4,756 research outputs found
Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico
Valve replacement remains as the standard therapeutic option for aortic
stenosis patients, aiming at abolishing pressure overload and triggering
myocardial reverse remodeling. However, despite the instant hemodynamic
benefit, not all patients show complete regression of myocardial hypertrophy,
being at higher risk for adverse outcomes, such as heart failure. The current
comprehension of the biological mechanisms underlying an incomplete reverse
remodeling is far from complete. Furthermore, definitive prognostic tools and
ancillary therapies to improve the outcome of the patients undergoing valve
replacement are missing. To help abridge these gaps, a combined myocardial
(phospho)proteomics and pericardial fluid proteomics approach was followed,
taking advantage of human biopsies and pericardial fluid collected during
surgery and whose origin anticipated a wealth of molecular information
contained therein.
From over 1800 and 750 proteins identified, respectively, in the myocardium
and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated
proteins were detected. Gene annotation and pathway enrichment analyses,
together with discriminant analysis, are compatible with a scenario of increased
pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by
complement activity and other extrinsic factors, such as death receptor
activators), acute-phase response, immune system activation and fibrosis.
Specific validation of some targets through immunoblot techniques and
correlation with clinical data pointed to complement C3 β chain, Muscle Ring
Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation
regulated kinase 1A (DYRK1A) as potential markers of an incomplete
response. In addition, kinase prediction from phosphoproteome data suggests
that the modulation of casein kinase 2, the family of IκB kinases, glycogen
synthase kinase 3 and DYRK1A may help improve the outcome of patients
undergoing valve replacement. Particularly, functional studies with DYRK1A+/-
cardiomyocytes show that this kinase may be an important target to treat
cardiac dysfunction, provided that mutant cells presented a different response
to stretch and reduced ability to develop force (active tension).
This study opens many avenues in post-aortic valve replacement reverse
remodeling research. In the future, gain-of-function and/or loss-of-function
studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic
targets. Besides, clinical studies in larger cohorts will bring definitive proof of
complement C3, MuRF1 and DYRK1A prognostic value.A substituição da válvula aórtica continua a ser a opção terapêutica de
referência para doentes com estenose aórtica e visa a eliminação da
sobrecarga de pressão, desencadeando a remodelagem reversa miocárdica.
Contudo, apesar do benefício hemodinâmico imediato, nem todos os pacientes
apresentam regressão completa da hipertrofia do miocárdio, ficando com maior
risco de eventos adversos, como a insuficiência cardíaca. Atualmente, os
mecanismos biológicos subjacentes a uma remodelagem reversa incompleta
ainda não são claros. Além disso, não dispomos de ferramentas de
prognóstico definitivos nem de terapias auxiliares para melhorar a condição
dos pacientes indicados para substituição da válvula. Para ajudar a resolver
estas lacunas, uma abordagem combinada de (fosfo)proteómica e proteómica
para a caracterização, respetivamente, do miocárdio e do líquido pericárdico
foi seguida, tomando partido de biópsias e líquidos pericárdicos recolhidos em
ambiente cirúrgico.
Das mais de 1800 e 750 proteínas identificadas, respetivamente, no miocárdio
e no líquido pericárdico dos pacientes com estenose aórtica, um total de 90
proteínas desreguladas foram detetadas. As análises de anotação de genes,
de enriquecimento de vias celulares e discriminativa corroboram um cenário de
aumento da expressão de genes pro-hipertróficos e de síntese proteica, um
sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular
(potencialmente acelerada pela atividade do complemento e por outros fatores
extrínsecos que ativam death receptors), com ativação da resposta de fase
aguda e do sistema imune, assim como da fibrose.
A validação de alguns alvos específicos através de immunoblot e correlação
com dados clínicos apontou para a cadeia β do complemento C3, a Muscle
Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation
regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta
incompleta. Por outro lado, a predição de cinases a partir do fosfoproteoma,
sugere que a modulação da caseína cinase 2, a família de cinases do IκB, a
glicogénio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condição
dos pacientes indicados para intervenção. Em particular, a avaliação funcional
de cardiomiócitos DYRK1A+/- mostraram que esta cinase pode ser um alvo
importante para tratar a disfunção cardíaca, uma vez que os miócitos mutantes
responderam de forma diferente ao estiramento e mostraram uma menor
capacidade para desenvolver força (tensão ativa).
Este estudo levanta várias hipóteses na investigação da remodelagem reversa.
No futuro, estudos de ganho e/ou perda de função realizados em
cardiomiócitos isolados ou em modelos animais de banding-debanding da
aorta ajudarão a testar a eficácia de modular os potenciais alvos terapêuticos
encontrados. Além disso, estudos clínicos em coortes de maior dimensão
trarão conclusões definitivas quanto ao valor de prognóstico do complemento
C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin
Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies
[ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito.
Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica.
Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV).
Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería.[CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit.
La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques.
La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV.
Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria.[EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates.
Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy.
Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF.
Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.Calvo Saiz, CJ. (2022). Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182329TESI
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Decellularised Normal and Tumour Scaffolds for Cancer Organoid Cultures as a Model of Colorectal Peritoneal Metastases
Peritoneal metastasis (PM) is one of the most common routes of dissemination for colorectal cancer and remains a lethal disease. PM development is caused by a cross-talk between invading cancer cells and the rearrangement of the extracellular matrix (ECM). This interplay is governed by biochemical and biomechanical events that allow the development of a specific microenvironment: the so-called metastatic niche. ECM remodeling may be critical for PM spread. In fact, it has been demonstrated that ECMs are not only able to provide structural support to the exfoliated neoplastic cells, but also to trigger specific molecular pathways, paving the path for the seed of cancer cells, directly to their "pre-educated" soil. The mechanisms that determine the interactions within cancer cells and the ECM are still obscure and could be elucidated by an in vitro 3D-culture system that integrates all the elements involved in PM development. Cancer organoids have shown a profound impact in the field of oncology since they better reflect the main characteristics of the native organs compared to the traditional cell culture models. However, they still fail to represent the heterogeneity of the microenvironment. Methodologies have been recently established to remove cells from tissues and obtain matrices in which ECM and tissue architecture are maintained (dECM models), that could be used as the most representative scaffold on which implant 3D cultures.
I aimed to obtain a 3D-model that closely recapitulates the microenvironment where the PM develops and includes d-ECM repopulated with PM-derived organoids (3D-dECM model). I removed the cellular component of ECMs derived from peritoneal cavity obtained from both PM samples and r matched normal peritoneum using detergents and enzymatic methods. dECMs analyses demonstrated that the procedure maintained the specific characteristics of their tissue of origin also in terms of distribution, localization, and architectural organization of ECM-related proteins. The obtained dECMs showed a different spatial rearrangement between normal and PM-derived peritoneum, suggesting that dECM scaffolds closely recapitulate the native PM microenvironment. Moreover, when I repopulated dECMs with PM-derived organoids I found that PM- and normal peritoneum-derived dECMs differentially regulated the localization and organization of the seeded organoids, which was the same as in the original tissue. The two 3D-ECM models presented different ability in supporting cell proliferation, where PM-derived 3D-dECMs showed a higher proliferation index and a major ability to maintain the stemness phenotype. PM- and normal peritoneum-derived 3D-dECMs differently modulated cell homeostasis and proliferation ratio.
A gene expression analysis of organoids, grown on different substrates reflected faithfully the clinical and biological characteristics of the organoids. The impact of the ECM on the response to standard chemotherapy treatment for PM was also observed.
This demonstrated the value of ex vivo 3D models obtained by combining patient-derived extracellular matrices depleted of cellular components and organoids to mimic the metastatic niche, which could provide tools to develop new therapeutic strategies in a biologically relevant context, to personalize treatments and increase their efficacy
Data aware sparse non-negative signal processing
Greedy techniques are a well established framework aiming to reconstruct signals which
are sparse in some domain of representations. They are renowned for their relatively low
computational cost, that makes them appealing from the perspective of real time applications. Within the current work we focus on the explicit case of sparse non–negative
signals that finds applications in several aspects of daily life e.g., food analysis, hazardous materials detection etc. The conventional approach to deploy this type of algorithms does not employ benefits from properties that characterise natural data, such
as lower dimensional representations, underlying structures. Motivated by these properties of data we are aiming to incorporate methodologies within the domain of greedy
techniques that will boost their performance in terms of: 1) computational efficiency
and 2) signal recovery improvement (for the remainder of the thesis we will use the
term acceleration when referring to the first goal and robustness when we are referring
to the second goal). These benefits can be exploited via data aware methodologies that
arise, from the Machine Learning and Deep Learning community.
Within the current work we are aiming to establish a link among conventional
sparse non–negative signal decomposition frameworks that rely on greedy techniques
and data aware methodologies. We have explained the connection among data aware
methodologies and the challenges associated with the sparse non–negative signal decompositions: 1) acceleration and 2) robustness. We have also introduced the standard data
aware methodologies, which are relevant to our problem, and the theoretical properties
they have. The practical implementations of the proposed frameworks are provided
here. The main findings of the current work can be summarised as follows:
• We introduce novel algorithms, theory for the Nearest Neighbor problem.
• We accelerate a greedy algorithm for sparse non–negative signal decomposition
by incorporating our algorithms within its structure.
• We introduce a novel reformulation of greedy techniques from the perspective of
a Deep Neural Network that boosts the robustness of greedy techniques.
• We introduce the theoretical framework that fingerprints the conditions that lay
down the soil for the exact recovery of the signal
Real-time quantum error correction beyond break-even
The ambition of harnessing the quantum for computation is at odds with the
fundamental phenomenon of decoherence. The purpose of quantum error correction
(QEC) is to counteract the natural tendency of a complex system to decohere.
This cooperative process, which requires participation of multiple quantum and
classical components, creates a special type of dissipation that removes the
entropy caused by the errors faster than the rate at which these errors corrupt
the stored quantum information. Previous experimental attempts to engineer such
a process faced an excessive generation of errors that overwhelmed the
error-correcting capability of the process itself. Whether it is practically
possible to utilize QEC for extending quantum coherence thus remains an open
question. We answer it by demonstrating a fully stabilized and error-corrected
logical qubit whose quantum coherence is significantly longer than that of all
the imperfect quantum components involved in the QEC process, beating the best
of them with a coherence gain of . We achieve this
performance by combining innovations in several domains including the
fabrication of superconducting quantum circuits and model-free reinforcement
learning
Infitseerunud haavadel kasutatavate antibakteriaalsete elektrospinnitud ravimkandursüsteemide disain ja omaduste analüüs
Väitekirja elektrooniline versioon ei sisalda publikatsiooneHalvasti paranevad haavad on kaasaegses ühiskonnas kiiresti kasvav sotsiaalmajanduslik probleem. Haavapatoloogiate kujunemises mängivad rolli mitmed faktorid, kuid järjest suuremat tähtsust selles omistatakse biofilmile ja mikrobioloogilise tasakaalu häirumisele haavakeskkonnas. Kaasaegsed haavakatted, kuhu on võimalik viia antimikroobseid raviaineid (RA) ning kontrollida nende vabanemiskineetikat, saavutamaks lokaalseid kliiniliselt olulisi RA kontsentratsioone pikema aja vältel, võivad oluliselt parandada ravikvaliteeti. Elektrospinnimine (ES) on lihtne ja paindlik meetod polümeersete nano- ja mikrofiibermaatriksite valmistamiseks, võimaldades lisada erinevaid RA-sid ning kontrollida nende vabanemist. Lisaks on fiibermaatriksitel mitmeid struktuurseid omadusi, mis teevad neist perspektiivikad haavakattematerjalid. Siiski on endiselt palju teadmata erinevate disainiaspektide mõjust ES-tud fiibermaatriksite funktsionaalsusele ja kvaliteedile. Käesolevas töös valmistati ES teel erinevate omadustega nano- ja mikrofiibermaatrikseid, kasutades erinevaid kandjapolümeere ja antibakteriaalseid RA-sid. ES mõjutas RA tahket vormi ning polümeeride kristallilisust, samuti kutsus esile interaktsioone erinevate maatriksi komponentide vahel. Erinevad fiibermaatriksid vabastasid RA-d erinevalt, kusjuures üheks olulisemaks, aga mitte universaalseks, faktoriks osutus nende märgumine ja puhverlahuse tungimine maatriksisse. Uudsed hüdrogeelidel põhinevad analüüsimeetodid RA vabanemise ja difusiooni hindamiseks jäljendasid võrreldes puhverlahustega paremini in vitro antibakteriaalse aktiivsuse testimise ja arvatavasti ka haavakeskkonna tingimusi. Difusioonitesti abil agarsöötmes sai hinnata vabanenud RAde efektiivsust erinevate mikroorganismide suhtes. Uudsete meetoditega sai lisaks tuvastada erinevusi erineva RA vabanemisprofiiliga maatriksite antibakteriaalses aktiivsuses. Selgus, et aeglane RA vabanemine aitab takistada fiibermaatriksile biofilmi moodustumist, ning et ilma RA-ta haavakate võib olla soodne pind biofilmi tekkeks. Fiibermaatrikseid oli võimalik erinevatel viisidel efektiivselt steriliseerida, kuid see protsess võis muuta maatriksi omadusi sõltuvalt konkreetsest steriliseerimismeetodist ja maatriksi materjalidest.Nonhealing wounds represent an escalating socioeconomic problem in modern society. Several factors contribute to the wound pathologies, but it is increasingly recognized that biofilm and microbial unbalance that overwhelms hosts’ immune responses play a major part in it. Advanced wound dressings that have the capability to deliver antimicrobial drugs to the site of action at controlled rate for extended period, establishing localized, clinically relevant drug concentrations, can potentially improve therapeutic outcomes. Electrospinning (ES) is a simple and flexible method to produce polymeric nano- and microfiber matrices, enabling to incorporate different drugs and control their release. In addition, fiber matrices have several structural properties that make them promising wound dressing materials. Still, much is unknown about different aspects of the design on the performance and quality of these matrices. In the present thesis, ES was used to produce different nano- and microfiber matrices, using different carrier polymers and antibacterial drugs. ES affected the solid-state form of the drug and polymer crystallinity, also induced interactions between different components of the matrix. Different matrices released the drug differently. One of the most important, although not universal, factors controlling drug release was the wetting and buffer penetration into the matrix. Novel hydrogel-based methods to study drug release and diffusion appeared to mimic the in vitro antibacterial activity testing conditions and probably wound environment better compared to the release into buffer solution. Traditional disc diffusion tests enabled to evaluate the efficacy of released drugs against different microorganisms, whereas novel methods helped to reveal differences in the antibacterial activity of differently designed electrospun fiber matrices. It was shown that prolonged release of the drug helped to prevent biofilm formation on the fiber matrix, whereas some carrier polymers could promote biofilm formation on matrices without the drug. Different sterilization methods can effectively sterilize fiber matrices, although this could change the matrix properties, depending on the process conditions and matrix materials.https://www.ester.ee/record=b548149
The flexibly ordered brain
I investigate the human brain systems involved in the cognitive control of behaviour.
Using novel cognitive paradigms and brain imaging, I identify brain systems that
support the flexible structuring of behaviour. I then observe how these systems are
implicated in patients with depression as they respond to psilocybin therapy. In the
first of three experiments, I observe the changes in healthy adult brain activation
that are associated with task-switching. This demonstrated that remapping rules
introduces a switching-cost to response speed and activates the multiple-demand
(MD) network. Critically, switching-costs and MD activation were greater when the
rules being remapped were of an abstract and higher-order nature. Going deeper, in
the second experiment, I investigate how healthy adult brains mitigate
switching-costs by structuring behaviour into efficient routines. I observe that
learning to optimise and structure behaviour covaries with changes in MD and
default mode network (DMN) activation alongside increases in between-network
connectivity. These concurrent behavioural and neural adaptations imply that
cognitive demand is minimised when behavioural routines are structured. Indeed,
these mechanisms are known to have broad roles in flexibly adapting behaviour
and, subsequently, they have been implicated in disorders such as depression.
Using these insights, in the third experiment, I examine the neural basis of the
treatment response to psilocybin in patients with depression. In two clinical trials, I
find that treatment response covaried with global increases in between-network
connectivity. Converging functional cartography measures indicated that this global
shift in network organisation related to increased dynamic flexibility and integration
of the MD and DMN. Together, the findings in this thesis indicate that a ‘flexibly
ordered brain’, the adaptive sequencing of neurocognitive states, is a necessary
feature of well-being and for successfully navigating the demands of daily life.Open Acces
A brain-computer interface integrated with virtual reality and robotic exoskeletons for enhanced visual and kinaesthetic stimuli
Brain-computer interfaces (BCI) allow the direct control of robotic devices for neurorehabilitation and measure brain activity patterns following the user’s intent. In the past two decades, the use of non-invasive techniques such as electroencephalography and motor imagery in BCI has gained traction. However, many of the mechanisms that drive the proficiency of humans in eliciting discernible signals for BCI remains unestablished. The main objective of this thesis is to explore and assess what improvements can be made for an integrated BCI-robotic system for hand rehabilitation. Chapter 2 presents a systematic review of BCI-hand robot systems developed from 2010 to late 2019 in terms of their technical and clinical reports. Around 30 studies were identified as eligible for review and among these, 19 were still in their prototype or pre-clinical stages of development. A degree of inferiority was observed from these systems in providing the necessary visual and kinaesthetic stimuli during motor imagery BCI training. Chapter 3 discusses the theoretical background to arrive at a hypothesis that an enhanced visual and kinaesthetic stimulus, through a virtual reality (VR) game environment and a robotic hand exoskeleton, will improve motor imagery BCI performance in terms of online classification accuracy, class prediction probabilities, and electroencephalography signals. Chapters 4 and 5 focus on designing, developing, integrating, and testing a BCI-VR-robot prototype to address the research aims. Chapter 6 tests the hypothesis by performing a motor imagery BCI paradigm self-experiment with an enhanced visual and kinaesthetic stimulus against a control. A significant increase (p = 0.0422) in classification accuracies is reported among groups with enhanced visual stimulus through VR versus those without. Six out of eight sessions among the VR groups have a median of class probability values exceeding a pre-set threshold value of 0.6. Finally, the thesis concludes in Chapter 7 with a general discussion on how these findings could suggest the role of new and emerging technologies such as VR and robotics in advancing BCI-robotic systems and how the contributions of this work may help improve the usability and accessibility of such systems, not only in rehabilitation but also in skills learning and education
Exploring how Interactions and Responses within the Servicescape combine to form Customer Experience – A Text Mining Approach
The core research objective in this thesis is to address the ways in which Customer Experience (CX) emerges through the combinational effects of multiple customer interactions at touchpoints and their resulting CX responses. The empirical study designed in this work is positioned to build upon existing literature within the Service Management field. According to extant work, CX can be viewed from both the provider’s perspective (e.g. ‘intended’ or designed), and the customer’s perspective (e.g. ‘realised’ or subjective). The thesis integrates both accounts through the presentation of a new conceptual model which forms the basis for the design of the empirical study.
Several limitations are addressed in this work. First, building on the notion that CX emerges across multiple touchpoint interactions (Lemon and Verhoef, 2016) the study explores the impact multiple interaction types, and their associated responses, have on overall CX. Extant studies have tended to view CX at single touchpoint interactions (Becker and Jaakkola, 2020). CX emerges across multiple touchpoint interactions, which each induce responses in the customer. As it stands, little is known about how this process occurs, or the relationships which exist between customer interaction, customer response, and overall CX. Second, the study widens the field and its understanding of the servicescape from an ‘unbounded’ perspective (Rosenbaum and Massiah, 2011). Traditionally, studies have explored CX through the impact of provider-owned touchpoints, predominantly within bounded service sites. The study addresses requests to explore the impact of wider, non-provider-controlled touchpoints on overall CX (Kandampully et al., 2018). Relating to this aim, very little existing work deals with the impact of natural servicescape touchpoints on CX. The case studies in this work have been chosen for their suitability to address this gap.
The study employs a comparative case study approach from the cultural heritage sector. Text mining (TM) and text analytics (TA) techniques are employed to capture and assess CX elements found within customer feedback data from an online review depository. Contrary to existing work in this field, the study employs a three-step annotation process to concept classification which can ensure rigour in the results. The purpose of the analysis process is to capture patterns of CX responses and customer interactions within the data and assess their relationship to overall CX ratings. Both quantitative measures (e.g. statistical analysis) and qualitative measures (e.g. verbatim text analysis) are used to explore a number of key questions relating to the core research objective.
The empirical study performed in this work results in several key findings. The study finds that CX arises as a combination of customer interactions and CX responses, with each pattern impacting the overall experience in different ways. Results suggest that pattern prevalence and prominence are not core drivers of customer rating, but rather that significance measures need to be employed. From a customer perspective, negative CX responses have a stronger effect on overall CX rating than positive responses. These can be induced through touchpoint interactions beyond the control of the provider. The emotional content of the experience is key, with customer surprise, anger, and sadness significantly impacting CX to a greater degree than other discrete emotions. The findings suggest that customer expectations play an important role in the delivery of CX. Customer expectations can be used to make sense of the differences in terms of patterns and the statistical significance of their relationship to CX rating. Several potential avenues for future work to further develop these themes are put forward in the final stages of the thesis.EPSRC and University of Exeter Business Schoo
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