10 research outputs found
The Glen Affric radar project: investigating applications of polarimetric SAR interferometry
No full textThe Glen Affric radar project: forest mapping using polarimetric interferometry
No full textIn this paper we describe the Glen Affric
radar project, a multi-disciplinary program addressing
the ability of polarimetric radar interferometry to
provide quantitative vegetation structural information of
importance in forest mapping and ecology studies
Alzheimer's disease -related genes and pathways special emphasis on seladin-1, [delta]opioid receptor 1 and BACE1
No full textO tráfego subcelular da Proteína Precursora de Amilóide de Alzheimer (PPA) é dependente de fosforilação
No full textDoutoramento em BiologiaA Doença de Alzheimer (DA) é uma das doenças neurodegenerativas mais
comuns, e apresenta uma incidência mundial de 2-7% em indivíduos com mais
de 65 anos e de cerca de 15% em indivíduos acima dos 85 anos de idade.
Apesar da sua etiologia multifactorial, há uma correlação bem descrita entre
esta patologia e um peptídeo neurotóxico denominado Abeta. Este peptídeo
deriva fisiológica e proteoliticamente de uma glicoproteína transmembranar
com características de receptor: a Proteína Percursora de Amilóide de
Alzheimer (PPA). As possíveis funções fisiológicas da proteína PPA, o seu
destino e vias de processamento celulares, conjuntamente com possíveis
proteínas celulares que com ela interajam, são assim tópicos de interesse e
objectos de investigação científica mundial. Neste contexto tem sido
amplamente descrito o envolvimento do processo de fosforilação de proteínas,
uma importante modificação pós-transducional que regula muitos e variados
acontecimentos intracelulares, na regulação do processamento da PPA.
Apesar do exposto, muito pouco é conhecido acerca da fosforilação directa da
própria PPA. Esta proteína possui na sua estrutura primária sequências
consenso para fosforilação, quer no seu ectodomínio quer no seu domínio
intracelular, já descritas como sofrendo fosforilação “in vitro” e “in vivo”. O
resíduo Serina 655 pertence a um motivo funcional da APP, 653YTSI656, que
forma um sinal de internalização e/ou de “sorting” basolateral. Este domínio é
também o local de ligação para a APPBP2, uma proteína que interage com os
microtubulos da célula. Embora ainda mal elucidados, os mecanismos pelos
quais a fosforilação proteica regula o processamento da PPA parecem incluir
uma alteração no tráfego desta proteína, sugerindo que o domínio fosforilável
653YTSI656 desempenha um papel importante nesse processo.
Esta dissertação visou assim contribuir para elucidar o papel da fosforilação
directa da molécula de APP, mais especificamente no seu resíduo Serina 655,
na regulação do direcionamento e tráfego subcelular da proteína, e nas suas
possíveis clivagens proteolíticas. De forma a respondermos a essas questões
desenvolvemos um modelo experimental para seguir o tráfego intracelular, que
usa uma combinação de biologia molecular, técnicas de microscopia de
epifluorescência e técnicas de cultura celular. Os resultados obtidos implicam
este resíduo como um sinal de direcionamento subcelular da proteína APP, e
revelam como o redireccionamento desta proteína por fosforilação favorece um
tipo de processamento não amiloidogénico desta. Adicionalmente, a
fosforilação do resíduo Serina 655 parece possuir um papel regulador da
actividade da PPA como molécula de transdução de sinais. As implicações
destas observações na DA e em novas aplicações terapêuticas para a doença
são subsequentemente discutidas.Alzheimer’s Disease (AD) is a common neurodegenerative disease affecting
individuals worldwide with an incidence of 2-7% of post-65 and 15% of post-85
years old. This disease is multifactorial in its etiology but central to its pathology
is a neurotoxic peptide termed Abeta. This peptide is physiologically derived by
a proteolytic process on the transmembranar Alzheimer’s Amyloid Precursor
Protein (APP). Protein phosphorylation-dependent APP processing has been
widely described and although the mechanisms involved remain far from
clarified, alterations in APP trafficking seem to occur as part of the answer.
Furthermore, the occurrence of consensus phosphorylation sites in the APP
intracellular domain has been known for long, but little was known regarding
the direct phosphorylation of APP. Efforts in unravelling the role of these
domains are finally being successful in placing them as key control points in
APP targeting and processing. Among these consensus sequences, the less
studied 653YTSI656 motif forms a characteristic internalisation and/or basolateral
sorting signal sequence, and is known to be the binding site for a microtubuleinteracting
protein (APPBP2). Phosphorylation of this motif was thus suggested
to be involved in APP targeting regulation, hitherto all attempts failed to confirm
it or even to reveal substantial evidences.
In this project, the role of the 653YTSI656 idomain, and in particular the
phosphorylatable serine 655, in APP trafficking and proteolytic processing was
studied. In order to address this question a new experimental methodology was
developed, which coupled molecular biology, fluorescence imaging, and cell
culture techniques. APP point mutants, mimicking serine 655 phosphorylatedand
dephosphorylated-status, and tagged with the green-fluorescent protein,
were used to study protein trafficking dynamics and processing. Results
obtained place serine 655 phosphorylation as a key signal in APP sorting and
targeting to specific subcellular locations. Also of high relevance was the
observed implication of serine 655 phosphorylation as a regulatory mechanism
that maybe involved in controlling APP function as a signal transducer. The
implications of these observations in AD pathogenesis and therapeutic
approaches are discussed.FCT - PRAXIS XXI/BD/16218/98FCT - POCTI/BCI/34349/1999Project DIADEM, QLK3-CT- 2001/02362Fundação Calouste GulbenkianFundação Astrazenec
Epidemiology of intra-abdominal infection and sepsis in critically ill patients: “AbSeS”, a multinational observational cohort study and ESICM Trials Group Project
No full textPurpose: To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). Methods: We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. Results: The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicrobial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation. Conclusion: This multinational, heterogeneous cohort of ICU patients with intra-abdominal infection revealed that setting of infection acquisition, anatomical disruption, and severity of disease expression are disease-specific phenotypic characteristics associated with outcome, irrespective of the type of infection. Antimicrobial resistance is equally common in community-acquired as in hospital-acquired infection. © 2019, The Author(s)
Key determinants of effective board of directors - evidence from Nigeria
No full textThis thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.The 2008 financial crisis that led to the collapse of companies and economic recession in most countries has also increased the concern for transparency, accountability and regulatory oversight and once more put corporate governance and board effectiveness on the front burner of big business issues all over the world. The board is seen as a key player in governance of companies and there is need for a better understanding of how this body works. Majority of the research work in these areas has been in developed economies and not much work has been done in the area of board effectiveness in the emerging markets of Africa.
This thesis examines the relationship between key board characteristics and board effectiveness. It also explored the impact of certain mediators on this relationship. Unlike most studies on board which focus on firm performance and mostly in developed markets, this study was conducted in an emerging market and the focus was on board effectiveness. Based on the work done by other researchers in developed economies the researcher developed a theoretical framework and a set of hypotheses to examine the relationship between board characteristics and board effectiveness and the impact of certain mediators on this relationship. Board characteristics considered in this research include board size, CEO duality, board independence, and board diversity. In addition, the impact of board human capital on board effectiveness was also considered. Additionally, the researcher examined if the relationships between board characteristics and board effectiveness will be affected by organization type, ownership, age and size.
The empirical examination of the hypotheses developed from the theoretical framework presented in this study show that board characteristics, apart from professional human capital, do not have any significant impact on board effectiveness. Board professional human capital was found to have a positive relationship with board operations and board cohesiveness and also with board effectiveness.
The results show that in Nigeria, board diversity and human capital are the most important board structural factors that impact board effectiveness. They also show that board processes of operations, cohesiveness and decision making have significant impact on board effectiveness. Finally the results show that board process factors are more important than board structural factors in determining board effectiveness. The study shows that these relationships were not significantly affected by organization type, ownership, age or size. The study contributes to understanding of board effectiveness in an emerging market where board roles and processes are still developing; by examining both traditional variables such as board size, CEO duality, board independence and other organizational attributes such as board job related diversity and board professional human capital variables. In addition, this is the first study to examine board effectiveness in publicly quoted companies in Nigeria. The study will also contribute to better governance practices in Nigeria, where lack of good governance has been blamed for the slow economic development and growth. The theoretical framework and the findings of this thesis are expected to stimulate scholars for further research into identifying the characteristics that boards must possess if they are to be active and effective. They should also stimulate practitioners and scholars of strategy, organizational behaviour and corporate governance to examine boards and their activities from many perspectives, particularly from the process side
SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease
No full textNeurological Motor Disorder
Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability
No full textParkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types
