Retinal drug delivery: rethinking outcomes for the efficient replication of retinal behavior

The retina is a highly organized structure that is considered to be "an approachable part of the brain." It is attracting the interest of development scientists, as it provides a model neurovascular system. Over the last few years, we have been witnessing significant development in the knowledge of the mechanisms that induce the shape of the retinal vascular system, as well as knowledge of disease processes that lead to retina degeneration. Knowledge and understanding of how our vision works are crucial to creating a hardware-adaptive computational model that can replicate retinal behavior. The neuronal system is nonlinear and very intricate. It is thus instrumental to have a clear view of the neurophysiological and neuroanatomic processes and to take into account the underlying principles that govern the process of hardware transformation to produce an appropriate model that can be mapped to a physical device. The mechanistic and integrated computational models have enormous potential toward helping to understand disease mechanisms and to explain the associations identified in large model-free data sets. The approach used is modulated and based on different models of drug administration, including the geometry of the eye. This work aimed to review the recently used mathematical models to map a directed retinal network.The authors acknowledge the financial support received from the Portuguese Science and Technology Foundation (FCT/MCT) and the European Funds (PRODER/COMPETE) for the project UIDB/04469/2020 (strategic fund), co-financed by FEDER, under the Partnership Agreement PT2020. The authors also acknowledge FAPESP – São Paulo Research Foundation, for the financial support for the publication of the article.info:eu-repo/semantics/publishedVersio

Bio-Inspired Computer Vision: Towards a Synergistic Approach of Artificial and Biological Vision

To appear in CVIUStudies in biological vision have always been a great source of inspiration for design of computer vision algorithms. In the past, several successful methods were designed with varying degrees of correspondence with biological vision studies, ranging from purely functional inspiration to methods that utilise models that were primarily developed for explaining biological observations. Even though it seems well recognised that computational models of biological vision can help in design of computer vision algorithms, it is a non-trivial exercise for a computer vision researcher to mine relevant information from biological vision literature as very few studies in biology are organised at a task level. In this paper we aim to bridge this gap by providing a computer vision task centric presentation of models primarily originating in biological vision studies. Not only do we revisit some of the main features of biological vision and discuss the foundations of existing computational studies modelling biological vision, but also we consider three classical computer vision tasks from a biological perspective: image sensing, segmentation and optical flow. Using this task-centric approach, we discuss well-known biological functional principles and compare them with approaches taken by computer vision. Based on this comparative analysis of computer and biological vision, we present some recent models in biological vision and highlight a few models that we think are promising for future investigations in computer vision. To this extent, this paper provides new insights and a starting point for investigators interested in the design of biology-based computer vision algorithms and pave a way for much needed interaction between the two communities leading to the development of synergistic models of artificial and biological vision

Artificial societies and information theory: modelling of sub system formation based on Luhmann's autopoietic theory

This thesis develops a theoretical framework for the generation of artificial societies. In particular it shows how sub-systems emerge when the agents are able to learn and have the ability to communicate. This novel theoretical framework integrates the autopoietic hypothesis of human societies, formulated originally by the German sociologist Luhmann, with concepts of Shannon's information theory applied to adaptive learning agents. Simulations were executed using Multi-Agent-Based Modelling (ABM), a relatively new computational modelling paradigm involving the modelling of phenomena as dynamical systems of interacting agents. The thesis in particular, investigates the functions and properties necessary to reproduce the paradigm of society by using the mentioned ABM approach. Luhmann has proposed that in society subsystems are formed to reduce uncertainty. Subsystems can then be composed by agents with a reduced behavioural complexity. For example in society there are people who produce goods and other who distribute them. Both the behaviour and communication is learned by the agent and not imposed. The simulated task is to collect food, keep it and eat it until sated. Every agent communicates its energy state to the neighbouring agents. This results in two subsystems whereas agents in the first collect food and in the latter steal food from others. The ratio between the number of agents that belongs to the first system and to the second system, depends on the number of food resources. Simulations are in accordance with Luhmann, who suggested that adaptive agents self-organise by reducing the amount of sensory information or, equivalently, reducing the complexity of the perceived environment from the agent's perspective. Shannon's information theorem is used to assess the performance of the simulated learning agents. A practical measure, based on the concept of Shannon's information ow, is developed and applied to adaptive controllers which use Hebbian learning, input correlation learning (ICO/ISO) and temporal difference learning. The behavioural complexity is measured with a novel information measure, called Predictive Performance, which is able to measure at a subjective level how good an agent is performing a task. This is then used to quantify the social division of tasks in a social group of honest, cooperative food foraging, communicating agents

A space-variant visual pathway model for data efficient deep learning

We present an investigation into adopting a model of the retino-cortical mapping, found in biological visual systems, to improve the efficiency of image analysis using Deep Convolutional Neural Nets (DCNNs) in the context of robot vision and egocentric perception systems. This work has now enabled DCNNs to process input images approaching one million pixels in size, in real time, using only consumer grade graphics processor (GPU) hardware in a single pass of the DCNN

Ohjelmistokehitys lämpötilakontrolloidun silmänpohjan epiteelisolujen lämmityslaitetta varten

Age-related macular degeneration (AMD) was the leading cause for unavoidable blindness in 2010 and continues to affect an estimated 150 million people worldwide. It has been suggested that heating the retinal pigment epithelium (RPE) could slow down the progress of the disease or even cure it entirely. The treatment consists of heating the retina of an eye to therapeutic temperatures to inflict the generation of heat-shock proteins (HSPs). A device that relies on electroretinogram (ERG) recordings while inflicting local hyperthermia on the RPE has been developed in our research team. The measured ERG responses can be characterised and shown a direct dependency to the experienced temperature at the retina. These in turn are utilised in controlling the heating of the retina to therapeutic temperatures. The aim of this thesis was to implement a new software for the use of such a device, while considering the needs this software must account for to facilitate a reliable, safe and useful software interaction for the RPE heating device. Eight distinct requirements for the new software were identified: maintainability; dynamicity; accuracy and precision; pulse sequences; automation; safety, error handling and user friendliness; testing and validation; as well as documentation. The software was implemented with National Instruments LabVIEW™ and MathWorks MATLAB®. The results were validated and verified with unit testing, bench testing and in a full experiment on a mouse subject. The bench testing and mouse experiment testing provided satisfying results. The software functioned without errors during both types of testing or only had very minute types of errors. The software could still be developed to contain more automation, such as factoring in safety features through eye movement detection and more importantly facilitating feedback-controlled heating through a PID controller, which would be of importance when planning clinical trials and use of the device in treatment of AMD.Silmänpohjan ikärappeuma (AMD) oli yleisin vailla parannuskeinoa oleva, sokeutta aiheuttava sairaus vuonna 2010, ja se vaikuttaa noin 150 miljoonan ihmisen elämään maailmanlaajuisesti. Kirjallisuudessa on esitetty, että silmänpohjan pigmenttiepiteelikerroksen (RPE) lämmittäminen voisi hidastaa taudin kulkua tai parantaa sen kokonaan. Tällainen hoito saavutettaisiin lämmittämällä silmänpohjaa terapeuttisiin lämpötiloihin, jolloin saadaan aikaan lämpösokkiproteiinien (HSP) muodostumista. Tutkimusryhmässämme on kehitetty laite, joka perustuu elektroretinogrammin (ERG) rekisteröintiin, samalla kun lämmityslaserilla aiheutetaan RPE:lle paikallinen hypertermia. Talteenotetulla ERG:llä voidaan estimoida silmänpohjan lämpötilaa. Estimoitua lämpötilaa hyödynnetään lämmityslaserin säätämisessä terapeuttiselle lämpötila-alueelle. Tämän diplomityön tavoitteena oli implementoida uusi ohjelmisto kyseistä laitetta varten, samalla ottaen huomioon luotettavuus- ja turvallisuusnäkökulmia, sekä muita hyödyllisiä ominaisuuksia laitteen ja ohjelmiston yhteistoiminnassa. Työssä määriteltiin kahdeksan eri vaatimusta uudelle ohjelmistolle: ylläpidettävyys; dynaamisuus; tarkkuus ja täsmällisyys; pulssisekvenssit; automaatio; turvallisuus, virheiden käsittely ja käyttäjäystävällisyys; verifiointi ja validointi; sekä dokumentointi. Ohjelmisto toteutettiin käyttäen ohjelmistoja: National Instruments LabVIEW™ sekä MathWorks MATLAB®. Ohjelmisto validoitiin testaamalla kaikki osiot erikseen (yksikkötestaus) sekä koko ohjelmisto mittausta simuloivassa tilanteessa. Lopuksi ohjelmisto testattiin myös oikeassa hiiren silmänpohjan lämmityskokeessa. Testauksissa ohjelmisto toimi halutulla tavalla ja esiintyneet virheet pystyttiin nopeasti korjaamaan viimeistä versiota varten. Ohjelmistoa voidaan jatkossa kehittää sisältämään enemmän automaatiota, kuten turvallisuusominaisuuksia silmän liikkeiden tunnistamiseen sekä lämmityksen säätämiseen takaisinkytkentämenetelmällä. Molemmat olisivat tärkeitä ominaisuuksia siirryttäessä kliiniseen tutkimukseen ja laitteen kliiniseen käyttöön AMD:n hoitamiseksi

Gaze control modelling and robotic implementation

Although we have the impression that we can process the entire visual field in a single fixation, in reality we would be unable to fully process the information outside of foveal vision if we were unable to move our eyes. Because of acuity limitations in the retina, eye movements are necessary for processing the details of the array. Our ability to discriminate fine detail drops off markedly outside of the fovea in the parafovea (extending out to about 5 degrees on either side of fixation) and in the periphery (everything beyond the parafovea). While we are reading or searching a visual array for a target or simply looking at a new scene, our eyes move every 200-350 ms. These eye movements serve to move the fovea (the high resolution part of the retina encompassing 2 degrees at the centre of the visual field) to an area of interest in order to process it in greater detail. During the actual eye movement (or saccade), vision is suppressed and new information is acquired only during the fixation (the period of time when the eyes remain relatively still). While it is true that we can move our attention independently of where the eyes are fixated, it does not seem to be the case in everyday viewing. The separation between attention and fixation is often attained in very simple tasks; however, in tasks like reading, visual search, and scene perception, covert attention and overt attention (the exact eye location) are tightly linked. Because eye movements are essentially motor movements, it takes time to plan and execute a saccade. In addition, the end-point is pre-selected before the beginning of the movement. There is considerable evidence that the nature of the task influences eye movements. Depending on the task, there is considerable variability both in terms of fixation durations and saccade lengths. It is possible to outline five separate movement systems that put the fovea on a target and keep it there. Each of these movement systems shares the same effector pathway—the three bilateral groups of oculomotor neurons in the brain stem. These five systems include three that keep the fovea on a visual target in the environment and two that stabilize the eye during head movement. Saccadic eye movements shift the fovea rapidly to a visual target in the periphery. Smooth pursuit movements keep the image of a moving target on the fovea. Vergence movements move the eyes in opposite directions so that the image is positioned on both foveae. Vestibulo-ocular movements hold images still on the retina during brief head movements and are driven by signals from the vestibular system. Optokinetic movements hold images during sustained head rotation and are driven by visual stimuli. All eye movements but vergence movements are conjugate: each eye moves the same amount in the same direction. Vergence movements are disconjugate: The eyes move in different directions and sometimes by different amounts. Finally, there are times that the eye must stay still in the orbit so that it can examine a stationary object. Thus, a sixth system, the fixation system, holds the eye still during intent gaze. This requires active suppression of eye movement. Vision is most accurate when the eyes are still. When we look at an object of interest a neural system of fixation actively prevents the eyes from moving. The fixation system is not as active when we are doing something that does not require vision, for example, mental arithmetic. Our eyes explore the world in a series of active fixations connected by saccades. The purpose of the saccade is to move the eyes as quickly as possible. Saccades are highly stereotyped; they have a standard waveform with a single smooth increase and decrease of eye velocity. Saccades are extremely fast, occurring within a fraction of a second, at speeds up to 900°/s. Only the distance of the target from the fovea determines the velocity of a saccadic eye movement. We can change the amplitude and direction of our saccades voluntarily but we cannot change their velocities. Ordinarily there is no time for visual feedback to modify the course of the saccade; corrections to the direction of movement are made in successive saccades. Only fatigue, drugs, or pathological states can slow saccades. Accurate saccades can be made not only to visual targets but also to sounds, tactile stimuli, memories of locations in space, and even verbal commands (“look left”). The smooth pursuit system keeps the image of a moving target on the fovea by calculating how fast the target is moving and moving the eyes accordingly. The system requires a moving stimulus in order to calculate the proper eye velocity. Thus, a verbal command or an imagined stimulus cannot produce smooth pursuit. Smooth pursuit movements have a maximum velocity of about 100°/s, much slower than saccades. The saccadic and smooth pursuit systems have very different central control systems. A coherent integration of these different eye movements, together with the other movements, essentially corresponds to a gating-like effect on the brain areas controlled. The gaze control can be seen in a system that decides which action should be enabled and which should be inhibited and in another that improves the action performance when it is executed. It follows that the underlying guiding principle of the gaze control is the kind of stimuli that are presented to the system, by linking therefore the task that is going to be executed. This thesis aims at validating the strong relation between actions and gaze. In the first part a gaze controller has been studied and implemented in a robotic platform in order to understand the specific features of prediction and learning showed by the biological system. The eye movements integration opens the problem of the best action that should be selected when a new stimuli is presented. The action selection problem is solved by the basal ganglia brain structures that react to the different salience values of the environment. In the second part of this work the gaze behaviour has been studied during a locomotion task. The final objective is to show how the different tasks, such as the locomotion task, imply the salience values that drives the gaze

Developmental insights and biomedical potential of human embryonic stem cells : modelling trophoblast differentiation and establishing novel cell therapies for age-related macular degeneration

Understanding the molecular pathways responsible for lineage segregation in the preimplantation human embryo is critical in order to fully elucidate the mechanisms involved in pluripotency and differentiation of embryonic stem cells. A significant increase in our comprehension of such processes will lead to an improvement in the quality and efficiency of these cells for applications requiring stem cell maintenance and differentiation, such as regenerative medicine. Through responsible and ethical research, such new knowledge can then be translated effectively and efficiently into future advancements in health and medical practices. This thesis focuses on two different applications of human embryonic stem cells (hESC): first, as an in-vitro model to investigate the genetic requirements for human trophoblast formation and second, as a cell replacement therapy for age-related macular degeneration (AMD) through the establishment of efficient, scalable, and clinically compliant protocols for their differentiation into retinal pigment epithelium cells (RPE). In paper I, we used human embryonic stem cells to model trophoblast establishment and differentiation in order to better understand the mechanisms governing trophectoderm segregation in the embryo. Combining this in-vitro model with the use of pharmacological inhibitors and CRISPR/Cas9 genome editing, we demonstrated that blockade of the YAP1/WWTR1-TEAD complex impairs not only trophoblast differentiation, but also survival of undifferentiated stem cells. Furthermore, through systematic targeting of the different components of the complex, we described a dominant role for YAP1 in these processes and a striking genetic and functional redundancy of the function of TEAD proteins. Altogether, the findings indicate a role for the Hippo signaling pathway, both in human trophectoderm segregation and in maintaining human pluripotency. In papers II and III, we developed xeno-free and defined methodologies for the differentiation of human embryonic stem cells into RPE with the potential for use in replacement therapies for common retinal degenerative diseases, such as age-related macular degeneration. These invitro derived cells exhibited specific morphological and molecular features and functional properties that are typical of native RPE. In addition, upon subretinal transplantation into a large-eyed animal model, hESC-derived RPE cells were able to integrate and survive for extensive periods of time and rescued the neuroretina from the damage induced at the moment of injection. Finally, we identified a set of unique cell surface markers that were able to distinguish the RPE from other potential contaminating cell types or undifferentiated remnants and demonstrated their utility in monitoring differentiation efficiency and in increasing the purity and homogeneity of the final cell product. Through this work, we demonstrate that human embryonic stem cells hold enormous potential for modeling specific aspects of human development, which can help to elucidate the complex mechanisms governing lineage segregation and support the production of bona fide differentiated cell types to serve in future replacement therapies