1,720,965 research outputs found
Age-related changes in human testicular function
Full text linkMain testicular functions are spermatogenesis and steroidogenesis. Androgen production, Testosterone (T) in particular, stimulates the differentiation of germ cells under the strict endocrine control of the pituitary gland via the two gonadotropins LH and FSH. Today we know that the reduction in serum T concentration (late onset hypogonadism) observed with age can be associated with an overall unhealthy status of the body. Moreover, the prevalence of obesity, metabolic syndrome and diabetes increases with age, and these conditions are significantly associated with hypogonadism, as assessed by sexual symptoms and low serum T levels in spite of normal LH. There is few information about mechanisms underlying androgen deficiency with age and little is known about human Leydig cell (LC) aging, in terms of number and function, mainly because of the scarce availability of the tissue.
In this study, we evaluated the age-related changes in testicular function in healthy human testicular tissues of different ages (19-85 years) obtained from heart-beating organ donors and from patients referred to the andrology clinic having normal spermatogenesis and hormone levels.
We demonstrated that aging is associated with changes in testicular morphology which are variable in different areas of the parenchyma. Changes included a significative reduction of the area occupied by seminiferous tubules coupled with an increased area occupied by interstitium, mainly composed by fibrotic tissue. In elderly donors, we noticed also peritubular thickening and the appearance of sclerotic tubules and empty tubules. Another morphological parameter evaluated was the LC micronodules frequency and size, since these aggregates composed by more than 15 LCs have been associated with a lower Testosterone/LH ratio. We did not find any correlation between age and micronodules distribution or size, pointing to a normal Hypothalamus-Pituitary-Gonad axis in our group of donors.
We found a significative reduction of both LC and Sertoli cell (SC) number with age indicating that cellular senescence generally observed in many tissues with advancing age affects also the testis.
Moreover, we evidenced a significative positive correlation between LC and SC number at all ages, which has not been described before in men.
Concerning the function of LCs, we analysed gene expression of steroidogenic pathway enzymes and other LC markers by qRT-PCR. We did not find a significative correlation between enzyme gene expression and age but a negative trend was observed for 17β-HSD3, StAR and CYP11A1 genes. In contrast, INSL3 transcript, which also reflects LC number, significantly declined in aged men, consistent with our observation that LC population size changed during aging.
Using the in vitro organ culture model previously developed in our laboratory, we demonstrated that three hours in vitro culture of both fresh and cryopreserved testis fragments allows to analyse the LC androgen production (testosterone (T), androstenedione (A), dehydroepiandrosterone (DHEA) and 17-Hydroxyprogesterone (17OHP)) secreted into the culture media and simultaneously measured by mass spectrometry both in basal conditions and under recombinant gonadotropin stimulation. We did not find any correlation between androgens secreted in basal conditions and age, indicating that LCs of the donors analysed were able to produce T, A, DHEA and 17OHP in an age- independent manner. The response to gonadotropin stimulation was found greatly variable among donors of different ages and not related to the age. The response to hCG was higher than that to LH when fresh tissue was used. Tissue cryopreservation did not alter interstitial compartment morphology but caused a significative reduction in T concentration, whereas A, DHEA and 17-OH-P levels increased, pointing to a particular vulnerability of specific enzymes to the freezing condition. These data are in line with the finding that the response to hCG was lost when the fragments were cultured after cryopreservation, reinforcing the idea that cryopreservation represents a stressor to the testicular tissue.
In conclusion, our data point to a cellular senescence of the aging human testis which is not associated to the in vitro ability to produce androgens. Thus, our results support the idea that LC dysfunction is largely driven by aging of the whole testicular microenvironment rather than aging of LC population alone
The interplay between NF-Y, AR and lipid metabolism regulates tumor aggressiveness in prostate cancer.
No full textProstate cancer (PCa) is the second most frequent cancer in Western men. Computational analyses linked the transcription factor NF-Y to progression from benign to localized PCa, aggressive signatures, response to androgen deprivation therapy (ADT) and metastasis.
The NF-YA gene encodes two alternatively spliced transcripts, NF-YAs and NF-YAl. We demonstrated that PCa samples are characterized by increased NF-YA levels, as well as higher NF-YAs/NF-YAl transcriptional ratio. In vitro and in vivo, NF-YA depletion affects PCa tumorigenicity and changes in NF-YA isoforms expression are associated with key clinical and molecular features of aggressive PCa. NF-YAs enhances tumor growth and metastasis, while NF-YAl increases cell motility. Stratification of patients based on NF-YAs expression is predictive of clinical outcome, although a significant decrease in the NF-YAs/NF-YAl ratio characterizes PCa circulating cells.
PCa cells depend on male sex hormones for growth and survival, which is the basis of ADT. While ADT is initially effective, patients eventually relapse with castration-resistant prostate cancer (CRPC). One of the cellular processes most affected by androgens is lipid metabolism, whose rewiring contributes to PCa development, progression, metastasis and recurrence. Androgens stimulate de novo lipogenesis and lipid uptake by activating SREBPs, the master transcription factors of cholesterol and fatty acid biosynthesis. SREBPs interact with target promoters in cooperation with NF-Y, which controls de novo lipid biosynthesis pathway. A feedforward mechanism between SREBP and the Androgen Receptor (AR) was also described.
We modulated NF-YA in androgen-sensitive healthy and cancer cell lines, performing cellular and molecular studies. RNA-seq analysis highlighted the alteration of lipid and cholesterol metabolic pathways and of the unfolded protein response (UPR) in NF-YAl-overexpressing cells. Bioenergetics metabolic profiling of NF-YA transduced cells confirmed the key role of NF-YAl in PCa cell metabolism. We found a reciprocal regulation of AR and NF-Y that relies in particular on NF-YAl.
Our data suggest that NF-Y, and specifically the longer NF-YA isoform, can participate in ADT responsiveness and resistance mediated by metabolic alterations. The characterization of these pathways could be useful in the stratification of PCa patients into sub-categories with different levels of aggressiveness and ADT sensitivity
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
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