1,720,980 research outputs found
New insights into physiology of aged-related cognitive disorders: the DNA repair protein ATR
Full text linkAging is a multifactorial process characterized by the slow decline of cellular physiology associated with a lowdown of brain functions (1,2). Neurological complications mainly reflect defects at the synaptic structure. Indeed, preclinical studies demonstrate that preserving functionality of synapses delays the occurrence of aged-related neurological and cognitive defects and prevents the progressive neuronal degeneration (3). Since defects in DNA repair mechanisms have a critical role in aged-related neurological diseases (4,5,6,7) and expression of core DNA repair genes is downregulated during aging across brain regions (8), we are investigating the impact of ATR (Ataxia Telangiectasia mutated-Rad3 related) protein, a kinase activated primarly by DNA damage, in synapse physiology and its potential role in aging neuropathology. Whereas in literature it has been reported that ATR deletion leads to the calcium sensor synaptotagmin2 (SYT2) upregulation at excitatory neurons conferring hyperexcitability (9), our electrophysiological and confocal studies indicate in wt neurons treated with a ATR kinase activity inhibitor higher inhibition. Thus, diverse phenotypes result from the genetic deletion or pharmacological inactivation of ATR kinase activity. Also, the specific block of ATR prevents the induction of long-term potentiation upon glycine stimulation in neurons suggesting impaired NMDA-mediated processes. Indeed, calcium imaging recordings confirmed reduced calcium elevations in neurons with impaired ATR kinase activity upon transient exposure to exogenous NMDA. Our data indicate that activity of ATR is essential to synapse functionality and that alterations in its activation may affect neuronal health beyond its expected responses to DNA damages and oxidative stress
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
The therapeutic potential of atm inhibition in rett syndrome: insights from behavioral and molecular studies
No full textLa proteina ATM, nota per il suo ruolo nel riparo del DNA, regola anche KCC2, un trasportatore di potassio e cloro necessario per il “GABA switch”, processo fondamentale per rendere il GABA un neurotrasmettitore inibitorio e permettere così la maturazione del sistema nervoso.
La Sindrome di Rett (RTT) è una grave patologia del neurosviluppo che colpisce principalmente le bambine ed è causata da mutazioni nel gene MeCP2. In questa condizione, i livelli di ATM risultano elevati nell’ippocampo, contribuendo così a ridurre l’espressione di KCC2 e ritardando il “GABA switch”. Questo contribuisce ai problemi cognitivi, motori e respiratori tipici della malattia.
Basandosi sui risultati promettenti ottenuti in laboratorio, abbiamo testato la somministrazione intranasale del composto KU-55933 (KU), un inibitore specifico di ATM, a un modello murino di RTT, come possibile terapia. I test comportamentali condotti hanno mostrato che KU migliora le funzioni cognitive ippocampali e riduce la frequenza delle apnee, sintomo critico della patologia, senza influire sui deficit motori.
Le analisi dei tessuti ippocampali hanno rivelato che KU preserva i livelli di KCC2 e normalizza quelli di vGAT, un marcatore delle sinapsi inibitorie. Possiamo così dedurre che KU porti a un parziale recupero del ritardato “GABA switch”. Tuttavia, gli effetti terapeutici risultano temporanei, poiché la maggior parte dei sintomi ricompare dopo l’interruzione del trattamento, sottolineando la necessità di una somministrazione continua. Tuttavia, il miglioramento delle apnee è stato più evidente dopo la sospensione del trattamento.
In conclusione, l’inibizione di ATM potrebbe rappresentare una strategia promettente per alleviare i sintomi della RTT, agendo direttamente sui meccanismi molecolari alla base della malattia. Tuttavia, sono necessarie ulteriori ricerche per comprendere meglio il suo ruolo nella regolazione delle apnee e la sua efficacia nei modelli femminili della malattia.Ataxia Telangiectasia Mutated (ATM) is primarily involved in DNA repair, but recent studies have revealed a novel function in regulating KCC2, a potassium chloride co-transporter essential for the excitatory-to-inhibitory “GABA switch”, fundamental during GABAergic system maturation.
In Rett Syndrome (RTT), a severe X-linked neurodevelopmental disorder affecting females and caused by MeCP2 mutations, ATM is abnormally upregulated in the hippocampus. This contributes to the reduced KCC2 expression and delay of the GABA switch, ultimately disrupting the excitatory/inhibitory (E/I) balance, involved in RTT’s socio-cognitive, motor, and respiratory impairments.
Based on promising in vitro results, we explored ATM inhibition as a therapeutic strategy by administering KU-55933 (KU), a selective ATM kinase inhibitor, intranasally to Mecp2y/- (KO) mouse model of RTT. Behavioral tests (Y-maze, Novel Object Recognition, Three-chamber, Rotarod, and Plethysmography) revealed that KU improved hippocampal cognition and reduced apnea frequency, a critical RTT symptom, though it did not improve motor deficits.
Biochemical analysis of hippocampal tissue showed that KU preserved KCC2 expression and normalized elevated vGAT levels, a marker of inhibitory synapses. These findings suggest a partial restoration of the delayed GABA switch and correction of the E/I imbalance. However, the therapeutic effects were transient, as most symptoms reappeared after the washout period, highlighting the need for continuous administration. Notably, the beneficial effect on apneas was more evident post-washout.
In conclusion, ATM inhibition via KU represents a promising therapeutic approach to mitigate RTT’s symptoms by targeting the underlying molecular dysfunctions. However, further research is needed to understand its specific role in preventing apnea worsening, investigating its influence on the respiratory centers, as well as its effects in female models
The Therapeutic Potential of ATM Inhibition in Rett Syndrome: Insights from Behavioral and Molecular Studies
Full text linkAtaxia Telangiectasia Mutated (ATM) is a protein known for its role in DNA double-strand break repair. Recent studies have discovered ATM’s new role in regulating KCC2, a crucial potassium chloride co-transporter, which induces the “excitatory-to-inhibitory GABA switch", a fundamental step in the maturation of the GABAergic system. In Rett Syndrome (RTT), a sever neurodevelopmental disorder caused by mutations in the MeCP2 gene, elevated ATM levels in the hippocampus are linked to decreased KCC2 expression, delaying the “GABA switch”, and disrupting excitatory/inhibitory (E/I) balance. This dysfunction contributes to the RTT’s socio-cognitive, motor, and respiratory impairments.
Our laboratory investigated the therapeutic potential of ATM inhibition through KU-55933 (KU), an ATM kinase inhibitor, in the Mecp2y/- (KO) mouse model of RTT, with the aim to restore KCC2 levels and correct the GABAergic dysfunction underlying the pathology. Two objectives were addressed: the evaluation of intranasal KU’s effects on socio-cognitive, motor, and respiratory functions, and the examination of the molecular changes associated with RTT and KU treatment.
Behavioral assessments, including Y-maze, Novel Object Recognition (NOR), Three-chamber test, Rotarod, and Plethysmograph, revealed that the intranasal KU administration significantly improved hippocampal cognitive functions and ameliorated respiratory abnormalities, such as the number of apneas, which are critical in RTT progression. Furthermore, KU treatment enhanced overall health and survival in RTT mice but had no effects on motor deficits.
Biochemical analysis of hippocampal tissues supported the cognitive improvements, showing that KU prevented the decline in KCC2 expression and normalized pathological increases in vGAT levels, a marker for inhibitory synapses, suggesting a correction of the delayed “GABA switch” and of the E/I balance.
However, the therapeutic effects of KU were transient, as demonstrated by behavioral data after the washout period, highlighting the need for continuous treatment to maintain these benefits and ensure long-term efficacy.
In conclusion, ATM inhibition via KU may represent a novel therapeutic approach for RTT, aimed at mitigating the pathological symptoms by addressing underlying molecular dysfunctions. However, further research is needed to deepen our understanding of the mechanism involved
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
- …
