115 research outputs found
The Remains of authoritarianism : bureaucracy and civil society in post-authoritarian Greece
No full textDimitrios A. Sotiropoulos. 30 cm. He presented this paper at a seminar held at the Center on October 21, 1994. - T.p. Includes bibliographical references (p. 31-35
Case Report: Laparoscopic hepatectomy in an elderly patient with major comorbidities
No full textSurgeons have been hesitant to proceed to hepatectomy in elderly patients, due to the higher rate of comorbidities and the reduced reserves. An 81-year-old male with hepatocellular carcinoma in the segment VI of the liver and several major cardiovascular, pulmonary and metabolic comorbid illnesses was referred to our department for treatment. He underwent transarterial chemoembolization of the liver tumor and afterwards he underwent laparoscopic resection of the hepatic segment VI, with an uneventful postoperative course. This case indicates that laparoscopic liver resections could be applied even to elderly patients with major comorbidities after optimization of their medical status. © 2017 Sotiropoulos GC et al
Proteostase Da Tau na disfunção neuronal induzida pelo stress: implicações na doença de Alzheimer
No full textDissertação de Mestrado em Ciências da SaúdeEnsaios clínicos e experimentais sugerem o stress como fator de risco para a doença de Alzheimer (DA),
uma vez que o stress crónico e níveis elevados de hormonas de stress, glucocorticoides (GC), induzem
hiperfosforilação da Tau, uma das principais características da DA. Embora estudos prévios tenham
demonstrado que o stress e os GC alteram os níveis de diversas chaperonas, produzindo alterações na
homeostasia da proteína Tau, os mecanismos que regulam a patologia da Tau induzida pelo stress, bem
como o seu efeito nos deficits cognitivos e emocionais, são ainda desconhecidos. Vários estudos sugerem
que as histonas desacetilases (HDACs) são importantes componentes epigenéticos na DA, mostrando
que a expressão da HDAC6 aumenta significativamente no hipocampo de pacientes e modelos animais
da doença. Entre outros, a HDAC6 está envolvida nas vias de sinalização dos recetores de GC, bem como
na indução de grânulos de stress (GS), densos agregados citoplasmáticos compostos por proteínas e
ARNs formados quando a célula é exposta a stress. Recentemente, demonstrou-se que os GS promovem
a agregação neurotóxica da Tau na DA. Posto isto, esta dissertação de mestrado monitoriza o potencial
envolvimento da HDAC6 e dos GS nos efeitos nefastos do stress na agregação da Tau e deficits
comportamentais associados. Recorrendo a murganhos transgénicos e modelos celulares da DA
expressando a proteína humana Tau com a mutação P301L, este estudo demonstra que a exposição
prolongada ao stress induz patologia da Tau no hipocampo das fêmeas, aumentando o nível desta
proteína e dos GS; o hipocampo dos machos demonstra uma clara resiliência aos efeitos do stress.
Adicionalmente, os nossos estudos in vitro confirmam a indução de GS e subsequente acumulação da
Tau após tratamento com um GC sintético, dexametasona, sugerindo que a indução dos GS depende
dos GC. Além disto, o uso de Tubacina, um inibidor seletivo da HDAC6, atenuou a formação de GS e a
acumulação de Tau induzidos pelo tratamento com GC, sugerindo um papel importante da HDAC6 na
agregação patológica da Tau induzida pelo stress e GC. Em suma, estes resultados providenciam novos
conhecimentos acerca dos mecanismos subjacentes ao papel neurodegenerativo do stress para o
desenvolvimento da DA, destacando a HDAC6 e os GS como componentes essenciais na patologia
induzida pelo stress.Clinical and experimental evidences suggest environmental stress as a risk factor for Alzheimer’s disease
(AD), as chronic stress and stress hormones, glucocorticoids (GC), trigger abnormal Tau
hyperphosphorylation and aggregation, one of the main pathomechanisms of the disease. Although
previous studies have shown that stress and GC influence the levels of molecular chaperones, disturbing
Tau proteostasis, the underlying mechanisms of the stress-induced Tau pathology, and its significance
for the related cognitive and emotional deficits remain unknown. Several studies suggest that histone
deacetylases (HDACs) are important epigenetic components of AD etiopathogenesis, reporting increased
expression of HDAC6 in the hippocampus of AD patients and animal models. Among others, HDAC6 is
involved in GC receptor signaling, as well as in the induction of stress granules (SG), dense cytosolic
aggregations composed of proteins and RNAs that appear when the cell is under stress. Recently, SG
were reported to promote neurotoxic Tau aggregation in AD brain. Therefore, this Master thesis monitors
the potential involvement of HDAC6 and SG in the detrimental impact of stress on Tau aggregation and
related behavioral deficits. Using AD transgenic animal and cellular models expressing mutant P301L
human Tau, this study shows that prolonged stress triggers Tau pathology in female hippocampus,
increasing the levels of Tau aggregates and SG, while male hippocampus exhibits a clear resilience to
stress. Furthermore, our in vitro studies confirm the induction of several SG markers and subsequent Tau
accumulation by the treatment with a synthetic GC, Dexamethasone, suggesting that the stress-driven
induction of SG is GC-dependent. In addition, treatment with Tubacin, a selective HDAC6 inhibitor,
attenuated the increased formation of SG and the accumulation of Tau induced by GC, suggesting a
potential role for HDAC6 in stress/GC-triggered pathological Tau aggregation. Altogether, these results
provide novel evidence about the molecular underpinnings of the neurodegenerative role of stress towards
the development of AD pathology, highlighting HDAC6 and SG as essential cellular partners in stressinduced
brain pathology
Unraveling the synaptic role of Rab35: implications for Alzheimer’s disease pathology
No full textTese de doutoramento em MedicinaDespite considerable progress in the understanding of molecular underpinnings of neuronal malfunction and
cognitive impairment associated with Alzheimer’s disease (AD), the physiopathology of the disorder is complex
and poorly understood. Chronic environmental stress and the major stress hormones, glucocorticoids (GC),
are suggested precipitating factors for AD, and have been shown to trigger APP misprocessing and Aβ
production as well as Tau hyperphosphorylation, accumulation and downstream neuronal atrophy and
malfunction. However, the mechanisms that regulate intraneuronal trafficking and homeostasis of Aβ & Tau
remain poorly understood. Given the critical role of Rab GTPases as master regulators of endosomal protein
trafficking, these PhD studies have explored the role of Rabs in Aβ & Tau proteostasis and their significance in
AD pathogenesis. We found that the levels of a specific Rab, Rab35, are significantly decreased aged animals,
as well in animals exposed to high GC levels or chronic stress, known triggers of APP misprocessing. Using a
gain-of-function screen of Rabs that regulate endocytic protein trafficking, we showed that Rab35 is the most
potent suppressor of the interaction of APP and BACE, the first enzyme involved in APP misprocessing towards
the generation of Aβ. On the contrary, reduced Rab35 may promote the APP misprocessing suggesting Rab35
as an important regulator of the intraneuronal cascade that generates Aβ. In another set of studies of this PhD
thesis, we demonstrated for the first time that Rab35 also controls degradation of Tau protein into the
endolysosomal pathway through the Rab35-driven induction of the endosomal sorting complex required for
transport (ESCRT) machinery. We also detected a phospho-dependent selectivity of Tau sorting into the
Rab35/ESCRT pathway, while high GC levels suppress Rab35 expression and ESCRT machinery leading to
Tau accumulation on both in vitro and in vivo studies. Importantly, AAV-mediated Rab35 expression rescues
both GC-induced Tau accumulation and neuronal atrophy in the hippocampus of experimental animals.
Altogether, the findings of these PhD studies suggest an essential role for Rab35 in the intraneuronal
mechanisms underlying Aβ generation and Tau accumulation in AD as well as their significance to the
precipitating role of chronic stress towards brain pathology. As emerging evidence suggest that the involvement
of Tau in multiple neuropathological conditions, including Alzheimer’s disease, frontotemporal dementia,
chronic stress and epilepsy, identifying the cellular pathways responsible for Tau intra- and extra-cellular
trafficking, as well as positive and negative regulators of these pathways, has broad therapeutic relevance.Apesar do progresso considerável na compreensão das bases moleculares do mau funcionamento neuronal e
do comprometimento cognitivo associado à doença de Alzheimer (DA), a fisiopatologia da doença é complexa
e pouco compreendida. O stress ambiental crónico e as principais hormonas do stress, os glucocorticóides
(GC), são sugeridos como factores desencadeantes da DA, e têm mostrado desencadear o mal processamento
da APP e a produção de Aβ, bem como a hiperfosforilação e acumulação da Tau, conduzindo a atrofia
neuronal. No entanto, os mecanismos que regulam o tráfego intraneuronal e a homeostase de Aβ e Tau
permanecem pouco compreendidos. Dado o papel crítico das Rab GTPases como reguladores do tráfico de
proteína endossomais, este trabalho de doutoramento explorara o papel das Rabs na proteostase da Aβ e da
Tau, assim como a sua importância na patogénese da DA. Descobrimos que os níveis de uma Rab específica,
Rab35, estão significativamente diminuídos em animais envelhecidos, assim como em animais expostos a
altos níveis de GC ou stress crónico, desencadeadores do processamento amiloidogénico de APP. Usando um
ensaio de ganho de função de Rabs, que regulam o tráfego de proteínas endocíticas, mostramos que a Rab35
é o supressor mais potente, entre estas, da interação entre APP e BACE, a primeira enzima envolvida no
processamento de APP em Aβ. Pelo contrário, a redução dos níveis de Rab35 pode promover o processamento
amiloidogénico de APP, sugerindo que a Rab35 é um importante regulador da cascata intraneuronal que gera
Aβ. Noutro conjunto de estudos desta tese de doutoramento, demonstramos pela primeira vez que a Rab35
também é capaz de controlar a degradação da proteína Tau na via endolisossomal através da indução do
complexo Endosomal Sorting Complex Required for Transport (ESCRT) pela Rab35. Detectamos também que
a selecção para a via Rab35/ESCRT é dependente do estado de fosforilação da Tau, enquanto que altos níveis
de GC suprimem a expressão de Rab35, levando à acumulação de Tau in vitro e in vivo. A expressão de Rab35
mediada por AAV é capaz de resgatar tanto a acumulação de Tau induzida por GC, como a atrofia neuronal
no hipocampo destes animais. Em conjunto, os resultados apresentados nesta tese de doutoramento, sugerem
um papel essencial para Rab35 nos mecanismos intraneuronais subjacentes à geração de Aβ e ao acúmulo
de Tau na DA, bem como a sua importância para o efeito do stress na indução de patologia cerebral. Evidências
emergentes sugerem que a Tau está envolvida em múltiplos mecanismos neuropatológicas, incluindo a doença de Alzheimer, demência frontotemporal, stress crónico e epilepsia, assim, identificar as vias celulares
responsáveis pelo tráfico intra e extra-celular da Tau, bem como os seus reguladores positivos e negativos,
tem uma ampla relevância terapêutica.The work presented in this thesis was performed in the Life and Health Sciences Research Institute
(ICVS), Minho University. Financial support was provided by grants from the Fundação para a Ciência
e Tecnologia (FCT) (PD/BD/105938/2014), by FEDER funds through the Operational Programme
Competitiveness Factors - COMPETE and National Funds through FCT - Foundation for Science and
Technology under the project POCI-01-0145-FEDER-007038; and by the project NORTE-01-0145-
FEDER-000013, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under
the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund
(ERDF)
Identification of the cellular mechanisms undelying the contribution of stress and glucocorticoids to Alzheimer's disease pathology
No full textClinical evidence suggests the involvement of stress and glucocorticoids (GC) in the etiopathogenesis of Alzheimer’s disease (AD), a disease marked by severe memory impairments as well as alterations in mood and emotional state. The experiments described in this dissertation represent an attempt to establish the cellular mechanisms through which stress and GC may impact on the development of AD. These studies focused on the hippocampus and prefrontal cortex (PFC), brain areas that are severely affected in AD; both areas were found to respond to stress and GC hypersecretion with neuronal atrophy and death, effects that are mediated by glucocorticoid receptors (GR). Furthermore, stress and GC were shown to induce impairments in cognitive behaviors which depend on the structural integrity of the hippocampus and PFC. The neurodegeneration which accompanies AD is characterized by mis-processing of the amyloid precursor protein (APP) and abnormal hyperphosphorylation of the microtubule-associated protein tau; the latter leads to cytoskeletal disruption and synaptic loss. Experiments in laboratory animals and cell systems established that stress/GC can contribute to AD pathology by triggering the amyloidogenic pathway of APP processing by increasing the expression of APP-cleaving enzymes (BACE and nicastrin), giving rise to the APP C-terminal fragment 99 (C99) which, after further processing, yields amyloid beta (A). While A is the APP product to which AD pathology is usually ascribed, C99 also has deleterious effects on neuronal survival and cognition. The present studies showed that stress/GC-induced changes in APP processing were paralleled by impairments in hippocampus- and PFC-dependent behaviors and anxiety (in animals), as well as by increased abnormal hyperphosphorylation of tau, decreased tau degradation, and reduced stability of microtubules; additional evidence obtained suggests that synaptic loss may also be a consequence of stress/GC-induced alterations in APP processing and tau biochemistry. A more detailed analysis of the mechanisms through which GC (the main physiological response to stress) might influence tau revealed the involvement of a number of kinases (GSK3, cdk5 and MAPK), all of which have been implicated in AD pathology. Since normal laboratory species do not develop AD pathology unless they are engineered to express human forms of APP or tau, one part of this work examined whether GC could induce their harmful effects in a rat neuronal cell line that had been stably transfected with htau. The results of those experiments confirmed the hypothesis that htau is responsible for making neurons sensitive to the AD-like pathological effects of GC; specifically, as compared to wild-type cells, those expressing htau showed increased sensitivity to GC and A, while at the same time increasing APP mis-processing to C99 and A, as well as tau hyperphosphorylation. In summary, these experiments describe, for the first time, the processes through which stress/GC can lead to AD-like pathology. They raise the hypothesis that stress/GC primarily trigger APP mis-processing, which then leads to tau kinase activation and tau pathology; the tau kinases then feeds back to exacerbate the pathobiochemistry in a positive feedback loop. Lastly, the results reported herein suggest new preventative and therapeutic strategies, and also suggest that the AD-related proteins tau and APP may be general key players in mediating the effects of stress and GC in stress-related disorders
(Dis)função da proteína Tau na plasticidade e patologia do cérebro – para além da Doença de Alzheimer
No full textTese de doutoramento em Ciências da SaúdeDespite that research efforts have been increasingly focused on Alzheimer’s disease (AD)
over the last decades, it was only recently that Tau protein was suggested as an essential regulator
of neuronal plasticity as well as pathology triggered by different intrinsic and extrinsic factors.
Consistent with suggestions that lifetime stress may be a clinically-relevant precipitant of AD
pathology, previous experimental studies showed that Tau is at the core of chronic stress-induced
pathological brain aging, raising Tau malfunction as a critical mechanism through which stress and
glucocorticoids (GC) exert their neuro-remodeling and neurodegenerative effects upon the substrates
of cognition and emotion. While experimental evidence, including some previous work from our
group, showed that chronic stress and GC trigger Tau hyperphosphorylation, accumulation and
aggregation, the molecular mechanisms by which Tau contributes to stress-driven brain malfunction
and pathology are poorly understood.
In this thesis, we investigated the cellular mechanisms through which chronic stress and/or
GC trigger Tau malfunction and pathology leading to cognitive and mood deficits. Our findings
demonstrate that prolonged exposure to high GC levels triggers two different Tau-related cellular
cascades in dendrites and dendritic spines, respectively: a) Tau hyperphosphorylation and
somatodendritic accumulation of different phosphorylated Tau isoforms accompanied by reduced
microtubule stability and dendritic remodeling and, b) synaptic missorting of specific
hyperphosphorylated epitopes of Tau and overactivation of GluN2B receptor leading to synaptic
atrophy/loss. Furthermore, this thesis aimed to clarify the molecular mechanisms of stress/GCdriven
neurotoxic accumulation and aggregation of Tau. We showed, using both in vitro and in vivo
studies, that chronic stress and GC evoke an mTOR-dependent blockage of autophagic clearance
machinery with parallel induction of histone deacetylase 6 (HDAC6) and formation of stress granules
(SGs). These findings implicate induction of HDAC6 and SGs as well as the inhibition of autophagy
in stress-driven Tau aggregation identifying novel mechanisms through which chronic stress
precipitates brain pathology, which may contribute for future improved therapeutic strategies.
While abnormal hyperphosphorylation and aggregation of Tau are well-established key
events in AD neuropathology, the impact of the loss of normal Tau in neuronal function in adult brain
is still under intense debate; e.g. while in vitro evidence supports an essential role of Tau for microtubule stabilization, axonal maintenance and transport, adult animals with constitutive deletion
of MAPT (and thus, Tau protein) fail to display obvious behavioral, neurostructural or functional
deficits highlighting a significance gap of knowledge about the actual role of Tau in neuronal function.
In order to avoid the developmental compensation mechanisms suggested to be present in the
currently available (constitutive) Tau knock-out (KO) mouse lines, these studies present and analyze
a novel mouse model of conditional deletion of Tau in adult brain, based on a tamoxifen-inducible
LoxP/Cre system, that offers temporal and brain-area specificity in knocking-out MAPT gene. After
confirming that the generation of this new mouse model didn’t affect the developmental, neurological
and behavioral profile of the animal, we show for the first time that CaMKII-driven conditional Tau
deletion in the adult forebrain doesn’t affect cognitive performance, but it triggers the induction of
anxious and depressive behavior in adult mice. Importantly, these behavioral deficits were
accompanied by neuronal atrophy and synaptic alterations in prefrontal cortex and amygdala, two
essential brain areas for the manifestation of mood deficits. These findings provide novel evidence
about the essential role of Tau on neuronal and brain homeostasis.
Overall, the findings of this thesis provide novel evidence about the involvement of Tau in
different parameters of brain plasticity as well as brain pathology.Ao longo das últimas décadas a investigação tem-se focado com mais intensidade na
Doença de Alzheimer, mas apenas recentemente foi sugerido a proteína Tau como um regulador
essencial da plasticidade neuronal e da patologia, despoletada por diferentes fatores intrínsecos e
extrínsecos (ex.: beta-amilóide, excitotoxicidade, epilepsia). De acordo com a hipótese de que o
stress crónico pode ser um fator clinicamente relevante na patologia da Doença de Alzheimer,
estudos experimentais sugerem que a proteína Tau pode ter um papel nuclear no envelhecimento
patológico induzido pelo stress crónico, relevando o mau funcionamento desta proteína como um
mecanismo crítico através do qual o stress e os glucocorticoides (GC) exercem efeitos neuroremodeladores
e degenerativos, levando a alterações na cognição e emoção. Apesar das provas
experimentais, incluindo alguns trabalhos anteriores do nosso grupo, mostrarem que o stress
crónico e os GC despoletam a hiperfosforilação, acumulação e agregação da Tau, os mecanismos
precisos através dos quais esta proteína contribui para um mau funcionamento do cérebro e
patologia induzidos pelo stress são pouco claros.
Nesta tese foram monitorizados os mecanismos celulares através dos quais o stress crónico
e/ou os GC despoletam o mau funcionamento e patologia da Tau que resultam em défices cognitivos
e de humor. Os dados atuais demonstram que uma exposição prolongada a níveis altos de GC
ativam duas cascatas celulares que estão relacionadas com a localização da proteína Tau nas
dendrites e espinhas dendríticas: a) hiperfosforilação e acumulação somatodendrítica de diferentes
epítopos fosforilados da Tau, acompanhadas de uma redução na estabilidade dos microtúbulos e
remodelação das dendrites e, b) localização anormal nas sinapses de isoformas hiperfosforiladas da
Tau e sobreativação do recetor GluN2B, que leva a atrofia/perda sináptica. Para além disto, esta
tese teve como objetivo esclarecer os mecanismos moleculares induzidos pelo stress/GC envolvidos
na agregação e acumulação neurotóxica da Tau. Os estudos in vitro e in vivo realizados
demonstraram que o stress crónico e os GC conduzem a um bloqueio da maquinaria de limpeza
autofágica, dependente da ativação da cascata de sinalização do mTOR, paralelamente, com a
indução da histona desacetilase 6 (HDAC6) e formação de grânulos de stress; os últimos estando
causalmente relacionados com a agregação da tau. Estas descobertas implicam a indução da
HDAC6 e dos SGs assim como a inibição da autofagia numa agregação da Tau induzida pelo stress, identificando assim novos mecanismos através dos quais o stress crónico precipita a patologia
cerebral, podendo no futuro contribuir para o desenvolvimento de estratégias terapêuticas mais
eficientes.
Apesar da hiperfosporilação e agregação anormais da Tau serem mecanismos-chave da
neuropatologia da Doença de Alzheimer, o impacto da perda da função normal da Tau no
funcionamento/mau-funcionamento neuronal no cérebro adulto está ainda debaixo de um intenso
debate: por exemplo, enquanto provas in vitro suportam o papel essencial da Tau na estabilização
dos microtúbulos, transporte e manutenção dos axónios, a deleção constitutiva da proteína não leva
a nenhuma alteração comportamental, neuronal ou funcional no animal adulto, demonstrando que
existe uma falha significativa no nosso conhecimento sobre o papel da Tau na função neuronal.
Desta forma, evitando mecanismos de compensação que estão descritos nos animais com deleção
constitutiva da Tau (KO), nestes estudos de doutoramento foi desenvolvido um novo modelo de
ratinho com uma deleção condicional da Tau no cérebro adulto, baseado no sistema LoxP-Cre
(indutível por tamoxifeno), que oferece flexibilidade temporal e de área cerebral na deleção do gene
mapt. Após se ter observado que esta nova linha de ratinhos não apresentava o perfil de
desenvolvimento neurológico e comportamental alterado, demostramos pela primeira vez que a
deleção condicional da Tau, induzida pelo promotor CaMKII no cérebro adulto, não afeta a
performance cognitiva dos animais, mas despoleta a indução de comportamento ansioso e
depressivo em ratinhos adultos. É de notar que estes défices comportamentais foram
acompanhados por atrofia neuronal e alterações sinápticas no córtex pré-frontal e na amígdala, duas
áreas do cérebro essenciais na manifestação de défices de humor. Estas descobertas providenciam
novas provas acerca do papel essencial da Tau na homeostasia neuronal e cerebral.
Em suma, as descobertas desta tese de doutoramento fornecem novas provas acerca do
envolvimento da Tau em diferentes parâmetros da plasticidade cerebral e também na patologia do
cérebro, com a monitorização das cascatas envolvidas na função, disfunção e patologia da proteína
Tau.The work presented in this thesis was performed in the Life and Health Sciences Research Institute
(ICVS), University of Minho. Financial Support was provided by a PhD grand
(SFRH/BD/88932/2012) from the FCT – Foundation for Science and Technology -, by FEDER funds
through the Operational Programme Competitiveness Factors – COMPETE and National Funds
through FCT under the project POCI-01-0145-FEDER-007038; and by the project NORTE-01-0145-
FEDER-000013, supported by Norte Portugal Regional Operational Programme (NORTE 2020),
under the PORTUGAL 2020 Partnership Agreement, though the European Regional Development
Fund (ERDF)
The neurodegenerative potential of chronic stress: A link between depression and Alzheimer’s disease
No full textModern lifestyle places individuals under increasingly greater loads of psychological and physical stress. Although the mechanisms that are triggered by stress are primarily adaptive to facilitate homeostasis, chronic stress can become maladaptive. Specifically, stress and its primary manifestation, glucocorticoid (GC) secretion, is strongly associated with neuronal atrophy/dysfunction, impaired cognition, and mood and affective disorders such as depression while a causal role of chronic stress in the etiopathology of Alzheimer’s disease (AD) has been also suggested. Although cumulative evidence suggests a continuum between depres-sion and AD, and stress is suggested to play a detrimental role in both diseases, considerably less attention has been given to the suggested role of stress as a connecting risk factor. Using both transgenic and non-transgenic animals, we investigate the sequential interrelationships between these various pathogenic ele-ments, in particular with respect to the mechanisms through which stress might precipitate brain pathology. Our studies show that stress and GC trigger APP misprocessing towards the production of neurotoxic amyloid-β (Aβ) as well as abnormal tau hyperphosphorylation and aggregation resulting in synaptic malfunc-tion and atrophy that leads to the associated cognitive (memory) impairments as well as mood deficits. In addition, we demonstrated increased vulnerability of female brain to the neurodegenerative potential to stress through this ability to regulate molecular chaperones related to formation of neurotoxic Tau aggregations showing that Tau protein and its malfunction has an essential role in detrimental role of chronic stress on brain and neuronal function providing molecular, electro-physiological, morphostructural, and behavioral evidence. These studies suggest an essential role of Aβ and Tau in a critical mechanism(s) through which stress and GC exert their neuro-remodelling and neurodegenerative effects upon the substrates of cognition and emotion. © Springer International Publishing Switzerland 2015
ATHENS City of Crossroads
No full textThe project investigates the possibility of an alternative movement pattern in the City of Athens. The crossroad condition is the one that demonstrates the new urban logic through three different case study. The movement takes the form of a multilevel labyrinth that penetrates the urban mass and forms a new collective space.Expolore LabArchitectureArchitecture and The Built Environmen
Corpus Callosum as a biomarker for Alzheimer and Multiple Sclerosis
No full textWith the increase of the life expectancy and the deterioration of the quality of life that neurodegenerative diseases can cause to the patients, they have been receiving more and more attention the last few decades in the developed countries. Two of the leading neurodegenerative diseases are Alzheimer’s Disease and Multiple Sclerosis. In diagnosis and assessment progression Magnetic Resonance Imaging (MRI) is playing an important role. MRI is a non-invasive tool and can achieve a great contrast between the different tissues that exist inside the brain. In the search of biomarkers for the faster diagnosis of these diseases, the Corpus Callosum appears to be an interesting brain structure, as it facilitates inter-hemispheric communication and it is not sensitive to brain hydration and dehydration effects. This thesis investigates if the regional and global shape and area changes of the Cor- pus Callosum could set the Corpus Callosum as a biomarker for Alzheimer’s Disease and Multiple Sclerosis. In order to achieve that a segmentation pipeline is proposed, so as to extract the Corpus Callosum from Magnetic Resonance brain images. After such a pipeline is constructed and validated, the quantification of the Corpus Callosum area is investigated for scans acquired in scanners of different vendors and in scanners of different magnetic field strengths, in order to gain better insights of the differences that can exist between such scans. Finally, the potential of the Corpus Callosum to be used as a biomarker is investigated, by attempting to correlate the global and regional shape and area changes of the Corpus Callosum with neurodegenerative diseases. During the thesis the segmentation algorithm showed a high segmentation accuracy performance with a mean dice of 93%, a segmentation reproducibility error of 1.93% and the clas- sification accuracy between AD and MS patients with NC was above 95% for both groups.BMEBioMechanical EngineeringMechanical, Maritime and Materials Engineerin
Integrated entangling gates: Creating GHZ States for Stabilizer Measurements in Distributed Quantum Computing
No full textHigh fidelity GHZ states among remote nodes is a precious commodity which can allow for non-local stabilizer measurements and thus pave the way for a modular fault-tolerant quantum computer. To this end, we extend the high fidelity intracavity gate introduced by Borregaard et al. (2015) to distributed paradigm, consisting of SnV-inspired atomic states in cavities connected by fibers. The adiabatic dynamics of this system can be solved efficiently using the effective operator formalism of Reiter and Sørensen (2012). We develop a Python framework that enables the analytical calculation of these effective dynamics reliably and swiftly, while being versatile and easily modifiable. The possibilities of this framework are showcased by obtaining results for a symmetric distributed setup and verifying its scalability. We present the ways that it can be optimized while taking into consideration experimentally inspired constraints, and proceed to optimize it for GHZ generation in color centers. These optimized gates are compared against an emission based protocol using the GHZ creation simulations of the Modicum protocol. As a byproduct of our investigation, we identify a specific set of Hamiltonians which, under certain conditions, can generate GHZ states with a single multi-qubit entangling gate.Applied Physics | Quantum Technolog
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