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 Technology and Medical Sciences – Natal Jorge et al. (eds)
© 2011 Taylor & Francis Group, London, ISBN 978-0-415-66822-4

Table of contents

Preface xi
Acknowledgements xiii

Full papers
Modelling, designing and simulating living systems with BlenX 3
P. Lecca
Measurement system of the eye vergence and accommodation with 3D hologram stimulation 15
J. Dušek, T. Jindra & M. Dostálek
3D modelling for FEM simulation of an obese foot 19
V.C. Pinto, N.V. Ramos, M.A.P. Vaz & M.A. Marques
A breast modelling application for surgeons 23
A. Cardoso, H. Costa, V. Sá & G. Smirnov
A framework model for e-Health services 29
M. Macedo & P. Isaías
A possibility for pos-EVAR surveillance: A novel smart stent-graft 35
I.C.T. Santos, J.M.R.S. Tavares, L.A. Rocha, S.M. Sampaio & R. Roncon-Albuquerque
Analysis of the contraction of the pelvic floor through the finite element
method considering different pathologies 39
T.H. da Roza, M.P.L. Parente, R.M. Natal Jorge, T. Mascarenhas, J. Loureiro & S. Duarte
Anticipatory postural adjustments in post-stroke subjects during reaching 43
S. Ferreira, C. Silva, P. Carvalho, A. Silva & R. Santos
Approaches to juxta-pleural nodule detection in CT images 51
A. Massafra
Blood flow in artificial bypass graft: A numerical study 57
L.C. Sousa, C.F. Castro, C.C. António & B. Relvas
Calibration of free hand ultrasound probe tracked by optical system 63
K. Krysztoforski, R. Będziński, E. Świątek-Najwer & P. Krowicki
Contact finite element with surface tension adhesion 69
R.A.P. Hellmuth & R.G. Lima
Crystalline lens imaging with a slit-scanning system 79
C. Oliveira, J.B. Almeida & S. Franco
Design of Medical Rehabilitation Devices: A case study 83
E. Seabra, L.F. Silva, P. Flores & M. Lima
Development of a flexible pressure sensor for measurement of endotension 89
I.C.T. Santos, J.M.R.S. Tavares, A.T. Sepúlveda, A.J. Pontes, J.C. Viana & L.A. Rocha
Development of an adaptable system for a stationary bike to convert mechanical
energy into electric power applied in indoor cyclism training 95
J.B. Soldati, Jr., L.A. Szmuchrowski, D.N. Rocha, F.L. Corrêa, Jr., T.S.P. Sono,
C.B.S. Vimieiro & M. Pinotti

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 Development of computational model to analyze the influence
of fiber direction in the Tympanic Membrane 101
C. Garbe, F. Gentil, M.P.L. Parente, P. Martins, A.J.M. Ferreira & R.M. Natal Jorge
Electronic device for temperature monitoring during the decompression
surgery of the facial nerve 107
S.S.R.F. Rosa, M.L. Altoé, L.S. Santos, C.P. Silva & M.V.G. Morais
Ethical aspects in the design of medical devices 111
J. Ferreira, F. Soares, J. Machado & M. Curado
Evaluation and implementation of technology in health care 115
R. Santos
Frequency domain validation of a tetrapolar bioimpedance spectroscopy
system with tissue equivalent circuit 119
A.S. Paterno, V.C. Vincence & P. Bertemes-Filho
Highly Focalized Thermotherapy: A minimally invasive technique
for the treatment of solid tumours 123
A. Portela, M. Vasconcelos & J. Cavalheiro
Identification of rib boundaries in chest X-ray images using elliptical models 129
L. Brás, A.M. Jorge, E.F. Gomes & R. Duarte
Improving diagnosis processes through multidimensional analysis in medical institutions 135
O. Belo
In vivo measurement of skeletal muscle impedance from rest to fatigue 143
O.L. Silva, I.O. Hoffmann, J.C. Aya, S. Rodriguez, E.D.L.B. Camargo,
F.S. Moura, T.H.S. Sousa, R.G. Lima, A.R.C. Martins & D.T. Fantoni
Influence on the mandible and on a condyle implant of the distribution
of the fixation surgical screws 147
A. Ramos, M. Mesnard, C. Relvas, A. Completo & J.A. Simões
Intensity inhomogeneity corrections in MRI simulated images for segmentation 151
R. Lavrador, L. Caldeira, N.F. Lori & F. Janela
Interactive collaboration for Virtual Reality systems related
to medical education and training 157
B.R.A. Sales, L.S. Machado & R.M. Moraes
Lissajous scanning pattern simulation, for development of a FLO 163
P. Nunes & P. Vieira
Measuring the pressure in a laryngoscope blade 169
A. Silva, J. Teixeira, P. Amorim, J. Gabriel, M. Quintas & R.M. Natal Jorge
Mechanical properties of temporalis muscle: A preliminary study 173
V.L.A. Trindade, S. Santos, M.P.L. Parente, P. Martins, R.M. Natal Jorge,
A. Santos, L. Santos & J. Fernandes
Medial-lateral CoP-rearfoot relation during stance 177
T.J.V. Atalaia & J.M.C.S. Abrantes
Multidisciplinary interactions for the development of medical devices 183
R. Simoes
Multi-objective optimization of bypass grafts in arteries 191
C.F. Castro, C.C. António & L.C. Sousa
Multiple Sclerosis subjects plantar pressure—A new tool for postural
instability diagnosis 197
L.F.F. Santos & J.M.C.S. Abrantes

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 Neurom: A motor treatment system for chronic stroke patients 205
F.L. Corrêa, Jr., R.C. de Araújo, D.N. Rocha, T.S.P. Sono, L.R. dos Santos,
A.M.V.N. Van Petten & M. Pinotti
Non-invasive diagnosis and monitoring of Cystic Fibrosis
by mass spectrometry of the exhaled breath 209
S. Gramacho, M. Piñeiro, A.A.C.C. Pais, A.M.d’A.R. Gonsalves, F. Gambôa & C.R. Cordeiro
Noninvasive assessment of Blood-Retinal Barrier function
by High-Definition Optical Coherence Tomography 215
T. Santos, R. Bernardes, A. Santos & J. Cunha-Vaz
OCT noise despeckling using a 3D nonlinear complex diffusion filter 221
C. Maduro, R. Bernardes, P. Serranho, T. Santos & J. Cunha-Vaz
Possible relations between female pelvic pathologies and soft tissue properties 227
P.A.L.S. Martins, R.M. Natal Jorge, A.L. Silva-Filho, A. Santos, L. Santos,
T. Mascarenhas & A.J.M. Ferreira
Processing and classification of biological images: Application to histology 233
B. Nunes, L.M. Rato, F.C. Silva, A. Rafael & A.S. Cabrita
Reducing and preventing drug interactions–An approach 239
R. Barros & F. Janela
Registration of bone ultrasound images to CT based 3D bone models 245
P.J.S. Gonçalves & P.M.B. Torres
Segmentation and 3D reconstruction of the vocal tract from MR images—A comparative study 251
S.R. Ventura, D.R. Freitas, I.M. Ramos & J.M.R.S. Tavares
Significance of fast and simple determination of catecholamines
and their metabolites in patients with Down syndrome 257
L.I.B. Silva, M.E. Pereira, A.C. Duarte, A.M. Gomes, M.M. Pintado, H. Pinheiro,
D. Moura, A.C. Freitas & T.A.P. Rocha-Santos
Study of pressure sensors placement using an Abdominal Aortic Aneurysm (AAA) model 261
L.A. Rocha, A. Sepulveda, A.J. Pontes, J.C. Viana, I.C.T. Santos & J.M.R.S. Tavares
Termographic assement of internal derangement of the temporomandibular joint 267
M. Clemente, A. Sousa, A. Silva, J. Gabriel & J.C. Pinho
The action of middle ear muscles using the finite element method 271
F. Gentil, C. Garbe, M. Parente, P. Martins & R.M. Natal Jorge
The contribution of the scapular patterns to the amplitude of shoulder external
rotation on thrower athletes 275
A.M. Ribeiro & A.G. Pascoal
Influence of an unstable shoe on compensatory postural adjustments 279
A.S.P. Sousa, R. Macedo, R. Santos & J.M.R.S. Tavares
The use of muscle recruitment algorithms to better assess problems
for children with gait deficiency 285
M. Voinescu, D.P. Soares, M.P. Castro, A.T. Marques & R.M. Natal Jorge
Using an Infra-red sensor to measure the dynamic behaviour
of N2O gas escaping through different sized holes 289
A.P. Slade, D. Convales, J. Vorstius & G. Thomson
Visual tracking of surgical instruments, application to laparoscopy 293
P.J.S. Gonçalves & A.M.D. Gonçalves
Wavelet analysis of the pupil’s autonomic flow 297
G. Leal, P. Vieira & C. Neves

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 White matter segmentation in simulated MRI images using the Channeler Ant Model 301
E. Fiorina

Abstracts
In-silico models as a tool for the design of medical device technologies 307
J.M. García-Aznar, M.A. Pérez, M.J. Gómez-Benito, J.A. Sanz-Herrera & E. Reina-Romo
3D biomechanical model of the human hand using FEM 309
D.N. Rocha, R.M. Natal Jorge & M. Pinotti
99m
Using radiobiology simulators for evaluation of Tc Auger electrons
for targeted tumor radiotherapy 311
A.A.S. Tavares & J.M.R.S. Tavares
Therapeutic contact lenses obtained by SCF-assisted imprinting processes:
Improved drug loading/release capacity 313
M.E.M. Braga, M.H. Gil, H.C. de Sousa, F. Yañez, C. Alvarez-Lorenzo,
A. Concheiro & C.M.M. Duarte
Supercritical solvent impregnation of natural bioactive compounds in N-carboxybutyl chitosan
membranes for the development of topical wound healing applications 315
A.M.A. Dias, I.J. Seabra, M.E.M. Braga, M.H. Gil & H.C. de Sousa
Potential and suitability of Ion Mobility Spectrometry (IMS) for breath analysis 317
V. Vassilenko, A.M. Bragança, V. Ruzsanyi & S. Sielemann
Phosphonium-based ionic liquids as new Greener plasticizers
for poly(vinyl chloride) biomedical applications 319
S. Marceneiro, A.M.A. Dias, J.F.J. Coelho, A.G.M. Ferreira, P.N. Simões, M.E.M. Braga,
H.C. de Sousa, C.M.M. Duarte, I.M. Marrucho, J.M.S.S. Esperança & L.P.N. Rebelo
New approach to bone surface reconstruction from 2.5D sonographic dataset 321
P. Krowicki, K. Krysztoforski, E. Świątek-Najwer & R. Będziński
Metal-Organic Framework as potential drug carriers against inflammation 325
I.B.V. Santos, T.G. da Silva & S. Alves, Jr.
Knowledge based system for medical applications 327
C.S. Moura, P.J. Bártolo & H.A. Almeida
In vitro method for test and measure the accuracy of implant impression 329
F.J. Caramelo, P. Brito, J. Santos, A. Carvalho, G. Veiga, B. Vasconcelos, J.N. Pires & M.F. Botelho
Improving the resolution of scintigraphic images with super-resolution:
Development of a dedicated device 333
R. Oliveira, F.J. Caramelo & N.C. Ferreira
Hyperbolic surfaces for scaffold design 337
H.A. Almeida & P.J. Bártolo
Finite element analysis of a three layered cartilage 339
D.M. Freitas, P.J. Bártolo & H.A. Almeida
External breast radiotherapy treatment planning verification
using advanced anthropomorphic phantoms 341
J.A.M. Santos, J. Lencart, A.G. Dias, L.T. Cunha, C. Relvas, A. Ramos & V.F. Neto
Blood Volume Pulse peak detector with a double adaptive threshold 345
J. Medeiros, R. Martins, S. Palma, H. Gamboa & M. Reis
Bilateral study on arterial stiffness assessment by a non-invasive optical
technique of Photoplethysmography 349
V. Vassilenko, A.C. Silva, A.M. Martin & J.G. O’Neill

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 A biomimetic strategy to prepare silica- and silica/biopolymer-based
composites for biomedical applications 351
R.B. Chim, M.E.M. Braga, M.M. Figueiredo, H.C. de Sousa, C.R. Ziegler & J.J. Watkins
Non-invasive biomonitoring of human health: Technical developments in breath analysis 353
V. Vassilenko

Author index 355

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 Technology and Medical Sciences – Natal Jorge et al. (eds)
© 2011 Taylor & Francis Group, London, ISBN 978-0-415-66822-4

Preface

The International Conference on Technology and Medical Sciences – TMSi is a roving meeting, organized
every two years since 2000 alternating between cities in Brazil and Europe, devoted to be an open and
multidisciplinary discussion forum on novel concepts, new developments and innovations relating to
Technology and Medical Sciences in order to solidify knowledge in these fields and define their key
stakeholders.
This book contains keynote lectures and full papers presented at TMSi 2010, the 6th International
Conference on Technology and Medical Sciences, which was held in Faculdade de Engenharia da Univer-
sidade do Porto (FEUP), Portugal, during the period 21–23 October 2010.
TMSi 2010 had 4 invited lectures, 57 oral presentations in ten sessions and 13 posters, representing
contributions from 12 countries: Brazil, Cuba, Czech Republic, France, Italy, Japan, Lithuania, Poland,
Portugal, Romania, United Kingdom and the United States of America. The received contributions
addressed many different topics, including Analysis and diagnosis, Applications in medicine, Bioengineer-
ing, Biomedical devices, Computational methods, Computer aided diagnosis, Computer assisted surgery,
Imaging, Minimally invasive devices and techniques, Prosthesis and orthosis, Rehabilitation, Technical
aids, Telemedicine and Virtual reality.
TMSi 2010 brought together researchers representing several scientific domains, including Biomechan-
ics, Computational Vision, Computational Mechanics, Computer Graphics, Mathematics, Medicine,
Robotics, Simulation and Statistics, that spanned a broad range of techniques and technologies.
The organizers of TMSi 2010 would like to take this opportunity to thank all the sponsors, members of
the Scientific Committee, Invited Lecturers and the Authors for submitting and sharing their work.

R.M. Natal Jorge

João Manuel R.S. Tavares
Marcos Pinotti Barbosa
Alan Peter Slade

xi

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 Technology and Medical Sciences – Natal Jorge et al. (eds)
© 2011 Taylor & Francis Group, London, ISBN 978-0-415-66822-4

Acknowledgements

The organizers of the 6th International Conference on Technology and Medical Sciences – TMSi 2010
acknowledge the support towards the publication of this book and the organization of TMSi 2010 by the
following organizations:
– Faculdade de Engenharia da Universidade do Porto
– Fundação para a Ciência e a Tecnologia (FCT)
– Instituto de Engenharia Mecânica—Pólo FEUP (IDMEC-Polo FEUP)
– Instituto de Engenharia Mecânica e Gestão Industrial (INEGI)
– Associação Brasileira de Engenharia e Ciências Mecânicas (ABCM)
– Grupo Publindústria

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 Full papers

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 Technology and Medical Sciences – Natal Jorge et al. (eds)
© 2011 Taylor & Francis Group, London, ISBN 978-0-415-66822-4

Modelling, designing and simulating living systems with BlenX

P. Lecca
The Microsoft Research—University of Trento, Trento, Italy
Centre for Computational and Systems Biology, Povo, Trento, Italy

ABSTRACT: In the past, many scientists and philosophers have been inspired by the parallel between
nature and human design, in mathematics and engineering. Today, the huge increase in biological knowl-
edge, together with the developments in computer simulation modelling, and in design engineering sys-
tems, have made more comprehensive system-level studies of nature possible. The modern biological,
medical, and pharmaceutical research approaches computing not only under the need of data mining
and processing, but also under the need of using new languages for describing, designing and simulating
biological entities and interactions. Although the techniques of the infinitesimal calculus have been rec-
ognized to provide valuable computational tools in simulating dynamic systems, they often do not offer
the possibility to nimbly capture the intrinsic concurrency, causality, compositionality and probabilistic
nature of biological interactions. This talk will present the BlenX language, that has been recently devel-
oped at CoSBi. BlenX is a programming language implementing the Beta-binders calculus. This calculus
is a process algebra developed to model the time evolution of biological systems at any scale (from molec-
ular to ecological systems). Namely, its syntactical and semantic structures have been specifically built to
represent a biological entities and the network of its interactions with the other entities and components
of a system. The richness and the level of abstraction of its syntax enable the modeler to describe through
this calculus either the biochemical interactions between atom, molecules, functional complexes, cells, tis-
sues at the micro- and meso-scale or the interactions and the relationships among the individuals of an
ecological system. Some examples of application of BlenX to model living systems are given.

1 INTRODUCTION equations the time evolution of the state of each

single variable of the system. If the system is com-
In these years the experimental and the compu- posed by a large number of elements it is possible
tational research approaches in the life sciences to obtain suitable local in space averages of their
are abandoning the reductionist vision to adopt a state in an elementary space volume ideally tending
system-level point of view. Unlike the reduction- to zero (Bellomo 2008). In this case the modelling
ist approach, the framework of the systems theory can be developed at the macroscopic scale, which
proposes an integrative planning out to model com- describes the time behavior of locally averaged
plex biological phenomena. The integrative model- quantities called macroscopic variables. Moreo-
ling is the main aspect of the systems biology. This ver, generally the modelling is deterministic. i.e.,
emerging discipline describes the activity of bio- it follows deterministic causality principles: unless
logical entities, such as biochemical networks, cells, some external noise is added, once a cause is given,
tissues, organs, and organisms, as the result of the the effect is determined. The macroscopic model-
properties and the mutual interactions of the sin- ling scale can still be applied when the number of
gle components of these systems. In particular, system components is sufficiently large and a suffi-
systems biology integrates the knowledge about ciently small volume still contains enough elements
structure and functions of the components of a to allow the averaging process mentioned above.
systems obtained by the past reductionist investi- It is generally believed that understanding the
gation methodologies with the current knowledge properties and the time evolution of a system fol-
about the dynamical processes concerning those low from a detailed knowledge of the state of each
components. of its elements. Consider as an illustrative example
Systems of living entities are composed of several a system composed by a certain number of parti-
interacting elements. This implies that mathemati- cles (proteins, molecules, ions, functional complex,
cal models can be designed at various observa- etc). At microscopic molecular level the states of
tion and representation scales. The microscopic the particles evolve according to the laws of classi-
scale corresponds to model, by integro-differential cal mechanics that describes with a system of first

TMSi 2010.indb 3 12/8/2010 5:21:44 PM

 order differential equations the time behavior of number of the system components is small and it
the position and velocity of each particle of the is exalted when the system includes parallel and/or
system. If the initial values position and velocity concurrent interactions. Biological processes often
are known, the system of differential equations can are stochastic, parallel and concurrent. Therefore,
be solved. and the macroscopic properties of the living systems require a descriptive approach sub-
physical system can be obtained as averages involv- stantially different from differential equations. It
ing the microscopic information contained in such has to be able to represent parallelism and concur-
a solution. However, it is very hard to implement rency of the interactions, that at the microscopic
such a program. Even in principle, it is impossi- scale derive from the multiple functionalities of
ble to predict the exact molecular population lev- the proteins and molecular functional complexes,
els at some future time unless we know the exact whereas at the ecological scale are the engine of
positions and velocities of all the particles of the Darwinian selection.
systems. D. Gillespie in (Gillespie 1977) points out In this article we first describe the BlenX lan-
that a reacting system of classical molecules is a guage and then we present two time-continuous
deterministic process in the position-momentum discrete stochastic models specified in BlenX
phase space, but it is not a deterministic process language (Dematté et al. 2008b) and simulated
in the multidimensional subspace of the species with Beta WB simulator (Dematté et al. 2008a):
population numbers. (i) a model of ubiquitin-proteasome system, and
An alternative to the deterministic approach is (ii) a simple predatory-prey model. BlenX imple-
the stochastic representation, where the state of ments a stochastic process calculus explicitly devel-
the whole system is described by a suitable prob- oped to represent biochemical entities and their
ability distribution function over the macroscopic interactions at the micro- and meso-scale. BlenX is
state of the interacting system. In this article, we part of the software platform CoS-BiLab, on which
will focus on the discrete-space continuous-time our group is currently working and that imple-
stochastic modelling, because the living systems ments a new conceptual modeling, analysis and
either at the molecular scale or at the ecological simulation approach—primarily inspired by algo-
scale are composed by a discrete number of parti- rithmic systems biology (Priami 2009)—to biologi-
cles and individuals, respectively. At the molecular cal processes. Algorithmic systems biology grounds
scale the adoption of stochastic representation is on the belief that algorithms and computer-science
recommended when the number of molecules is formalisms—like processes calculi—can help not
small, whereas at the large scale typical of ecologi- only in modelling well established knowledge but
cal systems it is recommended when the network also in coherently extracting the key biological
of interactions among species is inherently affected principles that underlie the experimental observa-
by factors of random noise. tions (Priami 2009).
The deterministic and the stochastic essence of The BlenX language offers to the modeler the
a natural process depends on the properties of the possibility to address parallelism and concurrency
components of the system and on the physics of the of interactions, to express causality of the interac-
characteristic interactions among them. For exam- tions, to represent multifunctionality of living enti-
ple, chemical reactions are due to random colisions ties. Moreover, BlenX formalisms is quantitative,
between interacting particles. Another example: interaction-driven, composable, scalable and mod-
random motion of genetic particles imbues the ular, and thus able to represent not only the main
cellular environment with intrinsic noise that fre- static features of modularity and compositionality
quently causes cell to cell variability and even sig- of a living system, but also the principal character-
nificant phenotypic differences within a clonal cell istic of its quantitative time evolution.
population. Extending our glance to ecosystems, if
population sizes are small, then models should be
stochastic: the effects of fluctuations due of popu- 2 THE BLENX LANGUAGE
lation size must be explicitly analyzed. Nowadays,
stochastic models in ecology have begun to be sys- BlenX is a programming language implementing
tematically studied because of their relevance to the Beta-binders calculus. here we provide a
biological conservation. descriptive user-point-of-view introduction to the
The difference between the deterministic and the fundamental units, operators, and “actions” of this
stochastic nature of a biological or physical proc- language. We refer the reader to (Dematté et al.
ess requires also different modelling languages. In 2008a, Dematté et al. 2008b, cos) for a detailed
life science differential equations are appropriate technical description of the language.
for continuous time, continuous space modelling In computer science, the process calculi (or
of systems composed by a large number of ele- process algebras) are a diverse family of related
ments. The stochasticity manifests itself when the approaches to formally modelling concurrent

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 systems. Beta-binders in particular is an extension
of the stochastic π-calculus (Priami 1995). Beta-
binders calculus, as the other members of the
family of process algebras, is based on the notion
of communication described through a set of tem-
porally ordered actions. The fundamental units of
the calculus are the interlocutors of this commu-
nication, represented by computational processes.
Just as in a conversation, the main actions that a
computational process can take are sending and
receiving messages. To denote a chain of events,
the action prefix operator is used, which is written
as an infix dot. For instance, a! . b? . P denotes a
process that may offer action on a, then offers an
action on b, and finally behaves as process P . a
Figure 1. A pictorial view of a box. The sites of
and b are the channels through which the commu- interaction are represented as binders on the box surface.
nication take place. The behaviour of the process In this figure, the box has only one binder identified by
a!.b?.P consists of sending a signal over the its name x and its type A, and an internal process P.
channel a (a!) and waiting for a message over a
channel b(b?). The processes can be composed in
parallel. Parallel composition (denoted by the infix of the interaction between boxes. Two boxes are
operator |, for instance P|Q) allows the descrip- likely to interact if their interface contains binders
tion of processes which may run independently in whose types are affine, i.e. binders whose affinity
parallel and also synchronize on complementary if non null.
actions (by complementary action we mean a send The BlenX language adds to the actions
and a receive over the same channel). Commu- defined in the original Beta-binders calculus new
nication between processes is always binary and actions that extend the possibilities to define and
synchronous. The rep operator replicates copies control the way in which a box evolves. The evolu-
of the process passed as argument. Only guarded tion of the interfaces of a box is driven by suitable
replication is used, i.e. the process argument of this actions that are defined by the processes inside the
operator must be prefixed by an action that for- box. Such actions are named hide,unhide,ch
bids any other action of the process untile the first (i.e. “change”) and expose. These actions corre-
action has been executed. In addiction to the par- sponds to the following transformation of the sta-
allel composition processes can be also composed tus of a binder: hide disables any communication
through a non deterministic choice, indicated with through the binder, by hiding it from the tentatives
the summation operator “+”. The sum of processes of communication with binders of other boxes;
P and Q,P + Q behaves either as P or as Q and selec- unhide takes the opposit action: it enable com-
tion of an alternative discards the other forever. To munication through the binder, by undisclosing it
represent a deadlock situation, where the process is to the view of other boxes; change changes the
unable to perform any sort of action or co-action, type of the binder; and expose adds a new binder
the nil operator is used. to the box interface. The evolution of the proc-
Beta-binders calculus adds to these simple syn- esses inside a box that do not directly affects the
tactical elements boxes, also called bio-processes, interface can be defined by the following actions:
that can be intuitively pictured as shapes encap- send/receive action between processes (called intra-
sulating processes. Formally, the boxes are defined communication; and delay action that imposes
by unique identifiers that express the interaction a delay of a certain amount of time before the
capabilities of the processes encapsulated. These execution of subsequent actions.
identifiers, called binders can be pictured as interac- The execution of the actions can be controlled
tion sites put in charge of allowing the inter-boxes with if-then statements, used to express condi-
communication. Consider Fig. 1. A binder is a pair tions that need to be satisfied before executing the
(x,A), written as x,A, where x is the name used actions defined in the statement. Finally, a box can
by the internal process P to perform send/receive be eliminated from the system by executing the
actions, while the binder identifier A, called type, action die.
expresses the interaction capabilities at the site x. Boxes can interact in different ways: the can join
The usefulness of the type of binder can be under- (join is the action verb), they can form complexes,
stood if we consider the interaction between boxes. they can send/receive information each to other
The type A is a syntactical structure through which through dedicated binders (inter-communication,
it is possible to quantitatively express the affinity and a box can split in tow boxes (split is the

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 verb of this event). New boxes can be created (new steps: 1. initialization of the number of molecules
is the corresponding action verb), boxes can be in the system, reactions constants, and random
eliminated (delete is the action verb). join, number generators; 2. (Monte Carlo step) gen-
split, new, delete are verbs of events. An eration of random numbers to sample from an
event is the composition of a condition and an uniform and an exponential probability density
action verb. namely, events are used to express respectively the next reaction to occur as well as
actions that are enabled by global conditions. the time interval. The probability of a given reac-
Boxes can be interpreted as biological entities, tion to be chosen is proportional to the number
i.e. components that interact in a model to accom- of substrate molecules. 3. Update: the time step
plish some biological function: proteins, enzymes, is increased by the randomly generated time in
organic or inorganic compounds as well as cells or step 2., and the molecule count is updated on
tissues. Binders of boxes are models of molecules the basis of the reaction that occurred. 4. Itera-
interaction sites, protein sensing and effecting tion: the algorithm execute all the steps from Step
domains. The biochemical interactions between 1 unless the number of reactants is zero or the
the biological entities are abstracted as commu- simulation time has been exceeded.
nications between boxes and join events, whereas In order to enable the reader to catch the potenti-
conformational changes, allosteric reactions, and alities and teh essence of BlenX, we show in Fig. 2 the
zero-th order degradation or production are estab- result of the execution of an inter-communication,
lished respectively by the processes inside the box, that will be largely used in our models. The proc-
by split actions, by delete and new actions. ess inside the first box can receive a message on
Regard to conformational change and allosteric channel x, that is bound to an active binder of
reaction, for instance, the internal structure of a the box ((x:1,A)). The process inside the sec-
box can codify for the mechanism that transforms ond box sends a message through the active binder
an input signal into a protein conformational ((x:1, A)) through the action y!(). The empty
change, which can result in the activation or deac- brackets in these actions mean that, in this model,
tivation of another domain. there is no need to specify the object of communi-
In order to obtain quantitative simulations of a cation. The exchange of information between the
BlenX model, a specific speed (or rate constant) is two box is permitted only if the binders involved
associated to each action. This attribute is a gen- in the communication are compatible, i.e., if their
eralization of the rate constant of a biochemical affinity is non null. Once the communication has
interaction. The affinity between two binder types occurred, their change of state if reflected by the
is a number that can quantify chemical affinity in a modification of the internal processes: the execu-
reaction, but also the degree of structural comple- tion of the inter-communication results in the
mentarity in key-lock reaction mechanisms. The “disappearance” of the channels x and y and with
magnitude The dynamics of a BlenX model is gov- the exposure of the subsequent action, that in this
erned by the values of these rate constants and is example is simply the deadlock process.
stochastically defined an efficient adaptation of the In Fig. 3 a small model of the interaction between
Gillespie algorithm (Gillespie 1977). The physical a nascent protein and a chaperone, and between
basis of the algorithm is the collision of molecules mis-folded protein and proteasome.
within a reaction vessel. It is assumed that colli- A Nascent Protein (NP) is a box. Its interface
sions are frequent, but collisions with the proper is defined by two binders (y:1, P) and
orientation and energy are infrequent. Therefore, (prot:1,PTSP). The number 1 after the name
all reactions within the Gillespie framework must of the binder indicate the value of th especific
involve at most two molecules. Reactions involving speed of the activity involving the binder. The
three molecules are assumed to be extremely rare internal structure is specified by the process
and are modeled as a sequence of binary reactions. in (1). This process expresses a non determin-
It is also assumed that the reaction environment istic choice (“+”) between the process y?().
is well mixed. The algorithm executes four main ch(100,y,DR).hide(1,ubi).nil and

Figure 2. Graphical representation of an inter-communcation.

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