1,720,972 research outputs found
Antidepressant-like effects of pharmacological inhibition of FAAH activity in socially isolated female rats
No full textPharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which terminates signaling of the endocannabinoid N-arachidonoylethanolamine (or anandamide, AEA), exerts favourable effects in rodent models of stress-related depression. Yet although depression seems to be more common among women than men and in spite of some evidence of sex differences in treatment efficacy, preclinical development of FAAH inhibitors for the pharmacotherapy of stress-related depression has been predominantly conducted in male animals. Here, adult female rats were exposed to six weeks of social isolation and, starting from the second week, treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle. Compared to pair-housed females, socially isolated female rats treated with vehicle developed behavioral (mild anhedonia, passive stress coping) and physiological (reduced body weight gain, elevated plasma corticosterone levels) alterations. Moreover, prolonged social isolation provoked a reduction in brain-derived neurotrophic factor (BDNF) and AEA levels within the hippocampus. Together, these changes are indicative of an increased risk of developing a depressive-like state. Conversely, pharmacological inhibition of FAAH activity with URB694 restored both AEA and BDNF levels within the hippocampus of socially isolated rats and prevented the development of behavioral and physiological alterations. These results suggest a potential interplay between AEA-mediated signaling and hippocampal BDNF in the pathogenesis of depression-relevant behaviors and physiological alterations and antidepressant action of FAAH inhibition in socially isolated female rats
(2S,4R)-4-fluoroglutamine is converted into (2S,4R)-4-fluoroglutamate by glutaminase activity and may be exploited as a PET tracer in glutamine-addicted cancers
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
Identification of Human Alanine–Glyoxylate Aminotransferase Ligands as Pharmacological Chaperones for Variants Associated with Primary Hyperoxaluria Type 1
Get PDF[Image: see text] Primary hyperoxaluria type I (PH1) is a rare kidney disease due to the deficit of alanine:glyoxylate aminotransferase (AGT), a pyridoxal-5′-phosphate-dependent enzyme responsible for liver glyoxylate detoxification, which in turn prevents oxalate formation and precipitation as kidney stones. Many PH1-associated missense mutations cause AGT misfolding. Therefore, the use of pharmacological chaperones (PCs), small molecules that promote correct folding, represents a useful therapeutic option. To identify ligands acting as PCs for AGT, we first performed a small screening of commercially available compounds. We tested each molecule by a dual approach aimed at defining the inhibition potency on purified proteins and the chaperone activity in cells expressing a misfolded variant associated with PH1. We then performed a chemical optimization campaign and tested the resulting synthetic molecules using the same approach. Overall, the results allowed us to identify a promising hit compound for AGT and draw conclusions about the requirements for optimal PC activity
Un approccio integrato per la caratterizzazione delle proprietà chimico-fisiche di NCEs in fase di discovery
No full textNegli ultimi vent’anni le piccole molecole sviluppate come nuovi farmaci hanno mostrato una complessità chimica crescente in confronto a quelle ottimizzate prima del 2000. Un esempio di questa tendenza è offerto dagli anfoliti, la cui caratterizzazione chimica e biologica è complessa. In tale contesto, lo scopo di questa tesi di dottorato è la definizione di un flusso di lavoro per la caratterizzazione delle proprietà chimico-fisiche di nuovi candidati molecolari allo stadio di ricerca o di primo sviluppo. L’approccio sperimentale include l’analisi di costanti di ionizzazione (pKa) lipofilia (log P or log D7.4) e solubilità ed è finalizzato alla caratterizzazione di composti disponibili allo stato solido (i.e. polveri). Tuttavia, sono inclusi saggi rapidi per l’analisi preliminare di candidati molecolari esclusivamente accessibili come soluzioni in dimetilsolfossido. Prima di essere applicate a nuove entità chimiche, le tecniche sperimentali sono state valutate su composti commerciali, così da definirne applicabilità, vantaggi e limiti.
L’ approccio definito per la caratterizzazione chimico-fisica si è dimostrato utile alle esigenze pratiche di un dipartimento di ricerca pre-clinica, restituendo dati funzionali alle prime fasi di sviluppo (e.g. indicazioni di massima per le condizioni di salificazione e di ottimizzazione della forma solida del principio attivo).
In aggiunta i risultati sperimentali di questo lavoro saranno inclusi nel set di calibrazione di software ad uso interno per la predizione di proprietà molecolari (pKas, lipofilia) e per la correlazione di dati in-vitro-in-vivo (solubilità). Di fatto tale strategia è la chiave per sviluppare sistemi di calcolo esperti, ragione per cui la determinazione sperimentale di proprietà chimico-fisiche è un’esigenza ancora attuale nella ricerca farmaceutica.In the last 20 years, small molecules developed as potential new drugs have shown an increasing chemical complexity in comparison to compounds optimized before the year 2000. Current research trend is well exemplified by ampholytes, for which molecular and biological characterisation is anything but trivial.
In this context, the aim of the present Ph.D. thesis was to outline an in-house integrated work-flow for physico-chemical profiling of new drug candidates at discovery and early development stage. Screening included ionization constants (pKas), lipophilicity (log P or log D7.4) and solubility. This approach was expected to be applied to new chemical entities freely accessible in solid form as well as to include medium/high-throughput preliminary assays suitable for those candidates that were exclusively available as DMSO stock solutions. Before transferring the techniques to actual drug candidates, those were tested on commercially available standards to evaluate their feasibility, advantages and drawbacks.
This in-house screening of physico-chemical properties provided reliable data for pre-development (e.g. guidelines for salt screening and solid form optimization). Moreover, experimental results from the present work will be included in the calibrating set of programs for in-house prediction of molecular properties (pKas, lipophilicity) and for in-vitro-in-vivo correlation (solubility). In fact, inclusion of discovery compounds is the key to develop expert systems and that is why experimental assays for measuring physico-chemical parameters are still warranted
- …
