1,720,953 research outputs found
Mitochondriale ROS als Ziel in der Ferroptose: Die Rolle von Drp1 und VDAC1 in neuronalen Zellen
No full textFerroptosis is an iron-dependent necrotic cell death pathway that has emerged as a central
mechanism in neurodegenerative diseases. The inhibition of ferroptosis has a strong potential
as effective strategy to prevent cell death that is mediated by oxidative stress. One hallmark
of ferroptosis is the lipid peroxidation mediated rupture of the cell membrane, in which ROS
play a vital role. Mitochondria are known as the main producer of ROS during oxidative
phosphorylation, a byproduct during energy metabolism, emphasizing a link between
mitochondrial dysfunction and ferroptosis. While mitochondrial ROS and lipid peroxidation are
central to ferroptosis, the specific role of Dynamin-related Protein 1 (Drp1) and the Voltage-
dependent Anion Channel (VDAC1) in mitochondrial pathways of ferroptosis remained
unclear.
The aim of the present study was to investigate how Drp1 and VDAC1 contribute to ferroptosis
by regulating mitochondrial integrity, ROS production and iron metabolism and to explore
whether inhibition or modulation of these two proteins can protect neuronal cells from
ferroptotic damage. Drp1 is the key protein to regulate mitochondrial fission. The study
proposed that inhibition of excessive Drp1-mediated mitochondrial fragmentation would
prevent mitochondrial ROS amplification, preservation of cellular bioenergetics and therefore
abrogate ferroptosis. Dysregulation of calcium and iron homeostasis is implicated as trigger
for mitochondrial dysfunction and therefore aberrant redox balance. VDAC1 transports ions
and metabolites bidirectionally in and out of the mitochondria for physiological mitochondrial
function. Inhibition of VDAC1 was anticipated to prevent mitochondrial ROS amplification
through the decrease of mitochondrial respiration and bioenergetic shift towards glycolysis to
abolish ferroptosis progression.
Mitochondrial dynamics and metabolic regulation are interconnected because mitochondrial
shape and function directly influence cellular energy metabolism and vice versa. Mitochondrial
morphology determines ATP generation, ROS production, and metabolite exchange, which
are critical for maintaining cellular energy demands. With this, the impact of both, Drp1 and
VDAC1, was investigated to elaborate on multiple possibilities to target mitochondrial ROS
during ferroptosis.
The model system used for the ferroptosis studies was the mouse hippocampal cell line HT22.
Drp1 was knocked out using a CRISPR/Cas9-based genome editing approach, while VDAC1
was inhibited pharmacologically using Akos-22. The methodological approach comprised cell
viability assessments and fluorescence-based assays to assess ROS, iron, lipid peroxidation,
86
Summary
calcium, as well as mitochondrial integrity and function. The Seahorse XF-analyzer was used
to study cellular bioenergetics.
The findings of the study demonstrate that genetical deletion of Drp1 increased the resilience
against ferroptosis by preventing excessive mitochondrial fragmentation and stabilizing
cellular bioenergetics. Mitochondrial integrity and function which are normally lost through
ferroptosis were preserved. Pharmacological inhibition of VDAC1 abolished ferroptotic cell
death by a metabolic shift towards glycolysis to reduce the mitochondrial contribution to
detrimental ROS signaling. Inhibition of VDAC1 decreased mitochondrial respiration and the
generation of mitochondrial ROS while decreasing cytosolic iron and calcium levels.
Alleviation of ferroptosis-mediated iron dysbalance by iron chelation and cellular iron uptake
inhibition also decreased oxidative phosphorylation, leading to the abrogation of detrimental
mitochondrial ROS signaling.
The present study provides valuable insights into mitochondrial pathways of ferroptosis. By
preserving mitochondrial integrity and alleviating mitochondrial ROS generation, mitochondria
are highlighted as important targets for novel strategies to combat ferroptosis-related
diseases, such as neurodegenerative diseases and conditions involving ischemic injuries. In
therapy-resistant cancers, mitochondria-targeted applications that lead to mitochondrial
dysfunction to increase the susceptibility towards ferroptosis might prove useful. The study
fills a critical gap in understanding how mitochondrial-specific processes contribute to
ferroptosis and how they can be modulated for therapeutic benefit.
These findings open new avenues for targeting mitochondrial dynamics and metabolite
exchange to combat ferroptosis-associated pathologies. Future work will focus on translating
these insights into therapeutic strategies for neurodegenerative diseases and cancer.Die Ferroptose ist eine eisenabhängige, nekrotische Form des Zelltods, die bei der
Progression neurodegenerativer Erkrankungen zunehmend als zentraler
pathophysiologischer Mechanismus erkannt wird. Das Hauptmerkmal der Ferroptose ist die
Lipidperoxidation, die zu einer Ruptur der Zellmembran und somit zum Zelltod führt. Reaktive
Sauerstoffspezies (ROS), und damit oxidativer Stress, spielen hierbei eine wesentliche Rolle.
Diese werden maßgeblich von den Mitochondrien als Nebenprodukt der oxidativen
Phosphorylierung produziert. So lässt sich eine Verbindung zwischen Ferroptose und
mitochondrialer Dysfunktion herstellen. Während die zentrale Rolle von mitochondrialen ROS
und der dadurch verursachten Lipidperoxidation in der Ferroptose gut erforscht sind, sind die
Rollen des Dynamin-verwandten Proteins 1 (Drp1) und des spannungsabhängigen
Anionenkanals (VDAC1) in der Ferroptose noch weitgehend unergründet.
Ziel der vorliegenden Arbeit war daher, zu untersuchen, wie Drp1 und VDAC1 zur Ferroptose
beitragen, indem sie die mitochondriale Integrität, die ROS-Produktion und den
Eisenstoffwechsel regulieren. Weiterhin sollte erforscht werden, inwieweit die Hemmung oder
Modulation dieser beiden Proteine neuronale Zellen vor dem ferroptotischem Zelltod schützen
kann. Drp1 ist das Schlüsselprotein für die Spaltung von Mitochondrien. Die Studie ging von
der Hypothese aus, dass die Inhibition der übermäßigen Drp1-vermittelten mitochondrialen
Spaltung die Verstärkung mitochondrialer ROS-Bildung verhindert, den zellulären
Energiemetabolismus bewahrt und folglich vor Ferroptose schützt. VDAC1 transportiert Ionen
sowie Metabolite in und aus den Mitochondrien und sorgt somit für eine intakte mitochondrielle
Funktion. Es wurde erwartet, dass eine Hemmung von VDAC1 zu einer Verringerung der
mitochondrialen ROS-Bildung durch eine Hemmung der mitochondrialen Atmung und einer
Verschiebung des zellulären Metabolismus zur Glykolyse führen würde. Dadurch sollten
ferroptotische Prozesse verlangsamt werden.
Die mitochondriale Dynamik und die Regulation des Metabolismus stehen in engem
Zusammenhang, da die Form und Funktion der Mitochondrien unmittelbar den zellulären
Energiemetabolismus beeinflusst. Die Morphologie der Mitochondrien hat Einfluss auf die
ATP-Generierung, die ROS-Produktion und den Austausch von Metaboliten, was essenziell
für die Aufrechterhaltung des zellulären Energiebedarfs ist. Infolgedessen wurden sowohl
Drp1 als auch VDAC1 ausgiebig untersucht, um die davon ausgehende Beeinflussung der
mitochondrialen ROS in der Ferroptose von mehreren Seiten zu beleuchten.
Als Modellsystem der neuronalen Ferroptose wurde die hippocampale Mauszelllinie HT22
benutzt. Drp1 wurde mit Hilfe eines CRISPR/Cas9-basierten Ansatzes ausgeschaltet,
während VDAC1 pharmakologisch durch Akos-22 gehemmt wurde. Die Methodik in dieser
Studie umfasste Analysen der Zellviabilität sowie fluoreszenzbasierte Assays zur Bewertung
von ROS, Eisen, Lipidperoxidation, Calcium sowie mitochondriale Integrität und Funktion. Die
zelluläre Bioenergetik wurde mittels Seahorse XF-Analyzer untersucht.
Die Ergebnisse der Studie zeigen, dass die genetische Modulation von Drp1 die
Widerstandsfähigkeit für Ferroptose erhöht, indem eine übermäßige mitochondriale
Fragmentierung verhindert und die zelluläre Bioenergetik stabilisiert wird. Der Verlust
mitochondrialer Integrität und Funktion, der durch Ferroptose vermittelt wird, konnte verhindert
werden. Die pharmakologische Hemmung von VDAC1 konnte den ferroptotischen Zelltod
durch eine Verlagerung des Stoffwechsels von der mitochondriellen Respiration auf die
Glykolyse abwehren. Die damit einhergehende Minderung der oxidativen Phosphorylierung
setzte den mitochondrialen Beitrag zur übermäßigen ROS-Produktion herab. Des Weiteren
konnte die Hemmung von VDAC1 auch die intrazellulären Eisen- und Calciumspiegel
verringern. Durch die Komplexierung des Eisens und die Hemmung der zellulären
Eisenaufnahme wurde die Ferroptose-vermittelte Eisen-Dysbalance aufgehoben und somit
die oxidative Phosphorylierung vermindert, was ebenfalls geringerer mitochondrieller ROS-
Produktion führt.
Die vorliegende Studie liefert wertvolle Einblicke in den mitochondrialen Mechanismus der
Ferroptose. Durch die Erhaltung der mitochondrialen Integrität und die Verringerung der
mitochondrialen ROS-Produktion werden Mitochondrien als wichtige Ziele für neuartige
Strategien zur Bekämpfung von mit Ferroptose assoziierten Krankheiten - beispielsweise
neurodegenerative Erkrankungen oder ischämische Zustände - identifiziert. Bei
therapieresistenten Krebserkrankungen könnten sich Behandlungen als nützlich erweisen, die
gezielt zu einer mitochondrialen Dysfunktion führen und die Anfälligkeit für Ferroptose
erhöhen. Die Studie schließt eine kritische Lücke im Verständnis, wie Mitochondrien-
spezifische Prozesse zur Ferroptose beitragen und wie sie für therapeutische Zwecke
moduliert werden können.
Die Ergebnisse dieser Studie eröffnen neue Wege zur Bekämpfung Ferroptose-assoziierter
Pathologien durch gezielte Beeinflussung der mitochondrialen Dynamik und des Austauschs
von Metaboliten. Zukünftige Arbeiten werden sich darauf konzentrieren, diese Erkenntnisse
in therapeutische Strategien für neurodegenerative Erkrankungen und Krebs zu übertragen
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
- …
