734 research outputs found
THE ROLE OF ACTIN CYTOSKELETON IN REGULATING NEURONAL FUNCTION IN PHYSIOLOGY AND DISEASE: ZOOM IN ON THE CYCLASE-ASSOCIATED PROTEIN 2
No full textLa malattia di Alzheimer (AD) è una patologia neurodegenerativa progressiva caratterizzata dalla
deposizione di placche extracellulari di beta amiloide (Aβ) e dall'accumulo intracellulare di proteina tau
iperfosforilata. Recenti studi indicano la perdita di sinapsi come il più significativo indicatore del declino
cognitivo nell'AD, portando alla classificazione dell'AD come “sinaptopatia”. Il citoscheletro di actina
svolge un ruolo critico nella plasticità sinaptica e le alterazioni delle dinamiche di actina contribuiscono
al deterioramento sinaptico nell'AD. Il mio progetto si è focalizzato sul ruolo della proteina Cyclase
associated protein 2 (CAP2), un modulatore dell'actina essenziale per l'architettura delle spine e la
trasmissione sinaptica e che risulta alterato nei pazienti con AD. In effetti, l'espressione di CAP2 è
ridotta nell'AD e, di conseguenza, i livelli sinaptici della forma dimerica di CAP2 sono ridotti, alterando
quindi l'associazione di cofilin con il dimero/monomero di CAP2. Inoltre, l'actina e le proteine ad essa
associate regolano la dinamica mitocondriale, per cui la disfunzione del citoscheletro di actina può
contribuire ulteriormente alla patologia dell'AD, aggiungendo un altro livello di complessità alla
malattia.
In questa tesi abbiamo riportato che i pazienti affetti da AD presentano livelli di CAP2 nel liquor più
elevati rispetto ai controlli e ai pazienti affetti da altre patologie neurodegenerative, che correlano
positivamente con la tau totale e la tau fosforilata in Thr181 (p-tau181). I livelli di mRNA di CAP2 sono
ridotti nell'ippocampo dei pazienti con AD. Pertanto, per evidenziare un potenziale legame biologico tra
CAP2 e tau, abbiamo ridotto l'espressione di CAP2 nei neuroni ippocampali e abbiamo misurato un
aumento significativo di p-tau181 e un concomitante aumento dell'attivazione della caspasi-3, senza
influire sulla vitalità cellulare. Inoltre, abbiamo dimostrato una maggiore variabilità, che suggerisce una
maggiore instabilità, del citoscheletro di actina delle spine dendritiche in seguito al silenziamento di
CAP2.
Inoltre, abbiamo dimostrato il coinvolgimento di CAP2 nei meccanismi rilevanti per la dinamica
mitocondriale actina-dipendente. Infatti, la delezione di CAP2 innesca un'evidente alterazione della
morfologia mitocondriale, mediata dalla inibizione delle dinamiche di fissione Drp1-dipendenti, e una
contemporanea perdita di massa mitocondriale causata da alterazioni nei processi di biogenesi.
Data la ridotta espressione di CAP2 nell'AD, abbiamo verificato gli effetti di un'aumentata espressione
di CAP2 nei topi AD e abbiamo osservato che questo approccio ripristina le vie sinaptiche mediate dal
complesso CAP2/cofilin e le vie di plasticità sinaptica, preservando così la funzione cognitiva.
L’overespressione di CAP2 riduce la formazione di cofilin-actin rods e attenua le anomalie della proteina
tau. CAP2 si accumula all'interno dei cofilin-actin rods specificamente indotti dagli oligomeri di Aβ.
Inoltre, la dimerizzazione di CAP2 è necessaria per prevenire la perdita di sinapsi indotta da Aβ, ma non
per proteggere i neuroni dalla formazione degli actin rods.
Nel complesso, questi risultati rafforzano il ruolo della disfunzione sinaptica nelle prime fasi dell'AD e
supportano la correlazione del deterioramento sinaptico dell'AD con le alterazioni del citoscheletro di
actina, evidenziando che CAP2 si trova al crocevia di molteplici vie biologiche alla base della patogenesi
dell'AD.Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the deposition
of extracellular amyloid-beta (Aβ) plaques and intracellular accumulation of hyperphosphorylated tau
protein. Recent studies point out synaptic loss as the strongest indicator of cognitive impairment in AD,
leading to the classification of AD as a “synaptopathy”. The actin cytoskeleton plays a critical role in
synaptic plasticity, and disruptions in actin dynamics contribute to synaptic failure in AD. We focused
on cyclase-associated protein 2 (CAP2), an actin-modifier essential for spine architecture and synaptic
transmission and altered in AD patients. Indeed, CAP2 expression is reduced in AD and, thereby, the
synaptic availability of CAP2 dimer is decreased, having an impact of cofilin association with the CAP2
dimer/monomer. Additionally, actin and its associated proteins regulate mitochondrial dynamics,
therefore actin cytoskeleton dysfunction may further contribute to AD pathology, adding another layer
of complexity to the disease pathology.
Here, we reported that AD patients show higher CAP2 CSF levels compared to controls and non-AD
patients, that positively correlate with total and tau phosphorylated at Thr181 (p-tau181). CAP2 mRNA
levels are reduced in the hippocampus of AD patients. Therefore, to assess a potential biological link
between CAP2 and tau, we downregulated CAP2 expression in hippocampal neurons and we measured
a significant increase in p-tau181 and a concomitant increase of caspase-3 activation without affecting
cell viability. In addition, we demonstrated a higher variance, suggesting increased instability, of
dendritic spine actin cytoskeleton upon CAP2 down-regulation.
Moreover, we show the involvement of CAP2 in those mechanisms relevant for actin-dependent
mitochondrial dynamics. Indeed, the ablation of CAP2 triggers an evident alteration of mitochondrial
morphology, mediated by the suppression of Drp1-dependent fission dynamics, and a simultaneous
loss of mitochondrial mass caused by alterations in mitobiogenesis processes.
Given the downregulation of CAP2 in AD, we described that CAP2 gene delivery in AD mice restores
synaptic CAP2/cofilin and plasticity pathways, thus preserving cognitive function. CAP2 overexpression
reduces cofilin actin rods formation and mitigates tau abnormalities. CAP2 is accumulated within
cofilin-actin rods specifically induced by Aβ oligomers. Furthermore, CAP2 dimerization is required for
preventing Aβ-induced synaptic loss but not to protect neurons from cofilin-actin rods formation.
Taken together, these findings strengthen the role of synaptic pathology in the early stages of AD and
support the correlation of AD synaptic failure with actin cytoskeleton dysfunction, highlighting CAP2 at
the crossroad of multiple pathways underlying AD pathogenesis
Nonlinear mixed-effects models to analyze actin dynamics in dendritic spines
No full textAbstract Fluorescence recovery after photobleaching (FRAP) allows to study actin-turnover in dendritic spines by providing recovery trajectories over time within a nested data structure (i.e. spine/neuron/culture). Statistical approaches to FRAP usually consider one-phase association models to estimate recovery-curve-specific parameters and test statistical hypotheses on curve parameters either at the spine or neuron level, ignoring the nested data structure. However, this approach leads to pseudoreplication concerns. We propose a nonlinear mixed-effects model to integrate the one-phase association model estimate with the nested data structure of FRAP experiments; this also allows us to model heteroscedasticity and time dependence in the data. We used this approach to evaluate the effect of the downregulation of the actin-binding protein CAP2 on actin dynamics. Our model allows the additional modelling of the variance function across experimental conditions, which may represent a novel parameter of interest in FRAP experiments. Indeed, the detected differential effect of the experimental condition on the variance component captures the increased instability of time-specific observations around the spine-specific trajectory for the CAP2-downregulated spines compared to the control spines. We hypothesise that this parameter reflects the increased instability of the actin cytoskeleton in dendritic spines upon CAP2 downregulation. We developed an R-based Shiny application, termed FRApp, to fit the statistical models introduced without requiring programming expertise
Dendritic spines in alzheimer’s disease : How the actin cytoskeleton contributes to synaptic failure
No full textAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ-driven synaptic dysfunction in the early phases of pathogenesis. In the synaptic context, the actin cytoskeleton is a crucial element to maintain the dendritic spine architecture and to orchestrate the spine’s morphology remodeling driven by synaptic activity. Indeed, spine shape and synaptic strength are strictly correlated and precisely governed during plasticity phenomena in order to convert short-term alterations of synaptic strength into long-lasting changes that are embedded in stable structural modification. These functional and structural modifications are considered the biological basis of learning and memory processes. In this review we discussed the existing evidence regarding the role of the spine actin cytoskeleton in AD synaptic failure. We revised the physiological function of the actin cytoskeleton in the spine shaping and the contribution of actin dynamics in the endocytosis mechanism. The internalization process is implicated in different aspects of AD since it controls both glutamate receptor membrane levels and amyloid generation. The detailed understanding of the mechanisms controlling the actin cytoskeleton in a unique biological context as the dendritic spine could pave the way to the development of innovative synapse-tailored therapeutic interventions and to the identification of novel biomarkers to monitor synaptic loss in AD
Riflessioni linguistiche sul tedesco e sul russo in Julya Rabinowich: un confronto tra narrazione autobiografica orale e il romanzo Spaltkopf
No full textLinguistic Reflections in German and Russian in Julya Rabinowich: A Comparative
Study of Oral Autobiographical Narrative and the Novel Spaltkopf.
The Austrian author Julya Rabinowich, born in Leningrad in 1970 to a family of Rus-
sian Jews and emigrated to Vienna at the age of 7, is one of the most renowned repre-
sentatives of contemporary literature in the German language. Rabinowich made her
literary debut in 2008 with Spaltkopf (Split Head), her most strongly autobiographical
novel. In 2012, the writer was interviewed by Michaela Bürger-Koftis as part of the
research project Polyphonie. Mehrsprachigkeit_Kreativität_Schreiben. This interview
can be understood as a linguistic biography, as Rabinowich recounts her experiences
related to the languages in her linguistic repertoire, focusing particularly on German
and Russian. From this account, the author’s Spracheinstellungen (linguistic attitudes),
as well as the impressions and emotions related to her two main languages, emerge.
The aim of this study is to compare the interview passages in which Rabinowich
expresses herself regarding German and Russian with excerpts from Spaltkopf where
the relationship of the protagonist, Mischka, with these two languages emerges. In this
162 Michaela Bürger-Koftis, Ramona Pellegrino
way, it will be possible to determine whether Spaltkopf reflects not only the author’s
migratory experience but also her linguistic biography. Furthermore, it will be analyz-
ed if and to what extent the expression of linguistic attitudes and emotions related to
German and Russian differs between the novel and the oral autobiographical account.
To examine how Rabinowich expresses her linguistic experiences and emotions relat-
ed to German and Russian, a qualitative analysis of the texts will be conducted, with
a theoretical approach based on the concepts of linguistic biography and verbalization
of emotions developed by Brigitta Busch and Reinhard Fiehler
Ramona Bennett, Tacoma, October 1976
No full textRamona Bennett (b. 1938) is a prominent Puyallap Tribe leader and activist. She was elected to the Puyallup Tribal Council in 1968, and served as Tribal Chairwoman from 1971 to 1978. Bennett is also a pioneer of fishing rights advocacy, co-founding the Survival of American Indians Association in 1964, and helping to bring “fish-in” protests to national prominence.
Much of Bennett’s work focuses on social welfare issues, mainly fighting for the rights of women, children and families. She began her social service work in the 1950s, with the Seattle’s American Indian Women’s Service League. In 1972, she co-founded the Local Indian Child Welfare Act Committee, where she developed a model for childhood and family services that she used to co-author and secure the national Indian Child Welfare Act of 1978, a Federal law that governs the removal and out-of-home placement of indigenous children. In the 1980s, she co-founded the Rainbow Youth and Family Services in Tacoma, a non-profit which she ran for many years.
This photo of Ramona Bennett was taken for a profile of her run by the Seattle Post-Intelligencer in October 1976. At the time, Bennett was chairwoman of the Puyallup Tribal Council.Caption information source: “Ramona Bennett,” The Seattle Civil Rights & Labor History Project, University of Washington, https://depts.washington.edu/civilr/bennett.htm
Caption information source: "Ramona Bennett - a Cool, Witty, Charming Leader" by Jack Wilkins, Seattle Post=Intelligencer, October 28, 1976, p. A71 photographic print: b&w; 8 x 10 in
Portrait of Helen Fiske Hunt Jackson, author of Ramona, [s.d.]
No full textPhotographic portrait of Helen Fiske Hunt Jackson, author of "Ramona", [s.d.]. Mrs. Jackson is pictured standing, wearing an elaborate dress with a huge bustle, made of what appears to be silk or satin. Her hands are folded across her waist while she looks to the right. She appears to be in her middle-age and wears the large locks of her curly hair pulled back from her face. She can be seen smiling, while a chair supports her dress to the right. Picture file card reads: "An American novelist, poet, and general writer, born at Amherst, mass. October 18, 1831; died at San Francisco, CA, August 12, 1885. She was the daughter of Professor Fiske, of Amherst. He first husband, Capt. E.B. Hunt, died in 1863. In 1870, she published a volume entitled "Verses". Her first prose volume, "Bits of Travel" (1872), was followed by "Bits of Talk About Home Matters" (1873), and "Bits of Travel at Home" (1878). In 1875 she married Mr. W.S. Jackson, of Colorado Springs. Here, she published "A Century of Dishonor", relating to the dealings of the U.S. Government with the Indians. This led to her appointment in 1883 as a special commissioner to examine into the condition and needs of the Mission Indians. After visiting the different tribes, she wrote "Ramona"(1884), a novel relating to the Mission Indians. Mrs. Jackson had previously written two novels in the "no Name" seires: "Mercy Philbric's Chioce" ["Choice"?] (1876) and "Hetty's Strange History"(1877). Besides these works, she published "The Story of Boon", a poem (1879), the training of children(1882), and several books for young people: "Nellie's Silver Mine" (1878), "Mammy Tittleback and her Family" (1881), and "The Hunter Cats of Connorloa" (1884). Since her death have appeared "Glimpses of Three Coasts", "Sonnets and Lyrics", "Zeph", a novel (1886), and "Between Whiles" (1887)"
Dance to the music of time. by Ramona Koval
No full textComing face to face with thousands of years of Aboriginal culture for the first time, the author found her modern values collapsing all around her
Cover or title page of "Ramona" by Helen Jackson, ca.1884.
No full textPhotograph of the cover or title page of "Ramona" by Helen Jackson, ca.1884. The cover reads: "Ramona. A Story. By Helen Jackson (H.H.), Author of 'Verses,' 'Bits of Travel,' 'Bits of Travel at Home,' 'Bits of Talk About Home Matters,' etc. Qui Legit Regit. Boston: Roberts Brothers. 1884"
Movement play as a facilitator of social development of 2-3 year old children
No full textDarba autore: Ramona Kravceva. Kvalifikācijas darba “Kustību rotaļa, kā 2-3 gadus vecu bērnu sociālās attīstības sekmētāja” mērķis – izpētīt, kā kustību rotaļas ietekmē bērnu attīstību ikdienā. Cik daudz var atvērties mazākās grupas bērni laika gaitā, izmantojot ikdienā rotaļas, cik liela nozīme kustību rotaļām ir bērnu ikdienā. Darba pirmajā daļā tika analizētas sociālās prasmes, kā tās veidojas un bērnu raksturojums veselumā. Otrajā nodaļā tika analizētas kustību rotaļas, kustību rotaļu procesa organizācija un metodika, to izmantošana veselības un fiziskajā mācību jomā. Trešajā nodaļā tika veikts pētījums, tā metodoloģiskais pamatojums un norises apraksts. Izpētīts tika konkrēta vecuma grupas bērni X pirmsskolas izglītības iestādē, sadarbībā ar grupas pedagogu un tā palīgu. Kvalifikācijas darbs sastāv no 43 lappusēm, tsk., - 6 tabulas, 4 attēli, 2 pielikumi. Izmantoti 33 informācijas avoti.Work author: Ramona Kravceva. The qualification work "Movement play as a facilitator of social development of 2-3 year old children" is to explore how movement play affects children's development in everyday life. How much children in the smaller group can open up over time through daily play, how important movement play is in children's daily lives. The first part of the work analysed social skills, how they are formed and the characteristics of children in the whole. The second chapter analysed movement play, organization and methodology of the movement play process, their use in the field of health and physical learning. In the third chapter, a study, its methodological rationale and description of the course were carried out. Children of a particular age group in X preschool educational institution were studied, in cooperation with the group teacher and its assistant. The qualification work consists of 43 pages, - 6 tables, 4 images, 2 annexes, 33 sources of information have been used
The Ramona Mission and The Mission Indians
No full textIntroduction
Ramona, the fascinating Indian story by H.H. -- Mrs. H.H. Jackson -- the scenes of which are laid in Southern California, is based upon facts learned and reported by the author on an official inspection of the Mission Indians there in 1883, and it very truthfully and graphically reveals the present condition and hardships, as well as the past sufferings, of those tribes.
The story is one of the saddest of many sad records of the race, and is in itself a most moving plea for whatever atonement it is now possible to make to that long-suffering people. But direct appeals for aid in their behalf have also come to The Women\u27s National Indian Association, first, from H. H. herself, and since then from others.
In response to these calls a mission is now to be opened by the Association, among the Coahuillas in the village of that name, extending later, it is hoped, to others of the about twenty villages occupied by these Mission Indians. From the official report of Mrs. Jackson, and from later official and other sources, the facts herein presented are taken. But in order to convey an intelligent, general view of the character and circumstances of these Indians, and in response to many requests, these facts are prefaced by a brief historical sketch, and a glance at their present general condition.https://digicom.bpl.lib.me.us/books_pubs/1177/thumbnail.jp
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