1,721,009 research outputs found
Specific Inhibitors of Mitochondrial Deacylase Sirtuin 4 Endowed with Cellular Activity
No full text: Sirtuins are NAD+-dependent protein lysine deacylases implicated in aging-related diseases. Mammalian Sirtuin 4 (Sirt4) is located in mitochondria and a potential therapeutic target for cancer and metabolic diseases, but no potent and selective Sirt4 inhibitors have been reported. Here, we describe the identification of potent Sirt4-specific small-molecule inhibitors. Testing hits from a target-based virtual screen revealed 12 active compounds. A focused screen based on two top compounds, followed by structure-assisted design of derivatives, yielded four first-in-class potent Sirt4 inhibitors. Kinetic analyses indicate compound competition with the acyl peptide substrate, consistent with the docking models and implicating Sirt4's unique acyl binding site. The compounds indeed show preference for Sirt4 over other isoforms, with one of them (69) being highly isoform selective, and they are active in cells. Our results provide first lead compounds and mechanistic insights for optimization toward Sirt4-specific inhibitors useful as experimental tools and potential therapeutics
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Bioinformatic and molecular study of the regulation of SIRT3 expression
No full textCalorie restriction (CR) is a dietary intervention that extends lifespan, delays the onset of age-related diseases, and induces a wide-ranging metabolic adaptation in multiple model organisms. One of its primary effectors is the mitochondrial NAD+-dependent deacetylase sirtuin 3 (SIRT3). SIRT3 expression is upregulated by CR in multiple tissues, yet the mechanism of this induction is unclear. We therefore pursued multiple avenues in the study of the regulation of SIRT3 expression. To study SIRT3 transcriptional activity, we developed a plasmid with the SIRT3 promoter driving expression of the reporter gene luciferase, and we used it to demonstrate that SIRT3 expression in human 293T cells is upregulated by rapamycin, an inhibitor of the nutrient-sensing Target of Rapamycin pathway. Because SIRT3 expression level is a predictor of clinical outcome in breast cancer, this construct could be applied as a diagnostic and prognostic tool. We next conducted a bioinformatic analysis to identify transcription factors that may induce SIRT3 expression and identified nuclear respiratory factor 2 (NRF-2) as a top candidate. We showed that SIRT3 levels respond to NRF-2 overexpression or knockdown and that NRF-2 binds the SIRT3 promoter. Notably, NRF-2 and estrogen-related receptor α – the only other transcription factor previously identified as binding the SIRT3 promoter directly – are both co-activated by peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), a major regulator of the expression of mitochondrial and metabolic genes. Future study will be necessary to determine whether this pathway underlies the upregulation of SIRT3 expression in CR. Finally, we also used high-throughput RNA sequencing to suggest that calorie restriction was capable of reversing not just age-related changes in gene expression, but also age-related changes in the usage of different isoforms of the same gene. This may be a new mechanism by which CR controls the biological activity of certain genes. Together, these studies provide novel tools and insights in the study of the regulation of SIRT3 expression and the effects of CR.sirtuin 3; SIRT3; nuclear respiratory factor 2; NRF-2; calorie restriction; dietary restriction; RNA-se
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
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Investigating the Fate of Ammonia in Breast Cancer
No full textAmmonia (NH3) is a ubiquitous by-product of cellular metabolism that is copiously generated by proliferating cells, especially cancer cells. Although NH3 is classically conveyed as toxic metabolic waste, it accumulates in the tumor microenvironment (TME) 10-fold higher than what is considered toxic to healthy tissue. Thus, we hypothesized that NH3 functions beyond a mere waste product in tumor biology. However, the fate of NH3 generated by tumor metabolism had never been explored. To address this, we developed a novel LC-MS assay to detect 15N and14N-isotopologues of NH3 (Spinelli et al., Sci. Rep. 2017), and performed stable isotope tracing experiments in breast cancer cells to track the fate of NH3. We discovered that breast cancer cells recycled NH3 generated by tumor metabolism with 60% efficiency through a “reverse” catalytic activity of glutamate dehydrogenase (GDH) to generate glutamate (Spinelli et al., Science. 2017). This nitrogen-scavenging pathway accelerated proliferation of breast cancer cells grown in 3D culture models and in vivo xenograft tumor models. Furthermore, using a novel method for rapid mitochondrial isolation for metabolomics, we tracked the compartmentalized nature of NH3 metabolism in breast cancer cells (Spinelli et al., submitted). Mitochondrial metabolomics revealed that NH3 is assimilated inside this compartment as a local nitrogen source for glutamate. Importantly, mitochondrial localization of nitrogen recycling is required for NH3 to stimulate proliferation, unveiling a limitation in the mitochondrial glutamate pool for breast cancer proliferation. We determined that the levels of mitochondrial glutamate dictate the rate of local translation. Thus, NH3 assimilation to produce mitochondrial glutamate increases cellular respiratory capacity to enable accelerated proliferation. Taken together, this thesis work reveals that breast cancer cells recycle the waste product NH3 to generate mitochondrial glutamate, which regulates local protein translation to accelerate proliferation.Chemical Biolog
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
PHD3 loss in cancer enables metabolic reliance on fatty acid oxidation via deactivation of ACC2
No full textWhile much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here, we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition
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
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