NARA INSTITUTE of SCIENCE and TECHNOLOGYR E S E A R C H H I G H L I G H T S 2015h tt p://www.na i s t .j p/ e n/

HIGHLIGHTS

Machine translation Page 13
Better bilingual dictionaries
Plant genetics Page 30
Wood-forming genes active
in mosses
Photovoltaics Page 64
Semiconductor sandwich
solution for solar cells

-Outgrow your limits-

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— aresupervised 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 environmentand supportive infrastructure. Moreover, the outstanding achievements of NAIST’sfaculty 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 and technology researchers become tomorrow’s global leaders.

webwebsitehttp://www.naist.jp/en

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NAIST Research Highlights
ISSN 2189 - 714X
For further information on the research published in
NAIST Research Highlights or arranging aninterview with a faculty, please contact:

NAURA (NAIST URA Team)
Institute for Research Initiatives
Nara Institute of Science and Technology
8916-5 Takayama-cho, Ikoma, Nara 630-0192, JAPANE-mail : naura@rsc.naist.jp
Printing : Kyodo Seihan Printing Co., Ltd.

Ⓒ2015 NAIST All rights reserved.

NAIST Research Highlights
showcases the most promising andimportant research achievements ofeach laboratory at NAIST andpresents their current research andcore technologies to the public. The
publication distills highly technical research papers
into short, easy-to-understand articles that appeal toa global audience of both specialists andnon-specialists. NAIST Research Highlights aims
to inform readers of the latest developments in
NAIST’s pioneering research, and to stimulate newand 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
NAURA
Research Highlights
under the auspices of the“Program for Promoting
the Enhancement ofResearch Universities”, which is fundedby Japan’s Ministry of Education, Culture,
Sports, Science and Technology (MEXT).
Through this program, NAIST further
supports its cutting-edge research while
expanding into new interdisciplinary ﬁelds
in science and technology toward
becoming a globally recognizededucation and research center.

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)
Japanese Ministry of Education, Culture, Sports,
Science and Technology (MEXT) launched the Programfor Promoting the Enhancement 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 theirrespective universities. NAIST is one of 22 universities/
research institutions selected to receive support
through this program.
NAIST continues to conduct frontier-opening research
while expanding into new interdisciplinary ﬁelds inscience and technology. With the establishment of auniversity-wide strategic research infrastructure, NAIST

Formulating strategies
and plans based on
objective analysis data

endeavors to leverage its abundant resources to attainthe new research materials and facilities necessary fornext-generation research, to disseminate its
achievements and human resources around the globe,
and to further expand its global research and education
network in order to contribute to the overall
advancement of science and 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 researchcapabilities, and (3) the Joint International Research
Program which raises the global visibility and standingof NAIST’s research capabilities.

Supporting thestrategic acquisitionof external competitive
research funds

Enhancing theinternational
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 to another prestigious MEXT initiative, theTop Global University Project. For a period of ten
years, MEXT will support outstanding universities intheir efforts to reform institutional governance andcollaborate with top universities worldwide in order tostrengthen international competitiveness.
Through the Top Global University Project, NAIST has
committed to enhancing its international graduate

courses by (1) including a joint degree scheme, (2)developing a new model for graduate education
based on top-notch research, (3) reforming
institutional governance and strategic agility, (4)creating a campus environment that supports
trans-disciplinary education and cultural diversity, and(5) reorganizing its three graduate schools into asingle entity toward establishing new, ﬂexible
research groups.

NAIST Research Highlights

01

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

Information Science
The core focus of the Graduate Schoolof Information Science is oncommunication between society,people and computers, as well as thecomputing infrastructure for the
Big-data era that will support
sustainable growth and societal
development well into the future. Ourworld-class faculty, staff, andcurriculum contribute to the cultivationof researchers and engineers who willbe leaders in tomorrow’s universallyconnected society.

●Software Engineering●Software Design and Analysis●Internet Engineering●Internet Architecture and Systems

Computer
Science●Computing Architecture●Dependable System●Ubiquitous Computing Systems●Mobile Computing

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

AppliedInformatics●Imaging-based Computational●Robotics
Biomedicine●Intelligent System Control●Large-Scale Systems Management ●Computational Systems Biology●Mathematical Informatics

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

Plant
Biology

Biomedical
Science●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 Developmental Biology●Molecular Signal Transduction●Tumor Cell Biology●Functional Neuroscience●Molecular Immunobiology●Gene Function in Animals●Molecular Medicine and Cell Biology●Functional Genomics and Medicine ●Developmental Biomedical Science●Molecular and Cell Genetics

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

Physics●Quantum Materials Science●Surface and Materials Science●Nanostructure Magnetism●Laser Nano-Manipulation Science●Theoretical Condensed Matter Physics

Information●Photonic Device Science●Information Device Science●Microelectronic Device Science●Sensing Device

Chemistry●Advanced Polymer Science●Synthetic Organic Chemistry●Photonic Molecular Science●Photofunctional Organic Chemistry

Biology●Biomimetic Materials Science●Complex Molecular Systems●Supramolecular Science●Biocompatible Materials Science

Materials Science
The main research area in the Graduate
School of Material Science is “Photonic
Nanoscience” which seeks tounderstand the mechanisms ofmaterials on the electron, atomic, andmolecular levels from the perspectiveof “seeing with light”, “creating withlight”, and “transmitting with light”.
Researchers aim to create newmaterials, structures, and functions.
We systematically educate students tobecome excellent leaders in researchand development ﬁelds in the global
society.

●Organic Electronics●Green Nanosystem●Nanomaterials and Polymer Chemistry

As of July 1, 2015

02

NAIST Research Highlights

CONTENTS

01 Innovative Research and Education Programs 02 NAIST Graduate Schools
05 Research Highlights
Information Science
05
06
07
08
09
10
11
12
13
14
15

More tolerance, less waste
Better built-in fault detection
Tailoring workout intensity
Swirl protocol cuts congestion
Acceptance testing accelerated
Method histories made easy
Security vulnerabilities detected
Efﬁcient data sorting for wired cars
Better bilingual dictionaries
Segmentation makes translation twice as fast
Dual strategy to boost underground Wi-Fi

76 faculty members
16
17
18
19
20
21
22
23
24
25

Biological Sciences
27
28
29
30
31
32
33
34
35
36
37
38

Self-recognition in pollination
Enzyme shatters cell skeleton
Key propagation protein identiﬁed
Wood-forming genes active in mosses
Surface signals control growth
Understanding how ﬂowers and leaves form
Understanding plant immunity, both near and far
Understanding female reproductive organ formation
Protein does double duty in cell migration
Signals that strengthen the brain
Stress response gene underlies loss of vision
Key quality control element revealed

39
40
41
42
43
44
45
46
47
48
49
50

53
54
55
56
57
58
59
60
61

Seamlessly removing objects from images
Augmented reality zoom now possible
Resolving translucent 3D objects
Appearance plays role in social perception
Gestures and ‘interruptivity’ boost interaction
Raising optical grid efﬁciency
Delays undermine multihop Wi-Fi
Improved modelling for three-dimensional scanning
Digital tool boosts preoperative skill baseMatching structure to function

71 faculty members

25 laboratories

Ribosome pause has critical role
Regulator of tumour suppression found
Understanding the role of a messenger
Ion channel mutations may cause disease
Repair enzyme also reboots genome copying
Gene function revealed in E. coli library
Yeast enzyme regulator recognized
Yeasts with better stress tolerance
Receptor role in protection unmasked
Protein groove aids membrane assemblySignal loop sets vertebrae numbers
How nerve cell axons become mobilised

Materials Science52

21 laboratories

Making simpler, cheaper organic crystals
120-fold boost in photoluminescence
Handedness theory usurped
Implant sensor images brain activity in vivo
Improving memory using hot spots
Microﬂow set-up boosts output
Hybrid skin for stable agents
Enzyme’s special bonds ﬁnally revealed
Growing enzyme diversity using mutations
Anti-fouling polymers demonstrate star quality

50 faculty members
62
63
64
65
66
67
68
69
70

20 laboratories

Generating power from waste heat
Laser switchable across waveguides
Semiconductor sandwich solution for solar cells
Bringing magnetism to gold
Probing exciton transitions
Detecting forces at cellular scales
Making waste heat into energy
Characterizing atomic orbitals
Switchable surface wettability

71 NAIST as an International Research University
NAIST Research Highlights

03crochip fault tolerance that consumes one-third less power may now
possiblewith
newActroid-SIT
hind bea roped-off
barrier.
Whenp design
could make gestures, more than 60% of theM

Now, Jun Yao, Yasuhiko Nakashima andcolleagues at NAIST have proposed a lowcost redundancy architecture called Explicit
Redundancy Linear Array (EReLA), which
offers greater flexibility and better automation than conventional architectures1.
Processors based on this novel design offer
the same functionality, consume less powerand have ten times longer lifetimes thanconventional processors.
TMR has been the preferred architecture
because it comes with configurable isolation(between input, output and power) and hot
swap technologies (which allow systems to be
switched without shutting down); the former
enables defective components, or failures,
to be detected and isolated, while the latter© 2013 Robotics Laboratory, Nara Institute of Science and Technology

subjects who approached her then spoke toher;a significantly
greaterensuressmooth runningofproportion
the system than
when
when
gestures were disabled.
a faulther
occurs.
The android also sports ‘motion interrupThe
EReLA
architecture
tivity’:when
she fails
to recogniseprovides
a speaka cost-effective
to maintainer’s remark
or detects anway
unusualresponse
growthin computer
fromthea person,she stops
the gestureperforshe ismance
for theafuture.
makingand selects
different gesture andspoken response.
The researchers
have incorporated
two
Peopleat the exhibition
talked to thenovel featuresin the designof EReLA:a fulandroidfor significantly
longerthan whenlyautomated
methodforlocating
failuresinmotion interruptivity was active.
the“Wesystemand a self-tuning
mechanismthatare interested
in service
robots, whichsimplifies
the tohardwareforapprodiagnosis.
need
to react
human needed
demands
To locatesays
permanent
failuresin TMR,
triplepriately,”
Takamatsu.
“This
research
redundancies
and
voter
logic
are
used:
three
has solved the issue of generating natural
systems performa function
and thegesturesin real time.
We believethisresultis ais processedby afirst
majority-voting
veryimportant
step.“There issystema long toway
produce
output —costinglike
boththistimetogo, buta Isingle
can imagine
androids
andmoney.
The
newly
proposedEReLA
does
providing information to people in shopping
not require
malls,
train either.
stations and airports.”“The EReLA can detect erroneous units
by itself,” says Nakashima. “It comes with an
Reference‘approximate computing mode’ that can tol1.
Y., Kondo,J., Takamatsu, T.,Ogasawara.
erate
errors K.,
in Takemura,non-importantcomputations.”
A gesture-centric
systemafor
multi-partychipThe
researchersandroid
have built
prototypehuman-robot interaction. Journal of Human-Robot
based
on
EReLA
(see
figure)andshowedInteraction 2, 133–151 (2013).
ctroid-SIT android made by Kokoro Company Ltd and programmed by the NAIST team.
that its fault tolerance — a measure of how
well the system performs in a failure — isinformation about the group’s research can be found at the Robotics Laboratory webpage:
similar to those based on TMR. In addition,/robotics.naist.jp/en/
the power consumption is reduced by a third
due to the simpler hardware. These findings
are significant for miniaturizing devices
and developing low-cost, low-power, highlyof Imaging-based Computational Biomedicine
www.naist.jp/en
reliable computers.
“The mean time between failures ofhigh-end computers is becoming shorterand shorter,” says Nakashima. “The EReLA
architecture provides a cost-effective way tomaintain the growth in computer performance for the future.”odern microprocessors containbillions of transistors that havesmall capacitances (ability to store
rical charge) and low supply voltages. Theseerties make them prone to failure since theyulnerable to background noise, cosmic raon and environmental vibrations. Engineers
mprove the reliability of a microprocessor
ncorporating extra copies (or redundancies)
itical components in the system, so thatn one component fails, another takes over.
owever, conventional redundancy archiures, such as the triple modular redundancyMR), have all their components — including
ndancies — hard-wired into the circuit.
sequently, the lifespan of devices is limited
heir least reliable unit.

“”© 2015 Yasuhiko Nakashima

Research Highlights

boostse skill base

Reference

Information Science
1. Yao, J., Nakashima, Y., Saito, M., Hazama, Y. &Yamanaka, R. A flexible, self-tuning, fault-tolerant
functional unit array processor. IEEE Micro 34,
54–63 (2014).

new EReLA architecture offers a cost-effective, lower-energy-consumption method to boost
puter performance.

e information about the group’s research can be found at the Computing Architecture Laboratory webpage:://arch.naist.jp/index-e.html

an artificial intelligence tool can help novice surgeonswww.naist.jp/en

nce plays role inrception

perceived as more capable than disguised humans

Research Highlights© 2015 Yoshinobu Sato, Nara Institute of Science and Technology

Ambient Intelligence Laboratory© 2015 Yoshinobu Sato, Nara Institute of Science and Technology

Research Highlights© Masayuki Kanbara

ally constructed surgical preoperative plan can help less-trained practitioners prepare© Masayuki Kanbarathat accumulating surgicalautomated systems to travel effortlessly toover the world in this way
many locations on demand, unlike an indip what he calls a ‘super-expevidual skilled surgeon. And with some actualeon’ using statistical machine
surgical procedures also becoming automatede methods have now moved
and robotically performed, there seems scope
eoretical and experimental
for fully automating every critical step, fromough the data have not yet beenplanning to surgery, in suitable cases.
ato reports “promising initialpreliminary clinical evaluations
Referencey orthopaedic surgeons at Osaka
1. jobs
Otomaru,I., Nakamoto,M.,suchKagiyama,
Takao, M.,
Hospital.
Robots have traditionally been used for dangerous
in remoteenvironments
as bombY.,disposal,
Sugano,N. dull,
et al.stressful
Automatedbutnow
couldlikeincreasingly
find theirwaysystem
into social settings
to fulfil
and preoperative
dirty tasks. planningdto evaluate
ourof femoral stem in total hip arthroplasty from 3D CT
pitals via the Internet,” he adds,
data: Atlas-based approach and comparative study.
Medical Image Analysis 16, 415–426 (2012).
e obvious potential of digital

looked and how they deserved to be treated.
The study offers useful insights into
Participants judged the robot to be the best
acceptable roles for robots in daily urban
for
all thethreeLaboratory
tasks. They also
the robot lifeand supports theBiomedicine
ongoing development
d atofassigned
Imaging-based
Computational
webpage:the lowest ranking for human-like attributes,
of guidance robots for social environments,
with the human,highest. suchas tour guides in museums and exhiNAISTscoring
Research
Highlights
04 as expected,
However, the researchers were surprised tobition spaces.
find that participants did not rate the person

Research Highlights
Information Science

Nara Institute of Science and Technology | Computing Architecture Laboratory

www.naist.jp/en

Computer engineering

More tolerance,
less waste
Microchip fault tolerance that consumes one-third less power may now be possible with new
chip design

M

Now, Jun Yao, Yasuhiko Nakashima andcolleagues at NAIST have proposed a lowcost redundancy architecture called Explicit
Redundancy Linear Array (EReLA), which
offers greater flexibility and better automation than conventional architectures1.
Processors based on this novel design offer
the same functionality, consume less powerand have ten times longer lifetimes thanconventional processors.
TMR has been the preferred architecture
because it comes with configurable isolation(between input, output and power) and hot
swap technologies (which allow systems to be
switched without shutting down); the former
enables defective components, or failures,
to be detected and isolated, while the latter© 2015 Yasuhiko Nakashimaodern microprocessors containbillions of transistors that havesmall capacitances (ability to store
electrical charge) and low supply voltages. These
properties make them prone to failure since they
are vulnerable to background noise, cosmic radiation and environmental vibrations. Engineers
can improve the reliability of a microprocessor
by incorporating extra copies (or redundancies)of critical components in the system, so thatwhen one component fails, another takes over.
However, conventional redundancy architectures, such as the triple modular redundancy(TMR), have all their components — including
redundancies — hard-wired into the circuit.
Consequently, the lifespan of devices is limitedby their least reliable unit.

ensures smooth running of the system whena fault occurs.

“

The EReLA architecture provides
a cost-effective way to maintainthe growth in computer performance for the future.

”

The researchers have incorporated two
novel features in the design of EReLA: a fully automated method for locating failures inthe system and a self-tuning mechanism that
simplifies the hardware needed for diagnosis.
To locate permanent failures in TMR, triple
redundancies and voter logic are used: threesystems perform a function and the result
is processed by a majority-voting system toproduce a single output — costing both timeand money. The newly proposed EReLA does
not require either.
“The EReLA can detect erroneous units
by itself,” says Nakashima. “It comes with an‘approximate computing mode’ that can tolerate errors in non-important computations.”
The researchers have built a prototype chip
based on EReLA (see figure) and showedthat its fault tolerance — a measure of how
well the system performs in a failure — issimilar to those based on TMR. In addition,
the power consumption is reduced by a third
due to the simpler hardware. These findings
are significant for miniaturizing devices
and developing low-cost, low-power, highly
reliable computers.
“The mean time between failures ofhigh-end computers is becoming shorterand shorter,” says Nakashima. “The EReLA
architecture provides a cost-effective way tomaintain the growth in computer performance for the future.”
Reference

The new EReLA architecture offers a cost-effective, lower-energy-consumption method to boost
computer performance.

1. Yao, J., Nakashima, Y., Saito, M., Hazama, Y. &Yamanaka, R. A flexible, self-tuning, fault-tolerant
functional unit array processor. IEEE Micro 34,
54–63 (2014).

More information about the group’s research can be found at the Computing Architecture Laboratory webpage:
http://arch.naist.jp/index-e.html
NAIST Research Highlights

05

Information Science

Research Highlights

Nara Institute of Science and Technology | Dependable System Laboratory© crstrbrt/iStock/Thinkstock

www.naist.jp/en

Testing customizable computer circuits with unused memory blocks can improve fault detection and lower the strain on system resources.

Microchip design

Better built-in fault
detection
A more effective way of testing integrated circuits can help manufacturers of digital devices
improve reliabilityA

new ‘built-in self-test’ (BIST) computer architecture that offers better fault
detection for custom-built circuits while
using fewer system resources has been developedby researchers at Japan’s NAIST1. The architecture enhances the safety and reliability of highly
complex, made-to-order devices, such as medical
electronics or optical transmission networks.
Field-programmable gate arrays (FPGAs)
are a modern type of computer chip basedaround a series of programmable components
known as ‘logic blocks’. Device designers
configure and wire the FPGA logic blocks tomeet their needs, instead of ordering traditional application-specific integrated circuits(ASICs) from chip manufacturers. This flexibility, which can cut development costs andshorten times-to-delivery, has currently given
FPGAs a US$4 billion slice of the lucrative
semiconductor market.
Monitoring FPGAs for defects, such astransistor ageing, however, is problematic.
ASIC-type chips have built-in tests, known
as scan-based BISTs, which send pseudo-ran-

dom data patterns through a series of ‘flip-flop’
circuits that can switch between one of two
bi-stable states. By comparing the observed
data signature with the expected results, thismethod can identify performance degradations or manufacturing defects. Unfortunately,
FPGAs do not have built-in ‘scan chains’ thatshift in and shift out the testing data from theprimary microchip design. Instead, redundancies have to be introduced that use the chips’
logic elements — a situation that can tax up to
50 per cent of a system’s resources.
Tomokazu Yoneda, Michiko Inoue and colleagues at NAIST’s Dependable System Laboratory discovered that self-testing with on-chip
memories could lessen the load on FPGA logic
elements. They configured unused memory
blocks to run ‘shift register’ circuits that use
clock signals to shift in or shift out data. Then,they carefully designed a way to insert the shift
registers as ‘test points’ into computer architectures to maximise FPGA reliability.
When the team tested their concept
with experimental circuits, they found aremarkable difference in delay test quality— a 5 to 6 per cent boost in fault detection compared to previous methods. “Testpoint insertion is a key factor in improved
fault coverage,” explains Yoneda. “Ourmethod can find more resources and insert
more test points, since it utilizes unused
memory blocks.”
Because memory blocks are inherent components of FPGA users, the new self-test design can be easily integrated into current chip
design flows and produce significant savings.
“Current dual- and triple-mode redundancy
solutions for products that require high fieldreliability are not cost effective,” says Yoneda.
“This work is promising since it can provide
high reliability without any redundancy.”
Reference
1. Ito, K., Yoneda, T., Yamato, Y., Hatayama, K. &Inoue, M. Memory block based scan-BIST architecture
for application-dependent FPGA testing. FPGA ’14
Proceedings of the 2014 ACM/SIGDA International
Symposium on Field-programmable Gate Arrays
85–88 (2014).

More information about the group’s research can be found at the Dependable System Laboratory webpage:
http://dslab.naist.jp/index-e.html
06

NAIST Research Highlights

Research Highlights
Information Science

Nara Institute of Science and Technology | Ubiquitous Computing Systems Laboratory

www.naist.jp/en

Ubiquitous computing

Tailoring workout
intensity
Smartphone technology can account for physical differences between individuals during walking to
optimize exercise intensityE

ven as fitness programs such as CrossFit and Zumba surge in popularity,
walking remains one of the mostreliable and effective forms of exercise forburning calories and building muscle mass.
Walking is free, requires no specialized
equipment, and can be done in small timeincrements. But achieving optimal heart rateis necessary for getting the most out of awalking workout and heart rate targets vary
dramatically depending on a person’s physicalfitness, age, health, and other factors.

Now, researchers at the Nara Institute of
Science and Technology have shown thatexisting smartphone technology has thecapacity to account for these individual differences, called ‘physical load’, to allow walkers toachieve optimal heart rate. Keiichi Yasumotoand colleagues at the NAIST Graduate Schoolof Information Science have proposed amethod for estimating physical load and minute-by-minute changes during walking routes,
taking into account the individual’s physicalcondition and exertion level.

Walking that is too strenuous can result inheart problems or joint injuries, particularlyin the elderly and in people with certain
conditions; meanwhile, insufficient exertion yields little benefit. Yet, achieving the
optimum exercise intensity is not clear-cut
or unambiguous without specialised equipment, such as heart rate monitors. But costand inconvenience of such equipment cankeep some people from taking advantage ofwalking as an exercise regimen.
To get a more reliable measure ofheart rate, the researchers constructed heart rate prediction models that
rely on walking data collected bysmartphones and heart rate data obtained by a monitor.

© lzf/iStock/Thinkstock

Existing smartphone applications areable to measure heart rate, but they rely on
capturing finger or face images, a systemthat does not work well during walking. To
get a more reliable measure of heart rate, theresearchers constructed heart rate prediction
models that rely on walking data collectedby smartphones and heart rate data obtainedby a monitor.
To account for fluctuations in heart rate
due to changing exercise intensity during awalk, the NAIST team developed a novel
technique to estimate oxygen uptake undervarying walking speeds and gradients. Theirtechnique also takes into account the physicalcondition of individuals. The team tested
their method in 18 subjects and five walking
routes, and found that they were able to predict heart rate accurately within a mean errorof seven heartbeats per minute.
Reference

NAIST research helps walkers achieve optimal heart rates using smartphone technology.

1. Sumida, M., Mizumoto, T., Yasumoto, K. Estimating heart rate variation during walking withsmartphone. UbiComp 2013, 8-12 September 2013,
Zurich, Switzerland.

More information about the group’s research can be found at the Ubiquitous Computing Systems Laboratory webpage:
http://ubi-lab.naist.jp/
NAIST Research Highlights

07

Information Science

Research Highlights

Nara Institute of Science and Technology | Mobile Computing Laboratory

www.naist.jp/en

Transit systems

Swirl protocol cuts
congestion
A system that directs traffic to circular routes in city centres reduces journey times“

The aim of GreenSwirl is to pump
the traffic out of the city centre into
the circular GreenWaves that surround the city.

”

Most traffic lights work independently of
those immediately before and after them,which means cars get stopped at red signals
repeatedly. The GreenWave system makes
lights on a major road turn green in a timed
sequence, allowing a continued flow of cars
across several lights without having to stop.
But trials of the protocol in several cities

worldwide have been disappointing — traffic
crossings become congested, and queues ofvehicles build up at intersections, waiting
to turn.
“GreenWave is usually implemented in themain streets going through the city centre.
But the amount of traffic soon exceeds thecapacity of the street, and any benefit is lost,”
says Naoki Shibata of NAIST. He and hiscolleagues had the idea of applying GreenWave, not to straight routes, but to circles
surrounding the city centre. They call thisapproach ‘GreenSwirl’.
“The aim of GreenSwirl is to pump the
traffic out of the city centre into the circular
GreenWaves that surround the city,” says
Shibata. Introducing GreenSwirl in isolation will not work, however, he cautions.
“People will be reluctant to go throughthe swirls because they will see them as adetour.” The answer is to jointly implementa navigation system, ‘GreenDrive’, which
recommends the fastest route through thecity to drivers with GPS systems in their

S’3

S’3
Ts(3) = 20 s

S3

Ts(2) = 10 s

Horizontal direction: red light
Vertical direction: green light
N
W

E
S

vehicles.The team ran simulations, taking
Manhattan in New York as an example. Using GreenSwirl alone reduced average travel
time by 10–20 per cent; moreover, adding
the GreenDrive navigation system reduced
travel time by as much as 60 per cent insome scenarios.
Shibata thinks that, although drivers
may initially be reluctant to divert to theswirls, they will soon learn that they will
get to their destination more quickly. “Ourobjective is to smooth out the traffic overthe city. The capacity of the whole network
is maximized when the amount of traffic
on each road segment is slightly less thanits capacity. The best way for a driver togo will then be the route the navigation
device suggests.”
Reference
1. Xu, J., Sun, W., Shibata, N. & Ito, M. GreenSwirl:
combining traffic signal control and route guidance
for reducing traffic congestion. Proceedings of the IEEE
Vehicular Networking Conference (IEEE VNC 2014),
179–186, 2014.

Ts(4) = 30 s

Ts(5) = 40 s

S4

S5

S3
S6
S2

Tt(1,2) = 10 s
Ts(1) = 0 s

Ts(6) = 50 s

S7
S1

S8

Ts(7) = 60 s

Ts(8) = 70 s

Poorly timed traffic lights are a cause of congestion in city centres, but a system that directs traffic to circular routes can drastically reduce journey times.

More information about the group’s research can be found at the Mobile Computing Laboratory webpage:
http://ito-lab.naist.jp/mediawiki/index.php/Main_Page/en
08

NAIST Research Highlights© phdinbs/iStock/ThinkstockP

oorly timed traffic lights are a causeof congestion in cities — wasting
drivers’ time, increasing air pollution
and fuel consumption. A protocol, known asGreenWave, exists for controlling lights to cut
congestion, but its effectiveness in city centres ispoor. Now, researchers at the Nara Institute of
Science and Technology (NAIST) have founda way to use GreenWave that, in simulations,significantly reduces journey times1.

Research Highlights
Information Science

Nara Institute of Science and Technology | Software Engineering Laboratory© Oleksiy Mark/iStock/Thinkstock

www.naist.jp/en

NAIST researchers have found a new way to increase the cost-effectiveness of software testing by incorporating fault prediction.

Software engineering

Acceptance testing
accelerated
Simulation approach helps optimize the cost-effectiveness of software testingQ

areas of collaboration. “I introduced them toseveral of our ongoing research topics, when
they expressed interest in using the fault prediction technique in acceptance testing,” Monden
recalls. “Assessing the cost-effectiveness of thisapproach was, of course, a priority for them —it was then that I got the idea to incorporate asimulation approach.”
In software engineering research, it was
Assessing the cost-effectiveness
unprecedented to apply a simulation apof this approach was, of course,
proach to optimize the cost-effectiveness ofa priority for them — it was thensoftware testing using fault prediction results.
that I got the idea to incorporate a
Monden notes that the overwhelming masimulation approach.
jority of fault prediction research is focusedon improving the fault prediction accuracy.
Akito Monden and colleagues at NAIST
While this is academically challenging, it
have collaborated with industry to develop asimulation approach to assess the cost-effective- is not a priority for industry practitioners.
In contrast, the NAIST research team’s
ness of fault prediction in acceptance testing.
The result is both academically stimulating and work “exactly targets industry as it focuseson the reduction of ‘cost’ — or effort — ofprovides tangible benefits to software developers1.The idea for this work arose from an initial acceptance testing, which is the main interestof practitioners.”
discussion between Monden and researchers
The simulation assessed resource allocationfrom the Nippon Telegraph and Telephone
West (NTT West) corporation about potential strategies for acceptance testing based on fault
uality assurance is crucial in softwaredevelopment: as programs become
more complicated and increasingly
integrated, it is essential to identify modules
where faults are likely to occur. One way of doing this is ‘acceptance testing’, where developers
check the software performs in accordance with
the needs of the end user.

“”

prediction results. Using data from NTT West
as a test case, they found that the best strategy
was to let the ‘test effort’ (or cost) be proportional to the number of expected faults in amodule, multiplied by the common logarithmof the module size. By using this strategy, theyfound that the test effort could be reduced by
an impressive 25 per cent.
This work is a success story for academicindustry collaboration, proving that addressing
industrial priorities and probing areas of academic interest are not mutually exclusive pursuits. Monden explains that the collaboration
with NTT West “acted as a bridge to transfer
research findings, such as fault predictions, toaddress industry priorities, such as reduction of
testing efforts.” The team’s next step is to test
the technique on larger software systems.
Reference
1.

Monden, A., Hayashi, T., Shinoda, S., Shirai, K.,
Yoshida, J., & Barker, M. Assessing the cost effectivenessof fault prediction in acceptance testing. IEEE Transactions on Software Engineering, 39, 1345-1357 (2013).

More information about the group’s research can be found at the Software Engineering webpage:
http://se-naist.jp/
NAIST Research Highlights

09Information Science

Research Highlights

Nara Institute of Science and Technology | Software Design and Analysis Laboratory© ilfede/iStock/Thinkstock

www.naist.jp/en

Two new tools, Historage and Kataribe, are set to improve the productivity of many software companies.

Software design

Method histories
made easy
Two new tools make it easier for developers to browse method histories and extract important
information from source codesT

he code repository is one of the mostvaluable tools in software development because it contains everything
there is to know about the source code —including, but not limited to, bug reports,
developer messages and file histories. Despite
its usefulness, however, retrieving method
histories (also known as fine-grained histories) from the data-rich code repository has
never been easy.
To overcome this problem, Hajimu Iidaand co-workers at NAIST have developed‘Historage’, a code repository specificallydesigned to store fine-grained histories; and‘Kataribe’, a hosting service for Historage
repositories1. Together, these technologies
make it easier for developers to browse method histories on the web and extract important information from source codes.
Iida and co-workers built Historage from
Git, an open source distributed revisioncontrol system designed to handle everythingfrom small to very large projects with speed
and efficiency. Equipped with a superb

branching system, Git can implement analmost endless number of workflows withrelative ease.
The researchers developed a tool for
converting a Git into a Historage repository.
Historage stores method histories in muchthe same way Git stores file histories. For
this reason, conventional mining software
designed to extract file histories from Git repositories are equally applicable to extracting
method histories from Historage repositories.
However, Historage is not so useful if developers cannot copy the code repository and haveeasy access to method histories. To tackle theseissues, the researchers built Kataribe, a hosting
service for Historage repositories that enables
developers to browse method histories on the
web and clone Historage repositories.
“We wanted Kataribe to be a developer-friendly web service,” says Iida. “At theend, we decided to extend the existing Git
hosting service (GitLab) to implement features of Kataribe, and that implementation
had been a great challenge.”

Iida and co-workers at NAIST’s Graduate
School of Information Science praised theinstitute for providing a cloud platform thatfacilitated the development of Kataribe. They
could easily create a testing server using thecomputational resource without having to go
through formal procedures. Several researchers have already used Kataribe to successfullyreconstruct method histories.
The team plans to further the capabilities
of Kataribe by expanding its dataset, webservices and functionalities. In fact, they havealready implemented a visualization featurefor displaying the semantics of changes in thecommit snapshot of a Historage repository. The
innovative technologies are set to promote thereuse of source code and improve the productivity of many software companies.
Reference
1.

Fujiwara, K, Hata, H., Makihara, E., Fujihara, Y.,
Nakayama, N. et al. Kataribe: A hosting service ofHistorage repositories. Proceedings of the 11th Working
Conference on Mining Software Repositories
380–383 (2014).

More information about the group’s research can be found at the Software Design and Analysis Laboratory webpage:
http://isw3.naist.jp/Contents/Research/cs-06-en.html
10

NAIST Research Highlights

Research Highlights
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Nara Institute of Science and Technology | Internet Engineering Laboratory© Melpomenem/iStock/Thinkstock

www.naist.jp/en

Cloud computing offers many benefits, but it can comprise security.

Cloud computing

Security vulnerabilities
detected

A security analysis highlights the vulnerabilities of popular cloud management software, OpenStackAn analysis of the most widely used
open-source cloud management
software, OpenStack, by NAIST
researchers confirm concerns about its security.
In particular, it exposes OpenStack’s susceptibility to security problems propagating between
different parts (or ‘trees’) of its system1.
Cloud computing offers individuals andcompanies many benefits, including convenient
access to data and the ability for team members
in different locations to simultaneously workon the same projects. But accompanying its
rapid rise in popularity are concerns regarding
security. In particular, software that provides
free tools for constructing and managing
cloud computing platforms for both public
and private clouds — known as open-source
cloud management software — has comeunder scrutiny.
The most popular open-source cloud
management software platform is OpenStack. In addition to having a reputation forbeing easy to use, it is backed by some of thebiggest names in information technology,

including Dell, NEC, Hewlett-Packard andIBM. Furthermore, it is supported by anenthusiastic global community of volunteers.
However, its security vulnerabilities havescored highly on the National Vulnerability
Database, a publicly accessible database forcomputer-related vulnerabilities managed by
the U.S. government.
To evaluate these concerns, Takeshi Okuda
and colleagues at NAIST’s Internet Engineering Laboratory performed a security analysisof OpenStack. They did these by performing a
fault tree analysis, to evaluate the vulnerabilitiesof the cloud management software. A fault tree
is a helpful tool for quantitatively analysing asystem, as it generates a graphical representation of an undesirable event in a system basedon Boolean logic.
Using this approach, the researchers wereable to generate high-level vulnerability trees,
which can be used by organizations wanting toquantify their own OpenStack cloud infrastructure. They found that the high degree ofinterconnectedness of OpenStack’s architecturemeans that security problems in one tree can
propagate to other trees.
However, the team was not able to evaluate
OpenStack’s security as completely as they
had hoped, because the currently used naming
system for vulnerabilities fails to account forsubcomponents of main components.
The results were not a complete surprise to
the researchers as they had “expected to findsome sort of vulnerability propagation between
the different components,” explains Fall Doudou, a doctoral student from Senegal. “But thefact that the security quantification could not
be more accurate came as a surprise.”
The researchers are now planning to comeup with a new naming system that takes into
account all the details of the components of
OpenStack while conforming with the current
standards in the community.
Reference
1. Fall, D., Okuda, T., Kadobayashi, Y. & Yamaguchi, S.
Towards a vulnerability tree security evaluation of
OpenStack’s logical architecture. Lecture Notes in Computer Science 8564, 127–142 (2014).

More information about the group’s research can be found at the Internet Engineering Laboratory webpage:
http://isw3.naist.jp/Contents/Research/cs-07-en.html
NAIST Research Highlights

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Information Science

Research Highlights

Nara Institute of Science and Technology | Internet Architecture and Systems Laboratory

www.naist.jp/en

Networking

Efficient data sorting for
wired cars
A more efficient system for data delivery should improve the performance of mobile apps for‘wired’ vehicles© Prykhodov/iStock/ThinkstockWe are rapidly moving towards aworld in which cars are continuously wired into mobile services
that help drivers avoid traffic, accidents andconstruction to arrive — and park — at theirdestination. To facilitate these developments,
researchers at NAIST have devised a systemthat could make it easier for such vehicularcommunication systems to obtain their data
without overly burdening wireless networks1.
In order to function, apps based on
vehicular communication systems draw on
traffic information and data transmitted fromconnected cars, pedestrians and other sources.
Given that only a tiny fraction of this data
will be of value to any user at a given time, anefficient system needs to act as a matchmaker— selectively delivering geographically
relevant information from across the entire
network. Atsuo Inomata, Kazutoshi Fujikawa
and colleagues at NAIST have proposed asolution that could streamline this process
and make it practical to bring vehicular communication systems and resources together
on a nationwide scale.
Their approach is based on what is known
as a publish–subscribe model. In this system,
data-generating ‘publishers’ indiscriminately
release resources into the network with classifying information that allows ‘subscribers’(in this case, apps running on vehicular communication systems) to recognize whether
those resources are relevant. For example,
one vehicular communication system mightreport a traffic jam bringing cars to a standstill, but this will only be of interest to otherdrivers using a navigation app that might
direct them onto the same highway.
Regulating the amount of information
circulating in the network is a criticalfactor, however. “Larger scope is preferable for resource discovery, [but] may cause
scalability issues,” the authors write, while“smaller scope may fail to discover potential publishers.”

An efficient vehicular communication system that links mobile applications with useful navigational
information can connect vehicles across a country as dense as Japan.

The team avoid swamping the system bylimiting data publication to instances whena given vehicle changes its speed or direction, rather than continuously broadcasting.
Communications between publishers andsubscribers will depend on the interaction
between mobile routers and devices with regional servers through what is known as the
GeoNetworking protocol, a framework thatmakes it possible to assign a target addressfor data transmission based on geographic
and topographic information.
In addition to demonstrating the theoretical feasibility of their system, the researchers

note that their models demonstrate that thisapproach could be affordably expanded toefficiently relay data between large numbers ofvehicles — “even in the highly-populated scenario in which all vehicles in Japan support the
proposed system.” As a next step, the researchers will be moving on to real-world implementation and testing.
Reference
1.

Noguchi, S., Matsuura, S., Inomata, A., Fujikawa, K.
& Sunahara, H. Wide-area publish/subscribe mobile
resource discovery based on IPv6 GeoNetworking. IEICE
Transactions on Communications 7, 1706–1715 (2013).

More information about the group’s research can be found at the Internet Architecture and Systems Laboratory webpage:
http://isw3.naist.jp/Contents/Research/cs-08-en.html
12

NAIST Research Highlights

Research Highlights
Information Science

Nara Institute of Science and Technology | Computational Linguistics Laboratory

www.naist.jp/en

Machine translation

Better bilingual
dictionaries
By combining two computational methods, NAIST researchers have enhanced the accuracy ofmachine-readable bilingual dictionaries

M

that are likely to correspond to individual
topic areas. The team applied topic models
to English and Japanese ‘real-world’ documents (or ‘corpora’) written on the same
subject, taken from the online encyclopaedia
Wikipedia. This gave them lists of English
and Japanese words that correspond to individual topics. Although these lists have theadvantage of being easier to deal with thanentire original texts, topic modelling did not
help the researchers correctly identify which
English words translated into which Japanesewords in each list.
“Let’s say each topic list contains about
500 English words and 500 Japanese words,”
says Duh. “There are then 500 × 500 translation possibilities in each list. Our insightcame when we realized that this problem issimilar to the word alignment problem in thefield of statistical machine translation.”
Word alignment is a computational
technique used for linking words that areclose translations of one another within texts.
Matsumoto’s team carried out word align-

ment after running topic models, enhancing
the chances of accurate bilingual translation.
In fact, they discovered that bilingual dictionary extraction became more accurate when
they incorporated more subject-specific documents from multiple languages. Additional
language data meant that each topic model
became more and more specific, allowing
word alignment to ‘zone in’ on more precisetranslations relevant to the original texts.
“Including multiple word phrases, such ascompound nouns, is an important next step
because they are so common in languages,”
explains Duh. “This is a surprisingly difficult task, because it dramatically increases
both the computation time and the numberof translation candidates. However, it will
enhance the usefulness of our method.”
Reference
1. Liu, X., Duh, K. & Matsumoto, Y. Multilingual topic
models for bilingual dictionary extraction. ACM
Transactions on Asian Language Information Processing
9, 39 2014.

© marcelmooij/iStock/Thinkstockachine-readable bilingual dictionaries aid computer translation, but
existing frameworks are plagued
with inaccuracies. To remedy this situation,
researchers at Japan’s NAIST have deviseda method for generating more accurate
bilingual dictionaries for machine translation;
this method combines two existing computational techniques — topic modelling andword alignment1.
“Bilingual dictionaries that focus on
specific domains, for example medicine or
tourism, are useful for many applications,”
explains Kevin Duh, who worked withNAIST colleagues Yuji Matsumoto and
Xiaodong Liu on the project. “Existing
topic models automatically group words into
specific domains, so we included this as anintegral component of our method. We are
the first to use topic models for this purpose.”
A topic model is a mathematical framework that predicts the proportion of words
related to different topics in a particulartext. It then generates groups of words

Multilingual Wikipedia entries on the same subject were used to create more accurate bilingual dictionaries by combining existing topic model and wordalignment techniques.

More information about the group’s research can be found at Yuji Matsumoto’s webpage:
http://www.naist.jp/en/about_naist/offices/administration_bureau/yuji_matsumoto/index.html
NAIST Research Highlights

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Research Highlights

Information Science

Nara Institute of Science and Technology | Augmented Human Communication Laboratory

www.naist.jp/en

SoftwareSegmentation makes
translation twice as fast
Segmentation algorithms show promise in boosting both the speed and accuracy of simultaneous
speech translationAn automated learning systemdeveloped by researchers in Japanthat identifies the most accurate
way to break down a sentence for simultaneous interpretation has cut waiting times
in half compared to conventional methods1.
The system can be used to improve theperformance of speech translation software,
including mobile apps.

“

We basically let the computerscome up with their own ideas.

”© 2015 Graham Neubig, Nara Institute of Science and Technology

Traditional systems translate speech one
sentence at a time, which means listeners
have to wait until the end of a sentence
before receiving the translation. To speed
this up, researchers have proposed dividing
sentences into smaller units, but finding
appropriate dividing points has been tricky.
Most suggestions are based on humanintuition, such as detecting a pause inrhythm and intonation, or predicting thelocation of commas. However, these markers

can be confusing for automated systems. A
quickening of speech or a dramatic pause for
emphasis, for example, could reduce translation speed and accuracy.
Now, a team of researchers led by Graham
Neubig, Yusuke Oda and Satoshi Nakamura
at NAIST has developed a method that
does not rely on heuristics. “In a way, themethod was born out of frustration, since it
was proving harder and harder to improveon existing methods,” says Neubig. “Webasically let the computers come up with
their own ideas.”
The researchers combined a greedy
algorithm, a grouping strategy and dynamic programming to develop a systemfor computing the accuracy of different
segmentation approaches and selecting the
optimal translation breakdown. They thenexperimentally assessed their computational
system using English-to-German and English-to-Japanese speech translation data.
The resulting translation speeds were twoto three times faster than those of sen-Without segmentation

I'm going to take you on a journey
皆様を…
With segmentation

I'm going totake youon a journey

予定です

皆様を案内する

旅に

Segmenting sentences into smaller units can increase the speed of simultaneous translation technology.

tence-based methods, while maintaining thesame accuracy. In some cases, the accuracy
was slightly improved — a surprising result
since segmentation removes the context
and flexibility afforded by sentence-scaletranslation. “Current machine translation
systems are occasionally confused by longer
sentences,” explains Neubig.

“

Human simultaneous interpreters are remarkably clever about
guessing what the speaker isgoing to say in the future, andusing these estimates to help improve the simultaneity of theirinterpretation.

”

His team is currently working on improving the machine-learning system by incorporating prediction techniques often employedby their real-life counterparts. “Human
simultaneous interpreters are remarkably
clever about guessing what the speaker isgoing to say in the future, and using theseestimates to help improve the simultaneityof their interpretation.”
The research is well timed given the proliferation of real-time translation applications,such as the preview version of Skype Translator, and the introduction of automated systems in universities. Neubig hopes to apply
the new technology to various situations.
“Being able to translate faster, while maintaining a high level of accuracy, is essential
to achieving smoother conversations or more
complete understanding of lecture contents,”
he says.
Reference
1. Oda, Y., Neubig, G., Sakti, S., Toda, T. & Nakamura, S.
Optimizing segmentation strategies for simultaneous
speech translation. Proceedings of the 52nd Annual
Meeting of the Association for Computational Linguistics (Short Papers) 2, 551–556 (2014).

More information about the group’s research can be found at the Augmented Human Communication Laboratory webpage:
http://ahclab.naist.jp/index_en.html
14

NAIST Research Highlights

Research Highlights
Information Science

Nara Institute of Science and Technology | Network Systems Laboratory

www.naist.jp/en

Wireless data

Dual strategy to boost
underground Wi-Fi
Combining two different signal systems promises to enable clearer Wi-Fi reception in undergroundcommuter trains

Underground train passengers may
soon be able to access Wi-Fi wherever they are, thanks to the discovery
by NAIST researchers that leaky cables canbe stacked up in tunnels to transmit andreceive digital signals.
Several major cities, including Tokyo andLondon, offer Wi-Fi to commuters at underground stations by installing antennas at various locations in public areas. However, it ismuch challenging to obtain a signal inside atunnel. This is because solid objects like trains
block the high-frequency radio waves that
Wi-Fi uses to transmit information when the
waves are funnelled down a tunnel.

One way to overcome this problem is torun a ‘leaky coaxial cable’ down a tunnel.
Such a cable resembles a hose pipe in thatit has many small holes drilled in it. But
instead of leaking jets of water, the cablereleases — and can receive — digital information through the tiny holes. Such cables
have already been installed in some underground systems, but because they transmit
limited amounts of data, the Wi-Fi signal
tends not to be very strong. Consequently,
the amount of data that can be downloaded
and uploaded is limited and transfer speeds
are slow.
Now, Minoru Okada and his colleagues at
NAIST in Japan have proposed overcoming
this problem by combining leaky coaxial
cables with another system known as multiple-input multiple-output (MIMO), which
is used in many home Wi-Fi systems1. In aclassic radio system, one antenna transmits
a signal and another antenna (for example,© Stockbyte/iStock/Thinkstock

Underground train passengers may
soon be able to access Wi-Fi wherever they are, thanks to the discovery
by NAIST researchers that leaky cables can be stacked up in tunnels totransmit and receive digital signals.

Passengers on underground trains may soon be able to access fast Wi-Fi thanks to a strategy proposedby NAIST researchers.

one in a laptop computer or a smartphone)receives it. In MIMO, multiple antennas
are used at each end and different data
streams are sent simultaneously; this strategy
enhances both the speed and the amountof data that is transmitted. Processors ateither end then detect tiny differences in thesignals, which are caused by distortions as thesignals bounce off different objects, and use
these differences to disentangle the different
data streams.
Okada and co-workers have mashed these
two systems together by combining two leaky
cables to create an underground MIMO system. So long as the holes in the cables release

the Wi-Fi signals in different directions,the differences in the data streams should
be large enough to distinguish the different
data streams.
The additional capacity that MIMO adds
to the system means that if multiple people
wanted to download an attachment fromtheir emails at the same time, they could doso more quickly.
Reference
1. Hou, Y., Tsukamoto, S., Ariyoshi, M., Kobayashi, K.
& Okada, M. 4-by-4 MIMO channel using two leaky
coaxial cables (LCXs) for wireless applications overlinear-cell. 2014 IEEE 3rd Global Conference on Consumer Electronics (GCCE 2014) 125–126 (2014).

More information about the group’s research can be found at the Network Systems Laboratory webpage:
http://isw3.naist.jp/Contents/Research/mi-03-en.html
NAIST Research Highlights

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Research Highlights

Nara Institute of Science and Technology | Vision and Media Computing Laboratory

www.naist.jp/en

Diminished reality in action: Left panel is the original image, right panel is the resulting image with signpost removed via the new diminished reality process.

Image processing

Seamlessly removing
objects from images

New state-of-the-art image processing methods may allow objects to be removed from still
photography — and even videoI

mage processing is no longer just about
removing cellulite from celebrities or lensflare from lakes. Beefed-up computing
power, combined with increasingly sophisticated image processing techniques, has madeit possible to remove unwanted objects fromvideo in real-time. “Real-time object removal
allows us to simulate various scenarios, such as
furniture arrangement and city planning, using
real video images,” notes Norihiko Kawai.

“

Diminished reality methods have notbeen deeply investigated – there arestill many issues to be addressed.

”

Kawai, along with colleagues from the
Graduate School of Information Science at
NAIST, have used two approaches for theremoval of objects from the foreground of animage: ‘in-painting’ for static images and, more
recently, ‘diminished reality’ for video images.
Diminished reality refers to the real-time
removal of objects from videos. It is the
opposite of augmented reality: the additionof computer-generated objects to videos inreal-time. “Whilst augmented reality techniques have been widely developed, diminished reality methods have not been deeply
investigated – there are still many issues to beaddressed,” explains Kawai.
In response, Kawai and his colleagues decided to build on the success of image in-painting— an established technique where an object isremoved from the image foreground, with theempty space being filled-in using an actual or
realistic background texture — and apply it todiminished reality.
His team developed a diminished reality process based on image in-painting, but a sophisticated one that uses multiple two-dimensional
planes to approximate a three-dimensional
background. First the scene to be modified isanalysed and a key frame, with the object to be
removed, identified and an appropriate mask
is fitted. After analysis, two processes are runconcurrently: image in-painting for the one key
frame, and real-time overlay of that in-painted
texture for subsequent frames.

More information about the group’s research can be found at Norihiko Kawai’s webpage:

http://yokoya.naist.jp/~norihi-k/research-e.html
16

NAIST Research Highlights

The results have been impressive, allowing
for an almost seamless removal of objects(see figure). Without the panel on the left of
the image in the figure above, it is unlikely
the viewer would know there had ever beena signpost at the beginning of the footpath. Surprisingly, the computational loadof this powerful method is comparable torelated techniques.
Further complications lie ahead for thistechnique, such as removing target objects thatare in motion, and dealing with increasingly
complex background textures. However, Kawai
looks forward to embracing the challenge ofaddressing these issues: “Adding virtual objects
and removing real objects from video enriches
our interactions with media for both entertainment and practical use,” he says.
Reference
1. Kawai, N., Sato, T. & Yokoya, N. From image inpainting to diminished reality. In Virtual, Augmented andMixed Reality. Designing and Developing Virtual andAugmented Environments. Lecture Notes in Computer
Science 8525, 363–374 (2014).

Reproduced, with permission, from Ref. 1 © 2014 Springer International Publishing Switzerland

Information ScienceResearch Highlights
Information Science

Nara Institute of Science and Technology | Interactive Media Design Laboratory

www.naist.jp/en

Computer vision

Augmented reality zoom
now possible“

Taketomi and co-workers ... have
now demonstrated an algorithm
that can simultaneously estimate
both intrinsic and extrinsic camera parameters during camera
zooming.

”

One way to perform this geometricregistration between real and virtual worlds
is to position the artificial image relative to
specific markers by using an algorithm thatcan estimate various operational parametersof the camera. Such parameters can include
extrinsic ones, such as position and orientation,and intrinsic ones, such as focal length andlens distortion.
“Many methods for estimating camera pose
have been proposed,” says NAIST researcher
Takafumi Taketomi. “However, these methods assume fixed intrinsic camera parameters,
which prevents zooming because the focal
length changes depending on zoom values.”
Taketomi and co-workers from the NAISTInteractive Media Design Lab together with

Proposed method
Previous methodAugmented reality adds computer-generated images, video and sound to
our own perception of the world
around us. For example, the technology
could aid navigation by superimposing street
directions onto the view of a user through ahead-mounted display. Researchers at Japan’s
NAIST have now developed a methodthat enables zooming in augmented-reality
systems, making them useful for an evenbroader range of applications1.
A common way to implement augmented
reality is to overlay virtual information on acamera image and then relay this information
to the user through a display device such as
glasses or goggles. This ‘video see-through’ technology requires the computer-generated image
to be accurately aligned with the objects in theuser’s field of view.

Reproduced from Ref. 1 and licensed under CC BY 4.0 © 2014 T. Taketomi et al.

A novel algorithm improves the registration between virtual and real images in dynamic
augmented reality

Augmented reality superimposes a virtual cube on a real Rubik’s cube. The alignment between the two
using the novel scheme (top right) is much improved relative to previous methods (bottom right).

colleagues from Capcom and the Tokyo Institute of Technology have now demonstrated
an algorithm that can simultaneously estimate
both intrinsic and extrinsic camera parameters
during camera zooming.
The team’s scheme starts with a pre-calibration procedure. This involves assessing the
intrinsic camera properties at each level ofmagnification. The calculation then accurately
estimates the intrinsic and extrinsic parameters
online. This approach uses the conventional
marker-based method, but improves it by adding a consideration for reprojection errors andthe continuity of zoom values.
The team demonstrated their technique by
superimposing a virtual cube on a real Rubik’s
cube. Whereas a displacement could be seen
between the two when zooming in using

a traditional camera-parameter estimation
technique, far improved alignment was possibleusing the new scheme (see figure).
Camera zooming is an important technique for video production, and so thismethod could allow augmented reality to be
used in entertainment-industry applications.
“Our method is designed for specific cameras
at the moment,” explains Taketomi. “In thenext step, we want to extend this method formore general camera settings, so that it canbe applied to mobile devices with a cameraand display.”
Reference
1.

Taketomi, T., Okada, K., Yamamoto, G., Miyazaki, J. &Kato, H. Camera pose estimation under dynamic intrinsic parameter change for augmented reality. Computers &Graphics 44, 11–19 (2014).

More information about the group’s research can be found at the Interactive Media Design Laboratory webpage:
http://imd.naist.jp/
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Research Highlights

Nara Institute of Science and Technology | Optical Media Interface Laboratory© 2015 Yasuhiro Mukaigawa, Nara Institute of Science and Technology

www.naist.jp/en

A new technology makes it possible to turn multiple pictures of translucent objects (left panel) into sharp and realistic 3D images.

Visual computing

Resolving translucent
3D objects
Decoding light information with an innovative imaging technique can help robots better navigate
their three-dimensional surroundingsResearchers from NAIST have developed
a method to measure the three-dimensional (3D) shapes of everyday objects
with translucent properties, such as food,clothing and dishes. The findings from Yasuhiro
Mukaigawa and colleagues may make it simpler
for robots to sense important environmental
clues — the difference between a slippery barof soap and a fragile vase, for example — thatare critical for operating in real-life conditions.
Humans can determine if an object has asmooth or bumpy surface just by looking at
it. But computers have a harder time making
this judgment because of their reliance on
flat, two-dimensional (2D) images. One way
to overcome this problem is to illuminate
an object and then capture images as thelight source moves over it. This ‘photometricstereo’ technique deduces the surface normal
vectors that project perpendicularly fromeach surface point by using the different
shading angles seen in the images. Algorithms then turn the surface ‘normals’ into
3D reconstructions.

Photometric stereo has applications ranging
from quality assurance to facial recognition.
However, translucent materials are tricky toresolve with this technology: the random
reflections of light inside such objects make it
hard to relate shading patterns to surface geometry, and images appear blurry. To compensate,
researchers have tried to develop models to
remove sub-surface light scattering components
from true surface shadings.
Implementing scattering models, however,requires a way to simultaneously inspect thematerial’s optical properties along with its 3D
shape. Mukaigawa and his co-workers solved
this problem by recording how a thin ray oflight reflects off a diffuse, uniformly scattering
surface before projecting the beam over thetranslucent target. Separating the incident
light radiance from the photometric stereo
measurements using computer algorithms
revealed the target’s ‘convolution kernel’ — amathematical image processing unit that
holds information about surface geometry andsub-surface scattering.

Using a straightforward setup — astandard digital SLR camera, light projector
and polarizers — the researchers examined
intricate figurines carved from substancessuch as soap and marble (see figure). Theirapproach generated true-to-life 3D images
that are remarkably sharper than conventional photometric stereo pictures of translucent
objects. Mukaigawa notes that the simplicity
and speed of this method could lead to improved types of computer vision technologies
in the future.
“Many objects in our environment are translucent, but even expensive commercial sensors
cannot measure their 3D shapes,” he says. “Ifvision systems can know these shapes with oursimple equipment, robots have a better chanceof working in our living environment.”
Reference
1. Inoshita, C., Mukaigawa, Y., Matsushita, Y. & Yagi, Y.
Surface normal deconvolution: photometric stereo for
optically thick translucent objects. In Lecture Notes in
Computer Science Volume 8690, 2014, pp 346-359.

More information about the group’s research can be found at the Mukaigawa Lab webpage:
http://omilab.naist.jp/
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Research Highlights
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Nara Institute of Science and Technology | Ambient Intelligence Laboratory

www.naist.jp/en

Robotics

Appearance plays role insocial perception
Robots doing menial jobs can be perceived as more capable than disguised humans© Masayuki KanbaraAdvanced social skills may not benecessary for robots undertaking dull,
stressful and dirty tasks. Researchers at
Japan’s Nara Institute of Science and Technology (NAIST) have found that for menial tasks,
people significantly preferred machines — evencompared to a human in disguise performing
the same job. This may be because robots arethought to lack feelings of anger, pain andself-respect.
“Even if a robot’s appearance is to somedegree human-like, people do not perceive
it as essentially human,” say researchers
at Japan’s ATR Intelligent Robotics andCommunication Laboratories, including its
former director Norihiro Hagita, now at the
Ambient Intelligence Laboratory at NAIST1.
These findings could inform the design ofrobots acceptable to urban societies.
From clearing bombs in a battlefield tofabricating parts with monotonous precision,
robots are used for dangerous, dirty and dulljobs — for this, they need few social skills.
In more urban settings, robots are being
developed to engage with and assist seniorcitizens, students and office workers. Studies
show that while people prefer robots for repetitive or hazardous tasks, for tasks involving
intelligence and communication they preferhumans. The research team set out to assess
the acceptance of robots for tasks that involvea mixture of drudgery and social interaction.
They prepared nine separate videos of arobot, a human, and a human dressed up asa rabbit; each was performing a dull, stressful or dirty task at a popular shopping mall.
Tasks included endlessly guiding visitors at an
information counter, responding to an angry
and threatening customer, and scooping keys
out of a garbage bin after a shopper accidently
dropped them there. The researchers invited
30 university students to watch the videos
and fill out a questionnaire on the appropriateness of each task for each subject; and toassess how ‘human’ they felt each character

Robots have traditionally been used for dangerous jobs in remote environments such as bomb disposal,
but could increasingly find their way into social settings to fulfil dull, stressful and dirty tasks.

looked and how they deserved to be treated.
Participants judged the robot to be the best
for all three tasks. They also assigned the robot
the lowest ranking for human-like attributes,
with the human, as expected, scoring highest.
However, the researchers were surprised tofind that participants did not rate the person
dressed as a rabbit on the same scale as thehuman, despite there being a real humaninside the costume – suggesting the importance of appearance in assigning human-like
cognitive ability.

The study offers useful insights into
acceptable roles for robots in daily urbanlife and supports the ongoing developmentof guidance robots for social environments,
such as tour guides in museums and exhibition spaces.
Reference
1. Hayashi, K., Shiomi, M., Kanda, T. & Hagita, N. Are
Robots Appropriate for Troublesome and Communicative Tasks in a City Environment? IEEE
Transactions on Autonomous Mental Development 4,
150–160 (2012).

More information about the group’s research can be found at the Ambient Intelligence Laboratory webpage:
http://isw3.naist.jp/Contents/Research/mi-07-en.html
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Research Highlights

Nara Institute of Science and Technology | Robotics Laboratory

www.naist.jp/en

Robotics

Gestures and ‘interruptivity’
boost interaction
Life-like gestures and self-correction allow better communication with an android

H“The goal of this research is to take androids beyond the ‘uncanny valley’,” says Jun
Takamatsu, a robotics scientist at NAIST1.
Using motion capture film techniques, hisgroup recorded the normal gestures of ten
volunteers and these movements became thebasis for the android’s gestures. “The gesturethat the android should use when answering
each type of question was defined and stored
in a database,” explains Takamatsu.
The Actroid-SIT android they haveprogrammed looks like a shop mannequin.
‘She’ turns to face any person who holds
a microphone. As the person speaks, the© 2013 Robotics Laboratory, Nara Institute of Science and Technology

elpful androids — robots in humanform — cannot yet be found in
shopping malls, but researchers from
NAIST are busy working to make this possible.
They have programmed an android to makerealistic gestures and recognize the speaker in agroup of people facing it.
Robots that look like humans need tobehave in a very life-like way. Otherwise, ahuman interacting with them will experience‘the uncanny valley’; a feeling of revulsion
experienced when an object is nearly, but notquite, like a human being — such as seeing acorpse or zombie.

android looks at them and makes small appropriate movements, such as nods and bows.
Actroid-SIT can glance to the side, turnher head and look directly at someone. She
makes meaningful gestures as she answers
their questions — pointing to the bathroom,for example.

“

This research has solved the issueof generating natural gestures inreal time. We believe this is a very
important first step.

”

The team measured the android’s effectiveness on 1,662 people attending an exhibition,
who encountered the android standing behind a roped-off barrier. When Actroid-SIT
could make gestures, more than 60% of thesubjects who approached her then spoke toher; a significantly greater proportion thanwhen her gestures were disabled.
The android also sports ‘motion interruptivity’: when she fails to recognise a speaker’s remark or detects an unusual response
from a person, she stops the gesture she ismaking and selects a different gesture andspoken response.
People at the exhibition talked to theandroid for significantly longer than whenmotion interruptivity was active.
“We are interested in service robots, which
need to react to human demands appropriately,” says Takamatsu. “This research
has solved the issue of generating natural
gestures in real time. We believe this is avery important first step.“There is a long way
to go, but I can imagine androids like thisproviding information to people in shopping
malls, train stations and airports.”
Reference

The Actroid-SIT android made by Kokoro Company Ltd and programmed by the NAIST team.

1. Y., Kondo, K., Takemura, J., Takamatsu , T.,Ogasawara.
A gesture-centric android system for multi-party
human-robot interaction. Journal of Human-Robot
Interaction 2, 133–151 (2013).

More information about the group’s research can be found at the Robotics Laboratory webpage:
http://robotics.naist.jp/en/
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Nara Institute of Science and Technology | Intelligent System Control Laboratory© Tom De Spiegelaere/iStock/Thinkstock

www.naist.jp/en

A new artificial intelligence system can considerably boost efficiency in an optical grid.

Applied informatics

Raising optical grid
efficiency
Dynamic decision-making tools can improve the flow of information over ultrafast optical grid networks

C

omputers that share processing powerand data storage through a grid of highspeed fibre-optic cables can maximize
their productivity with a new artificial intelligence system developed at Japan’s NAIST1.
Takuji Tachibana and colleagues at Kenji
Sugimoto’s Intelligent System Control Laboratory have worked out a technique for dynamic,
on-demand allocation of computer and optical-grid resources that can benefit applications
ranging from massive particle accelerator
experiments to consumer video editing.
Before individual computers can accessthe optical grid, they must make contact
with a machine known as a job manager.
This computer system establishes ‘lightpaths’(direct connections between nodes that cantransfer thousands of terabytes per second)
for the requested processing task. Because thelightpaths and computing power available
are finite, the job manager must carefully
manage the network connections to ensurethat computations run at smooth and stable
rates for all users.

Although much attention has been paid to
optimizing lightpath connections, Tachibana
and his co-workers realized that improving
connections between computers and the optical grid could considerably boost efficiency.
For example, one problem with the job
manager is that it needs to store a constantnumber of tasks in its memory buffer at all
times to complete job executions without
delays. Most existing job managers, however,lack the computing resources to satisfy
this requirement.
To solve this, the researchers used proportional-integral-differential (PID) control theory
to preserve the memory buffer by regulating thetasks sent to the job manager. Then, they implemented two kinds of model-predictive-control(MPC) methods to intelligently handle theneeds of both lightpath generation–releaseprocesses, as well as computing client demands.
“PID control has been used in industry for decades, and is widely recognized as practical,” says
Sugimoto. “MPC is rather new, but the qualityof this method is attracting much attention.”

The team’s simulations showed that theirapproach can make the number of tasks stored
in the buffer closer to ideal quantities thanother, contemporary controllers. Furthermore,
it had the ability to dynamically adapt tolower-specification computers appearing in the
network — features that can speed implementation of existing hardware into future opticalgrid systems.
Sugimoto has confidence that thisapproach could improve communication
between information technology researchers,
as well as within the optical grid. “Studies
of communication and control used to beclosely related, but they have progressed indifferent ways,” Sugimoto notes. “This work
brings them together through the problem of
optical grid.”
Reference
1. Matsui, G., Tachibana, T., Kogiso, K. & Sugimoto, K.
Dynamic resource management in optical grid.
IEEE Transactions on Control Systems Technology 22,
1607–1614 (2014).

More information about the group’s research can be found at the Intelligent System Control Laboratory webpage:
http://genesis.naist.jp/?lang=en
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Research Highlights
www.naist.jp/en© TCmake_photo/iStock/Thinkstock

Nara Institute of Science and Technology | Large-Scale Systems Management Laboratory

Multihop wireless networks allow for more versatile and dynamic deployments of wireless devices, such as sensors, but can be undermined by an overuse of
network-coding algorithms.

Wireless networks

Delays undermine
multihop Wi-Fi
Modelling shows that delays caused by a network-coding algorithm are a drain on theperformance of multihop wireless networks

W

ireless networking is nearly ubiquitous in our daily lives, but thetechnology is more than a mere
convenience. For scientific applications —such as industrial and environmental sensor
networks — wireless connectivity has madeit possible to connect and network devices
in previously unimaginable locations while
retaining the ability to view data remotely inreal-time.
To maintain wireless connectivity, thewireless device needs to be in ‘talking’ distanceto a base station — typically, in near line-ofsight and within a few tens of metres. Where
these requirements are difficult to meet,such as around the summit of a volcano orwithin the labyrinthine heart of an industrial
complex, the devices themselves can be used
to capture and retransmit data from nearby
devices so that the data eventually finds its
way to a wireless endpoint — and from there
to a wide area network like the Internet. This
type of ‘multihop’ wireless network has become
popular, but as the networks become larger

and carry more data, there is a need for
greater throughput and improved network performance.
Shoji Kasahara from Japan’s Nara
Institute of Science and Technology, withcolleagues from Kyoto University, has now
shown that the performance increases
obtained from a promising throughput-enhancing scheme called ‘network-coding’ areactually limited by the additional processing time incurred in the encoding process1.
Network-coding is a data transmission
algorithm that takes two or more received
packets of data and encodes them into asingle packet for broadcast to neighbouringmultihop nodes. This offers a theoreticalboost to throughput, but as the algorithm
is currently implemented as a network process rather than in hardware, the encoding
step requires computation, which can add
milliseconds to each packet transmission.
Kasahara and colleagues found throughmathematical analysis of a generalized threenode multihop network that throughput isonly increased above that of a network without
network coding if the computational delay
is less than 1,500 microseconds. Moreover,the performance benefits achieved at shortercomputational delays are significantly undermined by this ‘coding overhead’. “The mainachievement of this work is that the result was
obtained in a general setting, which makes thefinding applicable to any transmission situation,” explains Kasahara.
Since most multihop networks are implemented on low-power remotely deployablesensor devices, network coding may not be
as attractive as might first appear. In order torealize the true potential of this promising
wireless transmission scheme, hardware-based
network coding – with negligible coding
overhead – is essential.
Reference
1.

Yazane, T., Masuyama, H., Kasahara, S. & Takahashi, Y.
Effect of network-coding overhead on end-to-end
throughput for multihop wireless networks. Performance
Evaluation 70, 14–27 (2013).

More information about the group’s research can be found at the Large-Scale Systems Management Laboratory webpage:

http://isw3.naist.jp/Contents/Research/ai-03-en.html
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Nara Institute of Science and Technology | Mathematical Informatics Laboratory

www.naist.jp/en

Neuroimaging

Improved modelling forthree-dimensional scanning
A new computational method can build accurate three-dimensional images of brain activity fromnear-infrared spectroscopy dataFin that location peaks dramatically in response. Haemoglobin, the protein in red blood
cells that transports oxygen, takes different
forms when it is oxygenated and deoxygenated, and these forms absorb near-infrared lightto different extents. Hence, NIRS systems that
emit and then detect near-infrared light can
indicate which parts of the brain are active.
The complex process of combining NIRS
data to build 3D images is called diffuse
optical tomography (DOT). Recently,
Kazushi Ikeda and his colleagues at the
NAIST Graduate School of Information
Science, together with scientists across Japan,© TJohan Swanepoel/iStock/Thinkstockor some medical applications,near-infrared spectroscopy (NIRS)
imaging can provide cheaper, more
portable alternatives to magnetic resonanceimaging (MRI). In particular, NIRS is usefulfor tracking changes in the blood supply todifferent parts of the brain. But improving
the mathematical models used to interpret
NIRS data and construct three-dimensional(3D) images of brain activity has been a key
challenge, and one which NAIST researchers
have advanced.
When a specific part of the brain is activated, the flow and volume of oxygenated blood

succeeded in improving NIRS-DOT images
by enhancing the computational efficiency of
the DOT approach1.
Generally, DOT methods use informationfrom previous states of the brain to calculate
new states; in the language of Bayesian statistics, these are called the prior and posterior
states, respectively. Conventional DOT models utilize the ‘minimum norm estimation’ tocalculate the posterior state — but this cannot
fully account for localized brain activities.
The major advance made by Ikeda andco-workers was to introduce a new type of
input state for DOT modelling, called the‘automatic relevance determination’ (ARD)
prior. They also employed a variational Bayes
method to calculate the posterior state
more efficiently.
A similar approach had previously been employed for processing data from another brain
imaging technology, magnetoencephalography(MEG). However, MEG depends on thebrain’s magnetic permeability, which is almost
constant everywhere, whereas NIRS depends
on the optical transparency, which varies withposition. This meant the problem faced by the
NAIST team was considerably more difficult
to solve.
By performing a wide series of numericalexperiments using synthetic brain data, Ikeda
and his co-workers showed that their new
DOT method could create improved 3D images that were robust against variations in optical transparency across the brain. Since theirstudy was published, they have been working
to confirm the method using real brain data
recorded by more expensive techniques suchas MRI.
Reference

Near-infrared spectroscopy data can be used to generate three-dimensional images that indicate whichparts of the brain are active at different times.

1. Miyamoto, A., Watanabe, K., Ikeda, K. & Sato, M.
Variational inference with ARD prior for NIRS diffuse
optical tomography. IEEE Transactions on Neural
Networks and Learning Systems (Available online at
http://ieeexplore.ieee.org/xpl/articleDetails.jsp?arnumber=6839041).

More information about the group’s research can be found at the Mathematical Informatics Laboratory webpage:
http://isw3.naist.jp/Contents/Research/ai-04-en.html
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Research Highlights

Nara Institute of Science and Technology | Laboratory of Imaging-based Computational Biomedicine

www.naist.jp/enSurgery

Digital tool boosts
preoperative skill basePooling the experience of many surgeons, an artificial intelligence tool can help novice surgeons
prepare better preoperative plans© 2015 Yoshinobu Sato, Nara Institute of Science and Technology

Researchers in Japan are developing
automated systems that capture theskills of experienced surgeons to help
novices plan for total hip replacements andother surgical techniques. “Most patients wantto have surgery performed by an experienced surgeon rather than a beginner,” says
Yoshinobu Sato of NAIST, who is part of ateam developing artificial intelligence systems
to give all surgeons the benefits of experience
gained over many previous procedures.
Optimal planning for total hip replacement surgery requires careful considerationof each patient’s anatomy and requirements.
The precise size of the implant and its position relative to the patient’s bones must all beconsidered to prepare the preoperative planand select the best implant.
Working with colleagues at Osaka University and Kobe University, Sato — now at
the NAIST Graduate School of Information
Science — compiled computer-based ‘atlases’
that gathered and analyzed past surgicalexperience. The data came from selected
preoperative plans that had already been
prepared and used by experienced surgeons.
The digital atlases analyzed the surgeons’plans for the exact pattern of contact between
the implant and the femoral canal inside eachpatient’s femur bone, which received the stemof the implant. The information in the digitalatlases was then fitted to each new patient’s
data to generate a preoperative plan basedon the experience of many skilled surgeons,rather than just one.
The researchers tested their system byselecting 40 individual cases, and comparing
the automatically generated plans with those
prepared by experienced surgeons using existing interactive systems. They found that theirautomated system effectively reproduced theplans of highly experienced surgeons1. Thisconfirms that the system could assist less-experienced surgeons in matching the skills of
the best.

An automatically constructed surgical preoperative plan can help less-trained practitioners prepare
for surgery.

Sato says that accumulating surgical
data from all over the world in this way
could develop what he calls a ‘super-experienced surgeon’ using statistical machinelearning. The methods have now moved
out of the theoretical and experimental
stages. Although the data have not yet been
published, Sato reports “promising initial
results” from preliminary clinical evaluations
conducted by orthopaedic surgeons at Osaka
University Hospital.
“We would now like to evaluate our systemat many hospitals via the Internet,” he adds,
reflecting the obvious potential of digital

automated systems to travel effortlessly tomany locations on demand, unlike an individual skilled surgeon. And with some actual
surgical procedures also becoming automatedand robotically performed, there seems scopefor fully automating every critical step, fromplanning to surgery, in suitable cases.
Reference
1. Otomaru, I., Nakamoto, M., Kagiyama, Y., Takao, M.,
Sugano, N. et al. Automated preoperative planningof femoral stem in total hip arthroplasty from 3D CT
data: Atlas-based approach and comparative study.
Medical Image Analysis 16, 415–426 (2012).

More information about the group’s research can be found at the Laboratory of Imaging-based Computational Biomedicine webpage:
http://isw3.naist.jp/Contents/Research/ai-05-en.html
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www.naist.jp/en© Wavebreakmedia Ltd/Wavebreak Medai/Thinkstock

Nara Institute of Science and Technology | Computational Systems Biology Laboratory

Making sense of large amounts of data is helping NAIST researchers understand metabolites.

Metabolomics

Matching structure
to function
A systems biology approach pairs hundreds of structurally distinct metabolite groups to theircorresponding functionsO

rganisms — from bacteria and plants
to humans — generate a diverse arrayof chemicals called metabolites, whichplay many important roles, such as inducing
growth, serving as antimicrobial agents andfighting the growth of tumours.
“The result could aid in the identification of the functions of newly discovered metabolites and the designof new drugs.”

Now a team of researchers, including
Shigehiko Kanaya from NAIST, have used
databases they have developed that classify thechemical structure and biological function of
thousands of metabolites across many species,
to group metabolites with similar structures
into those with similar functions1. The result
could aid in the identification of the functions of
newly discovered metabolites and the design of
new drugs.
Metabolomics — the study of metabolites — is a very complex field. Some

metabolites are unique to a particular species,
while some are seen across multiple species.
Some metabolites have a unique function;some have multiple functions. The extent towhich clear themes can be identified in how
metabolites function will allow researchers
to fashion a better understanding of newly
discovered metabolites. Systems biology
approaches that aim to make sense of large
amounts of data are key drivers in understanding metabolomics.
Kanaya and colleagues therefore took asystems approach to the question of how
metabolite structure could provide insights
into metabolite function. They began by
studying the structure of over two thousand
metabolites across many species and grouping
together those metabolites that had similar
chemical structures.
The team identified 671 structurally
distinct groups among the metabolites
studied. They then categorised each metabolite according to 140 different biological
functions from a metabolite activity data-base, and looked for relationships between agiven chemical structure group and a given
biological function. This analysis revealed theexistence of 983 structure–function pairings.
Although more than 70% of the structuralgroups could be clearly linked to one or morebiological activities, the remaining structuralgroups could not be definitively classified inthis manner, in part because the metabolites
that made up those structural groups had
multiple divergent functions.
These analyses will provide a guide forresearchers in the field of metabolomics to beable to link a newly identified metabolite forwhich a structure is known with a biological
function, and could aid in the development of
new medicines.
Reference
1. Ohtana, Y., Abdullah, A.A., Altaf-Ul-Amin, M.,
Huang, M., Ono, N. et al. Clustering of 3D-structure
similarity based network of secondary metabolites
reveals their relationships with biological activities.
Molecular Informatics 33, 790-801 (2014).

More information about the group’s research can be found at the Computational Systems Biology Laboratory webpage:

http://isw3.naist.jp/Contents/Research/ai-06-en.html

NAIST Research Highlights25© 2015 Bessho Laboratory, Nara Institute of Science and TechnologyAxons are the long, slender projectionsof the neurons that make up thenervous system and conduct electrical impulses. As they grow towards theirtargets in the developing nervous system theyneed to generate traction forces, which allow
them to grab onto their substrate and extend
themselves to their final location. How dothey do it?
A research team led by Naoyuki Inagaki at Japan’s Nara Institute of Science andTechnology has found that chemo-attractant
molecules activate a signalling pathway ingrowing axons, allowing the generation of
mechanical forces that permit axons to propel
themselves toward their destination.

Netrin is an extracellular chemo-attracta
molecule that induces the growth of developing axons and the researchers thought th
could be because netrin induces traction fo
generation within the tip of the axon. To tethis, Inagaki and colleagues grew neurons oelastic gel embedded with fluorescent beadin the presence of netrin and observed thedisplacement of the beads. This suggested t
the axons were grabbing on to the substrat
order to propel themselves forward.
Netrin activates a wide range of intracellular signalling molecules, some of which— such as actin — may be responsible forstrengthening the link between structural
molecules within the axon and the substrat

The axial skeleton of a newborn mouse.

NaoyukiInagakiNaoyukiInagakiEmbryology

Signal loop set
vertebraenum
Research Highlights

A signalling feedback loop regulates the molecular cwww.naist.jp
in backbones

Nara Institute of Science and Technology | Laboratory of Plant Developmental SignalingR
Key propagation
protein
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Research Highlights
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Protein groove aids
Highlights“ assembly
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Plant science

investigatedthebyroleanesearchers
are unravelling
A fluorescence
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Biological Sciences

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© 2015 Keiji Nakajima, Nara Institute of Science and Technology“

Csion, we thought it might result in
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The protein RKD4 triggers embryogenesis in Arabidopsis plants: knocking out RKD4 means the plan
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formation;
insteadwe
foundplants,that
they
uncovered
the
role
of
RKD4.
evolutionary processes in plants.
Our findings pave the way for furembryos appearing a week later.”The
researchers
found that
RKD4
preferentherinvestigations
into
the molecReference
The overexpression of RKD4 essentiallytiallyularaccumulates
in developing
Hydrophilic groove
mechanismof YidC.seeds. Mutant
1. Waki, T., Hiki, T., Watanabe, R., Hashimoto, T. &reprogrammed differentiated cells and gavestrains without RKD4 showed severe germiNakajima, K. The Arabidopsis RWP-RK protein
them the potential to produce embryonic, or
nation— manyplantssimplynot
YidCdefects
is involvedin thefolding
anddidinsertion
RKD4 triggers gene expression and pattern forma
The membrane protein
YidC’shydrophilic,
positively
facilitates membrane
insertion
undifferentiated,
cells. The
team
concludedthat charged
grow,andmembranethose thatproteins,
did had truncatedtion ingroove
early embryogenesis.
Current Biology
21,of many
including roots
oneofproteins.
1277–1281 (2011).
RKD4 is an important regulator, which primes
withdisrupted
structureor noandroots
at all.
involvedin the cellreleaseof energy,
is thusessential for cell viability.
grooveis opentowardthe lipidofbilayer
Tsukazaki’s
team collecteddiffraction
data“Our findings
pave theway for further
More
information
about thegroup’s research
can bethat
found
at theLaboratory
PlantandDevelopmental
Signaling
webpage:cytoplasm, but closed on the extracellular side.
on YidC crystals at Japan’s SPring-8 syninvestigations into the molecular mechanism
http://bsw3.naist.jp/nakajima/English/
The groove has an affinity for water (is hydrochrotron facility, and refined the structure to
YidC,” says Tsukazaki.
philic) and positively charged (see figure).
a 2.4 ångström resolution. They then created“YidC also facilitates the proper folding o
A substrate protein interacts with thecomputer simulations mimicking the physicalmembrane proteins inserted by a protein-copositively charged cytoplasmic region of
movement of YidC in a lipid bilayer. To better
ducting channel — the SecYEG translocon
YidC, and is then captured in YidC’s hydro- and is essential for cell viability. We are tryin
understand YidC’s role, they compared theeffects of mutating the yidC gene to the effects philic groove; the positively charged groove
to determine the structure of the complex ofof mutating another gene involved in the mem- attracting the negatively charged residue on
YidC and Sec proteins in order to fully undethe substrate. An arginine residue that exists stand the conserved mechanism of membran
brane insertion process.
in the groove participates in recognizing
Previous studies suggested YidC formed aprotein biogenesis.”the substrate protein, which is then released
channel that facilitated membrane insertion ofReferenceby the groove into the membrane, partialprotein substrates, says Tsukazaki. His team’s
1. Kumazaki, K., Chiba, S., Takemoto, M., Furukawa
investigations revealed, instead, that YidC con- ly facilitated by the membrane potential
Nishiyama, K. et al. Structural basis of Sec-indepe
attracting the negatively charged residues on
tains a novel fold in which five independently
ent membrane protein insertion by YidC. Nature 5
516–520 (2014).
the substrate.
functioning transmembrane helices form a“

26

NAIST Research Highlights””© 2015 Kaoru Kumazaki, The University of Tokyo

Research

Embryonic development in animals includes loop regulates somite form
“Nrarp knock-out micea carefully choreographed interaction between
mal, but they have small ana moving chemical gradient and a ticking
molecular clock to measure out segments (called axial skeletons,” says Yasum
A key protein required for embryonicdevelopment and growth in plants has been uncovered
NAIST’s Graduate Schoosomites) along the body’s length. The segmentation clock involves oscillations in gene activity Sciences. In addition to th
he development of an embryonic plant that regulate a principal cell-to-cell communica- mutant mice have fewer ve
Nara Instituteof ScienceandTechnology
www.naist.jp
from a fertilized
seedfollows
a pro- | Membrane Molecular Biology Laboratory
grammed pattern of cell divisions. This tion mechanism, known as the Notch signalling Measuring the segmentati
that it ran slightly slower ipathway, as well as Notch intracellular domain
allows the differentiation of cells into specificcelltypes,
which enables healthy growth of tis- (NICD). By tuning these oscillations, eachCellfunctiondecrease that was linked tosues and the correct development of the plant.
When the team used a dspecies develops a specific number of somites,
A small number of transcription factors
levels, the segmentation cl
determining how many vertebrae it has.
contribute to this process, but little is known
more somites were formed
about the mechanisms and genes that control
I feel that the Nara Institute has an
the complex organisation of cells over timeings, the researchers specu
in seed plants (a process known as patternatmosphere in which we can wresNrarp feedback loop provi
formation). NAIST researchers have uncovered
segmentation clock.
tle with fundamental questions.
the critical role of protein RKD4, and the genes
During somite formatiothat respond to it, in the early development ofbetter understandthis process,a team for are
Arabidopsis plants1.
The crystal structure of a membraneToprotein
in soil bacteria
is describedthesynchronized
first time with the gsome of them are out of phof researchers at NAIST and other institutes
When we stopped the overexpres-

that
te in

-

te

on which the axon is growing. Pak1 is an enzyme within the axon tip that adds phosphategroups to other proteins to regulate theiractivity and shootin1 is a linker molecule that
couples actin to the substrate.

“

Our findings provide a key molecular mechanism for understanding the mechanical forcesthat are involved in human brain
development.

”© 2015 Bessho Laboratory, Nara Institute of Science and Technol

ant
his
orce
est
on
ds

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Intercellular Communications Laboratory

The researchers found that Pak1 can add
phosphate groups to shootin1 and that thisaddition could be increased by adding netrin
to the neuronal cultures. When shootin1 contains these phosphate groups that have been
added by Pak1, it leads to the strengtheningof the link between actin and the substrate.
When Inagaki’s team lowered the expression of shootin1 within the neurons,
the growing axons seemed to slip on theirsubstrate and netrin was not as effective at
inducing axonal outgrowth. If they expresseda modified Pak1 that blocked its ability to add
phosphate groups to shootin1, axon growth
was also inhibited. However, when theyexpressed a modified shootin1 that alreadycontained these phosphate groups, traction
force generation and axon outgrowth could
be restored.
Taken together, the data indicate that thegeneration of the mechanical forces required
for axons to be able to grow requires the induction of a signalling pathway that involves
the activation of Pak1 and shootin1. “Ourfindings provide a key molecular mechanism
for understanding the mechanical forces thatare involved in human brain development,”
says Inagaki.

Plant genetics

www.naist.jp/en

Self-recognition inpollination

ts Studies reveal a new way for plants to distinguish self from non-self during pollination
mbers
s

G

enetic diversity is crucial for ensuring

thethefitnessof a species.
One way plants
clock that controls
numberof vertebrae

promote diversity is by preventing
inbreeding — also known as self-fertilization.
1. Toriyama, M., Kozawa, S., Sakumura, Y. & Inagaki, N.
negative Notch
regulabations
the environment, suchchemicalConversion
of a signal into
forces forfrom
axon outgrowthPrevious
researchdemonstrated
thatasPetunia
through
Pak1-mediated shootin1rontrols theexpression
agentsphosphorylation.
or temperature changes, or intrinsic
Curr Bioluses
23, 529-34(2013)
a non-self-recognition system in whicheedback loop regulat- perturbations, such as cell division,” explainsa micepollen Bessho.
proteincalledS-locus F-box(SLF)
archers studied
Since
the out-of-phasecells don’t
disruptge:
how this feedback
somethingmuststyleresynchronize
interactsdevelopment,with a proteinin theS-RNase.
mation.
with their
Besshoand hisS-RNasethemis toxic,
andneighbours.
it preventspollen-tube
are almost norcolleagues suspect that Nrarp plays an important
growth unless
it isdegraded bymechanism.
an SLF protein.
nomalies in theirrole in thisresynchronization
Thus, pollen
functionsrecognizing
masa Bessho, fromTheSLFteam isnow testingby
thishypothesis by
ol of Biologicalnon-selfchecking
whetherknock-outmice are
S-RNasesandNrarp
degradingthem,
therehese defects, themore sensitive to a drug that causes embryonicbyallowing
growthtocontinue.
ertebrae than normal. abnormalities. So far, the results suggest that
p/en
been
puzzledion clock showedHowever,Nrarpresearchers
is necessary forhave
robustsomitedevelop-as
in the mutant to
mice,
a the
ment,
but researchis still ongoing.
why
genetic
diversityof the SLF gene isp/enReferences© 2015 Keiji Nakajima, Nara Institute of Science and Technology

o higher Notch levels.
drug to reduce Notch
lock ran faster andd. Based on their findulate that the Notchides robustness to theon, “most of the cells
gene oscillations, buthase because of pertur-“Nowadays, this kind of basic research may
be neglected,” says Bessho. “However, I feel that
the Nara Institute has an atmosphere in which
we can wrestle with fundamental questions.”
Reference

1. Kim, W., Matsui, T., Yamao, M., Ishibashi, M.,
Tamada, K., Takumi, K. et al. The period of the somite
segmentation clock is sensitive to Notch activity.
Molecular Biology of the Cell 22, 3541-3549. (2011)
doi: 10.1091/mbc.E11-02-0139

esartant

of
s
ate

a-

m of

of
onn—
ng
f
erne

a, A.,
end509,© 2015 Kaoru Kumazaki, The University of Tokyont
nd© 2015 Seiji Takayama, Nara Institute of Science and Technology

ne Regulation Research Laboratory webpage:

much lower than that of S-RNases in Petunia.
According to Seiji Takayama of NAIST
in Japan, “it remained a mystery how SLF
recognizes a large repertoire of non-self female
determinants.” To shed light on this enigma,
Takayama and colleagues sought to determine
the molecular mechanism of self-recognitionin Petunia.

“

It was tough work to show thateach SLF recognizes and detoxifies
a subset of non-self S-RNases.

”

The scientists solved this mystery when
they discovered that, unlike pollen of otherplant species, Petunia pollen expresses notone, but multiple SLF-like proteins. At thestart of their work, the team discovered several SLF-like genes that are expressed in pollen.
But this was just the beginning. “It was toughwork to show that each SLF recognizes anddetoxifies a subset of non-self S-RNases,”
Takayama explains. “To search for the actual
targets [S-RNases] of each SLF, we had tomake several hundred transgenic plants.”
Ultimately, they showed that these SLF
proteins work together to recognize and degrade diverse S-RNases to promote non-selfrecognition. According to Takayama, the data
provided convincing evidence that Petunia
uses a ‘collaborative non-self recognition
model’, which had never been described forother types of plants.
Since making these pioneering discoveries,
the team has continued to uncover the molecular mechanism of collaborative non-selfrecognition. Takayama notes that during the
research, “we identified six SLF genes.” They
then “thoroughly searched for SLFs using
next-generation sequencing and found that
16–20 SLFs collaboratively function to detoxify non-self S-RNases.”
They also “found evidence of gene conversion events,” Takayama says. He considers
these events to be “essential to the constitution of this ‘non-self recognition’ system andalso to contribute to self-compatible mutation.” The results of this work were recently
published in Nature Plants.
All of this work was facilitated by NAIST
which, according to Takayama, provided “a quiet and calm atmosphere suitable
for scientific research, properly maintained research facilities, and leading-edge
shared equipment.”
Reference

Close-up image of a petunia flower.

1. Kubo, K. et al. (2010) Collaborative non-self recognition system in S-RNase-based self-incompatibility.
Science 330, 796-799 (2010).

More information about the group’s research can be found at the Intercellular Communications Laboratory webpage:
http://bsw3.naist.jp/eng/courses/courses102.html
NAIST Research Highlights

27

Research Highlights

Biological Sciences

Nara Institute of Science and Technology | Plant Cell Function Laboratory

www.naist.jp/en

Cell biology

Enzyme shatters
cell skeleton

The process by which stress-activated enzymes destabilize a cell’s molecular scaffold could one day
be directed against cancerPlant and animal cells are supported bya framework of tubular proteins, calledmicrotubules, that are crucial in manycellular processes. In plants, environmental
stress can cause this framework to break down,
but the molecular mechanisms underlying thisdisintegration have remained elusive. NAIST
researchers have now discovered that a protein
known as PHS1 plays a key role in dismantling
the microtubule scaffold1.
Takashi Hashimoto and colleagues at
NAIST’s Plant Cell Function Laboratory
studied the function of the protein by using
mutants of Arabidopsis — small flowering
plants related to cabbage — that were deficientin PHS1. They found that PHS1 contains twoparts: a kinase and a phosphatase (see figure).

The kinase causes the transfer of a phosphategroup to microtubule proteins, which destabilizes the entire microtubule skeleton.
The kinase is usually inactive, but Hashimoto’s team showed that it is permanently
active in mutants with defective phosphatasedomains. This suggests that the phosphataseacts as a switch controlling the kinase. Furthermore, when the researchers applied stress suchas a high salt concentration, they found that thephosphatase ‘switched on’ the kinase. This, theyreport, “provides an efficient strategy for reversibly and rapidly regulating microtubule stability
in response to biotic and abiotic signals.”
Although proteins with multiple functions
are fairly common, ‘autoregulated’ proteinssuch as PHS1, with two opposing domains are

Reproduced, with permission, from Ref. 1 © 2013 Elsevier Ltd.

Salt/osmotic stress

PHS1
Tubulin kinase domain

Phosphate domain

ß-tubulin

Phosphorylation
α-tubulin
Polymerizationcompetent form

Polymerizationinefficient form

PHS1 comprises two domains: a kinase and its suppressor, a phosphatase. Environmental stress causes
phosphatase to release the kinase, which then transfers a phosphate group to a tubulin molecule. This
phosphorylation of tubulin results in the breakdown of cellular microtubule arrays.

rare, according to Hashimoto. “I do not recall
any kinase having a juxtaposed phosphatasedomain,” he notes.

“

Our current preferred idea is that
PHS1 acts to halt plant growth
temporarily under water stress, allowing the plant to adapt to changing water resources. This is one of
the most important questions wewant to address.

”

The functional significance of PHS1 innature remains unclear and is something theteam is actively investigating. “Our current
preferred idea is that PHS1 acts to halt plant
growth temporarily under water stress, allowing
the plant to adapt to changing water resources.
This is one of the most important questions wewant to address,” says Hashimoto.
PHS1 is thought to be unique to, but universal in, the plant kingdom. “All sequenced plant
genomes have PHS1 genes,” says Hashimoto,who has recently shown that mosses use thesame system.
The protein also provides a useful tool
for studying microtubule-based cellular
processes and, because microtubules arecentral to all cell division, it could potentiallybe used to stop cancer cells proliferating.
Tests on cultured monkey cells have shownthat PHS1 can also destabilize mammalian
microtubule arrays.
Hashimoto reasons that, since PHS1 also
acts on animal microtubules, “it could betargeted to cancer cells to dysfunction theirmicrotubules, thereby stopping proliferation.”In the shorter term, his research provides
useful experimental tools for studying
cellular processes.
Reference
1. Fujita, S., Pytela, J., Hotta, T., Kato, T., Hamada, T.
et al. An atypical tubulin kinase mediates stress-induced microtubule depolymerization in Arabidopsis.
Current Biology 23, 1969–1978 (2013).

More information about the group’s research can be found at the Plant Cell Function Laboratory webpage:
http://bsw3.naist.jp/eng/courses/courses103.html
28

NAIST Research Highlights

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Laboratory of Plant Developmental Signaling

www.naist.jp/en

Plant science

Key propagation protein
identified
A key protein required for embryonic development and growth in plants has been uncoveredT© 2015 Keiji Nakajima, Nara Institute of Science and Technology

he development of an embryonic plantfrom a fertilized seed follows a programmed pattern of cell divisions. This
allows the differentiation of cells into specificcell types, which enables healthy growth of tissues and the correct development of the plant.
A small number of transcription factors
contribute to this process, but little is known
about the mechanisms and genes that control
the complex organisation of cells over timein seed plants (a process known as patternformation). NAIST researchers have uncovered
the critical role of protein RKD4, and the genesthat respond to it, in the early development of
Arabidopsis plants1.

“

When we stopped the overexpression, we thought it might result in
new shoots or root formation; instead we found embryos appearing
a week later.

”“We originally began genetic screening toisolate a patterning regulator for post-embryonic roots,” explains Keiji Nakajima, fromthe NAIST Graduate School of Biological
Sciences, who worked on the study with hiscolleagues. “Instead, we uncovered a mechanism responsible for embryogenesis rather thanroot patterning. The protein RKD4 seems to beeven more important than simple patterning
regulators, because it can actually reprogram
cells in the earliest stage of plant growth.”
It took the NAIST team some time tounderstand what they had stumbled across,because at first they were focusing on the plantroots. It was only when Nakajima analyzed
microarray data from RKD4 overexpressing
plants, that they uncovered the role of RKD4.
The researchers found that RKD4 preferentially accumulates in developing seeds. Mutant
strains without RKD4 showed severe germination defects — many plants simply did not
grow, and those that did had truncated roots
with disrupted cell structure or no roots at all.

The protein RKD4 triggers embryogenesis in Arabidopsis plants: knocking out RKD4 means the plantdoes not develop properly, whereas overexpressing RKD4 can lead to the reprogramming of cells andthe creation of new embryos (above).

However, the overexpression of RKD4 had
an unexpected effect, as Nakajima explains:“We created transgenic seedlings with highlevels of RKD4, which resulted in the overproliferation of young leaves and root tissues, aswell as triggering the expression of early-embryo-specific genes. When we stopped theoverexpression, we thought it might result in
new shoots or root formation; instead we foundembryos appearing a week later.”
The overexpression of RKD4 essentially
reprogrammed differentiated cells and gavethem the potential to produce embryonic, or
undifferentiated, cells. The team concluded that
RKD4 is an important regulator, which primes

cells to activate embryogenesis, and promotes
the expression of genes required for kick-starting the correct growth and patterning of plant
embryos (see figure).
The discovery may prove useful for applications such as controlling the propagation ofendangered plant species. Nakajima’s team iscurrently extending the research to investigate
evolutionary processes in plants.
Reference
1. Waki, T., Hiki, T., Watanabe, R., Hashimoto, T. &Nakajima, K. The Arabidopsis RWP-RK protein
RKD4 triggers gene expression and pattern formation in early embryogenesis. Current Biology 21,
1277–1281 (2011).

More information about the group’s research can be found at the Laboratory of Plant Developmental Signaling webpage:
http://bsw3.naist.jp/nakajima/English/
NAIST Research Highlights

29

Biological Sciences

Research Highlights

Nara Institute of Science and Technology | Laboratory of Plant Metabolic Regulationwww.naist.jp/en

Plant genetics

Wood-forming genes active
in mosses
Key genes for wood development are expressed in mosses, hinting at an ancient evolutionary storyD© 2014 Bo Xu/NAIST; Kiminori Toyooka/RIKEN

espite the distance between mosses
carpeting a forest floor and the trees
above, researchers have discovered thatboth groups express key wood-development
genes. Although mosses lack wood, the genes
originally played a central role in the migrationof plants to the land.
When plants moved onto land, the absenceof water presented them with the challengeof holding themselves upright and keeping
aerial tissues hydrated. The evolution of special water-conducting cells, known as xylem,

solved both problems, providing a continuous
network of stiff tubes that support the bodyand deliver water. Vascular plants used thisevolutionary innovation to carry themselves
ever higher in the competition for light,
from little flowers to towering trees in which
xylem tissue forms the bulk of the biomassin the form of wood. Unlike vascular plants,
mosses transport water through hydroids
instead of xylem, and have remained small.
However, a group of key xylem development
genes are active in the moss Physcomitrella pat-ens, according to research carried out by a teamat the Nara Institute of Science and Technology (NAIST) and other Japanese institutes1.
The VND/NST/SMB (VNS) gene family
regulates the differentiation of woody cells invascular plants. While the P. patens genome is
known to include several VNS-like genes, theirfunction has remained unclear. The researchers
studied the genes’ expression patterns and used
knock-out mutants to figure out their role inthe development of P. patens.
“I didn’t expect such clear results at first,” says
Misato Ohtani of NAIST’s Graduate Schoolof Biological Sciences. Several of the genes are
expressed in tissues consisting of hydroids andother cells responsible for water transport andstructural support. Mutant P. patens, with multiple VNS genes knocked out, have defectivehydroids together with decreased water uptake.
The team is now looking downstreamof the VNS genes to understand how different water-conducting tissues evolved inmosses and vascular plants. “I first guessedthat P. patens would lack the second master
regulators of woody cells, MYBs, andthe biosynthetic genes for lignin,” says
Ohtani. To her surprise, homologs of bothgroups are expressed downstream of the
VNS genes in P. patens, suggesting that aprimitive form of the VNS-MYB pathway
evolved before the divergence of mosses
and vascular plants and became specialized
in both lineages.
“Amazing!” says Ohtani. “We’re starting touse several plant species, including a kind ofalgae, to explore this issue.” Understanding
how the VNS genes regulate the differentiation of water-conducting cells in different
species could provide versatile tools for
manipulating plant biomass.
Reference

Wild-type P. patens growing in soil.

1. Xu, B., Ohtani, M., Yamaguchi, M., Toyooka, K.,
Wakazaki, M. et al. Contribution of NAC transcription factors to plant adaptation to land. Science 343,
1505-1508 (2014).

More information about the group’s research can be found at the Laboratory Of Metabolic Regulation webpage:
http://bsw3.naist.jp/demura/?cate=137
30

NAIST Research Highlights

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Plant Growth Regulation Laboratory

www.naist.jp/en

Plant biology

Surface signals
control growth
The signalling processes governing plant organ growth have been found to originate within thesurface layers of the plantThe outermost cell layer in plants,
known as the epidermis, plays animportant role in interactions between
the plant and the environment. The epidermis
also communicates with cells in inner layers tomaintain optimal organ size by accelerating or
restricting cell proliferation. Recent investigations by researchers at NAIST indicate thatthe epidermis is capable of sending signals todeeper plant tissues in order to control cellproliferation and shoot organ growth.
The epidermis is covered by a hydrophobic barrier called the cuticle, which protects
plants from environmental hazards such as

drought, and also helps guard against pathogen attacks. The cuticle is made of the polymer ‘cutin’, and a substance called ‘cuticularwax’, which is made up of very-long-chain
fatty acids (VLCFAs).
Masaaki Umeda and co-workers at the
NAIST Graduate School of Biological
Sciences, together with scientists acrossJapan, have shown that VLCFA synthesis in
the epidermis, and subsequent VLCFA-derived signalling to inner cell layers, is important for shoot organ growth regulation in thesmall flowering plant known as thale cress(Arabidopsis thaliana)1.

Epidermis©2015 Yoko Okushima, Nara Institute of Science and Technology

Vasculature

Shoot apex

VLCFAsCytokininbiosynthesis
Cellproliferation

Inhibition of VLCFA
biosynthesis
Signals derived from very-long-chain fatty acids (VLCFAs) play an important role in maintaining organ
size during continuous plant development. VLCFAs synthesized in the epidermis of the Aribidopsis
thaliana plant can suppress the cytokinin accumulation around the vasculature and proliferation of cells
in internal plant tissues.

“Knocking out the genes that are requiredfor VLCFA synthesis in the plants resulted
in severely impaired cuticular wax layer formation,” explains Yoko Okushima, a memberof Umeda’s team. “This had such an impact
on plant development that it was difficult toascertain the exact outcomes related to low
VLCFA content.”
To examine the effect of disrupting
VLCFA synthesis in more detail, Umeda’s
team gradually reduced the levels of VLCFAin Arabidopsis plants using different doses ofa synthetic VLCFA inhibitor called cafenstrole, an active ingredient in commercial
herbicides. The results showed that reducing
VLCFA content increased the expressionof a protein called IPT3, which promoted
biosynthesis of a growth hormone calledcytokinin in the inner plant layers. This led toexcess cell proliferation.
“VLCFA synthesis in the epidermis
suppresses this excess cell proliferation ininternal tissues,” explains Okushima. “Signals
derived from VLCFAs regulate cytokinin
biosynthesis inside the plant and determine
shoot organ growth. Interestingly, the mild
inhibition of VLCFA synthesis using a low
concentration of cafenstrole actually produced larger aerial organs without inhibiting cuticular wax layer formation. VLCFA
synthesis may therefore be a possible
target for technologies aimed at increasing
plant biomass.”
Umeda and his team are continuing theirinvestigations into this interesting regulatory
signalling pathway. Their current studies aim
to uncover how VLCFAs regulate cytokinin
biosynthesis and cell proliferation via intercellular signalling.
Reference
1. Nobusawa, T., Okushima, Y., Nagata, N., Kojima, M.,
Sakakibara, H. & Umeda, M. Synthesis of very-longchain fatty acids in the epidermis controls plant organ
growth by restricting cell proliferation. PLOS Biology
11, e1001531 (2013).

More information about the group’s research can be found at the Plant Growth Regulation webpage:
http://bsw3.naist.jp/eng/courses/courses105.html
NAIST Research Highlights

31

Biological Sciences

Research Highlights

Nara Institute of Science and Technology | Plant Morphological Dynamics Laboratory© jojoo64/iStock/Thinkstock

www.naist.jp/en

An Arabidopsis flower.

Plant development

Understanding how
flowers and leaves form

Insights into the molecular mechanisms governing how buds develop leaves and flowers could help
improve agronomy and horticultureG

enes and molecular mechanisms thatallow the plant hormone auxin to control the formation of leaves and flowers
have been identified by NAIST researchers.
Understanding these complex systems involvedin plant development could contribute to advances in plant breeding and genetic engineering of benefit to agriculture and horticulture.

“

Our findings enable us to manipulate plant development, includingorgan growth orientation and plantarchitecture.

”

As we watch plants grow and buds form
and then develop into leaves and flowers, we
can’t fail to be impressed by the neatly ordered
and beautiful structures created by the hidden
chemistry within. Masahiko Furutani andcolleagues at the NAIST Graduate School of
Biological Sciences investigated the ebb andflow of chemicals that create the impressive
botanical architectures we can all admire. They
have worked with Arabidopsis, small flowering

plants widely used as model organisms to investigate plant genetics and genetic engineering(see figure). “The molecular mechanisms that
control these dynamic changes were unknown,”says Furutani.
The researchers did know that the formation of Arabidopsis leaves and flowers is
triggered by localised accumulations of auxin,a small and relatively simple plant growth
factor or plant hormone. The development oforgans such as the parts of a flower are initiated in a spiral manner in the outer layers of
the region of undifferentiated tissue at the tipof a growing shoot, known as the meristem.
Furutani and his colleagues found that afamily of genes known as the MAB4 genes
promote organ development by establishing adownwards flow of auxin1. This involved thecreation of an ‘auxin sink’ mechanism to promote the localised removal of auxin needed
to generate the necessary gradients in auxin
concentration. The crucial role of MAB4
genes in establishing the auxin sink is one of
the key insights from this research.

The actual flow of auxin from cell to cell ismediated by carrier proteins embedded in thecell membranes, known as PIN proteins. The
Furutani’s team investigated the role of these
proteins in the auxin gradients, and the mutualinteractions among auxin, the MAB4 genes
and the PIN proteins. Their findings allowed
them to propose a new model to describe thedetails of auxin gradient formation and auxin
transport during organ formation in the plants.
Although focused on Arabidopsis, theresearch is likely to have wider relevance forunderstanding plant development in general.
“Our findings enable us to manipulate plantdevelopment, including organ growth orientation and plant architecture,” says Furutani,
explaining the ultimate motivation for unravelling these complex molecular interactions.
Reference1.

Furutani, M., Nakano, Y. & Tasaka, M. MAB4-induced
auxin sink generates local auxin gradients in Arabidopsis
organ formation. Proceedings of the National Academy of
Sciences of the United States of America 111,
1198–1203 (2013).

More information about the group’s research can be found at the Plant Morphological Dynamics webpage:

http://bsw3.naist.jp/eng/courses/courses106.html
32

NAIST Research Highlights

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Plant Immunity Laboratory

www.naist.jp/en

Plant disease

Understanding plant
immunity, both near and far

Plants employ a two-fold defense against
disease: local immunity immediately
surrounding a pathogen, and systemic
immunity further away. However, the molecularpathways linking pathogen recognition withimmunity are poorly understood. NAIST researchers are investigating a cellular component
central to both local and systemic immunity,
providing a potential target for developing
disease-resistant crops1.
Plant immunity develops through detectionof both pathogen molecules and endogenous
danger signals. The latter include small protein
fragments called PROPEPs, which bind to
receptors (PEPRs) on the cell surface. The
NAIST team, led by Yusuke Saijo, formerlyof the Max Planck Institute for Plant Breeding Research, Cologne, Germany, is investigating how PEPRs coordinate local andsystemic immunity.

“

The components of the Arabidopsis
PEPR pathway are evolutionarily
conserved in higher land plants
including important crops.

”

Using mutant Arabidopsis – small flowering
plants related to cabbage and mustard – Saijo’s
team determined that PEPRs contribute to
local immunity, through perception of PROPEPs. They then tested systemic immunity
by inoculating PEPR-defective mutants witha pathogen and looking for defense-response
markers in uninfected parts of the plant. The
mutants had reduced numbers of markers, indicating that PEPR has a critical role in systemic
immunity, which is in turn vital to plant survival. As Saijo explains, “In contrast to animals,
plants don’t have specialized mobile immune
cells.” Systemic immunity enables pathogens
to be resisted, “not only in the infected cell, butalso in its neighbours and distant organs. Our
work indicates that local action of the PEPR
pathway strengthens an as-yet-unidentified
systemic signal from the pathogen-challenged

Systemic
immunity

Local
immunity

PEPR
PR
R
SA
JA

The NAIST team’s proposed model for the role of PEPRs in plant immunity. Pathogen attack causes
the release of Pep peptides which are received by PEPRs. This activates hormonal salicylic (SA) andjasmonic acid (JA) pathways, resulting in both local and systemic immunity to the pathogen.

site, enhancing systemic immunity in distant,unchallenged tissues.”
The team also catalogued the genes switchedon by PEPRs. They found that PEPRs
co-activate two branches of the plant immune
system, mediated by the hormones salicylic andjasmonic acid. However the detailed mechanisms underlying systemic immunity remain tobe elucidated, and the lab — which prides itself
on its intellectual flexibility and international
outlook — continues to investigate the molecular-genetic and biochemical pathways involved.
These results suggest that PEPRs provide
a critical control center in plant defense, connecting internal and external triggers, co-activating salicylic and jasmonic acid pathways
that would typically antagonize each other,and linking immediate local defense with

Image adapted from © Annegret Ross / Max Planck Institute for Plant Breeding Research

A signaling pathway, linking local and systemic immunity in plants, could be used to create
disease-resistant crops

long-distance systemic immunity (see figure).
According to Saijo, “The components of the
Arabidopsis PEPR pathway are evolutionarily
conserved in higher land plants including
important crops.”
He continues: “The systemic immune system
can enhance plant disease resistance against a
broad spectrum of pathogens in a sustainable
and cost-efficient manner. Thus, our workshows the potential of endogenous signals, suchas PROPEPs, and PEPRs, as tools to increase
disease resistance in crops.”
Reference
1. Ross, A., Yamada, K., Hiruma, K., Yamashita-Yamada, M., Lu, X. et al. The Arabidopsis PEPR pathway
couples local and systemic plant immunity. The EMBO
Journal 33, 62–75 (2014).

More information about the group’s research can be found at the Plant Immunity Laboratory webpage:
http://bsw3.naist.jp/eng/courses/courses111.html
NAIST Research Highlights

33

Research Highlights

Biological Sciences

Nara Institute of Science and Technology | Plant Development Biology Laboratory

www.naist.jp/en

Plant genetics

Understanding female
reproductive organ formation
A deceptively simple appearance belies the complex genetic interactions that occur during theformation of Arabidopsis thaliana’s female reproductive organs“

Elucidating the functions of
CUC1/CUC2 genes and their regulators in gynoecium development
will give us clues on how flowering plants evolved to elaborate
reproductive organ systems.

”

He and colleagues were interested inunderstanding how the gynoecium formed asa closed structure via the fusion of developmental units similar in form to leaves, known
as carpels. Previously, they had been working
on the CUP-SHAPED COTYLEDON genes,
CUC1 and CUC2 — investigating theirfunction as developmental regulators. While
CUC1 and CUC2 influence the developmentof seeds, over-expression of the genes can be‘too much of a good thing’ and stop adjacentorgans from fusing, which would impede theformation of closed gynoecia.

As closed gynoecium are common innature, Aida recalls, “We hypothesized that
there should be a factor that maintains
appropriate expression of CUC1 and CUC2
to ensure proper gynoecium development.”
They identified the SPATULA gene, SPT
as the most likely candidate since loss of
SPT function had been observed to result inplants with split gynoecia. Interestingly, the
SPATULA gene was named after the strange
shape of the mutant gynoecia.
This was followed by an extensive studyof CUC1, CUC2 and SPT expression andcorresponding gynoecium structures amongst
wild type and mutant variants of Arabidopsis
thaliana1, a Eurasian small flowering plantalso known as the thale cress.
The most significant finding was the domain-specific effect of SPT on CUC expres-sion — suppressing it in the apical domain(thus ensuring closure in the top section of
the gynoecium), while allowing it in the basal
domain — facilitating seed development in
the bottom section of the gynoecium.
It is possible that these interactions may be
responsible for the closed gynoecia in otherflowering plants. “Elucidating the functionsof CUC1/CUC2 genes and their regulators
in gynoecium development will give us clues
on how flowering plants evolved to elaborate
reproductive organ systems,” notes Aida.
Reference
1. Nahar, M. A-U., Ishida, T., Smyth, D. R., Tasaka, M. &Aida, M. Interactions of CUP-SHAPED COTYLEDON
and SPATULA genes control carpel margin development in Arabidopsis thaliana. Plant Cell Physiology 53,
1134–1143 (2012).

More information about the group’s research can be found at the Plant Development Biology webpage:
http://bsw3.naist.jp/eng/courses/courses108.html
34

NAIST Research Highlights© 2014 Mitsuhiro Aida, Nara Institute of Science and Technology

Flowers are not simply nature’s decorations, they serve a more practical
purpose — as plant reproductive
organs. A plant’s male reproductive organs,the stamens, are collectively known as theandroecium; whereas the stigma, style andovary are collectively known as the gynoecium,the female counterpart. Mitsuhiro Aida, fromthe Graduate School of Biological Sciences andcolleagues investigated the genetic interactions
involved in the formation of the closed structure of the gynoecium.
“Much of our daily food comes from fruits orseeds, all of which are products of the gynoecium,” notes Aida. What makes the gynoecium
special is its closed structure; this shields
developing seeds from changing environmental
conditions, allowing them to flourish. Flowering plants with this closed gynoecium structure
have proved to be the most successful plantgroup because “a delicate fertilization process isable to take place in a more regulated manner
under more stable conditions than is possible
for plants without a gynoecium,” explains Aida. The Arabidopsis thaliana flower; a popular model for plant studies.

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Molecular Signal Transduction Laboratory© Katie Nesling/Hemera/Thinkstock

www.naist.jp/en

A healthy brain, like this one, has many folds and grooves. A discovery by NAIST researchers could help treat lissencephaly, during which these features failto develop.

Embryology

Protein does double duty
in cell migration
Doublecortin protein has two different roles in controlling how the brain developsAs the fetal brain develops, young brain
cells known as neuronal progenitor
cells need to migrate from where they
are formed to their final home in the cerebral
cortex. When that fails to happen, the brain’s
folds and wrinkles don’t develop properly; acondition known as ‘smooth brain’, or lissencephaly, which leads to developmental delays,
seizures and respiratory problems.

“

Dual and coordinated regulationof two cytoskeleton systems by
one molecule was a very exciting
finding.

”

A number of different proteins and signalling molecules are involved in controlling that
migration, and a team of researchers at Japan’s
NAIST has mapped one pathway that controls
when and how the cells get moving.
Within that pathway, they found a surprise:a protein called Doublecortin (DCX) has two
different functions when it comes time forthe cell’s internal scaffolding — the cytoskel-

eton — to begin moving the cells along on
their journey.
“Dual and coordinated regulation of two cytoskeleton systems by one molecule was a very
exciting finding,” says Hiroshi Itoh, a molecularbiologist at NAIST who led the work.
Cellular migration is triggered when asignalling molecule called pituitary adenylyl
cyclase-activating peptide (PACAP) binds
to a receptor that spans the membrane of theneuronal progenitor cell. That receptor, part ofan important class of proteins called G-protein
coupled receptors, induces the activation ofprotein kinase A (PKA) in the cell. PKA thenchanges the behaviour of DCX, by adding
a phosphate group to one particular area ofthe protein.
Up until this point, DCX has been holding
the cell rigid by bundling one part of thecytoskeleton, the microtubules, together. But
once it is phosphorylated by PKA, DCX
releases the microtubules and switches its
attention to another part of that scaffolding,a protein called actin. It induces the actin toform long filaments that push against the cell
membrane from the inside and, freed fromthe stabilising effect of the microtubules, thecell begins to move towards its final home inthe developing brain.
The discovery could help with the treatmentof lissencephaly by allowing doctors to treat afetus with drugs that promote proper migrationof neuronal progenitor cells if genetic testing
reveals a mutation in the phosphorylation site
on DCX, says Itoh.
Itoh’s team is now investigating how another protein kinase, called CDK5, might beinvolved. CDK5 is known to regulate neuronalcell migration and, like PKA, also phosphorylates DCX, but at a different point on theprotein. They are analysing the relationshipbetween these two different versions of phosphorylated DCX in controlling cell migration.
Reference
1. Toriyama, M., Mizuno, N., Fukami, T., Iguchi, T.,
Toriyama, M. et al. The Journal of Biological Chemistry287, 12691-12702 (2012).

More information about the group’s research can be found at the Molecular Signal Transduction webpage:
http://bsw3.naist.jp/eng/courses/courses202.html
NAIST Research Highlights

35

Research Highlights

Biological Sciences

Nara Institute of Science and Technology | Functional Neuroscience Laboratory

www.naist.jp/en

Neuroscience

Signals that strengthen
the brain

Insights into an important signalling system for neural plasticity may enhance understanding ofbipolar disorder and schizophreniaT

he brain is capable of modifying itself
over time by creating and strengthening
synapses — the structures that carryelectrical signals between neurons. This process,known as neural plasticity, enhances cognitive
functions including learning and memory.
Researchers at NAIST are at the forefront ofinvestigations into the mechanisms surrounding
cognitive functioning, and a major study in2012 uncovered an important signalling system
in neural plasticity involving an enzyme calledneuropsin and a protein called NRG-11. The
dysfunction of the neuropsin-NRG-1 signallingsystem may be involved in psychiatric illnesses
such as bipolar disorder and schizophrenia.

“

Neuropsin is thought to influencecognitive brain function, and has
been implicated in working memory and bipolar disorders.

”

tor to stimulate a type of neuron called
GABAergic neurons.
Signalling from ErbB4 allows for thestrengthening of synapses between neurons,enhancing the brain’s ability to learn fromrepeated activities, a process known as earlylong-term potentiation. When Shiosaka andhis team created neuropsin-deficient mice, theyfound that the mice displayed both behaviouraland neuronal hyperexcitability, as well as impairments in early long-term potentiation.
These results show that neuropsin-NRG-1
processing is a vital part of neural plasticity,and that functioning neuropsin pathways allow
for the strengthening of synapses and normal
cognitive function. Shiosaka and his team believethat their work could help further understandingof bipolar disorder and schizophrenia, and may
one day provide a remedy for plasticity-related
conditions such as hallucination and delusion.
Reference
1. Tamura, H., Kawata, M., Hamaguchi, S., Ishikawa, Y.
& Shiosaka, S. Processing of neuregulin-1 by neuropsin regulates GABAergic neuron to control neuralplasticity of the mouse hippocampus. The Journal of
Neuroscience 32, 12657–12672 (2012).

© Svisio/iStock/Thinkstock“About 20-30 years ago, neural and synaptic
structures were thought to be rigid and immovable, even in neural plasticity processes likememory acquisition,” explains Sadao Shiosaka,of the NAIST Laboratory of Functional Neu-

roscience and one of the authors of the study.
“We hypothesized that neural plasticity actuallyinduces dynamic neural change, particularly inan area called the synaptic cleft, found between
pre- and post-synaptic neurons.”
The main problem with studying signalling systems in the synaptic cleft is that the
specific enzyme-protein interactions happen
very quickly and cannot easily be isolated andexamined. Shiosaka and his team therefore
pioneered a new method to uncover theprotein substrates processed by neuropsin in
the brains of mice.
“Neuropsin is thought to influence cognitive brain function, and has been implicatedin working memory and bipolar disorders,”
explains Shiosaka. “We modified neuropsin
so that it had a mutation which allowedbinding to target proteins, but did not thenrelease them. This allowed us to identify
several of neuropsin’s targets, including
NRG-1.”The team analysed samples taken fromthe hippocampus in the mice. They foundthat neuropsin processes NRG-1, which inturn activates the so-called ErbB4 recep-

A major signalling pathway involved in strengthening synaptic connections between neurons in the brain has been identified. Its disruption may be connected with psychiatric disorders such as schizophrenia.

More information about the group’s research can be found at the Functional Neuroscience webpage:
http://bsw3.naist.jp/eng/courses/courses205.html
36

NAIST Research Highlights

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Gene Function in Animals Laboratory

www.naist.jp/en

Genetics

Stress response gene
underlies loss of vision
A key gene protects retina cells from oxidative stress, but also causes them to age prematurelyA© aodaodaod/iStock/Thinkstock

ge-related macular degeneration is
the leading cause of severe, irreversible vision loss in people over
55. Its basis remains poorly understood,
and no effective treatment exists. Recent
research at NAIST has shown how a stressresponse gene plays a role, linking the genetic and environmental factors behind thisdebilitating disease.
In 2006, two research groups discovered alink between the HtrA1 gene and age-related
macular degeneration. Since then, increasing
evidence has demonstrated that high HtrA1
levels in the retinal pigment layer play acentral role in the disease – but the gene’sfunction in this tissue has remained a mystery. The retina is exposed to high levels ofphysiological stress in the form of oxidative
damage, prompting Masashi Kawaichi’s teamat NAIST to investigate whether HtrA1
activity modifies the retina’s stress-response.

“

We believe that the same senescence process is a major part ofthe physiological function of HtrA1
in ossification and its pathological
function in arthritis, both of osteoarthritis and rheumatoid arthritis.

”

The team used cultures of embryonic mouse cells and human retinal cells totest how HtrA1 responds to oxidants suchas hydrogen peroxide. Their experiments
showed that cells under oxidative stressactivate HtrA1 expression; this protects themfrom dying due to the stress, but also causes
them to senesce earlier1. The researchers
believe that increased senescence resulting
from persistent exposure to oxidative stresseventually causes retinal damage in the formof macular degeneration.
HtrA1 is also expressed in a variety ofother tissues, such as cartilage, ligaments andtendons, and has been linked with diseases
from pre-eclampsia to arthritis. Oxidative

NAIST researchers are studying the link between the HtrA1 gene and stress response of the retina.

stress is known to play a role in causing
arthritis, raising the possibility that similar
mechanisms may underlie the two conditions. “We believe that the same senescenceprocess is a major part of the physiological
function of HtrA1 in ossification and its
pathological function in arthritis, both ofosteoarthritis and rheumatoid arthritis,”says Kawaichi.
Unfortunately, the diversity of HtrA1’s
roles also presents a challenge to efforts totransform these findings into improved treatments. “Some researchers believe that HtrA1
is a tumour suppressor gene. A decreasein HtrA1 expression levels is frequently
associated with malignant transformation ormetastasis of ovary cancers, gastric cancers,
melanoma, and so forth,” explains Kawaichi.
“General administration of potent inhibitors of HtrA1 could have side effects, particularly in the long term. If we could havean effective inhibitor which could be used forocular instillation or topical injection into
joints, we hope those would provide promising remedies to these prevalent diseases,”
Kawaichi adds.
Reference
1. Supanji, Shimomachi, M., Hasan, M. Z., Kawaichi, M.
& Oka, C. HtrA1 is induced by oxidative stress andenhances cell senescence through p38 MAPK pathway.
Experimental Eye Research 112, 79-92 (2013).

More information about the group’s research can be found at the Gene Function in Animals Laboratory webpage:
http://bsw3.naist.jp/eng/courses/courses206.html
NAIST Research Highlights

37

Biological Sciences

Research Highlights
www.naist.jp/en© Kraivuttinun/iStock/Thinkstock

Nara Institute of Science and Technology | Functional Genomics and Medicine Laboratory

NAIST researchers are exploring the quality control function of the Upf1 enzyme in the protein production process.

Cell biology

Key quality control
element revealed
An RNA-scanning mechanism may help cells prevent production of potentially toxic truncated proteinsAmutation affecting a single nucleotide can be sufficient to interrupt
the synthesis of a protein, resulting
in a truncated product that may potentiallydisrupt the normal function of the cell. Researchers led by Yasumasa Ishida of NAIST
have uncovered a ‘quality control’ mechanismthat help detect and eliminate these prematurely-shortened RNA molecules1.
Within every messenger RNA (mRNA)
resides the recipe for building a protein, composed of a series of three-nucleotide ‘codons’
that each encode a particular amino acid.
These instructions are concluded by one ofthree different ‘stop codons’, which terminate
protein production. Genetic alterations canconvert an amino acid-encoding codon intoa stop codon, interrupting the translationof the affected mRNA prematurely. Thesemolecules are selectively recognized andeliminated via a mechanism known as ‘nonsense-mediated decay’.
Ishida’s team wanted to explore how
Upf1, a ‘molecular motor’ enzyme with thecapacity to travel along RNA and DNA
strands, contributes to this process. Before
an mRNA can be translated into protein, it
undergoes a splicing process that removes
various non-protein-coding segments;
these splice sites are marked by assemblies
of proteins known as the exon-junction
complex (EJC), which get removed as themRNA undergoes translation. In principle,
a prematurely terminated mRNA with anonsense mutation will retain at least someof these EJCs intact. Ishida and colleagues
experimented with various synthetic mRNAs to examine how interactions between
Upf1 and EJC contribute to nonsense-mediated decay.
Upf1 is associated with the protein translation machinery, and Ishida’s team found evidence that this protein uses its motor activity
to essentially ‘reel in’ the mRNA strand after
protein translation becomes stalled. If thishalt is due to a true stop codon, the translation machinery disassembles, and the mRNA
is released intact. In the event of a nonsense

mutation, Upf1 scans until it encounters an
EJC; this interaction sets the nonsense-mediated decay process in motion, eliminating
the damaged mRNA strand.
These data suggest that Upf1 fulfils a
critical quality control function to restrict
the production of defective — and possibly
toxic or tumorigenic — proteins. If futurestudies validate this model, it could also fillin critical gaps in our understanding of theprotein production process. “People still do
not know how a normal cycle of proteintranslation really ends,” explains Ishida. “Our‘reeling-in’ model could beautifully explain
both ribosome recycling, which is the last
step of a normal cycle of protein translation, and nonsense-mediated decay in a
unified manner.”
Reference
1. Shigeoka, T., Kato, S., Kawaichi, M. & Ishida, Y.
Evidence that the Upf1-related molecular motor scans
the 3’-UTR to ensure mRNA integrity. Nucleic Acids
Research 40, 6887–6897 (2012).

More information about the group’s research can be found at the Functional Genomics and Medicine Laboratory webpage:
http://bsw3.naist.jp/eng/courses/courses211.html
38

NAIST Research Highlights

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Molecular and Cell Genetics Laboratory

XBP1s mRNA

IntronAAA

AAA

3Pausing

HR2

XBP1s

AAA

1

Cytosol
ER

Transcription
factor2
HR2

ER Stress

IRE1α

1 Recruitment

2 Cytosolic splicing

3 Synthesis of XBP1s© 2014 Kenji Kohno, Nara Institute of Science and Technology

XBP1u mRNA

www.naist.jp/en

The NAIST team’s proposed model for the action of XBP1u in translational pausing, mRNA splicing, and production of active XBP1s.

Molecular biology

Ribosome pause
has critical role
A novel system in animal cells halts protein-synthesis to generate molecules that protect
against diseaseAlittle-known process in cell genetics — translational pausing — may
be more important than previously
thought. Scientists at NAIST have uncovered
a new system that protects against the accumulation of misfolded proteins in a cellularcompartment called the endoplasmic reticulum (ER). It may be involved in diabetes andneurodegenerative disorders.
Proteins, the building blocks of life, areassembled in a multi-stage process. First, theDNA code is ‘transcribed’ into a complementary molecule, messenger RNA (mRNA). Thisis then ‘translated’ into proteins at a structure
called a ribosome. Normally, proteins are notfunctional until released from the ribosome.
However, a team led by Kenji Kohno uncovered
one — XBP1u — which plays a crucial role
before it is even fully translated1. As XBP1uemerges from the ribosome, it drags the entire
complex — ribosome, mRNA and protein —to the ER’s external membrane. Here, a protein
called IRE1α splices a section out of the XBP1mRNA (see figure). The modified mRNAtranslates into a new protein, XBP1s, which
induces genes that prevent damaging misfolded
proteins from accumulating in the ER.

“

We want to know exactly how thistranslational pausing occurs andhow translation is then restarted.

”

Kohno’s team identified a section of
XBP1u, HR2, which causes the complex toattach to the ER membrane. Because HR2lies close to the end of XBP1u, there is a riskthat translation of XBP1u may be completed,and the protein released, before HR2 has hadtime to do its job. The scientists showed —by separating out the cell’s proteins according
to size and charge (a method called electrophoresis) — how this is prevented: anothersection of XBP1u causes translation to pause
before XBP1u is complete.
This leaves the protein attached to the complex both during movement to the ER membrane and mRNA splicing. In sum, says Kohno,“Translational pausing of XBP1u enhances the

distribution of its mRNA to the surface of theER, which increases the efficiency of cytoplasmic splicing of XBP1u, producing a newmRNA encoding XBP1s.”
Using mutants with reduced or extended
translational pausing, the team showed theimportance of the pausing process to both
membrane targeting and efficient splicing of
the mRNA. They also found that the pausing
sequence continues to function when attached
to other proteins, so could be used to study
protein folding in general.
The easy availability of novel equipment andstrong communication between laboratories has
made this ground-breaking research possible.
“Now,” says Kohno, “we want to know exactly
how this translational pausing occurs and howtranslation is then restarted.”
Reference
1. Yanagitani, K., Kimata, Y., Kadokura, H. & Kohno, K.
Translational pausing ensures membrane targetingand cytoplasmic splicing of XBP1u mRNA. Science
331, 586-589 (2011).

More information about the group’s research can be found at the Molecular and Cell Genetics webpage:
http://bsw3.naist.jp/eng/courses/courses207.html
NAIST Research Highlights

39

Biological Sciences

Research Highlights

Nara Institute of Science and Technology | Tumor Cell Biology Laboratory

www.naist.jp/en

Cell biology

Regulator of tumour
suppression foundNovel protein promotes degradation of cell cycle inhibitor p27 by facilitating its translocation fromthe nucleus to the cytoplasm© Drimafilm/iStock/ThinkstockC

ancer is a group of diseases characterized by out-of-control cell division. The
cyclin-dependent-kinase (Cdk) inhibitory protein p27 helps prevent the developmentof cancer by slowing or stopping cell division,
particularly that of tumour cells. Althoughmutations in p27 are rarely found in humantumours, reduced expression of the protein has
been associated with poor survival of patientswith breast and colorectal cancers.
Previous studies have identified several
mechanisms for the regulation of p27: for example, phosphorylation by the cyclinE/Cdk2
complex; degradation by the ubiquitin-proteasome pathway; and sequestration by thetranscription factor c-Myc. In 1999, Junya
Kato and co-workers at Japan’s Nara Instituteof Science and Technology (NAIST) identified another important mechanism for p27
regulation – they found a protein called p38
that specifically binds p27 and promotes its
degradation in mammalian cells1.
Kato and co-workers at NAIST’s Graduate School of Biological Sciences screened amouse T-cell lymphoma library to identify
genes encoding proteins that are able tointeract with p27. Among them was a mousegene that shared 91.5 per cent of its sequence
identity with the human gene Jab1. This gene
– the mouse homologue of Jab1 – encodes aprotein with a relative molecular weight of
38 kilodalton.
The researchers dubbed the protein p38,
and found that it binds to p27 but no otherproteins (eg., cyclinB1, cyclinE and Cdk2).
Moreover, they showed that overexpressionof p38 in mouse fibroblasts resulted in thetranslocation of p27 from the nucleus to thecytoplasm — the place where p27 is broken
down by degradation machinery.
Taken together, the findings showed that
p38 is a negative regulator of the cell cycle
inhibitor p27. The reduction or absenceof p27 in the nucleus can lead to a host of
detrimental effects, including, but not limited

The nucleus (blue) and cytoplasm (green) of fibroblasts.

to, the promotion of cell cycle progression
and the disruption of controlled cell division.
Although not well understood, these processes are likely contributing factors to thepoor survival of cancer patients observed inclinical studies.
“Our findings affected many fields and led
to a host of new discoveries, for example, thecombination of the upstream of proteolyticmachinery with cell cycle regulation andintracellular translocation with proteolytic
regulation,” says Kato. “We have recently
uncovered a novel mechanism by which Jab1

contributes to cancer. The discovery will form
the basis of our future development in drugs
for treating cancer.”
Kato and co-workers are still figuring out
the precise role of p38 in the regulation of
p27. Nevertheless, the protein may serve as apotential therapeutic target for the treatmentof breast and colorectal cancers.
Reference
1. Tomoda, K., Kubota, Y. & Kato, J. Degradation of thecyclin-dependent-kinase inhibitor p27Kip1 is instigatedby Jab1. Nature 398, 160–165 (1999).

More information about the group’s research can be found at the Tumor Cell Biology Laboratory webpage:
http://bsw3.naist.jp/kato/?cate=205
40

NAIST Research Highlights

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Molecular Immunobiology Laboratory© Sebastian Kaulitzki/iStock/Thinkstock

www.naist.jp/en

Influenza virus.

Antiviral defence

Understanding the role ofa messenger

A key component of the innate immune response may improve vaccines and anti-tumour assistanceT

he first line of defence against
pathogen infection, known as ‘innate
immunity’, could be boosted usingsynthetic copies of a small signalling molecule, called phosphatidylinositol-5-phosphate(PtdIns5P), which has been investigated by
NAIST researchers.
The molecule could be paired with adjuvants,
substances added to vaccines to provide additional assistance in fighting off infection. “Thisresearch suggests the possibility for developing
a new vaccine adjuvant,” says Taro Kawai, who
led the NAIST team.

“Innate immunity is also importantin anti-tumour immunity and so infuture we hope we can also develop anti-tumour adjuvants.

”

When a virus invades the body, various parts
are recognized by receptor molecules. These
trigger inside the cells complex multi-step
signalling pathways that activate elementsof the innate immune system. It is a generaldefence system not directed at any specificmicroorganisms; unlike ‘acquired immunity’,
which produces targeted antibodies against
unique invaders.
One of the most prominent aspects of innate
immunity triggered by the signalling pathways
is the production of interferon proteins. These
are so-named because they can interfere withthe multiplication of viruses and stimulate
other cells into fighting the infection.
Kawai and colleagues at the NAIST Graduate School of Biological Sciences and otherresearch centres in Japan investigated a partof the innate immune response that stimulates the production of type 1 interferon. The
pathway leading to this interferon was known
to involve two crucial proteins: a transcription factor that regulates gene activity, known
as interferon regulatory factor-3 (IRF3); andan enzyme called TBK1 that adds phosphategroups to IRF3 during the interferon-producing pathway.
The researchers say that the detailed
mechanisms for regulating what they call“the TBK1-IRF3 axis” remain unclear, butthey have been able to identify that ptdIns5P
plays a crucial role. In particular, the work
has revealed that PtdIns5P acts as a moleculethat carries a signal from receptors into otherparts of the cell, a process known as “second
messenger” activity.
Kawai explains that using this insight tocreate a new vaccine adjuvant will require a
suitable synthetic analogue of PtdIns5P, tomake the adjuvant soluble in water and able topenetrate into cells. The team has already madeand tested one such analogue and found that it
can boost immune responses in mice.
Turning to a wider possibility, Kawai adds,“Innate immunity is also important in anti-tumour immunity and so in future we hope wecan also develop anti-tumour adjuvants.”
Reference
1. 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).

More information about the group’s research can be found at the Molecular Immunobiology Laboratory webpage:

http://bsw3.naist.jp/eng/courses/courses209.html

NAIST Research Highlights

41

Research Highlights

Nara Institute of Science and Technology | Molecular Medicine and Cell Biology Laboratory

The binding to PI(4,5)P2 ＝ “Closed”

www.naist.jp/en

The absence of PI(4,5)P2 binding ＝ “Opened”

Exterior
Transmembrane

Plasma membrane
P

TRPV4

P P

PI(4,5)P2

Ankyrin Repeat domain
Ankyrin Repeat domain
Cytosol

The protein structure of PIP2 in complex with TRPV4 ARD.

Cell biology

Ion channel mutations
may cause disease
Mutations in the lipid-binding domain of one ion channel subfamily promotes function and cell
death linked to a variety of inherited diseases

Transient receptor potential channels (TRPs) are a large group of ionchannels found mostly in the plasma
membranes of animal cells. One is TRPV4, anon-selective positive ion channel that allows
the passage of several different cation species,
such as sodium and calcium (Na+ and Ca2+). It
has multiple regulatory sites and is activated byphysical stimuli including heat, chemicals andshear stress.
Recent genetic studies on some families havelinked mutations in TRPV4’s ankyrin repeat
domain (TRPV4 ARD) to inherited diseases,
such as spinal muscular atrophy (SMA) and
Charcot-Marie-Tooth disease. However, themolecular mechanisms underlying the pathogenesis of these diseases are unclear.
Shiro Suestsugu at NAIST and colleagues
have now examined the binding affinity of
TRPV4 ARD to various membrane lipids
using functional assays1. They found that
TRPV4 ARD binds most strongly to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2),
a membrane lipid known to regulate various

intracellular signalling cascades and TRPV4channel activity. Structural analyses revealed
that TRPV4 ARD consists of six ankyrin
repeats, which it uses to recognise PI(4,5)P2.
“We decided to study TRPV4 because its
mutations have implications for several hereditary diseases,” says Suetsugu.
The researchers confirmed that disease-associated mutations cause protein unfolding
and, they found, decrease the ability of TRPV4
ARD to bind PI(4,5)P2. The lack of interactions between TRPV4 ARD and PI(4,5)P2, in
turn, increases TRPV4 channel activity, raises
Ca2+ levels and promotes cell death due toincreased cytotoxicity. The latter is probably an
important factor contributing to the pathogenesis of SMA and Charcot-Marie-Tooth disease.
Suetsugu pointed out that the crystallizationof TRPV4 ARD with PI(4,5)P2 head grouphas been one of the greatest challenges in theirstudy because the domain is relatively unstable.
In a sense, ARD is very much like the‘off-switch’ for non-selective cation channels.
It suppresses channel activity, prevents cations

from permeating through the cell membraneand maintains the balance of Ca2+ level within
the cell. Understandably, a broken off-switch
could lead to all sorts of problems associatedwith malfunctioned cation channels.
Previous studies have identified ankyrin repeat domains (ARDs) in more than 400 humanproteins with diverse binding specificities andaffinities to proteins. The finding by Suetsugu
and his team represents the first demonstrationof the lipid-binding ability of ARD. Moreover,it may have important implications for thedevelopment of gene therapy for treating
inherited diseases.
“We are very much interested in the functionsof other ARDs,” says Suetsugu. “Examining
these widely expressed but poorly characterised
ARDs will be the next step for our study.”
Reference
1.

Takahashi, N., Hamada-Nakahara, S., Itoh, Y.,
Takemura, K., Shimada, A. et al. TRPV4 channel activity
is modulated by direct interaction of the ankyrin domain
to PI(4,5)P2. Nature Communications 5, 4994 (2014).

More information about the group’s research can be found at the Molecular Medicine and Cell Biology Laboratory webpage:
http://bsw3.naist.jp/suetsugu/?cate=278
42

NAIST Research Highlights© 2014 Shiro Suetsugu, Nara Institute of Science and Technology

Biological Sciences

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Microbial Molecular Genetics Laboratory

Specialized DNA polymerase

TLS

Pol

LesionLesion (DNA damage)translesion synthesis ‘TLS’

TLS

Pol

©2014 Hisaji Maki, Nara Institute of Science and Technology

UV, chemicals, oxygen

Replicative DNA polymerase

www.naist.jp/en

After a replicative DNA polymerase stalls at a lesion site (left), a specialized polymerase for translesion synthesis (TLS) helps overcome the DNA
damage (right).

Genetics

Repair enzyme also
reboots genome copying

DNA polymerase IV enzyme involved in damage tolerance also aids in DNA synthesis

A

special bacterial enzyme involved inrepairing the genome also helps restart
DNA replication after the process
has stalled1. The finding, from researchers at
NAIST in Japan, could shed light on the sourceof genetic mutations — a major cause of cancer
and other age-related diseases.
When the cell is exposed to a dangerous
chemical, sometimes a piece of DNA will forma bond with the chemical agent. This creates
what is known as a DNA lesion. These lesions
will block the genetic copying machinery, but
fortunately the cell has a class of enzymes todeal with these kinds of obstruction.
Humans and other eukaryotes use one setof enzymes, while bacteria and other prokaryotes use another. Through a process known astranslesional synthesis (TLS), these specialized
enzymes help overcome DNA lesions so thatthe standard gene copying enzyme can continue its normal function.
In the rod-shaped bacterium Escherichia
coli, an enzyme called DNA polymerase IV
was not thought to be involved in TLS for

major lesions (see figure). However, a teamled by Hisaji Maki at NAIST, along withcollaborators in France and the United States,
has now discovered multiple new functions of
this enzyme.

“

Polymerase IV can transiently andefficiently work in the replication
fork, instead of the normal type of
DNA polymerase.

”

The researchers exposed a circular piece of E.
coli DNA to a compound found in coal tar that
forms bonds with DNA. They then recreatedthe entire DNA copying process, and — in a
first — watched what polymerase IV did at the
replication fork, the junction where the double-stranded DNA splits apart into two single
strands during replication.
“Unexpectedly, we observed that polymerase
IV entered into the replication machinery very
effectively,” says Asako Furukohri, a biochemistat NAIST and one of the co-first authors of
the study.

Polymerase IV not only aided with gene synthesis over the damaged DNA — it helped withthe entire process of resuming gene copying.
“Polymerase IV can transiently and efficiently
work in the replication fork, instead of thenormal type of DNA polymerase,” Furukohrisays. “Our finding suggests the possibility thatpolymerase IV may play some role in genomic
DNA replication.” Polymerase IV is known
to make more copying mistakes than standard replication enzymes, and the mutations it
introduces have been linked to drug resistancein bacteria. The human equivalent of polymerase
IV has also been implicated in different formsof cancer. Knowing the role of polymerase IV ingenomic replication is thus “an important issue,”says Furukohri, because it could reveal the
genomic triggers of mutation-driven diseases.
Reference
1. Ikeda, M., Furukohri, A., Philippin, G., Loechler, E.,
Akiyama, M.T. et al. DNA polymerase IV mediates
efficient and quick recovery of replication forks
stalled at N2-dG adducts. Nucleic Acids Research 42,
8461–8672 (2014).

More infornmation about the group’s research can be found at the Microbial Molecular Genetics Laboratory webpage:
http://bsw3.naist.jp/eng/courses/courses301.html
NAIST Research Highlights

43

Biological Sciences

Research Highlights

Nara Institute of Science and Technology | Systems Microbiology Laboratory

www.naist.jp/en

Systems Microbiology

Gene function revealed in
E. coli library
A new library of thousands of bacterial strains could help scientists understand gene function in cellsTof many organisms having been determined,
it is still unclear what each gene does — evenin simple organisms like bacteria. Ascertaining
gene functions is crucial for gaining a complete
understanding of how cells work.
To assist scientists study the functions ofindividual genes, a team of researchers led byHirotada Mori at the NAIST Graduate Schoolof Biological Sciences has produced a libraryof thousands of strains of the K-12 variant of
the bacterium Escherichia coli; each strain in thislibrary has a single gene deleted1. Mori’s team© kirstypargeter/iStock/Thinkstock

he systematic deletion of each gene in
one strain of a bacterium widely usedin recombinant DNA studies has allowed researchers at Japan’s NAIST to createa library that could be crucial in discovering
how cells work.
Although many components of the molecular machinery inside cells are now wellunderstood, less is known about how these individual components work together as a system.
The genome is the blueprint for this system.
However, despite the entire genetic sequencesused an efficient, state-of-the-art technique torealize this, enabling them to succeed whereprevious attempts had failed.
The team substituted one gene at a timewith another gene that gave cells resistance to the antibiotic Kanamycin, enabling
selective growth of the modified K-12 cells.
The modified cells were then collected. The
antibiotic-resistance gene can be cut out if it
is desired to avoid polar effects — leaving the
DNA as though the gene had never existed.
The researchers repeated the process
4,288 times — once for each K-12 gene
— and successfully produced 3,985 unique
K-12 strains. The failure to produce bacteria
in which the approximately 330 remaining
genes were deleted indicates that these genes
are essential for the cell’s survival.
The team collated the bacterial strains into
a library, which they called the Keio collection, and made it available to all researchers.
“Making these resources open to the public
is so important for science,” explains Mori.
“Research can be performed in parallel acrossthe world, and accumulation of the results
will accelerate research to understand cells.”
The research not only produced a complete
library, but it allowed the team to perfecttheir technique and build on it. “Three years
were required to complete the first library,”says Mori, “but experience allowed us to construct a second, improved deletion library in
six months. We have also developed a method to generate double-knockout strains ofbacteria by combining two deletion strains.”
Mori says that these strains with two genes
deleted will enable researchers to study theinteractions of genes, with the potential
to provide even greater insight into how
cells work.
Reference

Systematic deletion of genes in K-12 bacteria created thousands of different strains that make up the
Keio collection.

1. Baba, T., Ara, T., Hasegawa, M., Takai, Y., Okumura, Y.
et al. Construction of Escherichia coli K-12 in-frame,
single-gene knockout mutants: the Keio collection.
Molecular Systems Biology 2, 2006.0008 (2006).

More information about the group’s research can be found at the Systems Microbiology Laboratory webpage:
http://bsw3.naist.jp/eng/courses/courses302.html
44

NAIST Research Highlights

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Laboratory of Cell Signaling

www.naist.jp/en

Cell signaling

Yeast enzyme regulator
recognized

A highly conserved cellular pathway is triggered by the presence — and absence — of glucose
in yeast© 2015 Hisashi Tatebe, Nara Institute of Science and TechnologyGlucose both positively and negatively
controls the activity of an enzyme
in a model yeast essential for cell
growth, division and stress resistance, find
NAIST researchers1. This finding could help
uncover the regulatory mechanism driving the
enzyme’s human homologue, which is active incertain cancers.
The enzyme target of rapamycin (TOR) has
been conserved during the evolution of various
species, indicating its critical importance for theviability of life forms. TOR forms two protein
complexes, each of which is controlled by, andcontrols, a distinct set of upstream and downstream proteins. Recent studies have shownthat the essential nutrients nitrogen and carbon
activate the TOR complex 1 (TORC1) protein
pathway — but the critical trigger for TORC2
had remained elusive.
Previously, the NAIST researchers had
demonstrated that a protein belonging to thesmall GTPase family of enzymes Rhy1 interacts with TORC2 to promote the phosphorylation of another enzyme — Gad8 2. But they
were keen to uncover the whole story. “Nobody
knew what stimuli or signals regulate fission
yeast Ryh1 and TORC2,” explains NAIST’s
Hisashi Tatebe, who led the study.
After testing the TORC2–Gad8 pathway’s
responsiveness to nitrogen, which proved
tenuous, the researchers considered glucose.
They transferred cells of the fission yeast
Schizosaccharomyces pombe (see figure) fromstandard growth media containing 3 per centglucose to media with only 0.02 per centglucose. Within 5 minutes, the glucose-starved
yeast cells stopped dividing and showed no signof Gad8 phosphorylation.
To identify the role of Ryh1 in the glucose-induced signaling process, the team tried
the same experiment with yeast models lacking
the Ryh1 protein. Given sufficient glucose
in its diet, the mutant yeast showed reduced
phosphorylation, confirming the importance of
Ryh1 in activating the TORC2–Gad8 pathway.

An important cellular pathway for cell growth, division and resistance to stress in the fission yeast
Schizosaccharomyces pombe is triggered by both the presence and absence of glucose.

However, after about 30 minutes ofsurviving under glucose stress, both normal
and Ryh1-lacking yeast strains made asurprising recovery, phosphorylating Gad8
at rates similar to those under glucose
abundance. This finding suggests an alternative, Ryh1-independent, mechanism of
TORC2–Gad8 activation, triggered by thevirtual absence of glucose.
“It was totally unexpected that the fission
yeast TORC2 pathway is regulated by thepaired positive and negative regulatory mechanisms,” says Tatebe.
The researchers will conduct genetic screensin yeast to investigate the mysterious resur-

gence and are eager to find a small GTPase in
humans that plays a similar regulatory role to
Ryh1 in yeast. “TORC2 activity is indispensable in various cancer cells, but not in normal
cells,” says Tatebe. “Our findings may offer
many clues about TORC2 in humans.”
Reference
1.

2.

Hatano, T., Morigasaki, S., Tatebe, H., Ikeda, K. &Shiozaki, K. Fission yeast Ryh1 GTPase activates
TOR Complex 2 in response to glucose. Cell Cycle
advance online publication, 15 January 2015 (doi:
10.1080/15384101.2014.1000215).
Tatebe, H., Morigasaki, S., Murayama, S., Zeng, C. T.
& Shiozaki, K. Rab-family GTPase regulates TOR
complex 2 signaling in fission yeast. Current Biology 20,
1975–1982 (2010).

More information about the group’s research can be found at the Laboratory of Cell Signaling webpage:
http://bsw3.naist.jp/shiozaki/?cate=207
NAIST Research Highlights

45

Nara Institute of Science and Technology | Laboratory of Applied Stress Microbiology

Oxidative
stressReactive
oxygenspecies

Tah18
Nitricoxide

www.naist.jp/en

Sod1
Sod1

Arginine

Sod1

Cu2+

?
Mac1

CTR1
Fre1
Ctr1

Ctr1
Cu+

Nitric oxide (NO) produced by yeast cells in response to oxidative stress triggers an influx of copper (Cu) through the activity of the regulatory protein Mac1.

Microbiology

Yeasts with betterstress tolerance

Copper helps yeast deal with temperature extremes, pointing to gains in fermentation and biofuelsYeast responds to the stress of hightemperatures by activating a genetic
pathway involved in copper uptake andmetabolism, researchers at Japan’s NAIST havefound1. The discovery could help bioengineersdevelop heartier yeast varieties for use in thefood and biotechnology industries.
“Environmental stresses induce growth
inhibition or cell death, which limits the fermentation ability of yeast,” says Hiroshi Takagi,
a molecular microbiologist at NAIST who
led the study. “Our findings could contributeto the construction of new yeast strains withhigher stress tolerance, leading to the effective
production of breads, alcoholic beverages
and bioethanol.”In 2013, Takagi and his colleagues discovered
a novel mechanism by which the budding yeast
Saccharomyces cerevisiae — widely used in winemaking, baking and brewing — deals with thepotential damage wrought by outside pressures
such as elevated temperatures. They found thatthe microorganism produces nitric oxide (NO),a molecule that confers protection against thedamaging reactive oxygen species created in thewake of extreme heat2. Takagi’s team showedthat a protein called Tah18 was involved in NO
production, but the mechanism underlying how
NO aids in stress tolerance remained unclear.
The researchers therefore analyzed the gene
expression profile of yeast cells exposed to NO
in the laboratory. They have now discovered thatgenes involved in the transport of heavy metal
ions, such as copper, are activated by the NO
treatment. These genes are under the control ofa regulatory protein called Mac1. Since Mac1 isimportant for tolerance to other types of stress,
Takagi’s team suspected that it might play a rolein NO-mediated stress responses as well.
Indeed, the researchers found that NO produced under stressful conditions of high temperatures activated Mac1 in the yeast. This set
in motion a molecular cascade that increased
the amount of copper inside the cell; and theinflux of copper in turn triggered an enzyme
called Sod1, a type of ‘superoxide dismutase’that destroys toxic free radicals and thus helps
to boost cell viability (see figure).

Putting all the pieces together, Takagi says:“Our main conclusion of this work is that
NO enhances the activity of Sod1, which
is one of the most important antioxidative
enzymes.” This knowledge could pave the way
for synthetic biologists to craft stress-resistantyeast strains for the fermented breads, beverages and biofuel sectors3. These designer yeast
strains could be a huge economic boost for thefermentation industries.
References
1.

2

3

Nasuno, R., Aitoku, M., Manago, Y., Nishimura, A.,
Sasano, Y. & Takagi, H. Nitric oxide-mediated antioxidative mechanism in yeast through the activation of thetranscription factor Mac1. PLoS ONE 9, e113788 (2014).
Nishimura, A., Kawahara, N. & Takagi, H. The
flavoprotein Tah18-dependent NO synthesis confers
high-temperature stress tolerance on yeast cells.
Biochemical and Biophysical Research Communications
430, 137–143 (2013).
Sasano, Y., Haitani, Y., Hashida, K., Ohtsu, I., Shima, J. &Takagi, H. Enhancement of the proline and nitric oxide
synthetic pathway improves fermentation ability undermultiple baking-associated stress conditions in industrial
baker’s yeast. Microbial Cell Factories 11, 40 (2012).

More information about the group’s research can be found at the Laboratory of Applied Stress Microbiology webpage:
http://bsw3.naist.jp/eng/courses/courses305.html
46

NAIST Research Highlights

Reproduced from Ref. 1 and licensed under CC BY 4.0 © 2014 R. Nasuno et al.

Research Highlights

Biological Sciences

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Structural Biology Laboratory

www.naist.jp/en

Plant growth

Receptor role inprotection unmasked
How a plant hormone receptor helps a vital process necessary for maintaining healthy plant
growth is finally understood© 2008 Toshio Hakoshima, Nara Institute of Science and Technology

Hormones play a crucial role in regulating the growth and developmentof plants. One group, called gibberellins (GAs), is involved in seed germinationand promoting new cells in stems, leaves andflowers. Only in the past decade have researchers begun to uncover the precise mechanisms involved in GA signalling in plants,
because very little has been known about thestructure and behaviour of GA receptors.
In 2008, researchers at NAIST, working with scientists in the United States,
established the first structural model of agibberellin receptor called GID1A, found in
thale cress plants (Arabidopsis thaliana), andwith that revealed a key process involved inprotecting healthy plant development1.
There are 136 known GAs, but only a
few of them function as hormones; thosethat do are known as bioactive GAs. Without the presence of bioactive GAs, plants
are stunted and dwarfed; but if too muchis present, the cells in the plant stems areelongated – producing plants that are talland often infertile.

Toshio Hakoshima and NAIST co-workers conducted a series of crystallographic andbiochemical studies of GID1A and observed
how it is activated by binding to a bioactive GA. Their aim was to verify how GA
and GID1A both bind to, and trigger, thedegradation of a negative transcriptional regulator of GAs called GID1-DELLA. DELLA
proteins can disrupt the regulation of GA,
causing significant damage to plant growth.

Following the initial binding, GA activates GID1A, triggering conformationalchange – an alteration in the shape of themacromolecule – in the folded N-terminal extension, creating a binding surface
for the GID1-DELLA protein. Once
GID1-DELLA is bound to GID1A, thereceptor sends out an explicit signal, targeting GID1-DELLA for degradation byother proteins.
Through this work, Hakoshima and his
team
deepened understanding of how cellular“Hakoshima and his team deepened
functionscan be regulated by signalling fromunderstanding of how cellular funchormones and their receptor molecules. Theirtions can be regulated by signallingfindings could help influence crop-selection
from hormones and their receptor
and the manipulation of plant growth. For
molecules.”example, it may be possible to develop derivatives of GAs to use as growth regulators in
They found that GID1A has a compact form some crop plants.
with a so-called ‘N-terminal extension’, as well
as a pocket for GA incorporated into its strucReferenceture (see figure). The N-terminal senses GA
1. Murase, K., Hirano, Y., Sun, T-P. & Hakoshima, T.
and, once GA binds to GID1A, folds back on
Gibberellin-induced DELLA recognition by theitself to cover the GA pocket. In this way, thegibberellins receptor GID1. Nature 456,
N-terminal acts as a shield to protect GA.
459–464 (2008).

DELLA proteinsGA
N-terminal
extension switch
N
GID1

N

Water

GID1

GRAS

GRAS

DELLA

GID1

The structural mechanism by which receptor GID1A binds with gibberellin hormones (GAs) and subsequently binds to and targets GID1-DELLA proteins for
degradation. The process helps protect correct plant growth and development.

More information about the group’s research can be found at the Structural Biology Laboratory webpage:
http://bsw3.naist.jp/eng/courses/courses306.html
NAIST Research Highlights

47

Biological Sciences

Research Highlights

Nara Institute of Science and Technology | Membrane Molecular Biology Laboratory

www.naist.jp/en

Cell function

Protein groove aids
membrane assembly
The crystal structure of a membrane protein in soil bacteria is described for the first time“

Our findings pave the way for further investigations into the molecular mechanism of YidC.

”

YidC is involved in the folding and insertionof many membrane proteins, including one
involved in the release of energy, and is thus
essential for cell viability.
Tsukazaki’s team collected diffraction dataon YidC crystals at Japan’s SPring-8 synchrotron facility, and refined the structure toa 2.4 ångström resolution. They then createdcomputer simulations mimicking the physicalmovement of YidC in a lipid bilayer. To better
understand YidC’s role, they compared theeffects of mutating the yidC gene to the effects
of mutating another gene involved in the membrane insertion process.
Previous studies suggested YidC formed achannel that facilitated membrane insertion ofprotein substrates, says Tsukazaki. His team’s
investigations revealed, instead, that YidC contains a novel fold in which five independently
functioning transmembrane helices form a

Extracellular

Intracellular

Hydrophilic groove
The membrane protein YidC’s hydrophilic, positively charged groove facilitates membrane insertionof proteins.

groove that is open toward the lipid bilayer andcytoplasm, but closed on the extracellular side.
The groove has an affinity for water (is hydrophilic) and positively charged (see figure).
A substrate protein interacts with thepositively charged cytoplasmic region of
YidC, and is then captured in YidC’s hydrophilic groove; the positively charged groove
attracting the negatively charged residue on
the substrate. An arginine residue that exists
in the groove participates in recognizing
the substrate protein, which is then releasedby the groove into the membrane, partially facilitated by the membrane potential
attracting the negatively charged residues on
the substrate.

“Our findings pave the way for further
investigations into the molecular mechanism of
YidC,” says Tsukazaki.
“YidC also facilitates the proper folding of
membrane proteins inserted by a protein-conducting channel — the SecYEG translocon —and is essential for cell viability. We are trying
to determine the structure of the complex of
YidC and Sec proteins in order to fully understand the conserved mechanism of membraneprotein biogenesis.”
Reference
1. Kumazaki, K., Chiba, S., Takemoto, M., Furukawa, A.,
Nishiyama, K. et al. Structural basis of Sec-independent membrane protein insertion by YidC. Nature 509,
516–520 (2014).

More information about the group’s research can be found at the Membrane Molecular Biology Laboratory webpage:
http://bsw3.naist.jp/eng/courses/courses309.html
48

NAIST Research Highlights© 2015 Kaoru Kumazaki, The University of TokyoC

ell membranes are semi-permeablebarriers, consisting of a bilayer of lipids
with embedded proteins that perform
vital functions. These proteins are so importantthat they have become the target of 60 per centof the medicinal drugs used today.
For newly synthesized membrane proteinsto properly function, they must be accurately inserted, folded and assembled into
the membrane.
To help understand how this process occurs,
Tomoya Tsukazaki and colleagues at NAIST
described, for the first time, the crystal structureof YidC, a protein in the cytoplasmic membrane of Bacillus halodurans, a gram-positivebacterium found in soil1. “We determined
the first high-resolution structure of the
YidC–Oxa1–Alb3 family of membrane proteins, and we propose an insertion mechanism
for membrane proteins,” says Tsukazaki.

Research Highlights
Biological Sciences

Nara Institute of Science and Technology | Gene Regulation Research Laboratory© 2015 Bessho Laboratory, Nara Institute of Science and Technology

www.naist.jp/en

The axial skeleton of a newborn mouse.

Embryology

Signal loop sets
vertebrae numbers

A signalling feedback loop regulates the molecular clock that controls the number of vertebrae
in backbones

Researchers at NAIST are unravelling
the regulatory mechanism determining
the number of vertebrae formed in theembryo, a critical process in the development ofback-boned animals.
Embryonic development in animals includes
a carefully choreographed interaction between
a moving chemical gradient and a ticking
molecular clock to measure out segments (called
somites) along the body’s length. The segmentation clock involves oscillations in gene activity
that regulate a principal cell-to-cell communication mechanism, known as the Notch signalling
pathway, as well as Notch intracellular domain(NICD). By tuning these oscillations, eachspecies develops a specific number of somites,
determining how many vertebrae it has.

“

I feel that the Nara Institute has an
atmosphere in which we can wrestle with fundamental questions.

”

To better understand this process, a teamof researchers at NAIST and other institutes

investigated the role of a negative Notch regulator, Nrarp. Since Notch controls the expressionof Nrarp, the two form a feedback loop regulating NICD levels. The researchers studied micelacking Nrarp to discover how this feedback
loop regulates somite formation.
“Nrarp knock-out mice are almost normal, but they have small anomalies in their
axial skeletons,” says Yasumasa Bessho, from
NAIST’s Graduate School of Biological
Sciences. In addition to these defects, themutant mice have fewer vertebrae than normal.
Measuring the segmentation clock showedthat it ran slightly slower in the mutant mice, adecrease that was linked to higher Notch levels.
When the team used a drug to reduce Notch
levels, the segmentation clock ran faster andmore somites were formed. Based on their findings, the researchers speculate that the NotchNrarp feedback loop provides robustness to thesegmentation clock.
During somite formation, “most of the cells
are synchronized with the gene oscillations, butsome of them are out of phase because of pertur-

bations from the environment, such as chemical
agents or temperature changes, or intrinsic
perturbations, such as cell division,” explains
Bessho. Since the out-of-phase cells don’t disrupt
development, something must resynchronize
them with their neighbours. Bessho and hiscolleagues suspect that Nrarp plays an importantrole in this resynchronization mechanism.
The team is now testing this hypothesis bychecking whether Nrarp knock-out mice are
more sensitive to a drug that causes embryonicabnormalities. So far, the results suggest that
Nrarp is necessary for robust somite development, but research is still ongoing.
“Nowadays, this kind of basic research may
be neglected,” says Bessho. “However, I feel that
the Nara Institute has an atmosphere in which
we can wrestle with fundamental questions.”
Reference
1. Kim, W., Matsui, T., Yamao, M., Ishibashi, M.,
Tamada, K., Takumi, K. et al. The period of the somite
segmentation clock is sensitive to Notch activity.
Molecular Biology of the Cell 22, 3541-3549. (2011)
doi: 10.1091/mbc.E11-02-0139

More information about the group’s research can be found at the Gene Regulation Research Laboratory webpage:

http://bsw3.naist.jp/eng/courses/courses308.html

NAIST Research Highlights

49

Biological Sciences

Research Highlights

Nara Institute of Science and Technology | Laboratory of Systems Neurobiology and Medicine

www.naist.jp/en

Neurobiology

How nerve cell axons
become mobilised
A signalling pathway stimulated in the tips of growing axons triggers the generation of traction
forces between an axon and its substrateA

Netrin is an extracellular chemo-attractant
molecule that induces the growth of developing axons and the researchers thought this
could be because netrin induces traction force
generation within the tip of the axon. To test
this, Inagaki and colleagues grew neurons onelastic gel embedded with fluorescent beads
in the presence of netrin and observed thedisplacement of the beads. This suggested thatthe axons were grabbing on to the substrate inorder to propel themselves forward.
Netrin activates a wide range of intracellular signalling molecules, some of which— such as actin — may be responsible forstrengthening the link between structural
molecules within the axon and the substrate

Naoyuki Inagaki

xons are the long, slender projectionsof the neurons that make up thenervous system and conduct electrical impulses. As they grow towards theirtargets in the developing nervous system theyneed to generate traction forces, which allow
them to grab onto their substrate and extend
themselves to their final location. How dothey do it?
A research team led by Naoyuki Inagaki at Japan’s Nara Institute of Science andTechnology has found that chemo-attractant
molecules activate a signalling pathway ingrowing axons, allowing the generation of
mechanical forces that permit axons to propel
themselves toward their destination.

“

Our findings provide a key molecular mechanism for understanding the mechanical forcesthat are involved in human brain
development.

”

The researchers found that Pak1 can add
phosphate groups to shootin1 and that thisaddition could be increased by adding netrin
to the neuronal cultures. When shootin1 contains these phosphate groups that have been
added by Pak1, it leads to the strengtheningof the link between actin and the substrate.
When Inagaki’s team lowered the expression of shootin1 within the neurons,
the growing axons seemed to slip on theirsubstrate and netrin was not as effective at
inducing axonal outgrowth. If they expresseda modified Pak1 that blocked its ability to add
phosphate groups to shootin1, axon growth
was also inhibited. However, when theyexpressed a modified shootin1 that alreadycontained these phosphate groups, traction
force generation and axon outgrowth could
be restored.
Taken together, the data indicate that thegeneration of the mechanical forces required
for axons to be able to grow requires the induction of a signalling pathway that involves
the activation of Pak1 and shootin1. “Ourfindings provide a key molecular mechanism
for understanding the mechanical forces thatare involved in human brain development,”
says Inagaki.
Reference

A fluorescence image of an axonal growth cone (green, shootin1 phosphorylated by Pak1; red,
actin filaments; blue, microtubules), showing the sites where the signal-to-force transduction foraxon outgrowth occurs.

More information about the group’s research can be found at the Inagaki Lab webpage:
http://nippon.naist.jp/inagaki_g/english/
50

on which the axon is growing. Pak1 is an enzyme within the axon tip that adds phosphategroups to other proteins to regulate theiractivity and shootin1 is a linker molecule that
couples actin to the substrate.

NAIST Research Highlights

1. Toriyama, M., Kozawa, S., Sakumura, Y. & Inagaki, N.
Conversion of a signal into forces for axon outgrowththrough Pak1-mediated shootin1 phosphorylation.
Curr Biol 23, 529-34 (2013)© 2015 Tsuyoshi Kawai, Nara Institute of Science and Technology

Research H

Nara Institute of Science and Technology | Synthetic Organic Chemistry Laboratory

Semiconductors© 2015 Yasuhiro Nishiyama, Nara Institute of Science and Technology

A bendable thermoelectric device made from modified carbon nanotubes can generate electricity from a temperature gradie

Generating power fromwaste heat
Additives improve the thermoelectric efficiency of carbon nanotubes

B

curved surfaces of an engine or pipe, maxianother additiv
endablethatusedconvertwastecyclobutanes.
Thedevices
photoreactor
to produce
mizing the power they generate.
(TCNQ). The dheat into useful electricity have
Unlike a metal wire, SWNTs do not carrypolymer and wr
become much more efficient, thankscurrent as a flow of electrons. Instead, thehotter at one en
to films madePhotochemistryof tiny carbon nanotubes
1
The team fou
developed at NAIST in Japan .These ther- nanotubes rely on the movement of positively charged ‘holes’ left behind by missing
difference of 20
moelectric films generate a voltage when
ed 110 nanowat
one side is hotter than the other and could electrons — they are known as p-type semi6 millivolts. “W
be used in a variety of applications, includ- conductors. The efficiency of thermoelectric
example of flexi
ing battery-free sensors and energy-saving devices made solely from p-type materials isvery low — unless teamed with n-type semi- this bipolar stru
technologies. “More than 5 per cent ofconductors, which have a surfeit of electrons.
The team’s su
the fuel consumption of gasoline-powered
Nara Institute of Science and Technology | Organic Electronics Laboratory
But researchers have previously struggled torevealed which
vehicles could be saved by thermoelectric
create stable and flexible n-type thermoelec- fine-tuning theheat recovery systems in the near future,”
tricamaterials.
says TsuyoshiPhotochemical
Kawai of the Laboratory
for inreactionsflow rather than a batch reactor whichlead istohelpin
easy
Kawai’s team studied 33 different carcient and stable
Photonic Molecular Science at NAIST,Nara Institute of Science and Technology | Photonic Device Science Laboratory
bon-based molecules to assess whether they
nowwww.naist.jp/
cooperatin
who led the research.
way is notvery amenable
to photochemical
pumpingchemical
reactions require
could transform
SWNTs
into n-type
sempanies for
futur
Most thermoelectric ost
devicesare solid,
reactions:“Light18cannot
penetratea small tu
energystart them. In almost
alliconductors.
They foundmolecules
thatsufficiently
says Kawai.
inflexible materials madefromtohighly
Photonics
reactors or high-concentration
solutioncases,
is heat, but
for The into
could.
bestlarge
was batch
triphenylphosphine(tpp),
toxic elements. So Kawai
andthathis energy
colleagues
solutions,”atoms
explains
Nishiyama.
“Thus, almost
known acertain andreactions,lightenergy must bewhoseused phosphorus
injectelectrons
created lightweightflexiblethermoelecReference
all photoreactions
show poor
conversion ina very th
instead.
Known
as photochemical
into the SWNTs.
The researchers
filtered
tric films madeof hollow
strawsof carbon reactions,batch reactors.”of theY.,tuOthese include one of the most effective ways
1. Nonoguchi,
atoms mere billionths of a metre wide, called the tpp-SWNTs from a liquid to createsmal
of producing cyclobutane rings — cyclic
Hata, The
K. et al.
Sy
air-stable n-type
films,
andpairedthem
withsingle-walled carbon nanotubes (SWNTs).
nanotube
If we need to scale up, we can alsocarbonwhichthstructures containing four carbon atoms,
p-type
SWNTs
that
had
been
enhanced
with
These films (seefigure)cancloselyhug
thebymoleculardorun multiple reactors in parallel, a
Photowhich are frequently found in naturally

Research Highlights
M© 2014 Masakazu Nakamura, Nara Institute of Science and Technology

Microflow
set-up Hig
Materials
ScienceResearch
boosts output

Research Highlights

Implant sensor images
brain activity in“ vivooccurring compounds with useful biologicalprocess called numbering up.

”

set-up arthan thosuchinsectpheromones.
More information
about
theas group’s
research
can be foundat theactivity
Photonic
ScienceImage
sensorproperties,
implant
makes
it possible
to record
the neuralofMoleculara living mouse
asLaboratory
it moves
The team investigated reactions that
Now, Yasuhiro Nishiyama and his
http://mswebs.naist.jp/LABs/kawai/english/index.html

Ateam at NAIST’s Graduate School ofproduce cyclobutanes from two alkenes (areaction.
of produ

Semiconductors© 2015 Jun Ohta, Nara Institute of Science and Technology

fluorescenceimaging Sciencesystem thatclass of hydrocarbons containing only carbon
reactor cMaterials
in canJapan, along withbe implanted in the brains of living
and hydrogen) in a microflow set-up. In this“If we ne
MichaelOelgemöller
at Australia’s James
Carbonnanotubes(CNTs)
and freely
movingmice allows
thelinked by protein molecules (blue) with a semiconducting core (purple). Orange arrows show elec
set-up, the reaction tubes have an internal
multiple
University,
shown
thatscattering.
photoCNTs.
Red
arrow haveindicates
phononneural activitiescoldofCookmice
tobe monitored
durchemical
like these can be done very diameter of just 1 millimetre and are wrapped numberi
ing different behaviours.
Thereactions
system, which1around the light source, allowing the whole
a flow chemistry set-up .
was developed by effectively
researchers in
at NAISTin Japan, has the potential
provide fresh
apparatus to be cooled easily (see figure).
Most toindustrial
chemical processes are
Refereinsights into howrun
neuralnetworks
functionin
Of particular interest is that one of the reain a so-called ‘batch set-up’, which is
1. Terao,
the brain.
gents — ethylene — is a gas. In a batch process,not unlike the procedure for baking a cake:Morim
The implantable fluorescence imaging
Diastethis would add a further difficulty, since theareofcombined
system, fabricatedreactantsby Jun Ohta
NAIST’s in known proportions
chiralreaction can only occur at the surface between
mixed fora setandtime. Each reaction batch
Graduate School andof Materials
Scienceuous fthe gas and liquid reagents. In flow, however,produces
a fixedamount of product. But thishis colleagues, consistsof a setof blue/Chemigreen light-emitting diodes (LEDs) anda tiny image sensor — a smaller and simMore
informationpler version of thosecommonly
found inabout the group’s research can be found at the Synthetic Organic Chemistry Lab
http://mswebs.naist.jp/english/courses/1414/
digital cameras. The
image chip contains
120 × 268 pixels and is just 1 millimetre wideand 3.5 millimetres long.
Light from the LEDs excites fluorescence
Masakazu Nakamura and co-workers at the“Peptides stickinhermoelectric
convert heatin brain cells that have been
doped withdevicesaMaking waste heat
into energy

Combining carbon nanotubes and protein molecules produces electricity from loheat sources

T

NAIST Graduate School of Materials Sciencesurface help thedeveloped a composite CNT material by insert- with the CNTs.
prevents the hea
ing biomolecules with semiconducting cores at
the junctions between CNTs1. The CNTs retain another, while thenergy from low-temperature waste heat, thanks high electrical conductivity, but the biomolecules the electric curre
voltage-sensitive dye. Consequently, the inhelp suppress thermal conductivity and enhance junctions effecti
to advances in nanoscale components such as
tensity of the excited fluorescence varies with
Heat scattered
the Seebeck coefficient.
carbon nanotubes.
changes in the membrane potential, which is
Two image sensor chips implanted in the two visual cortices of the brain of a mouse.
CarbonThe
nanotubes(CNTs) are strong, lighttions lowers the“Conventional modifications to improve
related to neural activity.
emitted fluoexcellent
conductorsof electricity, making
CNTs, and the s
thermoelectric properties in CNTs, such as
rescence is thenandcapturedby theimage sensor
promisingcandidates
at the CNT/modoping, usually improveor two to the animal,
the brain activity] ofimpurity
small experimental
and transferredthem
via a cable
to a computer
andas thermoelectrica cableone
connected
which concomponents.
thermal conductivity
whenas mice
Seebeck
coeffici
ofand
theserats
parameters,”
Nakamura.
“Ouranimals suchin a freely explains
additional electronics
where itTheiris analysed.
siderably
limitsits movement.
Anotherpla
movingcondition,” proposed
explains Ohta,“whichThis is performed
at a rateof however,60 framesisper
is todevelopa microimaging
devicethethatthc
in pureform,
too high.
For thisenhances
methodcontrols thethreeparameters
is working
importantlearning quiteand different
second, enabling
moviesresearchersof neural activity
to arebefromimplanted
in the limbic
systemreason,at NAIST
tofor studying
independently,
any previous
ciencyof—thea deeCNmemorybe recorded. improve the thermoelectric properties
brain region
associated with“Weemotionoffunctions.”
CNTs approach to thermoelectric materials
design.”needandvar
By installing two sensors in the left andWhile techniquessuchasconventional
addictionandhence
importantforstudyinfor use in tiny power generators and even wearvesting in the fu
The team’s main aim was to create a nanofluorescence microscopy and functional mag- right hemispheres of the brain, the team has
mental diseases.
able electronics.
structure which blocks heat transfer but enhanc- to create thermo
mainly used the system to study activity in
netic resonance imaging are capable of retricdevices
es electron
mobility.
To do this,they used the
NAIST
Research
Highlights
51clothes — e
the require
visual cortex of mice.
However,
Ohta says
cording activity inEffective
different thermoelectricparts of the brain,
Reference
highperfectly
electrical conductivity,
a cage-shaped
protein mol- produce energy
the system could be uniqueused to functions
investigateofotherthey require thematerials
subject towith
remain1. Novel implantable imaging system for enabling
low thermal conductivity, and a high ‘Seeecule designed at another NAIST
laboratory.
simultaneous
multiplanar and multipoint analysis“

into electrical energy without the

In contrast, the need
NAIST
imaging
for moving
parts, meaning theysystem canfunction evenwhen
are long-lasting,reliableand environmentalthe subject
is moving.
ly-friendly.
It is now even possible to harvest”

Materials Science

Research Highlights

Nara Institute of Science and Technology | Quantum Materials Science Laboratory

www.naist.jp/en

Optical devices

Making simpler, cheaper
organic crystals
Molecular materials could simplify the fabrication and reduce the cost of lasers

C

like the deposition of crystalline overlayers
on substrates, known as epitaxy. As an added
bonus, organic-based devices can be fabricatedon curved or even flexible substrates.
But much development is still needed
before these sources match the performanceand versatility of their inorganic counterparts. An electrically powered laser madeusing a molecular active region is particularly
challenging, for example.
Hisao Yanagi from NAIST’s Quantum
Material Science Laboratory, working withcolleagues in Japan and Italy, have now synthe-

Reproduced, with permission, from Ref. 1 © 1999, AIP Publishing LLC.

heap and efficient sources of light
could play an important role in futurecommunication systems. NAIST
researchers have now synthesized molecular
crystals that could be used in bright, but easily
manufactured, laser devices1.
Most optoelectronic light sources, such as
light-emitting diodes and lasers, are made frominorganic materials such as gallium arsenide,
which are expensive. Organic-molecule-basedmaterials offer a cheaper alternative because
they can be produced by solution and printing
processes rather than complicated methods

sized a novel organic-molecule-based material,and demonstrated that it can produce laser
light, paving the way to an electrically driven
molecular source of intense optical radiation.
“One of the advantages of molecular materials is that their emission colour is tunable bymolecular modification,” explains Yanagi. “So
we prepared blue-light-emitting molecular
crystals and investigated their laser properties.”
The researchers chose to use a molecule ina class of organic semiconductors known as
thiophene/phenylene co-oligomers (TPCOs).
Scientists are focusing a great deal of attention on TPCOs because they are robust andhave excellent semiconducting properties.
Yanagi’s team observed spectrally pure andbright emission with a wavelength of 500 nanometres when they illuminated their sample
with ultraviolet radiation. This so-called
optically pumped lasing is the first step in thedevelopment of electrically driven devices.
The most important part of many semiconductor light emitters is the p–n junction: an
interface between a positively and negatively
charged regions where the light is produced.
These charge regions arise in inorganic
materials because of atomic impurities. In
molecular materials, however, p and n regions
are created by adding ‘electron accepting’ or‘electron withdrawing’ molecular groups to theactive molecule.
Most previous TPCOs have been p-type.
Yanagi and co-workers managed to create
an n-type organic semiconductor crystal by
substituting in cyano groups, creating a molecular crystal called BP1T-CN. This work is
the first demonstration of optically pumped
lasing in an n-type TPCO. “We next hope
to fabricate light-emitting diodes with thismaterial,” says Yanagi.
Reference

NAIST researchers hope to soon fabricate light-emitting diodes based on BP1T-CN, an n-type TPCO
organic semiconductor crystal, which emits bright blue light when illuminated with ultraviolet radiation.

1. Mizuno, H., Maeda, T., Yanagi, H., Katsuki, H., Aresti,
M. et al. Optically pumped lasing from single crystalsof a cyano-substituted thiophene/phenylene co-oligomer. Advanced Optical Materials 2, 529–534 (2014).

More information about the group’s research can be found at the Quantum Materials Science Laboratory webpage:
http://mswebs.naist.jp/LABs/optics/eng/index-e.html
52

NAIST Research Highlights

Research Highlights
Materials Science

Nara Institute of Science and Technology | Surface and Materials Science Laboratory

www.naist.jp/en

Semiconductors

120-fold boost in
photoluminescence
Analysing and refining semiconductor surfaces dramatically increases the efficiency ofluminescent devicesC

few hundred nanometres — emits light. Thisis because material near the surface reabsorbs
light created deeper in the semiconductor.

“

Improving the quality of the layers
near the gallium nitride surface will
be key to making much higher performance luminescence devices.

”

Mechanical polishing is currently the
final stage in the commercial productionof gallium nitride crystals, but this process
can damage layers in the crucial region near
the surface. The relationship between thequality and chemistry of the surface layers,
and the material’s luminescence efficiency,© 2015 Ken Hattori, Nara Institute of Science and Technology

areful preparation of semiconductor surfaces can greatly enhance theefficiency of semiconductor materials
widely used in light-emitting diode (LED)displays and many other applications, according to research conducted at NAIST in Japan.
“Luminescence efficiencies can be increased bymore than 100 times,” says Ken Hattori, oneof the researchers in the study.
Hattori and colleagues at NAIST, working
with collaborators at Osaka University, investigated the semiconductor gallium nitride.
“Blue light from gallium nitride is now usedeverywhere in displays and other applications,” says Hattori. However, typically only avery thin surface region — no deeper than a

had not been well studied, a deficiency thisresearch addressed.
The team used sophisticated surface-science
techniques to examine the effects of removing
physically damaged layers and oxide-containing layers under ultrahigh vacuum conditions.
These techniques included specializedchemical etching and physical treatments withultrapure water and gas. The researchers also
investigated the role of hydrogen contamination, since hydrogen can penetrate crystals
from solutions used in their production.
The team found that removing physicallydamaged layers and oxides near the surface
and reducing the concentration of hydrogenin the crystals resulted in an approximately
120-fold improvement in photoluminescent
efficiency1. While semiconductor manufacturers have already attempted to remove damaged
and oxide-containing layers, they used a lesssophisticated process that is clearly much lessefficient than that developed by the NAIST
team and their colleagues.
“Improving the quality of the layers near thegallium nitride surface will be key to making
much higher performance luminescencedevices,” explains Hattori. Given the plethoraof LEDs and similar systems in all areas ofmodern technology, this research could lead toconsiderable industrial and economic benefits.
The researchers believe that the findings could
be applied to other semiconductor materials.
Their next step is to conduct similar studies
on other semiconductors to see if the striking
enhancements achieved with gallium nitride
can be replicated more generally. NAIST has
one of the biggest complex surface-analysis
systems in the world (see figure). “This gives
us significant advantages,” says Hattori.
Reference
1.

The NAIST complex surface-analysis system is one of the biggest and most sophisticated in the world.

Hattori, A. N., Hattori, K., Moriwaki, Y., Yamamoto, A.,
Sadakuni, S. et al. Enhancement of photoluminescence
efficiency from GaN(0001) by surface treatments.
Japanese Journal of Applied Physics 53, 021001 (2014).

More information about the group’s research can be found at the Surface and Materials Sciences Laboratory webpage:
http://mswebs.naist.jp/LABs/daimon/index-e.html
NAIST Research Highlights

53

Research Highlights

Materials Science

Nara Institute of Science and Technology | Advanced Polymer Science Laboratory

www.naist.jp/en

Polymer chemistry

Handedness theory
usurpedIt had long been accepted that right
Right-handed helix
Right-handed
circularly polarized light is needed tovisible photon
produce right-handed polymer molecules.
But to the surprise of researchers at NAIST,
right circularly polarized light can also give
Right-handed
handedrise to left-handed polymer molecules, andultraviolet photon
vice versa: polymer handedness depends onother factors, including the wavelength of thelight and the refractive index of the solvent.
Chemists often want to produce either
Left-handed
handeda left- or right-handed version of a chemultraviolet photon
ical. The two forms, which are known as
Achiral polymer
enantiomers, are identical except that they
are mirror images of each other — likeLeft-handed
left-handed and right-handed gloves. Howvisible photon
Left-handed helix
ever, they react very differently with otherenantiomers, which are frequently found in
NAIST researchers find that left circularly polarized light can give rise to right-handed molecules andbiological systems.
vice versa.

“The researchers anticipate that
their findings will lead to the production of various photoluminescent
substances and polymeric materials
that can be used for re-writable optical memory, efficient erasure, andlong-term data storage.”
An attractive way to produce enantiomers
is to use circularly polarized light, as thismethod can induce handedness without using
expensive chemicals. Up until now, conventional wisdom had dictated that left-handed
circularly polarized light preferentially produces left-handed molecules, and vice versa.
Furthermore, the handedness of a molecule
was thought to be independent of the wavelength of the light used. Now, Michiya Fujiki
and co-workers at NAIST have overturned
both these assumptions1.
Using a green-emitting chain-like polymer known as PF8T2, the researchers foundthat the handedness of PF8T2 depends
on both the wavelength and the handedness of the circularly polarized light used. Specifically, they found that when a right-handed

circularly polarized light in the visible regionis used, right-handed PF8T2 was produced;
whereas when right-handed circularly polarized light in the ultraviolet region was used,
left-handed PF8T2 was formed (see figure).

“

In the future, we will try to induce and control the helix senseof polymers and the chirality
hand of small molecules with a
100 per cent yield driven by circularly polarized light, spinningelectron beams, anti-neutrinos
and magnetic and electric fields.

”

They also found that, by precisely controlling the refractive index of an inexpensive organic solvent, they could
increase the yield of PF8T2 up to
10 per cent — the highest yield everreported for an enantiomer using thislight-based synthesis method.
The researchers anticipate that their findings will lead to the production of various

photoluminescent substances and polymericmaterials that can be used for re-writable
optical memory, efficient erasure, and longterm data storage. They also expect that thefindings will facilitate efficient switching
using a circularly polarized light source oncea detector for circularly polarized light has
been developed.
“In the future, we will try to induce andcontrol the helix sense of polymers and thechirality hand of small molecules with a
100 per cent yield driven by circularly polarized light, spinning electron beams, anti-neutrinos and magnetic and electric fields,” Fujiki
states. “This has probably been the ultimate
goal of chirality-related scientists in chemistry and physics over the last two centuries.”
Reference
1. Fujiki, M., Donguri, Y., Zhao, Y., Nakao, A., Suzuki, N.
Yoshida, K. & Zhang, W. Photon magic: Chiropticalpolarisation, depolarisation, inversion, retention
and switching of non-photochromic light-emitting
polymer in optofluidic medium. Polymer Chemistryadvance online publication, 08 December 2014
(doi: 10.1039/C4PY01337A).

More information about the group’s research can be found at Michiya Fujiki’s laboratory webpage:
http://mswebs.naist.jp/LABs/fujiki/english/index-e.html
54

NAIST Research Highlights

Modified, with permission, from Ref. 1 © 2014 Royal Society of Chemistry

Right circularly polarized light does not necessarily give left-handed molecules

Research Highlights
Materials Science

Nara Institute of Science and Technology | Photonic Device Science Laboratory

www.naist.jp/en

Photonics

Implant sensor images
brain activity in vivo
Image sensor implant makes it possible to record the neural activity of a living mouse as it moves

A“© 2015 Jun Ohta, Nara Institute of Science and Technology

fluorescence imaging system that canbe implanted in the brains of living
and freely moving mice allows theneural activities of mice to be monitored during different behaviours. The system, which
was developed by researchers at NAIST
in Japan, has the potential to provide fresh
insights into how neural networks function in
the brain.
The implantable fluorescence imaging
system, fabricated by Jun Ohta of NAIST’s
Graduate School of Materials Science andhis colleagues, consists of a set of blue/
green light-emitting diodes (LEDs) anda tiny image sensor — a smaller and simpler version of those commonly found indigital cameras. The image chip contains
120 × 268 pixels and is just 1 millimetre wideand 3.5 millimetres long.
Light from the LEDs excites fluorescencein brain cells that have been doped with a
In contrast, the NAIST imaging
system can function even when
the subject is moving.

”

voltage-sensitive dye. Consequently, the intensity of the excited fluorescence varies withchanges in the membrane potential, which isrelated to neural activity. The emitted fluorescence is then captured by the image sensor
and transferred via a cable to a computer andadditional electronics where it is analysed.
This is performed at a rate of 60 frames per
second, enabling movies of neural activity to
be recorded.
While techniques such as conventional
fluorescence microscopy and functional magnetic resonance imaging are capable of recording activity in different parts of the brain,
they require the subject to remain perfectly
still. In contrast, the NAIST imaging system
can function even when the subject is moving.
“The system we have developed makes
it possible to take real-time images [ofTwo image sensor chips implanted in the two visual cortices of the brain of a mouse.

the brain activity] of small experimental
animals such as mice and rats in a freely
moving condition,” explains Ohta, “which
is important for studying learning andmemory functions.”
By installing two sensors in the left andright hemispheres of the brain, the team has
mainly used the system to study activity inthe visual cortex of mice. However, Ohta says
the system could be used to investigate otherfunctional areas of the brain.
The researchers have several ideas for
future work. One idea is to create a wirelesssystem; this would eliminate the need to havea cable connected to the animal, which considerably limits its movement. Another plan
is to develop a microimaging device that canbe implanted in the limbic system — a deepbrain region associated with emotion andaddiction and hence important for studying
mental diseases.
Reference
1.

Novel implantable imaging system for enabling
simultaneous multiplanar and multipoint analysis
for fluorescence potentiometry in the visual cortex.
Kobayashi, T., Motoyama, M., Masuda, H., Ohta, Y.,
Haruta, M. et al. Biosensors and Bioelectronics 38,
321−330 (2012).

More information about the group’s research can be found at the Photonic Device Science Laboratory webpage:
http://mswebs.naist.jp/LABs/pdslab/index-e.html
NAIST Research Highlights

55

Research Highlights

Materials Science

Nara Institute of Science and Technology | Information Device Science Laboratory

www.naist.jp/en

Data storage

Improving memory
using hot spots
Localized hot spots are the key to the operation of low power consumption electronic memories

A

Reproduced, with permission, from Ref. 1 © 2014 AIP Publishing LLC

n increasing reliance on electronics
for processing information has drivena need for devices that can store allthis data. NAIST researchers have now used
thermal imaging to better understand thestorage mechanism in one possible type ofmemory device1, and provide insight that could
help reduce the power consumption of suchcomponents in the future.
Non-volatile memory — devices that retain
their data when power is switched off —should squeeze as much information into as
small a space as possible, be cheap to produce,and not consume too much energy. Resistive
random access memory (ReRAM) is one tech-

nology that fulfills these requirements. Resistive
devices operate by harnessing the ability ofsome materials to switch between high andlow electrical resistance states. This means that
ReRAM offers rapid reading and writing of
data, and can be easily integrated with existingsilicon-based electronics technologies.

“

Our future work will attempt toestablish a relationship between
heat and electrical characteristicsof the device.

”“But the operation mechanism of resistive
switching memories is not fully understood,”

1000 μm

100 μmHot spots imaged on the surface of a resistive random access memory 1,000 micrometres in diameterare a signature of current filaments that significantly alter the electrical resistance of the device.

More information about the group’s research can be found at Yukiharu Uraoka’s webpage:
http://mswebs.naist.jp/LABs/uraoka/PUBLIC/staffs/uraoka/uraoka.html
56

NAIST Research Highlights

says NAIST researcher Yukiharu Uraoka,
from NAIST’s Information Device Science
Laboratory. “So we chose to investigate the heatgenerated in the device to see if it affected theperformance of the memory.”
Uraoka and his co-workers studied thechanges in ReRAM during switching bymonitoring the surface temperature. They
created their ReRAM by sandwiching a
30 nanometre-thick layer of amorphous indium
gallium zinc oxide (a-IGZO) between two
platinum electrical contacts. They used an
infrared detector to create a spatially resolved
thermal map of the device as they applied avoltage of up to 1.5 volts across the electrodes.
The team noticed that the voltage created
hot spots on the surface of the device (seefigure). These localized regions, with a maximum temperature of 186 °C, were a sign ofelectrical pathways, or current filaments, thatpass through the a-IGZO. These filaments
significantly alter the resistance of the thin film,
thus enabling the switching that is central tothe operation of a ReREM.
Current filaments have been observed inresistive materials in the past using techniquessuch as scanning electron microscopy orelectron energy loss spectroscopy. But thesemethods weren’t able to observe the filaments
as the voltage was applied — which means they
didn’t provide much information on how thefilaments are formed.
“Our method can detect the location of
conductive filament, a main contributor to theresistive switching,” says Uraoka. “Our future
work will attempt to establish a relationshipbetween heat and electrical characteristics ofthe device.”
Reference
1. Kado, K., Uenuma, M., Sharma, K., Yamazaki, H.,
Urakawa, S. et al. Thermal analysis for observing conductive filaments in amorphous InGaZnO thin film
resistive switching memory. Applied Physics Letters105, 123506 (2014).

Research Highlights
Materials Science

Nara Institute of Science and Technology | Synthetic Organic Chemistry Laboratory© 2015 Yasuhiro Nishiyama, Nara Institute of Science and Technology

www.naist.jp/en

The photoreactor used to produce cyclobutanes.

Photochemistry

Microflow set-up
boosts output
Photochemical reactions in a flow rather than a batch reactor lead to easy scaling upM

ost chemical reactions requireenergy to start them. In almost allcases, that energy is heat, but for
certain reactions, light energy must be usedinstead. Known as photochemical reactions,these include one of the most effective waysof producing cyclobutane rings — cyclic
structures containing four carbon atoms,
which are frequently found in naturally
occurring compounds with useful biologicalproperties, such as insect pheromones.
Now, Yasuhiro Nishiyama and his
team at NAIST’s Graduate School ofMaterials Science in Japan, along withMichael Oelgemöller at Australia’s James
Cook University, have shown that photochemical reactions like these can be done very
effectively in a flow chemistry set-up1.
Most industrial chemical processes are
run in a so-called ‘batch set-up’, which is
not unlike the procedure for baking a cake:reactants are combined in known proportions
and mixed for a set time. Each reaction batch
produces a fixed amount of product. But thisway is not very amenable to photochemical
reactions: “Light cannot penetrate sufficiently
into large batch reactors or high-concentration
solutions,” explains Nishiyama. “Thus, almost
all photoreactions show poor conversion inbatch reactors.”“

If we need to scale up, we can also
run multiple reactors in parallel, a
process called numbering up.

”

The team investigated reactions that
produce cyclobutanes from two alkenes (aclass of hydrocarbons containing only carbon
and hydrogen) in a microflow set-up. In thisset-up, the reaction tubes have an internal
diameter of just 1 millimetre and are wrappedaround the light source, allowing the wholeapparatus to be cooled easily (see figure).
Of particular interest is that one of the reagents — ethylene — is a gas. In a batch process,this would add a further difficulty, since thereaction can only occur at the surface between
the gas and liquid reagents. In flow, however,pumping a gaseous and a solution reagent intoa small tube produces small gas bubbles in thesolution as it flows through the tube. This is
known as slug flow, and it ensures that there isa very thin film of reactant solution at the edgeof the tube, which is easily penetrated by light.
The small bubbles create a large surface area atwhich the reaction can occur.
Photoreactions performed in the flow
set-up are slightly more efficient and selective
than those performed in a small batch
reaction. Importantly, making a large amountof product is much easier: simply running thereactor continuously produces more product.
“If we need to scale up, we can also run
multiple reactors in parallel, a process callednumbering up,” says Nishiyama.
Reference
1. Terao, K., Nishiyama, Y., Tanimoto, H.,
Morimoto, T., Oelgemöller, M. & Kakiuchi, K.
Diastereoselective [2+2] photocycloaddition of achiral cyclohexenone with ethylene in a continuous flow microcapillary reactor. Journal of Flow
Chemistry 2, 73–76 (2012).

More information about the group’s research can be found at the Synthetic Organic Chemistry Laboratory webpage:

http://mswebs.naist.jp/english/courses/1414/

NAIST Research Highlights

57

Materials Science

Research Highlights

Nara Institute of Science and Technology | Biomimetic Materials Science Laboratory

www.naist.jp/en

Silicon chemistry

Hybrid skin forstable agents
Spherical vesicles formed from lipid bilayer membranes with an outer silica network show excellent
morphological stability

C

The molecular components of a cerasome-forming lipid comprise a hydrophobic tail, aconnector unit (for example, an amide or urea
function), and an ethyoxysilyl group, whichmust be removed by hydrolysis before assemblyof the lipid can occur. The cerasomes are between several tens of nanometers and microns
in diameter, and can exist as single-walled or
multiwalled vesicles.
Cerasomes, a close relative of phospholipid-containing vesicles (namely liposomes),
differ as a result of the siloxane frameworkthat covalently links several of the amphiphilic lipids together. “The cerasomes behave
as biomembrane models, but they have amuch enhanced morphological stability
compared with conventional liposomes,”
says Kikuchi. The siloxane framework thatconnects the surface together is the key
stabilizing factor and, in addition, imparts
the chemical and biophysical characteristics
of silica particles to the cerasomes.
The surface of these hybrid structures can beeasily adapted to a range of chemical species
including organic molecules, titanium dioxide,hydroxyapatite, and metals, which opens up
many possible functions. For example, the tita-

nium-dioxide-coated cerasomes are photocatalytically active, and the hydroxyapatite coating
enhances the biocompatibility of the vesicles.
The metal-coated cerasomes, or metallosomes, are formed by electroless plating of
palladium or gold onto the outer silica surface.
“Metallosomes have practical advantages asa new type of organic–inorganic–metallic
material in various applications, including energy conversion and information processing,” says
Kikuchi. “For example, the magnetic cerasome
can behave as a molecular vehicle manipulatedby an external magnetic field.”
In addition, cationic cerasomes have beendeveloped as gene delivery agents with hightransfecting capabilities and low toxicity in various cell lines2. The clinical translation of thesecerasomes is a future goal in this area.
References
1.

2.

Kikuchi, J.-I. & Yasuhara, K. Cerasomes: A new family of
artificial cell membranes with ceramic surface. Advancesin Biomimetics, Marko Cavrak (ed.), ISBN: 978-953-307191-6, InTech, DOI: 10.5772/14167 (2011).
Tahara, K., Moriuchi, T., Tsukui, M., Hirota, A., Maeno, T. et al. Ceramic coating of liposomal gene carrier
for minimizing toxicity to primary hippocampal
neurons. Chemistry Letters 42, 1265-1267 (2013).

© Creatas Images/Creatas/Thinkstock

erasomes – spherical vesicles with alipid bilayer membrane and ceramic surface and an internal aqueouscompartment – have exciting potential
for use in biomedical and electronic devices. These organic–inorganic hybrid
structures are made from the spontaneous
self-assembly of amphiphilic molecules(attracted to both water and fat) to form abilayer structure, followed by condensation
reactions on the structure’s exterior to form asilica-based network.
NAIST researchers Jun-ichi Kikuchi,
Kazuma Yasuhara and Keishiro Tahara are investigating new ways to make and modify thesehybrid materials to create gene delivery agentsor magnetic structures that can be manipulated
by external magnetic fields1.
They have prepared and characterizedcerasomes formed from lipids with different
molecular components — including thosewith cationic groups (positive ions) — andshown how their structure and stability,
across a pH range and in the presence of
surfactants, are influenced by the cerasomes’
composition and the reaction conditions used
to make them.

NAIST chemists have prepared and characterized cerasomes formed from lipids with different molecular components.

More information about the group’s research can be found at the Biomimetic Materials Science Laboratory webpage:
http://mswebs.naist.jp/english/courses/1417/
58

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Research Highlights
Materials Science

Nara Institute of Science and Technology | Laboratory of Bioenergetics and Biophysics

www.naist.jp/en

Biophysics

Enzyme’s special bonds
finally revealed
High-resolution crystallography uncovers the first view of bonds important for enzyme structureand function

Short ionic hydrogen bondLow-barrier hydrogen bonds“

The resolution we attained was thehighest in the world. Nobody had
ever conducted such high-resolution neutron crystallography.

”

Mikio Kataoka’s team at NAIST was able
to overcome these challenges in collaboration
with researchers at other Japanese institutes.
They developed a method to grow large crystalsof the light-sensitive photoactive yellow
protein (PYP) in heavy water, enabling themto determine its structure at an unprecedented
resolution with neutron diffraction1. “The resolution we attained was the highest in the world.
Nobody had ever conducted such high-resolution neutron crystallography,” says Kataoka,
adding that the team had to develop a new
analytical method to handle their data.
Work on the research spanned five years, including two years to develop the crystallization
conditions. “A talented and ambitious student
selected the project as his doctoral research,”observes Kataoka. “NAIST allows us to tackle
such time-consuming projects.”© 2015 Hironari Kamikubo, Nara Institute of Science and TechnologyIn 1994, a pair of papers published in Sciencesuggested that a special class of intramolecular bonds known as low-barrier hydrogenbonds (LBHB) play an important role inenzymatic reactions. But it took until 2009 fora high-resolution crystallography techniquedeveloped by Japan’s NAIST to allow scientists
to finally observe these elusive bonds.
LBHBs are exceptionally short hydrogenbonds, resulting in the hydrogen ion, a proton,
being more evenly shared between the partners.
This confers additional flexibility to the molecule, enabling it to change shape more easily
during reactions. However, the short lengthof LBHBs also makes them difficult to detect
directly, leading to some debate about their existence. Observation of an LBHB calls for very
high-resolution crystallography to determine
the position of the proton and the donor andacceptor atoms.

Visualization of a portion of the molecular structure of photoactive yellow protein, with insets showing
two different kinds of hydrogen bond.

The team was able to detect the positionof 87% of the hydrogen ions in PYP, anddetermine that one of them — buried within
the protein’s interior — forms an LBHB. In
addition to easing the protein’s conformation
change in response to light, the LBHB serves
to stabilize a negative charge, which would
otherwise be energetically unfavourable in
the interior environment of the protein.
Kataoka is now using time-resolved crystallography to follow changes in the LBHB
during PYP’s photoreaction. “Before practicalapplications, we must clarify the properties of
LBHB and the principle of LBHB formation.
Basic research will be still required,” he says.

A better understanding of LBHBs may
significantly improve our ability to engineer
molecules. “The formation of LBHBs is a
key element for efficient proton transfer,”
explains Kataoka. “If we can control theformation of LBHBs, it will allow us todesign artificial enzymes with high efficiency
and artificial proton pumps, as well as [more]
efficient medicine.”
Reference
1.

Yamaguchi, S., Kamikubo, H., Kurihara, K., Kuroki, R.,
Niimura, N. et al. Low-barrier hydrogen bond inphotoactive yellow protein. Proceedings of the National
Academy of Sciences USA 106, 440–444 (2009).

More information about the group’s research can be found at Mikio Kataoka’s webpage:
http://www.naist.jp/en/about_naist/offices/administration_bureau/mikio_kataoka/index.html
NAIST Research Highlights

59

Research Highlights

Nara Institute of Science and Technology | Laboratory for Supramolecular ScienceaMonomer

Monomer
–

H93

–

b
–
H93

–

c
–
H93

www.naist.jp/en

–

D141
+ K78
+ K79

–

+
H93

E85
D141
– E78
– D79

+

+
H93

E85
D141
– E78
– D79

+

–

+

H68

+

H93

+

E85

Dimer
K78 K79 E85
D141 + + –
H93
–

D141
+ K78
+ K79

H93

E85
K141

–
– + + D141
E85 K79 K78
D141
–

+ K78
+ K79

H93

K85
K141
H93

K85

– –

–

H93

+
+ + + K141
K85 K79 K78
D141
–

+ K78
+ K79

E78 D79 E85

E78 D79 E85
– –

–

H93

+
+ + + K141 H68
K85 K79 K78

Myoglobin dimer formation using (a) the natural protein monomer, (b) two mutant monomers obtained by switching the positions of the bridging residues(E78/K85 and D79/K141) and (c) two mutant monomers with switched bridging residues and different heme active sites (H93 and H68/H93).

Artificial proteins

Growing enzyme diversity
using mutations
A targeted protein mutation strategy opens the door to multifunctional artificial enzymesS

ite-specific modifications and pairing of
natural proteins are expected to generate
artificial enzymes capable of catalysing
multiple reactions simultaneously, reveals new
research by NAIST¹.
The work of enzymes relies on protein
folding. Existing protein design methods haveproduced several artificial enzymes that promoteoxidation, reduction, and hydrolysis reactions.
These methods have rested on metal ions orother additional compounds called co-factors
to control protein folding and achieve thesefunctions. Other self-assembly approaches have
led to similar results by forming protein pairs,
or dimers. However, the variety of synthetic
enzymes remains limited.
To expand this artificial enzyme library,
Shun Hirota, from the Graduate School ofMaterials Science, and co-workers have developed a new strategy that produces various
dimers by exchanging specific residues innatural proteins. As a proof-of-concept, they
applied this domain swapping approach toiron-containing proteins responsible for oxygen transport and storage in the body, known
as hemeproteins.

Having recently discovered that domain
swapping governed the polymerization andoligomerization of hemeproteins, such as
cytochrome c and myoglobin, Hirota’s team decided to exploit this phenomenon to create newpositively charged residues by two negatively
charged ones in one mutant, and two negatively
charged residues by two positively charged residues in the second mutant. These two mutants
gave a stable dimer upon pairing.
Moreover, to generate a dimer with two disDomain swapping with mutation
tinct active sites, Hirota and co-workers alteredallows us to construct artificial proone of the heme sites in the second myoglobin
teins possessing active sites withmutant before coupling it with the first mutant.
A spectrometric analysis of the resulting dimer
different structures.
demonstrated that the two sites exhibited
proteins containing a few monomer units, ordifferent reactivities upon exposure to a mild
oligomers. “Domain swapping with mutation al- reducing agent. These results suggested that thelows us to construct artificial proteins possessing sites operated independently — evidence for theactive sites with different structures,” he adds.
usefulness of domain swapping in the design of
By examining the X-ray crystallographic
multi-heme proteins.
structure of the natural myoglobin dimer in“We are currently designing other artifidetail, Hirota’s team identified four bridges
cial hemeproteins comprising different active
between each protein subunit. These bridges
sites by domain swapping,” says Hirota. By
resulted from electrostatic interactions between expanding their library, the researchers are also
positively and negatively charged residues, hold- planning to produce multifunctional enzymes.
ing the dimer together. Consequently, to control
Referencethe dimerization, the researchers engineered two
1. Lin, Y.-W., Nagao, S., Zhang, M., Shomura, Y. , Higuchi,
different myoglobin mutants by switching the
Y. & Hirota, S. Rational design of heterodimeric protein
positions of the charged residues in each mutant
using domain swapping for myoglobin. Angewandte(see figure). Specifically, they replaced two
Chemie International Edition 54, 511–515 (2015).

“”

More information about the group’s research can be found at the Laboratory for Supramolecular Science webpage:

http://mswebs.naist.jp/LABs/hirota/member1_e.html
60

NAIST Research Highlights

Modified, with permission, from Ref. 1 © 2014 WILEY-VCH
Verlag GmbH & Co. KGaA, Weinheim

Materials ScienceResearch Highlights
Materials Science

Nara Institute of Science and Technology | Biocompatible Materials Science Laboratory

www.naist.jp/en

Medical implants

Anti-fouling polymers
demonstrate star quality

Star-shaped polymer coatings show promise in fending off bacteria and blood clots in medical implants“

We designed the hetero-star as afirst step, and expected they would
show moderate inhibition of platelet and bacterial adhesion. But
they exhibited much higher inhibition than we expected.

”

The researchers, from NAIST’s Graduate
School of Materials Science, suspected that a
coating of star-shaped polymers — in whichpolymer chains radiate from a central polymer ball — would make it difficult for bacteria and platelets to attach. “We wanted tobuild a brush-like surface,” says corresponding author Tsuyoshi Ando, “but without the
cumbersome steps of surface chemistry.”
Rather than attaching the star-polymer‘brush bristles’ using covalent chemical bonds— difficult to do, as PET is quite inert —they designed star-polymers with hydrophobic chains that were naturally attracted to the
PET surface (see figure). “We chose polymethyl methacrylate (PMMA) as our model hydrophobic compound for attachment to thePET,” says Ando. The team synthesized three
star-polymer varieties: some made purely ofPMMA, some made from poly 2-hydroxyethyl methacrylate (PHEMA), and ‘hetero’star-polymers containing both PMMA andPHEMA. They then coated small strips of
PET with the polymers.
Ando’s team had expected the hydrophobic
PMMA stars to attach well to the PET surface,
and indeed it proved the most durable coating
trialled. However, the PMMA stars were notvery good at preventing platelet attachment.
The hetero stars provided the best of bothworlds: the PMMA chains allowed them tocling to the PET surface, while their PHEMA

chains discouraged clotting and bacteria. “We
had some surprises,” says Ando. “We designed
the hetero-star as a first step, and expected theywould show moderate inhibition of platelet
and bacterial adhesion. But they exhibitedmuch higher inhibition than we expected.”ThePHEMA stars inhibited platelet adhesion
effectively too, and to the team’s surprise, they
attached well to the PET surface. “They werestill attached even after seven days of being
washed with a surfactant.” says Ando. “We
think these two ‘stars’ are promising materials
for non-platelet adherence.”
Ando thinks improved versions of thesestar-polymers could prevent bacterial ‘fouling’
not only in devices in contact with body fluids,
but “also on surfaces like the toilet bowl or sink.”
Reference
1.

2.

Totani, M., Ando, T., Terada, K., Terashima, T., Kim, I. Y.
et al. Utilization of star-shaped polymer architecture in
the creation of high-density polymer brush coatings forthe prevention of platelet and bacteria adhesion. Biomaterials Science 2, 1172–1185 (2014).
Totani, M., Ando, T., Terada, K., Terashima, T., Kim,
I. Y. et al. Inside front cover. Biomaterials Science 2,1138–1138 (2014).

Star polymer
Functional units
Hydrophilic arms

Adherent units
Hydrophobic arms

© (left) Adapted from Ref. 2, with permission of The Royal Society of Chemistry;(right) 2015 Tsuyoshi Ando, Nara Institute of Science and TechnologyTwo polymers, designed by researchersat the Nara Institute for Science andTechnology (NAIST), may herald a
new class of ‘anti-fouling’ coatings for medical
implants such as heart valves and catheters1.
The problem with implants, made fromsilicone or polyethylene terephthalate (PET),
is that cells tend to stick to them. When blood
platelets (which promote blood clotting) attach
to an artificial heart valve, for instance, there isrisk of thrombosis, while adherent bacteria cancause secondary infections.

Schematic of (left) the ‘brush-like’ star-polymer surface and (right) a star-shaped heteropolymer.

More information about the group’s research can be found at the Biocompatible Materials Science Laboratory webpage:
http://mswebs.naist.jp/LABs/tanihara/index-e.html
NAIST Research Highlights

61

Materials Science

Research Highlights

Nara Institute of Science and Technology | Photonic Molecular Science Laboratory© 2015 Tsuyoshi Kawai, Nara Institute of Science and Technology

www.naist.jp/en

A bendable thermoelectric device made from modified carbon nanotubes can generate electricity from a temperature gradient.

Semiconductors

Generating power fromwaste heat
Additives improve the thermoelectric efficiency of carbon nanotubes

Bendable devices that convert waste
heat into useful electricity havebecome much more efficient, thanks
to films made of tiny carbon nanotubes
developed at NAIST in Japan 1.These thermoelectric films generate a voltage when
one side is hotter than the other and could
be used in a variety of applications, including battery-free sensors and energy-saving
technologies. “More than 5 per cent of
the fuel consumption of gasoline-powered
vehicles could be saved by thermoelectricheat recovery systems in the near future,”says Tsuyoshi Kawai of the Laboratory for
Photonic Molecular Science at NAIST,
who led the research.
Most thermoelectric devices are solid,
inflexible materials made from highly
toxic elements. So Kawai and his colleagues
created lightweight and flexible thermoelectric films made of hollow straws of carbon
atoms mere billionths of a metre wide, called
single-walled carbon nanotubes (SWNTs).
These films (see figure) can closely hug the

curved surfaces of an engine or pipe, maximizing the power they generate.
Unlike a metal wire, SWNTs do not carrycurrent as a flow of electrons. Instead, thenanotubes rely on the movement of positively charged ‘holes’ left behind by missing
electrons — they are known as p-type semiconductors. The efficiency of thermoelectric
devices made solely from p-type materials isvery low — unless teamed with n-type semiconductors, which have a surfeit of electrons.
But researchers have previously struggled tocreate stable and flexible n-type thermoelectric materials.
Kawai’s team studied 33 different carbon-based molecules to assess whether they
could transform SWNTs into n-type semiconductors. They found 18 molecules that
could. The best was triphenylphosphine (tpp),
whose phosphorus atoms inject electrons
into the SWNTs. The researchers filtered
the tpp-SWNTs from a liquid to create
air-stable n-type films, and paired them with
p-type SWNTs that had been enhanced withanother additive, tetracyanoquinodimethane(TCNQ). The device was sealed inside apolymer and wrapped around a pipe that washotter at one end than the other.
The team found that a temperature
difference of 20 degrees Celsius generated 110 nanowatts of power at a voltage of
6 millivolts. “We have demonstrated the firstexample of flexible thermoelectric sheets withthis bipolar structure,” says Kawai.
The team’s survey of different additives also
revealed which molecules are best suited tofine-tuning the behaviour of the SWNTs,
which is helping to design even more efficient and stable n-type materials. “We are
now cooperating with some industrial companies for future commercial applications,”
says Kawai.
Reference
1.

Nonoguchi, Y., Ohashi, K., Kanazawa, R., Ashiba, K.,
Hata, K. et al. Systematic conversion of single walledcarbon nanotubes into n-type thermoelectric materials
by molecular dopants. Scientific Reports 3, 3344 (2013).

More information about the group’s research can be found at the Photonic Molecular Science Laboratory webpage:

http://mswebs.naist.jp/LABs/kawai/english/index.html
62

NAIST Research Highlights

Research Highlights
Materials Science

Nara Institute of Science and Technology | Ultrafast Photonics Laboratory

www.naist.jp/en

Optical memory

Laser switchable
across waveguides
Optical buffer memories may be improved with a vertical-cavity surface-emitting laser that canswitch light into different waveguides

A

For applications requiring a larger
waveguide output power, the reflectivity of the DBR will be increased
by increasing the number of the
DBR layers.

”

When employed with a polarization bistable
VCSEL, such an arrangement may prove usefulfor creating compact and efficient all-opticalbuffer memories on a silicon chip that can temporarily switch and store optical data streams
without the need for free-space optics.
“We found that the output waveguide canbe switched by changing the lasing polarization of the VCSEL with an extinction ratioof 11.9,” says Kawaguchi. The light coupledmore strongly to the waveguide when it wasperpendicularly orientated to the polarizationof the resonant mode, rather than parallel. The
strongly coupled mode was found to be transverse electric, or perpendicular to the propagation direction of the beam.
The modelling assumes a VCSEL operating
at 1.55 micrometres in wavelength, consistingof an active gain region composed of a series of
InGaAsP (indium gallium arsenide phosphide)
quantum wells sandwiched between the HCG
below, and a Distributed Bragg Reflector

|Ex|

2

0

9
-10
Resonance polarization
6-20
3

x-waveguide output

-30

0

-3
-3

0

3

6

9

12

x (µm)© 2013 The Japan Society of Applied Physics“dB

y-waveguide output

12

y (µm)

design of a semiconductor laser thatemits light into different sets ofwaveguides depending on the polarization of the lasing beam has been theoretically investigated by NAIST researchers1.
Hitoshi Kawaguchi’s team at NAIST used
three-dimensional finite-difference time-domain modelling to study the behaviour of avertical-cavity surface-emitting laser (VCSEL)
coupled to two sets of silicon waveguides
arranged in orthogonal directions to eachother (see figure). The coupling takes place via
a square-shaped, polarization-independent,
high-index-contrast subwavelength grating(HCG) that is also made in silicon and forms
the bottom mirror of the VCSEL.

Simulation showing light exiting the VCSEL via the y waveguide only. By changing the lasing polarization, the output light switches to the x waveguide.

(DBR) above. The DBR is made from an alternating stack of 32 pairs of thin layers of InP(indium phosphide) and InGaAsP.
The HCG has a greater than 99 per centreflectivity for wavelengths around 1.55 micrometres, while the DBR has a reflectivity ofaround 90 per cent. The HCG is bonded to therest of the VCSEL structure using benzocyclobutene. According to the researchers, theoutput power coupled to the waveguide issimilar to the emission from a conventional
VCSEL, which is less than 1 per cent of opticalpower inside the laser cavity.
“This output will be sufficient for all-opticalmemory applications because the memory

works with a very low input power of 80 nanowatts,” explains Kawaguchi. “For applications
requiring a larger waveguide output power, thereflectivity of the DBR will be increased byincreasing the number of the DBR layers.”
Their simulations also suggest that theoutput power of the waveguide is roughly
proportional to the waveguide width.
Reference
1. Tsunemi, Y., Ikeda, K. & Kawaguchi, H. Lasing-polarization-dependent output from orthogonal waveguides
in high-index-contrast subwavelength grating
vertical-cavity surface-emitting laser. Applied Physics
Express 6, 092106 (2013).

More information about the group’s research can be found at the Ultrafast Photonics Laboratory webpage:
http://mswebs.naist.jp/LABs/kawaguchi/index-e.html
NAIST Research Highlights

63

Research Highlights

Materials Science

Nara Institute of Science and Technology | Laboratory for Photofunctional Organic Chemistrywww.naist.jp/en

Photovoltaics

Semiconductor sandwich
solution for solar cells
Improved chemical process offers simpler route to promising organic photovoltaics“

Our proof-of-concept system will
be further elaborated in the very
near future, so that much higher efficiencies can be achieved.

”

Building these cells can be troublesome andexpensive, not least because the crucial organic
molecules often dissolve into neighbouring
layers during production. Suzuki’s team solved
this problem by forming some of the layers
from precursor molecules containing chemicalgroups called ketones.
When the researchers exposed these precursors to a bright light, it triggered a reactionthat stripped away the ketones and generated
an insoluble semiconductor layer. After testinga range of different semiconductor combina-© satit_srihin/iStock/ThinkstockAn improved technique for making flexible organic solar cells with higher efficiencies, using a sandwiched configuration that is more cost-effective to manufacture,
could help to boost their application, according
to research from Japan’s NAIST.
Organic photovoltaic (OPV) devices, which
rely on carbon-based molecules to harvest light,
are lightweight and perform well in relatively
dim conditions, but currently have lower efficiencies than conventional solar cells. “Owing
to these characteristics, OPVs are likely to findapplications first as indoor or portable devices,rather than in large-scale power plants,” says
NAIST’s Mitsuharu Suzuki.
He and his colleagues have developed a way
to make OPVs that contain three layers ofsemiconducting molecules. One of the outerlayers is an n-type semiconductor, which has asurfeit of electrons; the other is p-type, which
has a deficit of electrons. The filling inside thissemiconductor sandwich is an ‘inter layer’ madefrom a mixture of p- and n-type materials.
When light hits these cells, it frees electricalcharge from the inter layer so that electrons— and the holes they leave behind — can flow
to the outer layers, thereby generating a current.

A technique for fabricating flexible solar cells with three layers of semiconductor molecules offers more
efficient organic photovoltaics.

tions, the team made a cell with an efficiency of
2.89 per cent — among the highest recorded
for this category of device1.
Using this approach meant that the researchers could build their cells using solutions of
the semiconductor molecules, a process thatis more cost-effective than alternative vacuum
evaporation. The strategy avoids extensive heat
treatments, so that the semiconductors can becoated directly onto thin plastic films. And
tailoring the layers in this way also allowed
the researchers to use materials that have ideal
properties for each different layer of the cell.
Suzuki notes that access to high-quality
instruments and well-trained operational staff

at NAIST’s facilities in Ikoma, Japan, was also
crucial to the success of their research.
His team of researchers are now tweaking
their molecules to absorb a greater quantityof light, and to carry current more effectively.
“Our proof-of-concept system will be further
elaborated in the very near future, so thatmuch higher efficiencies can be achieved,”says Suzuki.
Reference
1. Yamaguchi, Y., Suzuki, M., Motoyama, T., Sugii, S.,
Katagiri, C. et al. Photoprecursor approach as aneffective means for preparing multilayer organic semiconducting thin films by solution processes. Scientific
Reports 4, 7151 (2014).

More information about the group’s research can be found at the Laboratory for Photofunctional Organic Chemistry webpage:
http://mswebs.naist.jp/LABs/env_photo_greenmat/en/Yamada_Group/HOME.html
64

NAIST Research Highlights

Research Highlights
Materials Science

Nara Institute of Science and Technology | Nanostructure Magnetism Laboratory© Ninety1foto/iStock/Thinkstock

www.naist.jp/en

Layers of magnetic and non-magnetic materials are used in the read heads of computer hard drives.

Materials science

Bringing magnetism
to gold

The magnetic alignment of iron carries further into an adjacent non-magnetic gold layer than anticipatedM

any physical phenomena can arise at
the interface between two different
materials, and they are often important for many applications. In computer hard
drives, the electrical resistance of a non-magnetic material that is surrounded by magnetic
layers is very sensitive to external magnetic
fields, which is used to read the magnetic information on the hard drive.
Studying related magnetic structures,
Nobuyoshi Hosoito and colleagues fromthe NAIST Graduate School of Materials
Science, the Japan Synchrotron Radiation
Institute in Sayo and the Nara National College of Technology have discovered that themagnetic polarization can extend further into
the non-magnetic layer than previously anticipated1. “We have shown that gold atoms
within a few nanometres from the interface
with an iron layer behave more like a ferromagnet than a non-magnet,” says Hosoito.
The magnetic information carried byelementary particles, such as the electron, is
known as their ‘spin’. Whereas conventional

electronic devices, such as transistors, makeuse of the electrical charge of an electron,
researchers are working on devices that use thespin instead, because this offers benefits suchas a potentially lower energy consumption. In
particular, the combination of magnetic andnon-magnetic materials enables new avenues
for controlling magnetic properties.
An important aspect of these devices is
to understand how far the magnetism of amagnet extends into an adjacent non-magnet — in this case, that of iron into a layerof gold. This is possible using resonant X-ray
magnetic scattering, which probes the relative orientation of the electron spins in theatomic states of gold with high precision.
The expectation was that, away from theinterface with the iron alignment, the spins
within the gold layer drops off rapidly towards
the random orientations of a non-magnet.
However, the measurements show that the spinalignment extends further into the gold than
expected. This is due to the enhancements fromthe interface between the iron and the gold,

explains Hosoito. “Electrons approaching thisinterface are reflected differently according
to the orientation of their spins. This createsa polarization.”
The creation of an enhanced magnetic
polarization inside non-magnets could lead to
new fundamental physical phenomena, where
the aligned spins inside the non-magnet caninteract with other effects that typically do notexist in magnetic materials, such as superconductivity, to achieve new functionalities. Morepractically, in technical devices such as computer hard drives, the manipulation of magnetic
fields by complex magnetic/non-magnetic
structures could deliver its own advantages forthe manipulation of magnetism in enhanced
storage devices.
Reference
1.

Hosoito, N., Ohkochi, T., Kodama, K. & Suzuki, M.
Charge and induced magnetic structures of Au layers in
Fe/Au bilayer and Fe/Au/Fe trilayer films by resonant
X-ray magnetic reflectivity at the Au L3 absorption edge.
Journal of the Physical Society of Japan 83, 024704 (2014).

More information about the group’s research can be found at the Nanostructure Magnetism Laboratory webpage:

http://mswebs.naist.jp/LABs/hosoito/English/English.html

NAIST Research Highlights

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Materials Science

Research Highlights
www.naist.jp/en© agsandrew/iStock/Thinkstock

Nara Institute of Science and Technology | Theoretical Condensed Matter Physics Laboratory

NAIST researchers theoretically examined how terahertz spectroscopy would help analyse electrons and electron holes, as well as electronic plasma, andhow they behave around the exciton Mott transition – the point at which electron-hole pairings disappear.

Terahertz spectroscopy

Probing exciton
transitions
Electron interactions in semiconductors have been theoretically calculated using terahertz
absorption spectraTerahertz radiation — between the
mid-infrared and microwaves regions— is an important transition point on
the electromagnetic spectrum, and can be used
to visualize the boundary between quantum andclassical physics. It is a band with many potential
applications, from biotechnology to the development of low-energy optoelectronic devices.
Researchers at NAIST conducted a theoretical study examining electronic plasma (anelectrically-charged gas made up of free-flowing carriers) and paired electron-hole structuresin optically excited semiconductors, seeking tounderstand how terahertz spectroscopy might
help visualize phenomena1.
“The issue of electron interactions is very
difficult and has been studied for five decades,”states Takeshi Inagaki, who worked on the
study with colleague Yen Thi Hai Le at the
NAIST Graduate School of Materials Science.
“We needed a new way to tackle this problem.”
When light shines on an optically excited
semiconductor, electrons in the valence bandare excited to the conduction band, leaving

holes in the valence band. This process is analogous to the movement of electrons throughdifferent energy bands in a hydrogen atom. As
the negatively-charged electrons move, Coulomb’s law means they remain bound to theirpositively-charged electron holes — creating
electron-hole pairs called excitons.
Inagaki and Le used numerical analysis to
examine three-dimensional electron systems
in cuprate semiconductors under terahertz(THz) radiation. They were particularlyinterested in electron interactions around theexciton Mott transition; the point at whichelectron-hole pairs disappear because thedensity of the electrons and holes, and thedensity of the ionized electronic plasma, havereached certain critical levels.
“We developed a computer program tocalculate THz absorption spectra for different
exciton densities,” explains Inagaki. “NAIST
has a high-spec computing system which madethis job fairly straightforward.”
A previous experimental study had shownthat the spectral component left by electron

movements from the 1s to 2p energy bandremained the same regardless of exciton density.
The researchers were able to explain this phenomenon using their new theory.
They also found that the exciton Mott transition was clearly visible using THz radiation,observing a sudden increase in the densities
of both the electronic plasma and the electron-hole pairs just before the spectra fromexciton structures abruptly disappeared. At acertain level of ionization density, both excitonsand electronic plasma co-exist, the semiconductor becomes metallic and electric current flows.
“Understanding the nature of the systemnear the exciton Mott transition is very
useful,” states Inagaki. “It will help us incorporate electron interaction effects into new,low-energy devices.”
Reference
1.

Le, Y. T. H. & Inagaki, T. J. Density dependence of theterahertz absorption spectra in optically excited semiconductors. Physica Status Solidi B advance online publication,
25 November 2014 (doi: 10.1002/pssb.201451191).

More information about the group’s research can be found at the Theoretical Condensed Matter Physics Laboratory webpage:

http://mswebs.naist.jp/english/courses/1438/
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Research Highlights
Materials Science

Nara Institute of Science and Technology | Laser Nano-Manipulation Science Laboratory

www.naist.jp/en

Biophysics

Detecting forces atcellular scales
A platform for measuring nanoscale vibrations could help map the mechanics of cellular growthand development“

We are developing a technology toestimate the distribution of the mechanical properties throughout the
sample, which is impossible to do
by conventional methods.

”

Yoichiroh Hosokawa is an applied
physicist with a deep interest in exploring
the tiny forces that affect cell growth andbehaviour. “If we could successfully estimate
the distribution of mechanical forces in aplant or animal embryo,” he says, “we could
combine this with microscopic imaging datato achieve new insights into biomechanics
and mechanobiology.”
In prior research, his group developed astrategy for generating tiny forces by using theextremely short but powerful pulses of light
produced by a femtosecond laser. By using
a microscope to focus these laser pulses into
water, Hosokawa’s team was able to generatenanoscale explosions.
In subsequent work, Hosokawa and hiscolleagues applied such femtosecond laser
explosions to produce external forces, which
they used to analyse the stiffness of a stem androot of a plant (see figure). To do this, they
immobilized a segment of a thale cress plant inwater and focused a femtosecond laser pulse ona point in the water some distance away fromthe plant. The resulting explosion generated a
stress wave that spread outward from this focal
point and struck the plant stem. The movementand deformation in the stem induced by the
impact of the stress wave was detected by anatomic force microscope, whose curved siliconprobe (or ‘cantilever’) was placed in contact

with the surface of the stem. By analysing how
the probe bent, the researchers were able to derive information about the stiffness of the plant.
This set-up allowed the researchers to detect
minuscule movements — equivalent to introducing a bend of less than one-thousandth of adegree to the stem. Importantly, since the probethat detects the force is separated from the sourceof the physical stress, it becomes possible to domuch more sophisticated three-dimensional analyses of how forces affect a biological specimen.
Such measurements could, for example,
help chart the internal forces at work as cells
divide and reorganize in a developing embryo.
“We are developing a technology to estimate
the distribution of the mechanical properties
throughout the sample, which is impossible to
do by conventional methods,” says Hosokawa.
Reference
1. Takenaka, M., Iino, T., Nagatani, A. & Hosokawa, Y.
Nanoscale bending movement of biological micro-object induced by femtosecond laser impulse and its
detection by atomic force microscopy. Appl. Phys.
Express 7, 087002 (2014).

Impulse
AFM cantilever

Vibration (nm)Femtosecond laser

2
1
0

–1
Root ofarabidopsis

100 µm0100
Time (µs)

200

300

© 2015 Yoichiroh Hosokawa, Nara Institute of Science and TechnologyThroughout the life of an organism, its
cells are continually moving, stretching
and reorganizing; accurate detection of
the forces underlying these processes could givescientists deeper insights into many biologicalprocesses. A highly sensitive measurement
system developed by researchers at NAIST
in Japan now makes it possible to precisely
detect such biomechanical movements at thenanometre scale1.

An atomic force microscope (AFM) probe is positioned atop a plant root (left) immersed in water. An extremely short laser pulse targeted some distance away
creates a shockwave by heating and vaporizing water. The resulting vibrations in the plant root can be measured from the movement of the AFM probe (right).

More information about the group’s research can be found at the Laser Nano-Manipulation Science Laboratory website:
http://mswebs.naist.jp/english/courses/1447/
NAIST Research Highlights

67

Materials Science

Research Highlights

Nara Institute of Science and Technology | Organic Electronics Laboratory© 2014 Masakazu Nakamura, Nara Institute of Science and Technology

www.naist.jp/en

Carbon nanotubes (CNTs) linked by protein molecules (blue) with a semiconducting core (purple). Orange arrows show electric current flow from hot tocold CNTs. Red arrow indicates phonon scattering.

Semiconductors

Making waste heat
into energy

Combining carbon nanotubes and protein molecules produces electricity from low-temperature
heat sourcesT

hermoelectric devices convert heat
into electrical energy without theneed for moving parts, meaning they
are long-lasting, reliable and environmentally-friendly. It is now even possible to harvest
energy from low-temperature waste heat, thanks
to advances in nanoscale components such ascarbon nanotubes.
Carbon nanotubes (CNTs) are strong, lightand excellent conductors of electricity, making
them promising candidates as thermoelectriccomponents. Their thermal conductivity whenin pure form, however, is too high. For thisreason, researchers at NAIST are working to
improve the thermoelectric properties of CNTs
for use in tiny power generators and even wearable electronics.
Effective thermoelectric devices requirematerials with high electrical conductivity,
low thermal conductivity, and a high ‘Seebeck coefficient’ — the proportion of voltage
generated by temperature differences across thematerial. The higher the coefficient, the betterthe device performs.

Masakazu Nakamura and co-workers at the
NAIST Graduate School of Materials Sciencedeveloped a composite CNT material by inserting biomolecules with semiconducting cores at
the junctions between CNTs1. The CNTs retain
high electrical conductivity, but the biomolecules
help suppress thermal conductivity and enhance
the Seebeck coefficient.
“Conventional modifications to improve
thermoelectric properties in CNTs, such as
impurity doping, usually improve one or twoof these parameters,” explains Nakamura. “Ourproposed method controls the three parameters
independently, quite different from any previous
approach to thermoelectric materials design.”
The team’s main aim was to create a nanostructure which blocks heat transfer but enhances electron mobility. To do this, they used theunique functions of a cage-shaped protein molecule designed at another NAIST laboratory.
“Luckily, the ideal protein molecule for mywork had already been developed by a colleague,
so I neatly side-stepped one of the biggest
challenges in this study,” explains Nakamura.

“Peptides sticking out of the molecule’s
surface help the structure to self-assemble
with the CNTs. The soft shell of the molecule
prevents the heat transfer from one CNT toanother, while the semiconducting core helps
the electric current flow through the CNT
junctions effectively.”Heat scattered at the biomolecular junctions lowers the thermal conductivity of theCNTs, and the steep temperature gradientat the CNT/molecule interface increases theSeebeck coefficient. This combined effectenhances the thermoelectric conversion efficiency of the CNTs.
“We need various methods for energy harvesting in the future,” says Nakamura. “I wantto create thermoelectric stickers, thermoelectric clothes — even walls should be able toproduce energy from waste heat.”

Reference
1.

Ito, M., Okamoto, N., Abe, R., Kojima, H., Matsubara, R.
et al. Enhancement of thermoelectric properties of carbon
nanotube composites by inserting biomolecules at nanotube junctions. Applied Physics Express 7, 075102 (2014).

More information about the group’s research can be found at the Organic Electronics Laboratory webpage:

http://mswebs.naist.jp/LABs/greendevice/index_e.html
68

NAIST Research Highlights

Research Highlights
Materials Science

Nara Institute of Science and Technology | Green Nanosystem Laboratory

www.naist.jp/en

Materials science

Characterizing atomic
orbitals
Pulses of corkscrew-like X-rays prove useful for probing the properties of atomic orbitalsT

he properties of a solid material dependon the behaviour of its electrons:some electrons are localized near the
nucleus, whereas others travel throughout the
crystal lattice. Researchers at Japan’s NAIST
have now shown that an unusual propertyof electromagnetic radiation can provide
previously unavailable information on thesevalence band electrons, enabling more detailed
material characterization1.
An atom is made up a nucleus surrounded byelectrons. The outermost electrons, or valence
electrons, largely determine how an atominteracts with molecules and other atoms. So it
is important to fully understand the propertiesof these electrons.

“Copper is nonmagnetic, whereas nickel,
which has one less electron than copper,
is ferromagnetic,” says NAIST researcher
Fumihiko Matsui. “If we can selectively
excite a valence electron, then we can explore
the behaviour of key atomic orbitals responsible for these electronic properties.”
To achieve this, Matsui and his colleagues
from NAIST’s Green Nanosystem Laboratory and the Japan Synchrotron Radiation
Research Institute have applied their original
method called atomic stereography. In thistechnique, X-ray pulses provide the energy
needed for an electron near the core of an
atom to escape from its nucleus. The X-rays
used by the team have a property known

Modified, with permission, from Ref. 1 © 2015 American Physical Society

[011]
[101]

[010]

[100]

[110]

as angular momentum, which gives them acorkscrew-like shape. This angular momentum is transferred to the escaping photoelectron. By measuring the kinetic energy andemission angle of these photoelectrons, theresearchers can build a ‘stereograph’ of theatomic arrangement around the excited atom.

“

Our aim is to take out valence
electrons from a crystal surface
and study the property of the
newly created excited state.

”

Further electrons, known as Auger electrons, can also escape from the atom as theelectrons shuffle around to fill the gap left
at the core. Measuring the energy of these
Auger electrons can provide further information about the material’s electronic structure.
Matsui and his co-workers have now shown
that, contrary to expectation, Auger electrons
can also have angular momentum.
Matsui’s team fired a corkscrew-like beamof X-rays at a copper sample and measured
the angular distribution of the emitted
Auger electrons. From these maps, they wereable to identify the non-negligible circular properties of the Auger electron. Thisobservation suggests that the hole left behindby the photoexcited core electron is slightly
angular-momentum polarized, which is thenpassed on to the Auger electron.
“Our aim is to take out valence electrons
from a crystal surface and study the propertyof the newly created excited state,” says
Matsui. “By combining Auger electron
measurement and atomic stereography,
we have developed a new technology thatenables such physics.”
Reference

Corkscrew-like X-rays (red) enable electrons to escape from the surface of copper at various angles.

1. Matsui, F., Fujita, M., Ohta, T., Maejima, N.,
Matsui, H. et al. Selective detection of angular-momentum-polarized Auger electrons by atomic
stereography. Physical Review Letters 114,015501 (2015).

More information about the group’s research can be found at the Green Nanosystem Laboratory webpage:
http://mswebs.naist.jp/LABs/matui/index-e.html
NAIST Research Highlights

69

Materials Science

Research Highlights
www.naist.jp/en© MileA/iStock/Thinkstock

Nara Institute of Science and Technology | Nanomaterials and Polymer Chemistry Laboratory

Block copolymer films are promising candidates for stent coatings for controlled drug release.

Polymer chemistry

Switchable surface
wettability

Switchable spin-coated surfaces hold promise for controlled drug release in medical applications

C

ontrolled drug release is essential fora range of medical treatments, fromcontraceptive implants to chemotherapy and vaccinations, and a popular option
is the use of drug-eluting stents (see figure).
The key to this controlled release is being able
to manipulate the surface characteristics ofthe stent coatings — namely, their wettability
and degradability.
Hiroharu Ajiro, formerly of Osaka University, now leading the Nanomaterials and Polymer
Chemistry Laboratory at Japan’s NAIST,
investigated different block copolymer films
to see which afforded ‘switchable’ wettability(transitioning between hydrophilic and hydrophobic behaviour) and slow degradability.
Block copolymers are large polymer chainsconsisting of ‘blocks’ of simpler polymers. Ajiro
and colleagues decided to focus on spin-coatedfilms consisting of block copolymers of L-lactide (LA) and trimethylene carbonate (TMC)
derivatives with methoxyethyl groups. They
then systematically investigated the surface
structural control of their films using contact

angle measurements, X-ray photoelectron spectroscopy and degradation behaviour analysis.
There were some challenges that the researchers had to overcome to fabricate these coatings,
including designing the monomers and synthesizing the polymers to use as ‘blocks’. Ajiro
emphasizes that it was particularly important toattain a balance, “both between the hydrophilic
and hydrophobic properties, and between thesoft and hard domains of the polymers.”
Ultimately the researchers prevailed, producing controllable coatings based on poly(TMC)
and poly(LA) — with contact angle measurements showing dynamic changes betweenhydrophobicity and hydrophilicity1. The films
were tested in two different solvents: water andhexane, exhibiting hydrophilic and hydrophobic
behaviour, respectively. This switchable wettability is believed to be due to the interactionsin the copolymer between the TMC polymer
main chain and the methoxyethyl functionalgroups — the reorientation of the copolymer
making different moieties aggregate on thesurface, thereby influencing its wettability.

Understanding the degradation of the films
is of particular importance for biomedical
applications: the time the film takes to break
down must be appropriate for its intended use.
Ajiro’s team compared the degradation speedof amorphous and crystalline poly(LA) films totheir coating, and found that the degradation
was markedly slower for the crystallized block
copolymer film — making it a much more
appropriate coating for long-term drug release.
Ajiro, who is also a researcher with thePrecursory Research for Embryonic Scienceand Technology (PRESTO) programme of theJapan Science and Technology Agency, notesthat these films hold great promise for a range
of applications, not just in the medical field but
for anything that requires “a switchable coating
surface without degradation conditions.”
Reference
1.

Ajiro, H., Takahashi, Y., Akashi, M. & Fujiwara, T.
Surface control of hydrophilicity and degradability
with block copolymers composed of lactide and cycliccarbonate bearing methoxyethoxyl groups. Polymer
55, 3591–3598 (2014).

More information about the group’s research can be found at the Nanomaterials and Polymer Chemistry Laboratory webpage:

http://mswebs.naist.jp/english/courses/1844/
70

NAIST Research Highlights

NAIST as an International Research University
NAIST research collaborations
around the globe

Europe 555

Joint research publications
with collaborators inAsia 357

56 countries/regions

N. America 547

Japan 5187

Number of joint papers■1-99 ■100-499 ■500-999 ■1000data source: Thomson Reuters InCites Benchmarking (1993-2015)

Africa 11

L. America 11

M. East 31

Oceania 53

International students in NAISTEurope 25

International Students comprise
about

18.6%

N. America 4

Total: 200 students from43 countries/regions
Asia 149

Number of international students■1-9■10-19 ■20-29 ■30-

Africa 10

M. East 2
Oceania 4

As of July 1, 2015

4 research fields

NAIST’s global standing
TOP 1%

thein s tit ut

oni* The Top 1% of institutions is deﬁned by ESI thresholds based on citation
count over a 10-year period.

woglobally according to ESI citations in 4 research ﬁelds

rl d

NAIST ranks among

Top 1% of institutions*

L. America 6

s in the★ Plant & Animal Sciences★ Molecular Biology & Genetics★ Biology & Biochemistry★ Chemistrydata source: Thomson Reuters InCites Essential Science Indicators (2005-2015）

Cover story

NARA INSTITUTE of SCIENCE and TECHNOLOGYR E S E A R C H H I G H L I G H T S 2015
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 proliﬁc ancient heritage, Nara
Prefecture is also conveniently located inclose proximity to Kyoto and Osaka, and just90 minutes from Kansai International Airport.

NARA , JAPAN

8916-5 Takayama-cho, Ikoma, NARA
630-0192 JAPANResearchers at NAIST
unraveled the functions ofgenes responsible for wood
development expressed inmosses (P. patens). These
results will provide versatile
tools for manipulating plantbiomass. [p30]

The illustration on the cover is a traditional Japanese lighting tool
called a “tourou” (lantern), a lampshade protecting its ﬂame fromthe wind. Introduced to Japan together with Buddhism, the tourou
entered a massive production period around the Nara era(A.D.710-794). This traditional Nara craft illuminated the night with ajumping ﬂame and led to the discovery of a new world.
Researchers at NAIST value all local customs and practices
nurtured in the ancient capital of Nara and continue to uncover new
topics while working tirelessly to identify solutions to any and all
challenges that may arise.

NAIST Research Highlights

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y o u rl i m i t s －NAISTRESEARCHHIGHLIGHTS

h ttp : //w w w .nai st.j p/en/

2015