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PRESENILINS AND Ca2+ HOMEOSTASIS: ROLE IN ALZHEIMER'S DISEASE AND CELL PHYSIOLOGY
Full text linkAlzheimer's Disease (AD) is a progressive neurodegenerative disorder and the most common form of senile dementia. The characteristic histopathological hallmarks of AD are the intracellular neurofibrillary tangles and the amyloid plaques, made of aggregated amyloid peptides (Aβ), that deposit in the extracellular matrix of the brain. Aβ peptides are the result of two sequential cleavages of the amyloid precursor protein (APP); Aβ is eventually released by the γ-secretase enzyme. The most abundant Aβ peptide species, both physiologically produced throughout life, are Aβ40 and Aβ42, which is more insoluble and aggregation-prone.
Although most AD cases are sporadic, a small percentage of patients is affected by the hereditary form of AD (Familial Alzheimer's Disease, FAD), caused by dominant mutations in one of three genes. These genes code for the APP, presenilin-1 (PS1) and presenilin-2 (PS2); PSs are the catalytic subunits of the γ-secretase enzyme complex. FAD-linked mutations in PSs lead to an increased Aβ42/Aβ40 ratio, that promotes Aβ plaques deposition. Beside this effect on Aβ production, many mutations in PS1 and PS2 have been extensively demonstrated to cause alterations in the intracellular Ca2+ homeostasis, thus making neurons more sensitive to excitotoxic stimuli and apoptosis. Nevertheless, the effects and the mechanisms of this interference in the Ca2+ balance are still unclear and under intense investigation. For a long time, the most popular hypothesis has been the "Ca2+ overload" hypothesis, which claims that mutated PSs give rise to exaggerated Ca2+ responses upon stimulation, sustained by intracellular stores, and the endoplasmic reticulum (ER) in particular, overloaded with Ca2+. However, an increasing number of studies has recently began to critically question this hypothesis and different possible targets of PSs action have been proposed.
Previous works from our laboratory showed that a number of FAD-linked PS1 and PS2 mutants reduce the ER Ca2+ content; starting from this evidence, we investigated the mechanism(s) leading to this effect.
The SERCA-2 pump was identified as the most likely target of FAD-linked PS2-T122R action and indeed the two protein interact, as co-immunoprecipitation assays demonstrated. PS2-T122R was shown to impair the pump activity by decreasing its maximal Ca2+ uptake rate, while leaving its protein level unaltered. Interestingly, similar results were obtained with wild-type (wt) PS2: transient expression of wt PS2 in a PSs null background led to a lower steady-state ER Ca2+ concentration and a slower ER Ca2+ uptake rate. Consistently with this observation, knocking down the endogenous PS2 level by small interefering RNAs increased both parameters. These results suggest a physiological role for PS2 in regulating intracellular Ca2+ handling, acting as a brake for the SERCA pumps. Finally, over-expression of SERCA-2B together with PS2-T122R rescued the ER Ca2+ content and the pump uptake rate at the respective values observed in control cells.
A long-term goal of the project is studying intracellular Ca2+ dynamics, both in vitro and in vivo, in the brain of AD mouse models based on APP and FAD-linked PS mutants, through single cell live Ca2+ imaging experiments with FRET-based cameleon Ca2+ probes. Thus, the second part of this work has been dedicated to a preliminary set up of the suitable experimental conditions to be employed with two cameleon sensors genetically targeted to the lumen of the ER and the Golgi apparatus. While the results obtained with the ER-targeted cameleon probe matched those previously obtained with an ER-targeted aequorin probe, an unexpected result was obtained with a novel cameleon localized to a specific sub-compartment of the Golgi apparatus. This new sensor helped us to better define the mechanism of action of PS2-T122R, showing that it selectively acts on SERCA-2 but not on SPCA-1 pumps.La malattia di Alzheimer (Alzheimer's Disease, AD) è una patologia neurodegenerativa progressia e rappresenta la forma più comune di demenza senile. Le caratteristiche istopatologiche dell'AD sono le fibrille intraneuronali e le placche amiloidi, formate da aggregati di peptidi amiloidi (Aβ), che si depositano nella matrice extracellulare del cervello. I peptidi Aβ sono il prodotto di due tagli sequenziali della proteina precursore dell'amiloide (amyloid precursor protein, APP). L'ultimo taglio proteolitico di APP, che porta al rilascio degli Aβ nella matrice extracellulare, è opera dell'enzima γ-secretasi. Le forme più abbondanti di peptidi Aβ, entrambe fisiologicamente prodotte nel corso della vita, sono Aβ40 e Aβ42, che è più insolubile e incline ad aggregare.
Sebbene la maggioranza dei casi di AD sia di origine sporadica, una piccola percentuale di pazienti è affetta dalla forma ereditaria di AD (Familial Alzheimer's Disease, FAD), causata da mutazioni dominanti in uno dei tre geni che codificano per l'APP, per la presenilina-1 (PS1) e la presenilina-2 PS2). Le preseniline (PSs) sono le subunità catalitiche del complesso enzimatico dellaγ-secretasi. Mutazioni associate a FAD nelle PSs portano ad un aumento del rapporto Aβ40/Aβ42, che favorisce il depositarsi delle placche amiloidi. Oltre a questo effetto sulla produzione di Ab, è stato ampiamente dimostrato che molte mutazioni nelle PS1 e PS2 causano alterazioni nell'omeostasi intracellulare del Ca2+, rendendo così i neuroni più sensibili a stimoli eccitotossici e all'apoptosi. Ciò nonostante, gli effetti e i meccanismi di questa interferenza nel normale equilibrio intracellulare del Ca2+ sono ancora poco chiari e oggetto di intensa indagine. A lungo, l'ipotesi più popolare è stata l'ipotesi del "sovraccarico di Ca2+", la quale afferma che le PSs mutate danno origine a esagerate risposte Ca2+ in seguito a stimolazione, sostenute da depositi intracellulari (in particolare, il reticolo endoplasmatico, ER) sovraccarichi di Ca2+. Tuttavia, un crescente numero di studi ha di recente iniziato a mettere in discussione questa ipotesi e diversi possibili bersagli dell'azione delle PSs sono stati proposti.
Studi precedenti condotti nel nostro laboratorio hanno mostrato che un certo numero di PS1 e PS2 mutate associate a FAD riducono il contenuto di Ca2+ dell'ER; partendo da queste osservazioni, abbiamo indagato il/i meccanismo/i alla base di questo effetto.
La pompa SERCA-2 è stata identificata come il bersaglio più probabile dell'azione della mutazione associata a FAD T122R nella PS2 (PS2-T122R) e infatti le due proteine, SERCA-2 e PS2-T122R, interagiscono, come dimostrato da esperimenti di co-immunoprecipitazione. E' stato dimostrato che la PS2-T122R danneggia l'attività della pompa riducendo la sua velocità massima di trasporto, mentre il livello della proteina rimane inalterato. E' interessante notare, inoltre, che risultati simili sono stati ottenuti con la PS2 non mutata (wild-type, wt): l'espressione transiente della PS2 wt in un modello cellulare privo di PSs ha avuto come conseguenze un abbassamento della concentrazione di Ca2+ nell'ER all'equilibrio e un rallentamento della velocità di importo del Ca2+ nell'ER. Coerentemente con questa osservazione, l'abbattimento dell'espressione della PS2 endogena mediante la tecnica di RNA interference ha portato ad un incremento di entrambi questi parametri. Questi risultati suggeriscono un ruolo fisiologico della PS2 nella regolazione intracellulare del Ca2+; la PS2 agirebbe come un freno per le pompe SERCA. Infine, la sovra-espressione della SERCA-2B assieme alla PS2-T122R ha permesso di riportare i valori del contenuto di Ca2+ nell'ER e della velocità della pompa ai valori di controllo.
Uno degli obiettivi a lungo termine di questo progetto è studiare le dinamiche intracellulari del Ca2+, sia in vivo che in vitro, nel cervello di topi transgenici usati come modello di AD, in quanto basati su mutazioni nell'APP e in PS associate a FAD. L'approccio scelto è monitorare le variazioni di Ca2+ in singola cellula attraverso sonde per il Ca2+ basate su FRET, i cameleons. Pertanto, la seconda parte di questo lavoro è stata dedicata alla messa a punto preliminare delle condizioni sperimentali più adatte da adottare con due sonde cameleons, geneticamente indirizzate nel lume dell'ER e dell'apparato di Golgi. Mentre i risultati ottenuti con il cameleon indirizzato all'ER corrispondono a quelli ottenuti in precedenza con un'equorina indirizzata all'ER, un risultato inaspettato è emerso utilizzando un nuovo cameleon localizzato in uno specifico compartimento del Golgi. Questa nuova sonda ci ha aiutato a definire meglio il meccanismo di azione della PS2-T122R, mostrando che agisce selettivamente sulle pompe SERCA-2 ma non sulle pompe SPCA1
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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