal, using a PD-1 or PD-L1 antibody to prevent thecancer cells triggering PD-1 activation, and allowing the body’s T cells to
attack tumours. When successful, the altered T cells become serial killers
and even a small number can wipe out a large tumour.
These new immunotherapies have been led by PD-1 antibody drug,
nivolumab — which has been approved since 2014 and 2015 by the US
Food and Drug Administration for use as a targeted therapy to treat
melanoma and certain lung and kidney cancers. Nivolumab has beenyielding outstanding results in people with metastatic cancers that haven’t
responded to other treatments. In many cases it has been shown to cause
aggressive tumours to shrink rapidly before disappearing. The benefits
appear to be long-lasting, without the need for ongoing intense treatment.
Alongside this, there is a mounting body of research from the UnitedStates, Australia and India suggesting that PD-1 might also be central
to chronic conditions such as HIV, hepatitis, tuberculosis and malaria.
Further evidence indicates that PD-1 also plays critical roles in theregulation of autoimmunity, transplantation immunity, allergy andimmune privilege.
In addition to cancer immunotherapies, pharmaceutical companies
are looking into the development of new PD-1-related drugs for thetreatment of autoimmune conditions such as rheumatoid arthritis; using
the stimulation of PD-1 to prevent the immune system from attacking
the normal host cells.
“PD-1 appears to be protecting cancer cells from attack by the immune
system. Is PD-1 on our side, or on the side of cancer cells?” Ishida asks.
“Why do almost all of the ‘bad guys’ — cancer cells, chronically virusinfected cells, Mycobacterium tuberculosis, malaria parasites, and more
— target PD-1 for their long-term survival in our body? These are theremaining unanswered questions.”
At the NAIST Functional Genomics and Medicine laboratory, Ishida
and his colleagues are now focussed on creating a coherent explanationof how the PD-1 gene influences the immune system. Their hypothesis isthat the gene plays a pivotal role in how the body distinguishes between
what is self and what is foreign. To test this, the lab is using functional
genomics to further investigate when and why the PD-1 gene is expressed
and what impact this has on the body over time.
These questions have personal significance for Ishida. He explains: “I
am obliged to carry out this project because explanation of the molecularmechanisms involved in self–nonself discrimination by the immune
system was the ultimate goal for me from the very beginning of my career
as a scientist.”

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses211.html
Researcher: Yasumasa Ishida

NAIST Research Highlights 35

Molecular Immunobiology Laboratory | Professor Taro Kawai

Molecular immunity

On the pathway tosuccessful therapies
Molecules that trigger innate immunity could be potential targets for
new antiviral drugs

36 NAIST Research Highlights© Jezperklauzen/iStock/Getty Images Plus/Getty

Biological Sciences

R E S E A R C H H I G H L I G H TS

“W

hen a person is infectedby a virus or otherpathogen, the immune
system must be activated quickly for
it to detect invading cells and prevent theinfection spreading. Researchers at NAIST
are investigating this response, focusing
on the role of individual proteins andlipids and how they aid the work of innate
immune receptors1.
It is the job of innate immune receptors,
including RIG-I-like receptors (RLRs), tosense pathogen replication within cells
and trigger the production of the body’s
protective agents, such as type 1 interferon(IFN). Taro Kawai from NAIST’s Molecular
Immunobiology Laboratory and colleagues
are investigating the molecules responsible
for triggering and regulating innate immune
responses, with the goal of developing new
antiviral and anticancer therapies.
“By understanding the molecularmechanisms and signalling processes thatlead to the production of IFN, we can findways of boosting the body’s natural immunity
in the face of illness,” Kawai explains. In
2013, he and his co-workers uncovered therole of a lipid called phosphatidylinositol-5phosphate (Ptdlns5P), which plays a key partin activating IFN production2. They foundthat levels of Ptdlns5P, which is produced
from a kinase called PIKfyve, increase
rapidly upon viral infection. Ptdlns5P thendirectly binds to the transcription factor
IRF3 and its associated kinase TBK1. Thisin turn activates the signalling pathway thatinduces IFN.
Knocking down PIKfyve resulted indecreased Ptdlns5P and IFN levels, leading
to a rise in viral replication. Perhaps mostimportantly, the researchers found that when
they added an artificial version of the lipid,
called C8-Ptdlns5P, to a vaccine, they wereable to significantly boost immune responses

in mice. “Ptdlns5p might be a good target
for the design of vaccines against viruses like
Influenza A,” Kawai says. “Further in-depth
analysis of C8-Ptdlns5P will tell us more.”
Kawai’s other recent work includes thediscovery of a protein crucial to the correctfunctioning of RIG-I-mediated innate
immunity. Kawai’s team believes that thesignificance of the protein, known as MEX3C,
means it could be targeted for inactivation by
evolving viruses3.
Although RLRs help protect the bodyagainst invading pathogens, a carefullybalanced regulatory system is needed tomediate their behavior and prevent thedevelopment of excess inflammation andautoimmunity. Kawai is working to pinpoint
the key players in this regulatory system,and his findings may one day guide thetreatment of inflammatory diseases such as
multiple sclerosis. He hopes that in future
it will be possible to enhance natural innate
immunity via designed therapies inspired bysuch research. 
References
1. Kitai, Y., Takeuchi, O., Kawasaki, T., Ori, D.,
Sueyoshi, T., Murase, M., Akira, S. & Kawai, T.
Negative regulation of melanoma differentiation-associated Gene 5 (MDA5)-dependent antiviral innate
immune responses by Arf-like Protein 5B. The Journalof Biological Chemistry 290, 1269–1280 (2015).
2. Kawasaki, T., Takemura, N., Standley, D.M., Akira, S.
& Kawai, T. The second messenger phosphatidylinositol-5-phosphate facilitates antiviral innate immune
signaling. Cell Host & Microbe 14, 148–158 (2013).
3.

Kuniyoshi, K., Takeuchi, O., Pandey, S., Satoh, T., Iwasaki, H., Akira, S. & Kawai, T. Pivotal role of RNA-binding
E3 ubiquitin ligase MEX3C in RIG-I–mediated antiviral
innate immunity. PNAS 111, 5646–5651 (2014).

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses209.html
Researcher: Taro Kawai

NAIST Research Highlights 37

Biological Sciences“

By understanding
the molecularmechanisms and signalling
processes that lead to the
production of IFN, we can findways of boosting the body’s
natural immunity.

Applied Stress Microbiology Laboratory | Professor Hiroshi Takagi© Ryo Nasuno, 2016

Biological Sciences

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Using structure-based molecular design, NAIST researchers have created the thermostable yeast
protein Mpr1 that could increase tolerance to heat stress of industrial yeasts.

Molecular design

Brewing aheat-loving
yeast species
The crystal structure of a protein is helping generate
yeast strains with increased stress tolerance

38 NAIST Research Highlights

Biological Sciences“

The support of a multidisciplinary team at
NAIST enabled us
to visualise Mpr1 inatomic-level detail.

“© Science Photo Library - STEVE
GSCHMEISSNER/Brand X Pictures/Getty

Yeasts have been used for centuries forindustrial applications such as foodproduction and there is much potential in developing strains capable of withstanding heat shock, freezing temperaturesand ethanol treatment. NAIST scientists havebeen exploring the structure and functionof individual molecules within yeast species
and using their results to generate morerobust modern strains.
Recently, Hiroshi Takagi, head of NAIST’s
Applied Stress Microbiology Laboratory, andco-workers have been examining an unusual
yeast protein from the Gen5-related N-acetyltransferase (or GNAT) superfamily called
Mpr1, homologs of which are found in most
species of yeast and fungi.
They have established that in Saccharomyces cerevisiae — a yeast species that’s
been used for centuries in wine and breadmaking and brewing — Mpr1 reduces levelsof reactive oxygen species in cells via theconversion of an imino acid known as P5C,
and this lends a degree of protection fromenvironmental stresses.
Mpr1 also appears to mediate a
metabolism process that results in thecreation of nitric oxide, another aid toincreased tolerance.
In 2013, Takagi and his team successfully
visualized the crystal structure of Mpr1 andits complex with substrate cis-4-hydroxy-Lproline (CHOP) in high resolution for the
first time1. Their findings have since allowed
the team to work on Mpr1 mutant forms ofyeast with higher heat tolerance.
“It took considerable time and repeatedattempts to achieve crystallization of Mpr1 at
a high enough quality to determine its structure,” explains Ryo Nasuno, Takagi’s graduate
student. “The support of a multi-disciplinary
team at NAIST enabled us to visualise Mpr1
in atomic-level detail.”
The researchers found that, while Mpr1
shared a folding structure with other GNAT
proteins, it exhibited a unique reaction
mechanism. The team was surprised to
discover that Mpr1 uses one of its own
amino acid residues, Asn178, as a catalyst— a unique feature. A further amino acid,
Asn135, plays a critical role in substrate recognition and directly binds Mpr1 to CHOP.
“We then examined the roles of Asn135
and Asn178 in more depth by creating

mutant forms of Mpr1,” Nasuno says.
“Making these amino acid substitutions hada knock-on effect on levels of P5C. These
insights helped us learn how to manipulate
yeast cells’ reaction to heat stress.”
Takagi and his team have recently
designed Mpr1 mutants with higher thermostability based on the crystal structureof Mpr12. They also hope to breed newindustrial yeast strains with the ability tosupport fermentation at higher temperatures. Their insights into the antioxidative
properties of yeast mediated by Mpr1
could also help with the development ofanti-fungal drugs.
References
1.

Nasuno, R., Hirano, Y., Itoh, T., Hakoshima, T., Hibi, T. &Takagi, H. Structural and functional analysis of the yeast
N-acetyltransferase Mpr1 involved in oxidative stress tolerance via proline metabolism. Proceedings of the National
Academy of Science USA 110, 11821–11826 (2013).

2.

Nasuno, R., Hirase, S., Norifune, S., Watanabe, D. &Takagi, H. Structure-based molecular design for thermostabilization of N-acetyltransferase Mpr1 involvedin a novel pathway of L-arginine synthesis in yeast. The
Journal of Biochemistry 159, 271–277 (2015).

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses305.html
Researchers: Ryo Nasuno and Hiroshi Takagi

NAIST Research Highlights 39

Plant Symbiosis Laboratory | Associate Professor Satoko Yoshida

Satoko Yoshida

Planting seeds of
wisdom
A career spent looking for answers in the natural world continues
on a prestigious path
40 NAIST Research Highlights© 2016 Satoko Yoshida

Biological Sciences

F E AT U R E

Biological SciencesW

hile she was at high school, Satoko
Yoshida began noticing that her
biology textbook was sometimes
short on facts. More than a decade
later, she’s about to join NAIST’s
G ra d u a te S c h o o l o f B i o l og i c a lSciences as a tenure track associate
professor and it’s f itting that she’s
chosen an institute with a reputation for rewriting text books.
“I remember that some of the descriptions in my books were
ambiguous,” Yoshida recalls. “For example, one text read: ‘The
presence of a flowering hormone is expected, but hasn’t beenfound.’” In 2007, the late NAIST plant molecular geneticist,
Ko Shimamoto, found the first such hormone, a protein known as
florigen Hd3a, which induces flowering in rice.
“Until that point I believed that textbooks must contain only
facts,” Yoshida says. “But then my high school teacher pointed outthat information had changed even since the book was written.”
Yoshida — a plant biologist with particular expertise inmolecular biology, genetics and genome biology — specialises
in parasitic plants. Fascinated by the diversity and flexibilityof botanical structures, she has focused her research on plant
symbiosis: the phenomenon of organisms living in close association with each other, often to the detriment of one but benefit tothe other.
“I have always been interested in plant science, but my current
research f ield is entirely a coincidence,” Yoshida says. After
finishing her PhD on leaf senescence at the University of Tokyo,
she felt that her research area was becoming crowded.
“I was working on Arabidopsis and at that time the research
field was becoming more competitive,” she says, referring to
the flowering plant Arabidopsis that is used as a model system inbotanical genetics. Yoshida shifted her attentions to the species
Lotus japonicus and plant symbiosis, when she accepted a postdoc
position at The Sainsbury Laboratory in the United Kingdom. She
became fascinated by inter-organism interactions and fortunately
her path crossed with that of molecular biologist, Ken Shirasu,
who specialised in the area. At the time he was a group leader in
the Sainsbury lab and he went on to become Yoshida’s mentor forthe next decade.
After leaving the United Kingdom, Shirasu became a groupdirector at the Japanese research institute, RIKEN, and encouraged
Yoshida to join him. Within a decade she had become a seniorresearch scientist at RIKEN’s Center for Sustainable Resource
Science. “Ken invited me into the world of parasitic plants. He
supported me for almost 10 years in RIKEN,” Yoshida says of her
long-time mentor. “He taught me how big the agricultural problemof parasitic plants is and explained how only a few laboratories areworking on the molecular biology of parasitic plants. He let mework freely as I liked.”
The parasitic plants that Yoshida is currently studying include
Striga spp, some of which are major agricultural pests, andPhtheirospermum japonicum. (See Exploring the secrets of parasitic
plants p42). Because some species of Striga cause twisted growthand discolouration in the plants they infect, the group has thecommon name of witchweed.
“We are trying to understand the molecular mechanisms ofplant parasitism; how they recognise host plants, develop theinvasion organ and connect compatible vasculatures between
plants,” Yoshida says. “We are also working on how to make hostplants resistant, in order to prevent parasitic weeds from taking
over.”In recent years, Yoshida and her team have been working onplant models to identify the genes that regulate parasitism. “We
can now identify mutated genes by a process of forward genetic
screening,” she explains. “During the last few decades, mutation
identification has become easier and can be done in a shorter
time. You used to only be able to do it in model species. But now,
because sequencing techniques have improved dramatically, anyplants can be sequenced.”
Yoshida hopes that future analysis of plants at the molecularlevel will lead to breakthrough developments in scientists’ understanding of plant diversity. After a decade working at RIKEN,
Yoshida will this year move to NAIST and is excited about what
this will mean to the next stage of her career.
“NAIST scientists and the facilities are some of the best in theworld. I think that if you gather top-class professors in the samebuilding then this synergy will increase the quality of science
output,” Yoshida says. “People with diverse skills and expertisehave a very positive effect on the progress of research.”
Having worked closely with mentors for much of her career,
Yoshida understands the importance of close professional relationships between professors and students. “The students at NAIST
are very motivated and high calibre, which makes it an attractive
place to work for me,” she says. “Because there are no undergraduate courses, all students actively decide to come to NAIST.
So that focus on science discovery and education is decisiveand clear.”
Yoshida believes that scientists need to remain fresh to thechallenge of pushing the boundaries of research throughout theircareers. She points out that many subject areas require decades of
exploration before yielding results.
In 1966 for example, Yoshida explains, researchers identified aclass of compounds known as strigolactones, secreted from theroot systems of certain weeds that were found to germinate theseeds of parasitic plants and stimulate the growth of symbiotic
fungi. But that wasn’t the end of the story for this compound’s role,
she points out. More recently, researchers have discovered that it
also plays an important part in regulating plant growth above theground.
“There are definitely still more answers like this to be found,”Yoshida says, “so that’s why it’s very important that scientists
maintain their curiosity, keep asking questions and making a
big effort.”

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses113.html
Researcher: Satoko Yoshida

NAIST Research Highlights 41

Plant Symbiosis Laboratory | Associate Professor Satoko YoshidaA Phtheirospermum root with anhaustorium and haustorial hairs. (Image
originally in Fig. 1 of Ref. 1)

42 NAIST Research Highlights

Reprinted with permission from Ref. 1. Copyright 2016 American Society of Plant Biologists

Biological Sciences

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Biological Sciences

Parasitic plants

Exploring the secrets ofparasitic plants
Mutants expected to reveal key steps in plant parasitism as part of new researchResearchers are using a model plant to
explore the physiology and genetics of
one of the world’s worst agricultural
pests, Striga, in the hope of finding a way tocontrol it.
Striga is a parasitic weed genus that afflictssorghum, maize, and rice crops across Africa
and Asia. Nine years ago, plant geneticist
Satoko Yoshida joined a project in Ken
Shirasu’s Plant Immunity Research Groupat the Japanese research institute RIKEN to
study the pest. “It’s quite a high impact weed,”
explains Yoshida, who this year joins NAIST
to start up the Plant Symbiosis Laboratory tocontinue her work. “The estimated annual loss
could be several billion dollars. It was listed
as one of the world’s seven worst agricultural
pests in a 2010 Science paper.”Striga is an obligate parasite, which makes
it difficult to work with in the lab. “We
decided we needed a model plant,” Yoshidasays. Accordingly, she tested ten different
species in search of an ideal candidate.
“Some of the mountain plants just didn’t
germinate, or they germinated and died, or it
took forever to get seeds.”
Yoshida eventually settled on Phtheirospermum japonicum as a model species toinvestigate how these parasites work andhow to control them. Parasitic plants such as
Phtheirospermum and Striga detect chemicals
released by their host’s roots and respond byforming a specialized organ called an haustorium. Hairs on the haustorium help it adhere
to a hosts’ root before it invades to connect
with the hosts’ internal transport network.
To understand haustorium formation,
Yoshida’s RIKEN team chemically mutagenized Phtheirospermum seeds, grew theminto plants, and then exposed the mutants
to an haustorium-inducing chemical1. Most
formed haustoria, but a few mutations did
not. The team recovered one mutant thatformed elongated haustoria, two mutants
lacking haustorial hairs, and a mutant that
didn’t form haustoria at all.
“The mutants without haustorial hairs
have been easy to work with, while the onethat doesn’t form haustoria has been a bit
more difficult,” Yoshida says. Analysis of thehaustorial-hair mutants revealed that haustorial hair development is controlled by thesame genetic program controlling root hairs
and demonstrated that haustorial hairs areimportant for maintaining physical contact
with the host root.

“Nobody has ever made a mutant withparasitic plants,” Yoshida says. Next, theteam will use whole-genome sequencing to
identify the mutated genes.
At NAIST, Yoshida will lead a team ofresearchers trying to understand how theseplants prey on others. She hopes it will eventually be possible to find the master genes
controlling haustorium formation. “If we canfind the genes that switch haustoria on andoff, it may help us combat these parasitic
weeds,” she says.
Reference
1. Cui, S., Wakatake, Y., Hashimoto, K., Saucet, S. &Toyooka, T. et al. Haustorial hairs are specialized
root hairs that support parasitism in the facultative
parasitic plant, Phtheirospermum japonicum. Plant
Physiology in press* To read more about the work of
Satoko Yoshida, one of the newinternational researchers to join
NAIST, see “Planting seeds of
wisdom” on page 40.

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses113.html
Researcher: Satoko Yoshida

NAIST Research Highlights 43

Plant Growth Regulation Laboratory | Professor Masaaki UmedaThe expression of the gene CCS52A1 in thisArabidopsis root is shown in green and the cell wallis shown in red. Cytokinin signaling regulates theexpression of CCS52A1 to control root meristem size.

Plant hormones

Getting to the rootof what lies beneath
The hormone cytokinin halts cell division to control root growth
44 NAIST Research Highlights© 2016 Masaaki Umeda

Biological Sciences

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Biological Sciences“

Our findings showthat cytokinin
signaling promotes
the degradation of cell
cycle regulators andrestricts cell division.

“A

plant’s roots play an essential role in
keeping it alive and flourishing, withthe cells inside elongating root tips
exploiting finely tuned hormonal signaling
networks to control root growth.
Now researchers at NAIST have pinpointed
the function of one type of plant hormone— cytokinin — involved in this elaborate
regulatory cross-talk. They have foundthat cytokinin not only shuts down thesignalling of another hormone involved incell proliferation, it also causes cells to stop
dividing while continuing to duplicate the
DNA in the cell nucleus.
This is an essential process for root celldifferentiation, explains plant biologist, Naoki
Takahashi, an assistant professor at NAIST’s
Plant Growth Regulation Laboratory. “It
was elusive how plant hormones regulate
cell cycle progression in roots,” he explains.
“Our findings show that cytokinin signaling
promotes the degradation of cell cycle
regulators and restricts cell division.”
A team led by the laboratory’s head

Masaaki Umeda and Takahashi used theweed thale cress (Arabidopsis thaliana)
to study hormonal action in the root’s
transition zone — between the meristem,
where cells actively divide, and theelongation zone, where cells expand andtake on more defined roles.
They showed that cytokinin, through anintermediary regulatory protein, induced
the expression of the gene called CCS52A1.
This encodes an activator of an enzyme that
controls root meristem size. Specifically,
this enzyme — known as an E3 ubiquitin
ligase — degrades certain regulators of cell
division, causing the cell division cycle tocease. This pathway is notably distinct fromthe way in which cytokinin counteracts theactivity of another hormone called auxin tohalt cell division. The researchers reported
their findings in the prestigious journal
Current Biology1.
The dual nature of cytokinin signalling is
unlikely to be restricted to just Arabidopsis

or related plant species, Takahashi notes.
“Most of the genes involved in root growth
regulation are highly conserved between
plant species,” he says, “suggesting thatsimilar mechanisms controlling root growth
exist in other plant species.”
Takahashi anticipates that a better
understanding of cytokinin’s roles in root
growth will prove useful in crop breeding andother agricultural applications. “We may beable to control the speed of root growth bychanging the activity of cytokinin signalling,so that root growth may not be arrested, evenin stressful environmental conditions,” hesays. This, he adds, would lead to an “increasein the yield of crops and plant biomass.”
Reference
1. Takahashi, N., Kajihara, T., Okamura, C., Kim, Y.,
Katagiri, Y., Okushima, Y., Matsunaga, S., Hwang,
I. & Umeda, M. Cytokinins control endocycle
onset by promoting the expression of an APC/C
activator in Arabidopsis roots. Current Biology 23,
1812–1817 (2013).

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses105.html
Researchers: Naoki Takahashi and Masaaki Umeda

NAIST Research Highlights 45

Molecular and Cell Genetics Laboratory | Professor Kenji Kohno

Genetics

Inflammatory disease study
yields knockout results
Research provides insight into how a protein might help protect
against bowel disease46 NAIST Research Highlights© Juan Gartner/Science Photo Library/Getty

Biological Sciences

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Biological Sciences© 2016 Akio Tsuru

Slides showing the effect of the stress sensor IRE1β on regulation of mucin production in digestive
tract cells. Main: An artistic image of an endoscope of an intestine affected by Chrohn’s disease.

T“

Finding the locationof cells expressing
IRE1β and identifying
the relationshipbetween IRE1β andmucin production
are breakthroughs in
our understanding ofIRE1β function.

he occurrence rates of digestive
tract disorders known collectively as
inflammatory bowel diseases (IBDs)
appear to have been rising in Westerncountries for about 70 years, and the reasonsremain unclear.
IBDs, of which the most common forms
are Crohn’s disease and ulcerative colitis, areautoimmune disorders that cause the body’s
immune system to attack the colon andsmall intestine of the digestive tract1. NAIST
researchers have been using gene knockout
mice to explore the function and physiologicalsignificance to IBD of a poorly understood
stress sensor known as inositol-requiring
enzyme 1β (IRE1β), which is expressed
selectively in the mammalian digestive
tract. This is involved in activating a process
called the unfolded protein response (UPR),
although researchers don’t know how.
“There are several stress sensors in the UPR
pathway, but among these IRE1β is one of
the least understood,” explains Akio Tsuru,
from NAIST’s Molecular and Cell Genetics
Laboratory. “Previous studies suggested that
IRE1β plays a role in preventing intestinal
bowel disease, but the mechanism behind thisfunction is completely unknown.”
The correct topology — shape, geometry
and orientation — of proteins is vital forcells to function correctly. Newly synthesized
proteins pass into the endoplasmic reticulum(ER), a specialized cellular subunit that folds
and modifies them to their required topology.
If, however, the influx of proteins to the ER
exceeds its capacity, unfolded or misfolded
proteins accumulate and ER stress results.
Activating the UPR is an important way thatcells respond and if the UPR is unable to deal
with the stressed conditions, then apoptotic(programmed) cell death is initiated.
“The UPR is now a popular area of
research because of the links between ER
stress and many other diseases as well, suchas Parkinson’s,” says Tsuru. “Our study has
revealed that IRE1β located in the ER ofgoblet cells in the digestive tract regulate
and optimize mucin [the main componentof mucus] production. It enables theefficient secretion of mucin, which protects
the digestive tract surface from intestinal
bowel disease.
“Finding the location of cells expressing
IRE1β and identifying the relationshipbetween IRE1β and mucin production are
breakthroughs in our understanding of IRE1βfunction.”
Reference
1. Tsuru, A., Fujimoto, N., Takahashi, S., Saito, M., Nakamura, D., Iwano, M., Iwawaki, T., Kadokura, H., Ron,
D. & Kohno, K. Negative feedback by IRE1β optimizes
mucin production in goblet cells. Proceedings of the National Academy of Sciences USA 110, 2864–2869 (2013).

“

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses207.html
Researchers: Akio Tsuru and Kenji Kohno

NAIST Research Highlights 47

Plant Immunity Laboratory | Associate Professor Yusuke Saijo

Plant immunity

Decrypting plant
defense signals
A genetic approach sheds new light on danger-associateddefense mechanisms in plants

48 NAIST Research Highlights© Carlo Zamora/EyeEm/Getty

Biological Sciences

R E S E A R C H H I G H L I G H TS

Biological Sciences
MAMP receptor

PERP (DAMP receptor)

Pathogen
BAK1

SERK

Activation of the dangerassociated molecular pattern(DAMP) receptor PEPR is a backup for the microbe-associated(MAMP) pathway during basal
resistance upon pathogeninduced BAK1 depletion.

BasalresistanceReliable food production hinges on
the ability of plants and animals tofight infections by recognizing andresponding to microbes. New research from
NAIST provides insight into the mechanisms
controlling basal resistance in plants, paving
the way for the development of next-generation
sustainable disease-resistant crops¹.
Plant immunity involves cell membranelocalized receptors that detect and recognize
microbe-specific molecular signatures, such asbacterial flagellin and fungal chitin. Evidence
suggests that the membrane-bound receptor
kinase BAK1, serving as a co-receptor forthese pattern-recognition receptors, plays apivotal role in the resulting immune response.
Its perturbation occurs during pathogen
infection, which is typically perceived by
the plant, but the underlying mechanisms
remain unclear. Other receptors sense dangerassociated molecular patterns originatingfrom pathogen-infected plants, which
elicits an immune response. Specifically, thedetection of elicitor-active Pep portions by
so-called PEPR receptors produces a similar
response to microbe-associated patterns.
However, the mechanism that activates thisimmunity is also unknown.

To fill this knowledge gap, Yusuke Saijo
and colleagues from NAIST’s Plant Immunity
Laboratory used a genetic approach toassess the contribution of BAK1 to PEPRmediated immunity.
Many researchers had previously assumed
that microbe and danger-associatedreceptors worked in parallel. But, Saijo’s teamenvisioned a layered structure involving
functional interactions between different
receptors. “This helped us hypothesize amodel in which danger-induced PEPR
signaling acts as a back-up when BAK1dependent microbe-associated receptors
become dysfunctional upon BAK1
disruption,” Saijo explains.
The researchers discovered that PEPR,
which was initially considered as a simple
BAK1-dependent receptor, retained its
function better without a co-receptor,
validating its role as a back-up (see image).
To their surprise, mutant plants devoid of
BAK1 exhibited an increase in Pep peptideinduced growth inhibition; a proxy for
defense activation.
Furthermore, Saijo’s team demonstrated
that a PEPR ligand precursor acted asa danger-associated protein presenting

increased production that was released incorrelation with pathogen virulence and hostcell death. They showed that infection by thefungal pathogen Colletotrichum higginsianum
resulted in BAK1 depletion in Arabidopsis
plants and PEPR participated in anti-fungal
resistance. “This dramatic decrease in BAK1
accumulation during the fungal infection was
also an unexpected but important finding,”
Saijo says.
The researchers are currently evaluating
the role of BAK1 in balancing salicylic
acid and jasmonic acid hormone-based
defense responses in the PEPR pathway,
an important trade-off between theseantagonistic hormones. To generate new
disease-resistant crops, they are also
investigating the PEPR-mediated immunity
against Colletotrichum fungi, which affecta wide host range and cause enormous
agricultural yield losses.
Reference
1. Yamada, K., Yamashita-Yamada, M., Hirase, T.,
Fujiwara, T., Tsuda, K., Hiruma, K. & Saijo, Y. Danger
peptide receptor signaling in plants ensures basal
immunity upon pathogen-induced depletion of
BAK1. The EMBO Journal 35, 46–61 (2016).

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses111.html
Researcher: Yusuke Saijo

NAIST Research Highlights 49© 2016 Yusuke Saijo

PROPEP

Plant Stem Cell Regulation and Floral Patterning Laboratory | Professor Toshiro Ito

Toshiro Ito

Exploring
the fundamentalsof plant growth

A renowned plant geneticist’s move to NAIST continues a tradition
and marks a return homeFor Toshiro Ito, the chance to join NAIST’s
biological sciences faculty meant returning to
his roots.
This inter nationally respected plant
geneticist was born in Japan and completed
his undergraduate, master's and PhD studies
here, but had been living abroad, mostly in

50 NAIST Research Highlights

the United States, since taking up a postdoctoral position withthe prestigious California Institute of Technology in 1997. There,
Ito had risen through the ranks to become a senior principal
investigator, before relocating to Singapore in 2005 to lead thePlant Systems Biology Group at Temasek Life Sciences Laboratory.
His most recent move has been to NAIST, for the opportunity to
step into a senior role left vacant by one of Japan’s leading plant© 2016 Toshiro Ito

Biological Sciences

F E AT U R E

Biological Sciences
researchers. At NAIST, Ito will be picking up
the mantle of Ko Shimamoto who passed awayin 2013. This well-regarded professor of plant
genetics was in Singapore to deliver a seminarjust months before he died, and his visit inspired
Ito to move to Nara.
“He was one of the greatest plant scientists inJapan in recent times. He died six months after I
met him, and I inherited his laboratory,” Ito says,
acknowledging that he has large shoes to fill in
the new role.
Ito also had other heartfelt reasons forwanting to return to his country of birth. “Mysons are 13 and 11, and were born in America.
After that, we moved to Singapore where isit always hot,” Ito explains. “My memories ofchildhood in Japan are about the four seasons.
But my children have never had a cold winter! I
want them to enjoy spring, summer, autumn andwinter, and have nature close by.”
Ito opened NAIST’s new Plant Stem Cell
Regulation and Flora Patterning Laboratory,
where research areas covered by major projects
will include the developmental coordination ofcells to produce flowers and the environmental
response and acclimation of plants.
“Plants have really robust structures. The
largest living thing on Earth is a sequoia in
California that has been growing for two
thousand years,” Ito says, explaining that thefundamentals of plant life are ubiquitous, fromthe largest species to the smallest. “In my lab,
we work with Arabidopsis, tiny plants with alifespan of six weeks. They are geneticallypredetermined to terminate their own growthand save the nutrients to build the next
generation of flowers. We are looking at thepowerful molecular mechanisms behind thisactivity.” (See "The timer that controls flowersize" on page 52.)
Ito’s team is also studying how plants adapt
to their environments and hopes this research
could be useful in the future for managing theeffects of climate change on natural habitats.
“Plants have no brains, but they can still
remember environmental change and respondaccordingly,” he explains. “If you move a plantfrom a cold climate to a very hot one, it will die.
But if you incubate the plant before moving it,then it can get used to the higher temperature
and adapt.
“Once we understand the mechanism behind
this, we can manipulate genes and make plantsthat are more resistant to severe conditions.”

Ito wasn’t always as interested in plants.
He began his career researching animal
development: “I discovered I needed to killhundreds of mice and I didn’t like that, so I
changed to plants.”
For Ito, joining NAIST felt like a naturaltransition. In his field of research, he had visitedthe campus many times and become familiar
with the faculty staff. “Due to its small size,
the atmosphere is very friendly. It also meansthat it’s easy to get things done. Things can bechanged quickly to suit your work needs without
any hassle,” he says.
Since joining the team, Ito has enjoyed therelaxed style of collaboration, and says it’sunlike anything he’s experienced in Singapore
or America. “Recently we went on a faculty
retreat to the hot springs,” he says. “Some of
our faculty members are more than 60 years
o l d , b u t t h e y s t i l l s t aye d u p u n t i l 2 a mdrinking sake, and talking about education,
research and the future of NAIST. Spendingtime together like this enables us to develop astrong bond, and build up trust.”
Ito is looking forward to following, andperhaps being involved in, the next big
breakthroughs in the biological sciences.
“Biolog y has changed rapidly in the past
15 years,” he says. “While I want to be a pioneer
in my field, I also accept we need to nurture
the next generation who will be responsible formaking the next scientific leaps.”
Ito will be bringing his own traditions to
NAIST, which include a firm emphasis on hard
work. His strong sense of self-discipline wasinstilled in him by his PhD supervisor at Kyoto
University.
“I remember that I came in one morning andfound a note on my desk,” Ito recalls. “It wasa piece of writing by [the eminent molecularbiologist] James Watson from 1984, which said:‘I’m not interested in people who won’t work
10 hours a day and be there on Saturday and
Sunday, because someone will be. In this world,
there are clever people who never seem to study
and still get good grades in exams. You do not
see that in science.’”
For Ito, the quote underlined the importanceof working hard to achieve his goals: “It was
simple advice but sometimes you forget it.
Nowadays we can’t force students to work
10-hour days, or weekends. But we can still
remind ourselves that success will be rooted in
our work. It’s the basis for great science.” More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses112.html
Researcher: Toshiro Ito

NAIST Research Highlights 51

Plant Stem Cell Regulation and Floral Patterning Laboratory | Professor Toshiro ItoA microscopic look at developing buds, with the flowers in red. The green represents
expression of the KNUCKLES gene, which instructs helps control cell division.

52 NAIST Research Highlights

From Ref. 1. Reprinted with permission from AAAS.

Biological Sciences

R E S E A R C H H I G H L I G H TS

Biological Sciences

Plant genes

The timer that
controls flower size
A biological clock triggers a key event in flower development

P

lants grow by the continuous division ofsmall groups of cells, called meristems,
at the tips of shoots and roots. Somemeristems divide indefinitely, but those thatform flowers terminate according to specificgenetic programs. They divide a specificnumber of times before completely differentiating into floral organs.
NAIST researchers have now revealed abiological timer that determines when cell
divisions are switched off in flower buds1.
Continuous growth of above-ground meristems is maintained by the WUSCHEL gene.
In floral meristems, WUSCHEL is repressedby another gene, KNUCKLES, which sets
the meristem on the path to termination.
KNUCKLES is switched on by AGAMOUS,
the same gene that promotes reproductive
organ development, although KNUCKLES
isn’t activated until 2 days later.
“The timing of KNUCKLES induction isreally key to the balance between proliferation and differentiation,” explains Toshiro Ito,
head of NAIST’s Plant Cell Regulation
and Floral Patterning Laboratory, who led
the study. Flowers develop extra organs if
KNUCKLES is switched on too late and notenough if it is switched on too early.
Ito’s team showed that KNUCKLES
is activated after a certain number of cell
divisions rather than a specific period of time.
When they used drug treatments to accelerate or inhibit cell divisions, KNUCKLES was
activated either earlier or later.
KNUCKLES expression is epigeneticallycontrolled; it is normally repressed by achemical modification of a specific lysine

residue of the histone H3 protein — a
process known as methylation — that blocks
transcription. Methylation is maintainedby Polycomb-group (PcG) proteins and theteam showed that these are responsible forthe delay between AGAMOUS and KNUCKLES. “Once AGAMOUS is induced, it binds
to KNUCKLES and causes the eviction of
Polycomb,” Ito explains.
Without PcG to maintain the histone
methylation, the bio-timer starts ticking.
Cell divisions dilute the repressive histone
modification and KNUCKLES is eventually activated.
The team showed that attaching the
Polycomb binding sites from KNUCKLES toa ubiquitously expressed fluorescent reporter
was enough to switch it off. “It was a result
we expected, but, at the same time, it worked
beautifully, so we were excited,” Ito says. They
then designed an artificial protein to mimic
AGAMOUS by targeting Polycomb sites andevicting the protein. “It worked!” Ito says.
“We saw induction of the reporter.”Work continues in Ito’s team to unravel
the genetic cascade at the heart of floral
development. “Flowers are really importantfor human life as a source of food,” he says.
“We research flowers and flower development
because what we eat, fruits and vegetables, areall products of flowers.”
Reference
1. Sun, B., Looi, L.-S., Guo, S., He, Z., Gan, E.-S. et al.
Timing mechanism dependent on cell division is
invoked by Polycomb eviction in plant stem cells.
Science 343, 1248559 (2014).

* Toshiro Ito is another of
NAIST’s newest professors. To
read more about his career, see“Exploring the fundamentals ofplant growth” on page 50.

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses112.html
Researcher: Toshiro Ito

NAIST Research Highlights 53

Systems Neurobiology and Medicine Laboratory | Professor Naoyuki InagakiCell growth

A creative flow finds the forces
behind cell migration
Insights into the molecular actions that drive cell movements could enhance our understanding of diseasesThe correct migration of cells in the
body is necessary for normal growthand functioning. Disruption of this‘directional cellular motility’ is implicated inmany diseases, including immune disorders
and cancer. Interdisciplinary research at
NAIST aims to enhance our understandingof the molecular mechanisms inherent in cell
motility, particularly the forces that propelcells forward.
Directional cellular motility plays a vitalrole in embryogenesis, neuronal network
formation, immune responses and tissue
repair. Neurons — nerve cells — contain long,thin, specialized extensions called axons that
protrude from their surface and transmit
information to other neurons and cells.
At the tips of axons are ‘growth cones’;highly sensitive structures that respond rapidly
to chemical signals from axon guidance
molecules outside the cell and create thedriving forces to push the cell forward.
Growth cones contain a variety of molecular
structures, including dynamic linear polymers
called ‘actin filaments’ (or F-actin). With thesignal from axon guidance molecules, F-actin
polymers move away from the leading edge ofthe cell membrane to allow new molecules totake their place. This backwards movement is
known as F-actin retrograde flow.
“We believe that the forces required to drive
cell motility are generated during F-actin
retrograde flow by the coupling of F-actinwith substrates outside the cell,” explains
Naoyuki Inagaki, head of NAIST’s Systems
Neurobiology and Medicine Laboratory. “We
think this is achieved via F-actin linking withcell adhesion molecules on the cell membrane,
but the molecular basis of this process remains
unclear. Using fluorescent tagging, we traced
the movement and behavior of molecules ingrowth cones to find out more.”
Inagaki and his team revealed that the
coupling process requires the extra help of
two binding molecules; one, called cortactin,

acting on F-actin itself, and the other linked
to the cell adhesion molecule L1-CAM andknown as shootin11.
Cortactin is ‘caught’ by shootin1 andmediates the link between F-actin retrograde
flow and L1-CAM. This in turn promotes
traction forces for axon outgrowth. The
researchers also found that an axon guidance
molecule, netrin-1, induces the cortactinshootin1 interaction. Stimulation with netrin-1
can promote forces for axonal outgrowth.
“Without the creative environment at
NAIST, which encourages collaborations
between disciplines, this kind of project
would be very difficult,” Inagaki explains.

Contact

2“We were lucky to work alongside colleagues
in Information Science and in Materials
Science to create a unique picture of the forces
generated by this coupling process.”
Inagaki hopes these insights into theinteractions between F-actin and L1-CAM
will enable further examination of diseases
involving axon outgrowth dysfunction.
Reference
1.

Kubo, Y., Baba, K., Toriyama, M., Minegishi, T.,
Sugiura, T., Kozawa, S., Ikeda, K. & Inagaki, N.
Shootin1–cortactin interaction mediates signal–force
transduction for axon outgrowth. The Journal of Cell
Biology 210, 663–676 (2015).

Contact1
pN/µm2
100

50
Netrin-12Netrin-11Forces generated by molecular interactions in axon growth cones help cells move correctly whenrequired. NAIST researchers have uncovered some of the molecular mechanisms at play in growth cones,
and shown how forces can change under stimulation with axon guidance molecule netrin-1.

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses204.html
Researcher: Naoyuki Inagaki

54 NAIST Research Highlights0© 2015 Kubo et al. Journal of Cell Biology. 210:663-676. doi: 10.1083/jcb.201505011

Biological Sciences

R E S E A R C H H I G H L I G H TS

High-resolution structure of Membrane
Sec transloconMolecular(SecYEG) Biology Laboratory | Associate Professor Tomoya Tsukazaki

The crystal structure of a bacterial SecYEG
complex has been revealed at high resolution for
the first time.

SecG loop (Cap)Membrane© 2016 Tomoya Tsukazaki

SecY

SecE

Plug

SecG

Crystals

Membrane biology

Protein-secretion
machinery
The structure of a bacterial protein complex involved inmoving proteins through cell membranes is seen in high resolution
for the first timeProteins fulfil many tasks in the
body. They need to move in andbetween cells, passing throughmembranes without causing structural
damage. NAIST researchers areinvestigating how cell membrane channels,
known as ‘translocons’, open to allow
proteins through.
Translocons themselves can be made up
of multiple proteins and, although theirstructure varies, their function in different
organisms is the same. In bacteria,translocons have a central protein
complex called SecYEG that comprises
three components; SecY, SecE and SecG.
This undergoes conformational changes
from a resting state, to the point wherea ‘gate’ in the translocon opens to allow
proteins through. When bacteria invadea host, some secretory proteins cause
acute poisoning in host cells. For disease
control, it is crucial to understand exactly
how translocons function.
Tomoya Tsukazaki of NAIST’s
Membrane Molecular Biology Laboratory
recently led a project that achieved thehighest resolution crystal structures of
SecYEG to date, both in a resting stateand peptide-bound state, which is thefirst stage before the opening of thechannel gate 1.
“SecYEG has several flexible regions,which prevent defect-free crystallization,”
Tsukazaki explains. “Most SecYEG crystals
are poor quality. To overcome this, we had
to collect X-ray diffraction data from adozen SecYEG crystals from the bacteria
Thermus thermophilus to build up a clear

picture at high resolution.”
His team’s results revealed the hourglass structure of SecY, which is stabilized
from behind by SecE. They also foundthat the SecG protein contains a loop thatcovers the cytoplasmic side of the channel.
Tsukazaki and his team believe the SecG
loop may play a key role inside the cellin blocking the movement of proteinsthrough the translocon. The channel issealed on the periplasmic side, outside of
the cell membrane, by a plug, or ‘gate’ that
opens at a given signal when a protein isready to pass through (see image).
A second stage — the peptide-boundstate of SecYEG — was also identified by
Tsukazaki’s team. Their results indicatethat the cytoplasmic side of SecYEG
responds to signal peptides changing
conformation in preparation for the
periplasmic ‘gate’ to open.
“Bacterial Sec machinery is an essential
system,” Tsukazaki says. “Perhaps our
SecYEG structure will help scientists find
new antibiotics to target Sec proteins.
We also know that SecYEG interacts
with other important proteins in themembrane, forming a larger complex
that we hope to determine using X-ray
crystallography in future.”
Reference
1. Tanaka, Y., Sugano, Y., Takemoto, M., Mori, T.,
Furukawa, A. et al. Crystal structures of SecYEG in
lipidic cubic phase elucidate a precise resting and a
peptide-bound state. Cell Reports 13, 1561–1568 (2015).

More information about the group's research can be found at http://bsw3.naist.jp/eng/courses/courses309.html
Researcher: Tomoya Tsukazaki

NAIST Research Highlights 55

Biological Sciences

RESEARCH HIGHLIGHTSMaterials
ScienceSurface and Materials Science Laboratory | Professor Hiroshi Daimon

Making use of an
ultra-small world

A WEALTH OF
MATERIALS AWAITSDISCOVERY BY
SCIENTISTS SCRATCHINGTHE SURFACE OF
NANOMETRES© CaiaImage/Caiaimage/Getty

H

Crystal clear: the difference in the way carbon atoms arearranged distinguishes soft graphite from ultra-harddiamond. Exploring these arrangements has been a lifelong passion for NAIST’s professor Hiroshi Daimon.

iroshi Daimon uses a simple question to draw people into hiscomplex area of research: What’s the difference between adiamond and the ‘lead’ in a pencil? The answer: only the way
their carbon atoms are arranged.
The household implement and the object of great desire are constructedfrom the same atomic components, but being tightly bonded in a cubic
structure in the super-hard gemstone and layered in loose sheets of soft
graphite in the pencil, their properties and uses are worlds apart.
Daimon, who heads NAIST’s Surface and Materials Science
Laboratory, is known professionally as a quantum physicist, but
describes himself simply as an explorer of atoms. He and his team
aim to analyse the structures of atoms in nanomaterials and theirelectronic properties. A nanometre is one billionth of a metre or
about 1/100,000th of the thickness of a sheet of paper. Unusual
features emerge when materials are examined below this very tiniest
of scales. Iron, for example, loses its magnetic properties, and gold,
a non-active metal, becomes chemically active below 1 nanometre.
These changes emerge because their atomic arrangements differ
from those at the large scale and the resultant altered capabilities canhelp yield new kinds of materials with diverse applications.

NAIST Research Highlights 57

Materials Science

IMPACT© 2016, The Japan Society of Applied Physics

Materials Science
The DIANA device that Professor Daimon and his colleagues developed allows researchers to visualize the positions of atoms
within material, such as the three atoms circled in these images. In a viewer, pairs of stereoscopic holograms combine to form athree-dimensional image.
In recent years, for example, nanotubes of carbon have been appliedin a wide range of uses, from toughened sporting equipment and bodyarmour to efficient water filters. These lattices of carbon moleculesarranged at the nanoscale into tubes resembling the structure of wire
mesh are stronger than steel and yet extremely lightweight. They’re also
a good example of a novel material born from atomic engineering, adiscipline that emerged during the late 20th century.
Daimon and collaborators believe research into the properties of
surface materials could have similar revolutionary applications. An
example is nanodots that change polarity to represent binary digits,
offering the possibility of magnetic memory that is much faster and more
dense than current technology. Also in their sights are materials foundto behave like superconductors, even at room temperature, that could

58 NAIST Research Highlights

dramatically accelerate computer speeds and help save energy.
To unravel the structure of atoms and determine their relationship withother atoms, Daimon and his collaborators at NAIST use the only one-ofa-kind instrument invented by Daimon; a display-type spherical mirror
analyzer known as DIANA. When an atom in a sample material such asa graphene monolayer is irradiated with circularly polarized X-rays, itemits photoelectrons that are reflected off a spherical mirror in the device.
These photoelectrons then converge on an aperture and are projected
on a screen. The emission angles of the photoelectrons are preserved inthis process and the angular distribution patterns they show are referred
to as a hologram. These can reveal the positional relationship of atoms
and are extracted into stereoscopic images. Displayed on the DIANA
screen, the holograms viewed simultaneously can combine to form aMaterials Science“

Daimon likens DIANA to a new kindof microscope that can peer directly into
atoms. The technique allows for real-time
analysis of the atomic motion of a specificatom in nanomaterials, which plays a keyrole in its special nanofunction. The factthat no special glasses or other apparatus
are needed to view the imagery is anadded bonus: to illustrate that, Daimon has
demonstrated the holograms on Nintendo
3DS video game consoles, which can rendergraphics in 3D.
Daimon has been fascinated by the atomic structure of molecules since
his early graduate studies at the University of Tokyo, where he focusedon developing simpler methods of atomic structure measurement.
Apart from Nintendo 3DS demos, one of the most effective ways ofcommunicating his research interests to the public during outreach
events is to show people molecular mockups.
“Even kids love atoms, especially building the plastic models ofmolecules, because you can see the structure directly,” says Daimon, who
is passionate about getting younger generations interested in scientificresearch. “You can also show how impurities are working in things likethe silicon used in computer chips, and we’re researching exactly how that
happens with our holography and stereoscopic imagery techniques.”

“© Stanimirov/iStock/Getty Images Plus/Getty

Other devices can only
measure in one direction,
but this one can measure
in all directions at thesame time, making it
highly efficient and thebest machine for analyzing
holograms.

three-dimensional image of the atomic
structure of the material being examined.
Some look like fuzzy dots but they canshow the arrangement of the atoms in thetarget material.
“Other devices can only measure in
one direction, but this one can measure
in all directions at the same time, making
it highly efficient and the best machine foranalyzing holograms,” Daimon says.
Daimon has been collaborating withresearchers such as Toshio Hakoshima, a
structural biologist at NAIST, as well as private-sector researchers working
on sensors and solar cell technology. Another important collaboration
partnership involves the RIKEN SPring-8 synchrotron radiation facility
in Harima Science Park, Hyogo Prefecture; the largest facility of its
kind in the world. Using as much as 8 gigaelectron volts of power, thissynchrotron can accelerate electron beams close to the speed of lightwhile guiding them along a circular route with magnets. While Daimon
and his team use the facility for photoelectron spectroscopy, synchrotron
radiation produced there can be used to analyse proteins and materials,
including impurities, isolated during forensics investigations. Daimon
aims to promote his unique research and methods overseas, particularly
Europe, which also hosts several good synchrotron radiation facilities.

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1341/
Researcher: Hiroshi Daimon

NAIST Research Highlights 59

Sensing Device Laboratory | Professor Takayuki Yanagida

Takayuki Yanagida

A scintillating career
After great commercial success, a brilliant physicist returns
to basic research to shed light on old mysteriesTakayuki Yanagida was torn between two
career paths as a 21-year-old undergraduate:
join a company and go into business or
become a scientist.
He recalls that two people influenced him
to pursue the second choice. “I remember
learning about Einstein’s theory of generalrelativity and being very inspired,” Yanagida says. “At that time, I
thought time is something absolute, but Einstein showed me thattime is also relativistic; it was totally surprising to me!”His second source of inspiration was a fellow student. “When
I was at university, I’d study during the day, and then, every
evening, I would head for the basketball court to play with afriend,” Yanagida explains. “In Japan, it’s unusual for people tobe good at sports and at science, but my friend excelled at both.
“One day he told me he was going to become a scientist,
which surprised me because I associated him with the basketballcourt. Up until that point, I’d never thought of myself at thatlevel. Few people from my hometown of Sendai are even offereda place to study at the University of Tokyo, let alone become
scientists. But, I thought, if he can do it… so can I.”
A gifted physicist, Yanagida set out early in his career to focus
on basic research into the phenomenon of scintillation: the flashof visible light produced as X-rays pass through a transparent
material. He pursued a master’s and then PhD in astrophysics at the
University of Tokyo, during which he used scintillation detectors to
observe X-rays emitted from parts of the universe known as ‘starforming regions’, to better understand how stars are formed.
“After finishing my PhD, my aim was to find industrial uses for
my discoveries,” Yanagida says. “In my final thesis I identified
compounds that had great potential, and I was keen to work on
the applied side of my research.”
In 2007, Yanagida joined Tohoku University as a research
assistant and concentrated on scintillator materials andscintillation detectors — which, as radiation detectors, haveapplications in areas as diverse as security and medicine. Soon
his work was attracting serious commercial attention.
“I designed quicker and more accurate scintillator detectorsthat could improve the resolution of X-ray images,” heexplains. “This technology was bought and developed bymany companies. It’s now used in security inspection systems
in airports.”
Moving in 2012 to the Kyushu Institute of Technology to
become an associate professor, Yanagida continued to work
closely with industry before relocating to NAIST in 2015 tobecome a professor and head of the Sensing Device Laboratory.

Yanagida says his commercial success has taught him to value
the importance of basic research. And here, at NAIST, he has
been given the support to shift his attention back to pure scienceand away from researching the practical applications of his work.
(To read about a recent success from Yanagida’s lab see "Bright
future for radiation detection" on page 62.)
“In many universities, there is little time to focus on yourresearch. You have to teach many lessons and spend hours
preparing your material,” he says, explaining that professors
at NAIST are in an enviable position. “At NAIST there are noundergraduate students, so faculty members have more timeaway from teaching to pursue their own goals. There is far, farless teaching time so I can spend many hours on basic research.”
Yanagida now hopes to be able to unlock many of thesecrets of scintillators that have evaded scientists for a century.
“Scintillators were discovered more than 100 years ago. But
even though we use them in many industries — from medicine
to security — we still haven’t opened that black box to explain
exactly how they work,” Yanagida explains. “I am doing
experiments that I hope will solve the basic process. But this
could take another 10 years or more.”
In comparison to other research institutions, Yanagida believes
that the general setting for the institute in Nara make it anexcellent place to settle and focus his attentions. “The NAIST
campus has a different atmosphere to other universities,” hesays. “It is a calm place. The students are older so they mostly
study. When students are younger, a university environment canbe a little more crowded and noisy.”
The support of his family, has been crucial for Yanagida. “Mysecretary is my wife, and has been ever since I worked at Kyushu
University,” he says. “In fact, she’s the reason that I work inmaterials science, rather than astrophysics.”
Two decades ago, after completing his PhD in astrophysics,
Yanagida was expecting to find work in his original researchf ield. But then his wife, Satoko, developed leukaemia. "Weneeded to move to her hometown so she could go to hospital,”
he says, recalling what turned out to be a serendipitous career
move to Tohoku University. “In northern Japan, there’s little callfor astrophysicists. The biggest university is Tohoku University
and they are strong on materials research. So I became amaterials scientist.”
Now the couple have an 11-year-old girl, Shiona, who loves
to come and visit Yanagida in his NAIST laboratory, which
he joined just under a year ago. “She thinks it is fun to see
luminescent materials,” he smiles. “I make many of these in mylab, so she comes and checks the colour for me.”

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1989/
Researcher: Takayuki Yanagida

60 NAIST Research Highlights© 2016 Takayuki Yanagida

Materials ScienceF E AT U R E

Materials Science
NAIST Research Highlights 61

Sensing Device Laboratory | Professor Takayuki Yanagida

Scintillators

Bright future forradiation detection
New crystalline material shows promise for security
and medical applications© 2016 Takayuki Yanagida

Materials Science

R E S E A R C H H I G H L I G H TS

62 NAIST Research Highlights

Materials Science
Reprinted from Ref 1., Copyright 2011, withpermission from Elsevier

The new scintillator can detect complex shapes made from a neutron-blocking material.

N

AIST scientists have developed analternative to the rare gas used todetect radiation in medical imaging,astrophysics and security screening.
This function has routinely been done with
low-energy (or ‘thermal’) neutron detectors
fuelled by helium-3. However supply ofthis gas, which is highly sensitive to neutrons, is extremely limited and demand far
outstrips supply.
Takayuki Yanagida and colleagues from
NAIST’s Sensing Device Laboratory have,
however, come up with a readily available alternative: crystals of lithium calcium
aluminum hexafluoride (LiCaAlF6) dopedwith traces of the metal, europium1. Energy
detecting materials such as this emit lightwhen exposed to thermal neutrons and are
known as scintillators.
The materials for this new scintillator
include lithium fluoride enriched in lithium6, a light isotope of the metal that is sensitive
to thermal neutrons. When a neutron hitslithium-6, the collision produces two particles: an alpha particle made of two protons
and two neutrons and a triton, which contains
one proton and two neutrons. These two particles speed through the crystal, and in theirwake excite electrons that eventually transfer
their energy to the europium ions, whichemit photons (measurable particles of light).
The researchers found that for every neutronthat hits the material, the europium produced
about 29,000 photons.
The team then tested the scintillator’sability to image two hidden objects, known

as masks. One mask contained a series ofholes, while the other had a more complex
interlocking ring pattern. The scintillator sat
on one side of the mask, while a beam of neutrons fired at it from the other side. Because
the neutrons could only pass through holes in
the masks, the light emitted by the scintillator
formed a sharp shadow image of the objects
after about 10 minutes, revealing features
smaller than a millimeter in size (see image).
This material, which is now available fromJapan-based chemical manufacturer Tokuyama Corporation, offers thesecond-highest light yield of any commercial
scintillator. “One application is security,” Yanagida says. “Neutron detectors are required toprevent nuclear terrorism.” He and his collaborators have, for example, used the scintillator
to develop a security instrument for airports
and are also testing it for medical applications
that use neutrons to treat disease.
Yanagida has subsequently invented aneven more luminous scintillator — a form of
cerium-doped gadolinium aluminum gallium
oxide, which is also commercially available.
He is now developing an improved theoretical model of the scintillation process, whichshould help to design even more sensitive
radiation detectors.
Reference
1. Yanagida, T., Kawaguchi, N., Fujimoto, Y., Fukuda,
K., Yokota, Y. et al. Basic study of Europium doped
LiCaAlF6 scintillator and its capability for thermal
neutron imaging application. Optical Materials 33,
1243-1247 (2011).

*To read more about the work of
Takayuki Yanagida, another of
NAIST’s newest researchers, see
A scintillating career on page 60.

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1989/
Researchers: Takayuki Yanagida and Go Okada

NAIST Research Highlights 63

Photonic Device Science Laboratory | Professor Jun Ohta

Photonics

Glucose monitor
gets under your skinAn implantable device offers continuous glucose monitoringfor diabetes sufferers“

Our sensor has features
which are suitable forbioimplantabledevices.

64 NAIST Research Highlights“

Materials Science

R E S E A R C H H I G H L I G H TS

Materials Science© 2016 Takeshi Tokuda

2 mm

NAIST’s new implantable glucose monitoring device promises to make life easier for diabetics.

D© moodboard/Cultura/Getty

iabetes can lead to cardiovasculardisease, foot ulcers, serious eye
problems and even stroke. People
with the condition must regularly takeblood samples to check their glucose levels;
an effective, but onerous task. In some cases,
when it is necessary to take more frequentor even continuous readings, extracting
blood samples is simply not feasible.
Now, researchers from NAIST’s Photonic
Device Science Laboratory have madeglucose monitoring easier by designing andtesting in vivo a small, implantable glucosesensing device for on-demand or evencontinuous glucose monitoring1.
They used hydrogel containing a
glucose-responsive fluorescent dye that was
illuminated using a light-emitting diode(LED) attached to the gel. The presenceof glucose enhanced the fluorescence,
which was quantified using a sensor. “Oursensor has features which are suitablefor bioimplantable devices, such as thoseusing a small number of control wires. It is

minimally invasive, and so there is little riskof infection,” explains Takashi Tokuda, whoworked on the project. “The CMOS image
sensor used in our work uses basically thesame mechanism as that used for digital
cameras. It consists of a two-dimensional
pixel (photosensor) array and sequential
readout circuit. In most CMOS image
sensors, including ours, the light-sensing
circuit in each pixel can detect a very small
amount of light.”
The pixel sensor array allows thedevice to operate at multiple sensitivities
simultaneously. It was most sensitive at theborders of the pixel array, whereas higher
levels of glucose could be measured byanalysing the central pixels.
The researchers assessed the device’s
performance in a rat model and compared
the readouts to standard self-monitoring ofblood glucose. The animals were injectedwith specific glucose concentrations andthe data read using both approaches.
The sensor had to be calibrated as it

read glucose from an interstitial medium
rather than blood. But once calibrated, it
successfully monitored glucose levels over
several hours.
The sensor lagged the blood glucose
measurements by 60 minutes, so theresearchers modified the device structure,application protocol, hydrogel thickness andsensor placement. They have now reported
sensor performance in which the lag timeis the same as that for conventional selfmonitoring of blood glucose2. References
1. Tokuda, T., Takahashi, M., Uejima, K., Masuda,K., Kawamura, T. et al. CMOS image sensor-based
implantable glucose sensor using glucose-responsive
fluorescent hydrogel. Biomedical Optics Express 5,3859–3870 (2014).
2. Kawamura, T., Masuda, K., Hirai, T., Ohta, Y.,
Motoyama, M. et al. CMOS-based implantable glucose monitoring device with improved performanceand reduced invasiveness. Electronics Letters 51,
738–740 (2015).

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1408/
Researcher: Takashi Tokuda

NAIST Research Highlights 65

Supramolecular Science Laboratory | Professor Shun Hirota

H2© PASIEKA/Science Photo Library/Getty

The nickel-iron active site within a hydrogenase
enzyme needs an electron pathway to reversibly split hydrogen gas. New findings show thatiron–sulfur clusters can turn this flow on or off.

Electron pathways

A gateway tosplitting hydrogen
The discovery of a reaction control switch during a crucial
biological reaction brings hope of a fuel cell closerHydrogen gas (H2) is known as‘nature’s fuel’ because of the role itplays keeping bacteria and othermicroorganisms alive and plentiful.
Through the action of enzymes known ashydrogenases, these microbes can both
rip apart and generate H2 — releasing andstoring electrons in the process. Now, ateam from NAIST has identified criticalelectron transfer sites that may help
researchers control this activity by switchinghydrogenases on or off1. It brings therealization of low-cost hydrogen fuel cells, asa lightweight, emission-free energy source, astep closer.
The core activity of hydrogenases occurs
within their ‘catalytic centres’, which containnickel (Ni) and iron (Fe). These metals
reverse the oxidization of H2 into protons
and electrons through electron transfer.
Many fuel cells perform this same function
by using expensive platinum catalysts.
Reproducing the hydrogenase-based
biochemical technique within artificial
devices, however, would be challenging
because H2 cleavage and creation involves
complex, multi-step processes in microbes.
“Even though this chemical reaction
is very simple, the mechanism is quite
complicated,” explains Shun Hirota,from NAIST’s Supramolecular Science

Laboratory. For example, he notes,
one particular enzyme called [NiFe]
hydrogenase has at least seven intermediate
states that either participate in the reaction
or are activated by H2. “And now we’ve
found another one in the catalytic cycle,
making it eight,” Hirota says.
To produce H2, an enzyme’s active siteneeds an external source of electrons.
Usually, charges come from a carrier protein“

The electrons haveto pass through thecluster — it’s like agate, the more weknow about what
is going on in thisreaction, the better we
can utilize it.

“

Materials Science

R E S E A R C H H I G H L I G H TS

that attaches to the outer surface of thehydrogenase. Hirota, in collaboration with
Hulin Tai, and colleagues at the Universityof Hyogo, discovered that a light-generated
intermediate known as the ‘Ni-L’ state plays
a vital role in ensuring that electron transfer

to the NiFe active site proceeds normally.
Hirota says that the light sensitivity ofhydrogenases has been established for
decades, but the Ni-L state was neverconsidered as part of the catalytic cycle.
The team proved it was included bywatching infrared vibrations of bonds at the
NiFe centre under light and dark conditions.
They used laser irradiation to initiate the
Ni-L state, and captured it for analysis
at 138 kelvin.
Electron transfer to and from the active
site is controlled by three iron-sulphur (FeS)
clusters located within the small subunit of
the enzyme. The researchers’ analysis revealed
that opening this electron pathway requiredoxidation of the FeS cluster closest to the NiFe
centre: the catalytic reaction stops and the
Ni-L state is trapped when the FeS cluster isreduced. “The electrons have to pass throughthe cluster — it’s like a gate,” says Hirota. “The
more we know about what is going on in thisreaction, the better we can utilize it.”
Reference
1. Tai, H., Nishikawa, K., Suzuki, M., Higuchi, Y. &Hirota, S. Control of the transition between Ni-C and
Ni-SIa states by the redox state of the proximal Fe–S
cluster in the catalytic cycle of [NiFe] hydrogenase.
Angewandte Chemie International Edition 53,
13817–13820 (2014).

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1421/
Researchers: Shun Hirota and Hulin Tai

66 NAIST Research Highlights

Materials Science

RESEARCH HIGHLIGHTS
Information Device Science Laboratory | Professor Yukiharu Uraoka

Nano-fabrication

Bleeding-edge scienceto improve digital memory
A protein found in blood has been used to help create theworld’s smallest transistor

threshold. Typically, a semiconductormaterial with these properties, such as
silicon oxide, is used in the junction. But at
sub-10 nanometre scales the semiconducting
properties of silicon become unstable.
Uraoka’s team fabricated a V-groove
junction with a nanodot of semiconducting
iron oxide ‘floating’ on a wedge of insulating
silicon dioxide in the groove. “By charging
or discharging electrons into the nanodot
embedded in the gate oxide, the thresholdvoltage of the junction changes to high or
low, corresponding to memory states of
1 or 0,” explains Uraoka.
The challenge for the research team was
fabricating the nanodots consistently andthey came up with an ingenious solution.
They used the cage-shaped protein ferritin,which stores iron in the cells of humans
and other mammals, to ‘biomineralize’ ananodot with predictable and well-defined
dimensions. “The nanodot size is uniform
because it is designed by DNA,” says Uraoka.
“As a memory element, we achieved
low-voltage operation and a wide thresholdvoltage shift, but the technique is also
potentially applicable to displays, sensors orenergy harvesting devices such as solar cells
and thermal transducers.”
Reference
1. Ban, T., Uenuma, M., Migita, S., Okamoto, N., Ishikawa,Y., Yamashita, I. & Uraoka, Y. Ultra-short channel junctionless transistor with a one-dimensional nanodot array
floating gate. Applied Physics Letters 106, 253104 (2015).

© 2016 Yukiharu Uraoka

Advances in computing performance
rely on the incremental downscaling of theindividual switching elements on which
digital technology is based. The elements arethe ‘bits’ that can be switched to either on or
off to give the binary states of 0 and 1, andare realized using electronic semiconductortransistors.
Technological advances in micro- andnano-fabrication techniques have taken
the industry to transistor scales below
10 nanometers, but researchers are finding
that, at this level, existing fabrication
techniques are not reliable enough forcommercial production of the next
generation of digital memory.
Yukiharu Uraoka and colleagues from
NAIST’s Information Device Science
Laboratory and the National Instituteof Advanced Industrial Science andTechnology (AIST) — one of Japan’slargest public researcher organizations —have used a biological process to createa transistor as small as 4 nanometres.
“We have demonstrated the memory
operation of a semiconductor device
with the shortest channel length in theworld, utilizing nanodots fabricated using
biotechnology,” says Uraoka. “This is afusion of semiconductor technology andbiotechnology that has proved to be very
effective for fabricating new functional
semiconductor devices.”
A semiconductor transistor consistsof a junction between two electronic
terminals that only conducts electrons
when the voltage across it reaches a certain“

We havedemonstrated thememory operationof a semiconductor
device with theshortest channel
length in the world.

“

N

AIST researchers have fabricated thesmallest transistor to date, forming
the possible basis for the next
generation in digital memory1, using ferritin
protein molecules to form nanodots in short
V-grooves.

Iron oxide nanodots can be fabricated in the V-groove of a junction transistor using ferritin protein.

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1410/
Researcher: Yukiharu Uraoka

NAIST Research Highlights 67

Photofunctional Organic Chemistry Laboratory | Professor Hiroko Yamada© 2016 Hiroko Yamada

Materials Science

R E S E A R C H H I G H L I G H TS

Nanotechnology

Stacking the odds
in graphene’s
favourEye-catching 2D carbon sheet arrangements can act as stable,
multi-charge storage devices for memory applications

68 NAIST Research Highlights

When we saw thetrimer, we thought, whata beautiful structure.

targeted the PAH peripen­­tacene. Flat,
rectangular, and composed of 14 inter­locked benzene rings, this molecule has
been identified as a ‘missing piece’ of thesimplest PAHs because it is unstable understandard ambient conditions. Part of the
problem is that electrons in peripentacene
are delocalized and can exist as reactive
free radicals.
To trap peripentacene in a usable form, theresearchers turned to a PAH with a central
core of four flat aromatic rings surroundedby several other ring systems. By mixing thisPAH with the strong oxidizing agent ironchloride, the team removed electrons fromthe precursor and caused it to spontaneously
fuse into a nanographene sheet composed of
56 carbon atoms.
When the team used X-rays to observe
the atomic arrangement of their new

peripentacene, a curious result was apparent. Instead of a single sheet, their nanographene was identified as a three-layered
stacked complex that, when viewed fromabove, took on a symmetric, star-shaped
appearance (see image). “When we saw thetrimer, we thought, what a beautiful structure,” recalls Aratani.
The nanographene in solution also
imparted unique electronic capabilities.
Electrochemical measurements revealed thenew peripentacene could reversibly releaseand take in five electrons — one of the largest
positive charge storage values ever recorded
for an all-carbon organic framework.

“We were so excited by this behaviour,” says
Aratani. “This multi-charge storage ability
makes the peripentacene a nice counterpart toC60 buckyballs.”
Reference
1. Matsumoto, A., Suzuki, M., Kuzuhara, D.,
Hayashi, H., Aratani, N. & Yamada, H. Tetrabenzoperipentacene: Stable five-electron donating ability anda discrete triple-layered β-graphite form in the solidstate. Angewandte Chemie International Edition 54,
8175–8178 (2015).

Bottom-up Approach

Pd

FeCl3

Three-layered Stacked Complex in the Solid StateA star-shaped, triple-layered complex of flat carbon sheets can store surprising amounts ofelectronic charge.

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1432/
Researchers: Naoki Aratani and Hiroko Yamada

NAIST Research Highlights 69

Materials Science

“

“

A

tomically flat graphene sheets are a
speedier alternative to silicon transistors, but integrating these materials
into confined nanoscale devices is challenging. Now, a NAIST team has discovered how
to synthesize graphene into tiny, triplelayered clusters that can release unusuallylarge amounts of electric charge1.
Graphene sheets are usually isolated bypeeling graphite crystals apart layer by layer.
Early ‘sticky tape’-based methods to do
this have been replaced by more efficientliquid-phase exfoliations, but mechanicallyagitating the atom-thin layers makes it
hard to control final product morphologies.
Some researchers have been experimenting with bottom-up approaches, such as
surface-directed chemistry, that assemble
graphene into desired shapes from molecular precursors.
Naoki Aratani, Hiroko Yamada andcolleagues from NAIST’s Photofunctional
Organic Chemistry Laboratory investigateda different bottom-up method based onpolycyclic aromatic hydrocarbons (PAHs) —organic molecules containing multiple
rings. These compounds, which arefound naturally in coal, oil, and gas,
resemble graphene networks attrun­cated, nanoscale dim­ensions.
Synthesizing PAHs with custom
frame­works, however, is tricky
due to their low solu­bility andcumbersome structures.
For their nano­graphene
synthesis, the NAIST team

Quantum Materials Science Laboratory | Professor Hisao Yanagi© Roc Canais Photography/Moment/Getty

Materials Science

R E S E A R C H H I G H L I G H TS“

Sugar and magnets
may have little incommon, but wefound that a sugar
film covered with red
dye looks to circularly
polarized light like amagnet.

“70 NAIST Research Highlights

Optical phenomena

The sweet lureof light to sugar

A red dye–sugar combination interacts with light in an
unexpectedly magnetic waypolarization, also interacts differently with
left- and right-handed chiral molecules
depending on the light’s own ‘handedness’.
This effect is exploited in the spectroscopic
measurement of concentrations of specificchiral proteins in biological solutions. Suchbiological molecules are said to be optically
active, and their interaction with circularly
polarized light produces an effect calledcircular dichroism.
“In absorptive chiral molecules, rotationof circular polarization is accompanied bycircular dichroism due to the absorption
difference between the left- and righthanded circularly polarized light,” explains
Satoshi Tomita, a researcher in NAIST’s
Quantum Materials Science Laboratory,
Circularly polarized light can also be
manipulated using magnetism. By passing
this sort of light through a magnetic fieldwith a particular orientation, it is possible
to flip the polarization plane and reverse
the light’s rotation. Tomita and his NAIST
colleagues have discovered that a thin filmof glucose topped with rhodamine red dye

can achieve this same polarization reversal
at the absorption wavelength of the dye. Thisis the first non-magnetic medium known to
do this.
“Sugar and magnets may have little incommon, but we found that a sugar film
covered with red dye looks to circularly
polarized light like a magnet,” Tomita
says. “Although the origin of the reversal
we have discovered is still unclear, theinterface between the transparent chiralglucose molecules and the absorptive
achiral dye in the double-layer films
is essential to this effect. It is a ‘chiralmeta-interface’ that could pave the wayfor exploring new optical phenomena
and could be used as an optical isolator
without magnetic fields.”
Reference
1. Tomita, S., Kosaka, Y., Yanagi, H. & Sawada, K.
Chiral meta-interface: Polarity reversal of ellipticity
through double layers consisting of transparent chiraland absorptive achiral media. Physical Review B 87,
041404(R) (2013).

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1162/
Researchers: Satoshi Tomita and Hisao Yanagi

NAIST Research Highlights 71

Materials Science:© Ralf Hiemisch/Getty

A

possible new research focus into
optical phenomena and light manipulation has been exposed throughthe discovery at NAIST of a non-magnetic
double-layer film that can interact likemagnetic materials with light1.
Light interacts with materials in a wide
range of ways, from complete absorption
by some metals to perfect transmission bytransparent glass. Some materials — such as
the liquid crystal used in computer displays— interact with light in ways that change theorientation of its polarization. However, oneof the more scientifically useful light–material interactions is biological.
Most biological molecules, such as proteins for example, come in mirror-image
versions with either left- or -right-handed
symmetry. This ‘chirality’ is key to thefunctionality of many biomolecules; a righthanded version, for example, may be able tocombine with other molecules in a way theleft-handed form cannot.
Light with a corkscrew-like rotating
polarization (see image), known as circular

Circularly polarized lighttwists through space likea corkscrew in either aclockwise (right-handed)or anti-clockwise (lefthanded) direction.

Materials Science

R E S E A R C H H I G H L I G H TS
Photonic Molecular Science Laboratory | Professor Tsuyoshi Kawai

© Pasieka/Science Photo Library/Getty

Photonics

Feeding a growing need forshrinking devices
New material could improve processes for sub-microscopic manufacturing

The increasing demand for miniaturization of electronic devices, such as
semiconductors and transistors, down
to nanoscale dimensions is pushing thecapacity of the optical lithography processes
used to produce them. There is a strong needfor new light-sensitive materials, known as
photoresists, that can meet the demands ofmore advanced micro-photolithographic
techniques.
Micro-photolithography is used in the
fabrication of super-miniature and highly

72 NAIST Research Highlights

complex patterns such as those on integrated circuit boards. It allows for patterns
that are only a few tens of nanometersin size to be etched or deposited onto
photoresists.
Among the critical components ofphotoresists are photoacid generators(PAGs). These produce the strong acids
required to engrave or deposit patterns on
to substrates. More efficient PAGs could
lead to improvements in the performanceof micro-photolithographic processes, butalso of rapid prototyping (3D printing) andphotocuring systems.
NAIST researchers have been investigating a new type of PAG by irradiating photochromic triangle terarylenes with ultraviolet
light, inducing an electrocyclic reaction that
produces a closed-ring structure and triggers
the release of methanesulfonic acid by the
PAG1. By introducing hydrogen atoms andthe acid’s conjugate base to both sides of thestructure a self-contained PAG was formed.
“We had already developed highly effi-Materials Science“

This breakthroughcould lead to
improvements in
3D printing as wellas in processes that
produce sealants,
protective gloves andrubber stoppers forpharmaceuticals.

cient photo-quantitative compounds basedon compounds with a triangle terarylene
structure,” explains Tsuyoshi Kawai, from
NAIST’s Photonic Molecular Science
Laboratory. “Although this new type of
PAG only achieved a quantum yield of 52%
during the study, it promises the possibilityof super-efficient photoresists in the futurewith quantum yields close to 100%.”
PAGs with higher quantum yields are
more efficient at producing photoacids andcould lead to better performing photoresists
and improvements in photolithographic
processes. The PAG developed in the study
was also capable of photoinitiating the cationic polymerization of
cyclohexene oxide — an epoxy monomer.
This could lead to improvements in 3D
printing as well as in photocuring processes
that produce materials used for such prod-

ucts as sealants, protective gloves and rubber
stoppers for pharmaceuticals.
“Although photochromic reactions thatlower the pH of photoacids have beenreported, they are not able to generatesufficiently strong and reactive acids forcationic polymerization to occur,” Kawaisays. “Employing the PAG as a phototriggerof cationic polymerization indicates that the
new PAG is compatible with photopolymer
systems and represents another significant
outcome from our research.”
Reference
1. Nakashima T., Tsuchie K., Kanazawa R., Li R., IijimaS., Galangau O., Nakagawa H., Mutoh K., Kobayashi
Y, Abe, J. & Kawai T. Self-contained photoacid
generator triggered by photocyclization of triangle
terarylene backbone. Journal of the American
Chemical Society 137, 7023−7026 (2015).

“

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1427/
Researcher: Tsuyoshi Kawai

NAIST Research Highlights 73

Bio-Process Engineering Laboratory | Professor Yoichiroh Hosokawa© 2016 Yoichiroh Hosokawa

Materials ScienceF E AT U R E

74 NAIST Research Highlights

Exploring cells withintense light
Physics meets biology in a flash of brilliance as a novel
use of lasers opens a bold new field of researchT

he lab of Yoichiroh Hosokawa provides af ine example of the interdisciplinary andcollaborative research approach that has
become a hallmark of NAIST in recent years.
Its name — the Bio-Process Engineering
Laboratory — describes both the physicsbased technology at its core and the biologicalworld that is the focus of the lab’s research. Its
students and young researchers have a range of backgrounds, fromphysics and chemistry to biology and medicine.
Hosokawa is keen to see the collaborative approach adopted in all
directions. “Although I like to apply the most advanced laser-basedengineering for biological research, I think that we could also apply
biological phenomenon for engineering,” he explains. Through suchinnovative research, he is hoping to foster students who can work
creatively beyond orthodox paths of thinking and communicate wellwith other people with various backgrounds.
Hosokawa embarked on a career based on laser technology in1995 when he began a master’s degree at Osaka University. His
supervisor in the university’s Department of Applied Physics, Hiroshi
Masuhara, who is now retired, told him: “Laser has huge potential,
so you won’t have trouble finding a job if you can operate advanced
laser devices.”
But, by the time Hosokawa had earned his PhD, five years later,
laser-manufacturing technology had greatly advanced and thedevices had become user-friendly and already widely used in many
areas. “I had to think of a way to take advantage of my skills,” hesays. Hosokawa turned his attention to biotechnology, where the useof lasers for cell manipulation had barely been explored.
Even today, laser for many biologists is used as a tool mostly
to visualize cells under microscopes. Fluorescent probes are
an example. As a result, the weakest possible light is usuallyconsidered best, to avoid disturbing the cellular environment. But,
what Hosokawa now offers his biological collaborators is the exact
opposite: the laser he applies for cell manipulation is more than
1,000 times stronger than lasers used for fluorescent visualization.
“People won’t normally do such a crazy thing,” he acknowledges.
“I know it is reckless, but if we understand the properties of lightand cells well and stop just a few steps before going out of control,
we can open a new research field.”
Hosokawa uses a femtosecond laser, which is usually used for
precision cutting of hard materials, such as the silicon substrates
for solar cells and glass in liquid crystal displays. Hosokawa
repurposeds it for manipulating and measuring cells under the
microscope without direct contact.
Because the intense ultrashort laser pulses for just one
quadrillionth of a second, it is too short a blast for heat generation,
temperature doesn’t interfere with the processes of manipulationand measurement. This way, researchers' understanding of cellinteractions and their responsiveness is enhanced.
It’s a bold approach that wouldn’t work without a steady streamof suitable sample material provided by biologists. And so, soonafter Hosokawa became a researcher at Osaka University in 2000,
he began visiting the laboratories of biologists to seek possible
collaborations. Many of them showed interest. “But I was not anexpert in cells, so our conversations were very clumsy,” he recalls.
Hosokawa says his move to NAIST in 2008, as a research
associate professor with Masuhara when he opened a newlaboratory here, helped him take a big leap forward. “NAIST is acompact institute with many powerful scientists, and provides agreat opportunity to effectively work with top-level researchers fromother institutions,” he says. “Until then, my network was mostly
confined to within Osaka University.”
In 2011, he became independent and established his ownlaboratory within the Graduate School of Materials Science. A
breakthrough soon followed as part of a collaboration with AkihikoIto, a pathologist in Kinki University’s Faculty of Medicine in Osaka.
Their team developed a new way to investigate cell–cell adhesion
strength using the femtosecond laser.
In their method, the laser is focused in the vicinity of targeted
cells. The irradiation generates a shockwave and an impulsive force
that propagates toward cells in a micron-sized region and breaks theadhesion between them.
Further practical achievements were reported in 2015 as part ofa collaboration with Kazusato Oikawa and Mikio Nishimura fromthe National Institute for Basic Biology in Okazaki. Hosokawa
and collaborators studied the mechanism of photosynthesis andsucceeded in estimating the adhesion strength in plant cells without
breaking cell walls (see "Shedding new light on plants" on page 76).
Hosokawa says NAIST’s operational environment suits his current
working style. The institute appreciates freedom and appraises
performances based purely on research outcomes, unlike many
Japanese universities that also require a lot of administrative workand long hours doing paperwork in an office.
This flexibility is critical for the father of two young boys, because
his wife, Chie, is also a busy researcher, at the National Institute ofAdvanced Industrial Science and Technology in Osaka. When she istravelling for work, Hosokawa leaves his laboratory mid-afternoon totake care of their children at home.
Although they share the same research interests, the couple
spend more time talking about their children. “Child-raising is themost difficult thing,” Hosokawa says. “As for the limited time, I
can’t compete with researchers who work 24 hours a day.” But heis producing good outcomes. In fact, his performance has been sogood that NAIST has recently made him a professor, a promotionthat will be effective from April 2016.

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1447/
Researcher: Yoichiroh Hosokawa

NAIST Research Highlights 75

Materials Science

Yoichiroh Hosokawa

Bio-Process Engineering Laboratory | Professor Yoichiroh Hosokawa

Laser science

Test of strength sheds
new light on plants
Ultrashort laser pulses reveal dynamic subcellular interactions during
photosynthesis
76 NAIST Research Highlights© 007ea8_930/ iStock / Getty Images Plus

Materials Science

R E S E A R C H H I G H L I G H TS

Materials Science© 2016 Yoichiroh Hosokawa

Peroxisomes co-locating with chloroplasts and mitochondria: a laser pulse breaks the adhesion
between chloroplast and peroxisomes.

F

rom the food we eat and clothes we wear,
to the fuels we burn, plants underpin
most aspects of our lives. Now, a NAIST
team has used laser technology to come up
with fundamental new insights into how
plants photosynthesise — that is, how theyuse sunlight to transform carbon dioxide andwater into glucose1.
The research team, led by Yoichiroh
Hosokawa from NAIST’s Laser Nano-Manipulation Science Laboratory, in collaboration with the National Institute for Basic
Biology, was interested in how subcellularfeatures inside plant cells interacted during
photosynthesis. Using a two-photon excitation laser scanning microscope they observedthat in darkness, small structures called
peroxisomes, which are responsible for carrying vital metabolites, floated unresponsively
in the cellular cytoplasm.
But, when exposed to light the peroxisomes became active. They co-located withchloroplasts, substructures that are key forphotosynthesis, and mitochondria, which
generate energy, before changing shape andappearing to spread over the surface of thechloroplasts.

The researchers then focussed intense
ultrashort laser pulses at the site of contact
between peroxisomes and chloroplasts. The
laser light caused a mini-explosion — ofabout 1 micrometre in diameter — at its
point of focus and the resulting shockwave
broke the adhesion. The strength of the adhesion was estimated from the laser intensitythat was required to break it. “Normally thislaser is used for metal or semiconductor processing,” Hosokawa explains. “Our new idea
was to use it to probe plant cells under the
microscope. The laser can transmit throughthe cell wall and focus to a point size smaller
than the cell itself.
“So, for the first time we could estimate
adhesion strength inside a plant cell without
breaking the cell wall and while maintaining
physiological conditions.”
The data from the experiments suggested
that adhesion strength between the subcellular structures increased under light. The
researchers believe the adhesion is likely to
be involved in ensuring an efficient flow of
metabolites between the organelles at thecontact site.
They also examined how the quality andwavelength of light modified peroxisomebehaviour and found that peroxisome-chloroplast interactions, as well as electron transport
processes in chloroplasts, are key to healthy
photosynthesis.
“At a practical level, these insights might
be useful in agriculture, ultimately to findseeds with excellent crop yield,” Hosokawa
says. “But, our laser method is not limited
to plant biology. It offers a general way toquantify binding strength between of all sorts
of different complex integrated micro-objects
in biology or technology.” Reference
1

Oikawa, K., Matsunaga, S., Mano,S., Kondo, M. et al.
Physical interaction between peroxisomes and chloroplasts elucidated by in situ laser analysis. Nature
Plants 1, 15035 (2015)*To read more about the careerof Yoichiroh Hosokawa, one of
NAIST’s newest professors, see“Exploring cells with intenselight” on page 74.

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1447/
Researcher: Yoichiroh Hosokawa

NAIST Research Highlights 77

Nanomaterials and Polymer Chemistry Laboratory | Associate Professor Hiroharu Ajiro

Polymer printing

Dissolving obstacles to asuperior drug solution
Inkjet printer forms layer-by-layer coating of polymers loadedwith an anti-cancer cargo

Inkjet systems can print alternating layers
much more quickly than LbL without theneed for washing between each layer. But,
it is difficult to print thin films of synthetic
polymers in this way because the polymers
are typically dissolved in solvents that
evaporate during the process, leaving solid
residues that clog inkjet printer nozzles.
Hiroharu Ajiro of NAIST’s Nanomaterials
and Polymer Chemistry Laboratory andcolleagues have used a water-soluble
polymer to overcome this problem. The
polymer is based on a strand of polyethylene
glycol (PEG) with long sections of

a

1cm

b

2mm

c

Reference
1. Ajiro, H., Kuroda, A., Kan, K. & Akashi, M. Stereocomplex film using triblock copolymers of polylactide
and poly(ethylene glycol) retain paxlitaxel on
substrates by an aqueous inkjet system. Langmuir 31,
10583–10589 (2015).

d

2mm

2mm

Mixing solutions of the PEG-PLLA and PEGPDLA polymers forms a gel that is held together
by stereocomplex formation.

More information about the group's research can be found at http://mswebs.naist.jp/english/courses/1844/
Researcher: Hiroharu Ajiro

78 NAIST Research Highlights

0.04mm1,000
drops/line

Reprinted with permission from Ref. 1. Copyright 2015 American Chemical Society.

“This compound,which is difficult todissolve in water,
could be released
from the thin films
into water.

polylactide (PLA) attached to each end.
Crucially, PLA can take two different
mirror-image forms, depending on how
chemical groups are arranged along its
polymer backbone. Known as poly(L,L-lactide) (PLLA) and poly(D, D-lactide)(PDLA), these forms can bind together toform a relatively strong ‘stereocomplex’(see image). This helps stabilize thin films
that contain alternating layers of PLLA
and PDLA.
The researchers dissolved separate batchesof the PEG-PLLA and PEG-PDLA polymers
in a mixture of water and the solventacetonitrile, which helps stereocomplex
formation, and added the anti-cancer drug
paclitaxel to each solution. They then loaded
the mixtures into an inkjet printer, which
could spit out individual liquid droplets
containing just 20 picolitres (20 trillionths ofa litre). Under computer control, it printed
50,000 droplets of the first mixture in asquare pattern onto a glass substrate andadded the second mixture on top in the same
pattern. Repeating this cycle 1,000 times
created a thin film on the glass substrate.
When this was dipped in a saline solution,
the film released about 60–70 per cent of
its paclitaxel cargo over the course of anhour. “This compound, which is difficult todissolve in water, could be released fromthe thin films into water,” Ajiro explains.
The team now aims to study how the rate of
drug release is affected by variables such aschanges in the polymers’ structures or thenumber of cycles used to print the layers.

2mm

L

ayer-by-layer (LbL) assembly has beena superior method used to create thinfilms and other advanced composite
materials, by repeatedly and alternately
dipping a substrate in two different chemicalsolutions. But these dipping and washingcycles can be time consuming and waste a
lot of chemicals.
Now, NAIST researchers have used an
inkjet printer to deliver droplets of dissolved
polymers to build up a biocompatible thinfilm that releases an anti-cancer drug1.
Such films could be used to coat thesurfaces of medical implants to preventthe body rejecting them, or to improvedisease treatments.

“

Materials Science

R E S E A R C H H I G H L I G H TS

Innovative Research and Education Programs
NAIST constantly strives to renew its research and education programs toward producing science andtechnology researchers prepared to meet the demands facing tomorrow’s global scientiﬁc community. These
programs are regularly awarded external funding for their wide-ranging beneﬁts.

Program for Promoting the Enhancement of Research Universities (2013–2023)
The Japanese Ministry of Education, Culture, Sports, Science andTechnology (MEXT) launched the Program for Promoting theEnhancement of Research Universities in October 2013, which
is a new type of research funding in Japan that aims to enhanceresearch capabilities by utilizing university research administrators(URA) who implement intensive reforms to strengthen the research
environment at their respective universities. NAIST is one of 22
universities and research institutions selected to receive support
through this program.
NAIST continues to conduct frontier-opening research
while expanding into new interdisciplinary ﬁelds in scienceand technology. With the establishment of a university-wide
strategic research infrastructure, NAIST endeavors to leverage

Formulating strategies
and plans based on
objective analysis data

its abundant resources to attain the new research materials andfacilities necessary for next-generation research, to disseminate
its achievements and human resources around the globe, andto further expand its global research and education networkin order to contribute to the overall advancement of scienceand technology.
Projects being supported through this program include (1)the Creating New Research Streams Program, which creates
new research domains promising a high global proﬁle, (2) the
Sustainable Development of Research Capabilities Program,which enhances NAIST’s world-class research capabilities, and(3) the Joint International Research Program, which raises theglobal visibility and standing of NAIST’s research capabilities.

Supporting
the strategic acquisitionof external competitive
research funds

Enhancingthe international
collaborative
research network

Reforming the research system to enhance
NAIST’s research capabilities
Top Global University Project (2014–2024)
In October 2014, NAIST was one of 37 universities selected
for another prestigious MEXT initiative, the Top Global
University Project. For a period of ten years, MEXT will support
outstanding universities in their efforts to reform institutional
governance and collaborate with top universities worldwide inorder to strengthen international competitiveness.
Through the Top Global University Project, NAIST has
committed to enhancing its international graduate courses

NARA, JAPANby (1) including a joint degree scheme, (2) developing a newmodel for graduate education based on top-notch research,(3) reforming institutional governance and strategic agility, (4)creating a campus environment that supports transdisciplinary
education and cultural diversity, and (5) reorganizing its three
graduate schools into a single entity with a view to establishing
new, ﬂexible research groups.

NARA INSTITUTE of SCIENCE and TECHNOLOGYRESEARCH HIGHLIGHTS 2016

NAIST is located in Ikoma City, in Japan’s historic Nara
Prefecture. Home of the ﬁrst ofﬁcial capital of Japan, Nara
Prefecture has an incredibly rich history as a center forinternational trade and relations. In addition to its proliﬁcancient heritage, Nara Prefecture is also conveniently
located in close proximity to Kyoto and Osaka, and just 90
minutes from Kansai International Airport.
8916-5 Takayama-cho, Ikoma, NARA
630-0192 JAPANh ttp://w w w .nai st.j p/en/