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• W1562974583 abstract "The developing prostate gland is regulated by its hormonal milieu, most notably androgens, which dictate its growth and differentiation (Price, 1936; Lasnitzki and Mizuno, 1980). In addition, the developing prostate is sensitive to estrogenic exposures (Price, 1963). During prostate morphogenesis, elevated levels of endogenous estrogens (maternal or excess local production) or exogenous estrogens (diethylstilbestrol [DES] or, potentially, environmental estrogens) have been shown to induce permanent disturbances in prostate growth and predispose to precancerous lesions, a process referred to as developmental estrogenization or estrogen imprinting (Santti et al, 1994). The rodent prostate has evolved as a useful model to study early estrogenic exposures since the gland develops postnatally and can be used to model in utero events for human prostate development. The specific model used in our laboratory to study developmental estrogenization of the prostate gland is the Sprague—Dawley rat given injections of 25 μg of estradiol on neonatal days 1, 3, and 5. It is important to mention that although this is considered “high-dose,” the majority of neonatally administered estradiol is bound to α-fetoprotein, which circulates at high levels in neonatal rat serum (Sheehan and Young, 1979). Consequently, neonatal estradiol is 75-fold less potent than an equivalent dose of DES (Sheehan and Branham, 1987) or, put another way, 25 μg of estradiol per pup is equivalent to 0.33 μg of DES per pup. Recent work from our laboratory has examined a dose—response relation for increasing neonatal estradiol exposures and have observed a monotonic effect on the prostate, with growth inhibition and reduced androgen receptor observed at doses of 10 μg per pup (equivalent to 0.13 μg of DES per pup) and no prostatic stimulation at lower estradiol levels (Putz et al, 2001). Neonatal exposure to high-dose estradiol results in a permanent reduction in prostatic growth and activational response to androgens during adulthood, an effect mediated in part through a permanent reduction in androgen receptor (AR) expression (Prins, 1992; Prins et al, 1993; Prins and Birch, 1995; Woodham et al, 2003). Upon aging, prostatic hyperplasia and dysplasia are prominent in neonatally estrogenized rats and PIN-3 (prostatic intraepithelial neoplasia) lesions are observed when these animals are given exogenous testosterone (Prins, 1997; Putz and Prins, 2002). Structural and functional epithelial cytodifferentiation during development is perturbed or, for some endpoints, permanently blocked by neonatal estrogens as determined by markers for basal and luminal cytokeratins and secretory proteins (prostate binding protein [PBP], dorso-lateral prostate [DLP] protein, urokinase, 26-kD protease) (Prins and Birch, 1995; Chang et al., 1999; Prins et al, 2001a). Recent evidence indicates that estrogen-induced changes in the expression of E-cadherin and the gap junction proteins connexin 32 and connexin 43 in the adult prostate epithelial cells may result in impaired cell—cell adhesion and defective cell—cell communication, which may be one of the key mechanisms through which changes toward a dysplastic state are mediated (Habermann et al, 2001). Estrogen action in the rat prostate gland is mediated through stromal estrogen receptor α (ERα) (Prins and Birch, 1997) and epithelial estrogen receptor β (ERβ) (Prins et al, 1998). Importantly, studies with ER knockout mice (αERKO and βERKO) showed that stromal cell ERα is the dominant ER mediating developmental estrogenization of the prostate (Prins et al, 2001a). During the first 5–10 days of life, ERα is present in the mesenchymal cells of the proximal regions of the growing ducts. After estrogenic exposure, there is a transient up-regulation of this protein within periductal stromal cells along the length of the ducts that allows for amplification of estrogenic action during this critical period (Prins and Birch, 1997). This, in turn, leads to a transient expression of progesterone receptor (PR) in those same stromal cells that do not normally express this receptor (Sabharwal et al, 2000). In addition, prostatic retinoid receptors (RARs and RXRs) and intraprostatic retinoid levels are immediately and permanently elevated after neonatal estrogenic exposure, which allows for amplification of retinoid signals during development and with aging (Prins et al, 2002; Pu et al, 2003a). It is particularly significant that these increases in ER, PR, and RAR levels occur at the same time that AR is drastically down-regulated (Prins and Birch, 1995; Woodham et al, 2003). These changes are summarized in the schematic shown in Figure 1. After a brief exposure to high levels of estrogen during the neonatal critical period, the temporal expression patterns as well as quantitative levels of several key steroid receptors (transcription factors) are drastically altered. Thus, the prostate is no longer under predominant androgen-AR regulation but is rather driven by estrogenic and retinoid signals through the ERs, PR, RARs, and RXRs. We propose that the net effect of these changes is that the programming and organizational signals, which normally dictate and determine prostate development during discrete temporal windows, are permanently and irretrievably altered. . Schematic representation of steroid receptor expression in a postnatal day 5-10 developing prostate from control (oil) and neonatally estrogenized (neo E2) rats. In the normal developing prostate (top), androgen receptor (AR) is the dominant steroid receptor in both epithelial and stromal cells. Under the influence of androgens, the stromal cells produce and secrete specific paracrine factors that dictate growth and differentiation of the gland. As epithelial cells differentiate, AR levels markedly increase and ERβ expression is induced. It is hypothesized that paracrine factors from the differentiating epithelium in turn affect the differentiation of the immediate surrounding stromal cells. In addition, other steroid receptors are expressed in a cell-specific manner and are most likely involved in “fine-tuning” prostate development through induction of specific genes during critical developmental windows. Estrogen receptor α (ERα) is expressed at low levels in periductal stromal cells in the proximal region of the elongating ducts. RARβ is expressed in basal epithelial cells, whereas RARα and γ are localized to periductal stromal cells along the ductal length. After a brief exposure to high levels of estrogens during the neonatal critical period, the prostatic steroid receptor profile is drastically altered (bottom). AR is absent in epithelial cells and is present at very low levels in stromal cells, thus dampening the androgen signaling pathway in the developing prostate. ERα is up-regulated and expressed at high levels in periductal stromal cells along the length of the ducts and progesterone receptor (PR) is induced in those same cells under the estrogen influence. The number of cells expressing RARα and RARβ is markedly increased. Thus, estrogen exposure has switched the developing prostate from an androgen-dominated tissue to one that is regulated by estrogen, progesterone, and retinoids. Continuous branching morphogenesis of glandular structures is dictated by time-specific and region-specific expression of master regulatory genes (Hogan, 1999). Although common morphogenetic paradigms exist for all branched structures studied to date, the critical difference is that spatial and temporal combinations of these genes give rise to unique structures. The morphogenetic codes for lungs and limbs have been studies extensively and serve as excellent models (Hogan, 1999). While the “prostatic code” is not well defined at the present time, recent activity in this field has led to an early map (Bieberich et al, 1996; Kopachik et al, 1998; Bhatia-Gaur et al, 1999; Podlasek et al, 1999b,c; Sreenath et al, 1999; Thomson and Cunha, 1999; Prins et al, 2001b; Lamm et al, 2002). On the basis of these reports as well as work from our laboratory, we have schematized the temporal expression pattern and spatial localization of several of the critical genes involved in prostate development (Figure 2). We are currently interested in determining whether neonatal exposure to estrogens can alter prostatic development through changes in expression of these key developmental genes. . Chronologic (top-left) and spatial (bottom-right) expression of selected genes in the developing rat prostate. The classification of developmental stages of the prostate is shown in colored gradient bars (top-left). Gradients in black and white bars represent relative levels of gene expression in the various stages of prostate development as determined by reverse transcriptase—polymerase chain reaction and in situ hybridization analysis (see text for references). The shifting temporal combinations are critical in determining normal prostate development. Similarly, the spatial distribution (bottom-right) of gene expression is critical in determining the prostate phenotype. The day 5 developing ventral prostate in cross-section serves to highlight the epithelial and mesenchymal localization of gene expression for molecules involved in prostate development. Further complexity exists with regard to restricted expression of some of these genes in proximal and distal regions of the developing gland (see text for details). Several specific homeobox genes have been identified within developing prostate tissue and are thought to account for prostate determination and morphogenesis. These include members of the Hox gene family (Warot et al, 1997), the NK gene family (Bieberich et al, 1996), and the HNF (FOX) gene family (Peterson et al, 1997; Kopachik et al, 1998). Importantly, a growing body of evidence supports a role for steroids in regulating developmental genes. This first came to light with studies on retinoic acid, which was shown to markedly affect Hox gene expression and produce homeotic transformations, that is, acquisition of adjacent structure morphology (Marshall et al, 1996; Wood et al, 1996). Hox genes are arranged in four clusters (A, B, C, and D) on separate chromosomes, each cluster containing up to 13 Hox genes expressed sequentially (3′ to 5′) along the anterior to posterior body axis. Although retinoids have the strongest effect on anterior Hox genes, recent data have shown regulation of posterior Hox genes by estrogens and progesterone. Fetal or neonatal exposure to 2 μg of DES resulted in strong down-regulation of uterine Hoxa-10 (Ma et al, 1998) and progesterone receptor directly up-regulated Hoxa-10 in the uterus during implantation (Lim et al, 1999). These observations are particularly relevant to the estrogenized prostate, which presents with a proximalized phenotype, that is, the formation of the distal prostate is suppressed while the proximal phenotype is extended into a larger portion of the tissue (Prins et al, 2001b). We postulate that the effect of estrogen in creating a proximalized phenotype in the prostate gland reflects a change in the positional identity of this structure, perhaps mediated by changes in the expression of genes related to specification of appendicular (proximal—distal) position. Furthermore, we postulate that estrogens may disturb the expression of specific genes that regulate differentiation of the prostate stromal and epithelial cells. A generalized model for regional tissue specification is that nested, partially overlapping expression domains of several genes in a Hox cluster determine segment identity. Hox-13 genes, the most posterior of the Hox clusters, are involved in prostate gland development (Warot et al, 1997). Hoxa-13 and Hoxd-13 are expressed in high levels in the mouse urogenital sinus (UGS) mesenchyme during fetal life and prostatic expression declines postnatally (Oefelein et al, 1996; Podlasek et al, 1999b). In contrast, Hoxb-13 has been localized to central duct and distal tip epithelial cells in the adult mouse prostate (Sreenath et al, 1999; Economides and Capecchi, 2003). To examine the presence of these genes in the rat prostate and to determine the influence of estrogens on their expression level, we quantified Hox-13 mRNAs in developing and adult rat ventral prostates (Prins et al, 2001b). As described for mouse prostate, Hoxa-13 mRNA was present in the day 6 prostate in control rats and levels declined with development by day 30. No immediate differences were observed in Hoxa-13 mRNA levels after estrogen exposure; however, the maturational decline was delayed in the estrogen-exposed prostate. In contrast to what was found in the mouse, rat prostate levels of Hoxd-13 mRNA remained steady during postnatal development and significantly increased in the mature prostate (day 90). However, levels for Hoxd-13 did not increase in estrogenized adult ventral prostates but rather remained at the low expression levels found in postnatal prostates (Prins et al, 2001b). Epithelial Hoxb-13 expression in the rat prostate is low at birth and markedly increases as epithelial cells differentiate between days 6 and 15. Thereafter, high expression of Hoxb-13 is maintained in the luminal epithelium throughout adulthood (Prins et al, 2001b). After neonatal exposure to estrogen, Hoxb-13 expression was immediately and permanently suppressed. This is highly significant since a recent study has shown that Hoxb-13 is required for normal differentiation and secretory function of the mouse ventral prostate (Economides and Capecchi, 2003). Thus we propose that loss of Hoxb-13 in the estrogenized prostate may be involved in mediating some of the positional and differentiation defects observed in the developmentally estrogenized prostate gland. Although the role of Hox genes has not been determined in adult structures, evidence suggests that its expression may be involved in maintaining differentiated states since levels are lost in many cancers (Friedman et al, 1994). It has also been hypothesized that normal adult expression of Hoxa-10 maintains glandular architecture in the uterus (Miller and Sassoon, 1998) and a similar role for Hoxd-13 and Hoxb-13 may exist in adult prostate. A novel member of the NK family of homeobox transcription factors was identified in 1996 and its expression in the male reproductive tract was restricted to UGS-derived prostate and bulbourethral gland epithelium (Bieberich et al, 1996; Schiavolino et al, 1997). Importantly, this gene is expressed in the fetal mouse UGS epithelium at bud sites before bud formation, suggesting a role for Nkx3.1 in prostate determination (Bieberich et al, 1996; Bhatia-Gaur et al, 1999). Continued expression of this gene is believed to be important for epithelial cell differentiation. To determine the effects of early estrogen exposure on Nkx3.1 expression, we performed in situ hybridization (Prins et al, 2001b) and real-time reverse transcriptase—polymerase chain reaction (RT-PCR) on developing and adult prostates of control and estrogenized rats. At day 6, Nkx3.1 mRNA was expressed in a gradient fashion throughout the rat prostate, with low levels in the proximal ducts and high levels in the distal tips. Immediately after estrogen exposure, Nkx3.1 mRNA was significantly reduced in all prostate lobes as compared to control levels (Figure 3). However, this effect was transient and by day 30, Nkx3.1 expression in the estrogenized prostates was equivalent to that in oil controls (Prins et al, 2001b). We propose that a transient disruption in Nkx3.1 expression at a critical time when epithelial cells normally differentiate into basal and luminal layers (Prins and Birch, 1995) may play a direct role in the differentiation defects observed in the estrogen-exposed prostates. . Real-time reverse transcriptase—polymerase chain reaction of Nkx3.1 in day 6 and 10 ventral (VP), dorsal (DP), and lateral (LP) lobes of the rat prostate after exposure to oil or 25 μg of estradiol benzoate on days 1, 3, and 5 of life. Samples were amplified in duplex using a SYBR-green assay and data was normalized to the ribosomal protein, RPL19, mRNA co-amplified for each tissue. n = 4-10 assays/group. *P < 0.01. In addition to developmental determination by homeobox genes, branching morphogenesis occurs as a complex interplay between epithelial and mesenchymal cells. Although many secreted epithelial—mesenchymal signals have been characterized, a small number of signaling molecules have been found to be critical during embryogenesis (Hogan, 1999). In particular, combinations of Hedgehogs, Wnts, bone morphogenetic proteins (BMP)s, and fibroblast growth factors (FGF)s to a large extent control soft tissue development. These positive and negative regulatory molecules are spatially and temporally regulated and communicate signals between cells via their cognate receptors. We have recently examined the ontogeny and localization of sonic hedgehog (Shh), BMP-4, and FGF-10 in the normal developing rat prostate lobes and those exposed neonatally to estradiol to determine if alterations in their signaling pathways are involved in the estrogenized phenotype. Shh is a secreted glycoprotein produced by epithelial cells at mesenchymal interfaces in developing tissues. In branched structures, Shh is thought to be a master gene involved in bud initiation and outgrowth (Bellusci et al, 1997a). Importantly, Shh is has been shown to regulate many other developmental genes including Hox genes as well as Nkx3.1. The murine UGS and prostate epithelial cells produce Shh as early as fetal day 17 and levels decline with development (Podlasek et al, 1999a). Secreted Shh protein activates target cells through a membrane receptor, patched (ptc), localized in mesenchymal cells. After a cascade of molecular signals, this ultimately results in increased levels of gli transcription factors (Walterhouse et al, 1999). We recently characterized the Shh expression patterns in the developing rat prostate lobes and examined the effects of early estrogen exposure using whole-mount in situ hybridization (ISH) and real-time RT-PCR (Pu et al, 2003b). Similar to the mouse prostate, Shh was highly expressed in the fetal day 19 prostatic buds where it was localized to epithelial cells in the distal tips of the outgrowing ducts of the ventral, dorsal, and lateral lobes. Thereafter, a marked decrease was observed in Shh expression from days 1 to 15 of life in control prostates, with the greatest decrease between days 1 and 6. Neonatal estradiol exposure resulted in a significant inhibition of Shh expression in the dorsal and lateral lobes by neonatal day 1, which persisted throughout development. Although values were always lower in the estradiol-exposed ventral prostate as compared to controls, the difference never approached significance. This differential effect on Shh expression by estrogens may play a role in the previously noted lobe-specific estradiol response. The lateral and dorsal rat prostate lobes exhibit a greater reduction in branching than observed in the ventral lobe in response to neonatal estrogens (Prins, 1992). Developmental studies have shown a critical role for FGF-10 in initiation and directional outgrowth of buds as well as ductal branching in lung and more recently, prostate (Bellusci et al, 1997b; Thomson and Cunha, 1999). FGF-10 interacts with a unique splice variant of the FGF transmembrane receptor family, the FGFR2iiib. This receptor variant is expressed on prostatic epithelial cells (Finch et al, 1995) and recognizes FGF-7 (KGF) and FGF-10 produced by the mesenchyme, thus establishing a specific paracrine communication. Using both whole-mount ISH and real-time RT-PCR, we recently determined that FGF-10 mRNA is expressed in the distal mesenchyme of the 3 prostate lobes at day 1 of life and that it condensed most strongly around the distal tips of the outgrowing ducts as the prostate undergoes branching morphogenesis over the next several days (Huang et al, 2003). Neonatal estradiol exposure immediately reduced FGF-10 expression in the dorsal and lateral lobes between days 1 and 5, whereas expression in the ventral prostate was unaffected. Since Shh is known to regulate FGF-10 expression in other developing tissues (Haraguchi et al, 2001; Perriton et al, 2002), we propose that FGF-10 is a downstream gene of Shh in the prostate gland and that a reduction in Shh and FGF-10 expression in the dorsal and lateral lobes in response to estradiol together contribute to a greater reduction in branching in those regions. Bone morphogenetic proteins (BMP) are members of the transforming growth factor-β superfamily and, in general, act as inhibitors of proliferation during development (Hogan, 1996). BMPs initiate cell signaling by activating type I and type II transmembrane receptors with intracellular pathways involving Smads. In the mouse prostate, BMP-4 mRNA is localized to the mesenchyme and levels decline postnatally (Thomas et al, 1998; Podlasek et al, 1999c). Although targeted disruption of BMP-4 is embryonic lethal, heterozygotes possessed an increased number of branching tips in the murine ventral prostate (Podlasek et al, 1999c). We have recently localized and quantified BMP-4 expression in the prostate lobes of the developing rats after estradiol exposure (Huang et al, 2003). BMP-4 expression was initially intense and broad throughout the mesenchyme of all lobes at day 1 and subsequently condensed to cells proximate to the elongating ducts as morphogenesis progressed. Although BMP-4 mRNA levels rapidly declined in all control prostate lobes between postnatal days 1 and 6, its expression remained high in the estrogenized prostate lobes until after day 30. We postulate that the continued expression of prostatic BMP-4 in estrogen-exposed rats prolongs its inhibitory actions and contributes to reduced growth in all 3 prostate regions. In summary, we have shown that early exposure to high levels of estrogens creates a morphologic imprint in the prostate gland, which can be described as a proximalized phenotype. We propose that this effect is initiated through up-regulated levels of stromal ERα, which in turn result in altered steroid receptor expression throughout the developing gland. Rather than being an androgen-dominated process, prostatic development becomes regulated by alternate steroids including estrogens and retinoids. This, in turn, leads to disruptions in the coordinated expression of several critical developmental genes including the homeobox genes Hox-13 and Nkx3.1 as well as secreted ligands Shh, FGF-10, and BMP-4 (schematized in Figure 4). Since a precise temporal expression pattern of these and other molecules is normally required for appropriate growth and differentiation of the prostatic epithelium and stroma, the estrogen-initiated disruption in this pattern would lead to permanent growth, branching, and differentiation defects of the prostate gland. The ultimate consequences of this developmental estrogenization are a prostate predisposed to hyperplasia and dysplasia in adulthood and sensitized to more severe lesions, including cancer, as the animals age. . A schematic representation of the estrogen-induced alterations in expression and localization of critical developmental genes in the rat prostate gland. In the normal prostate (left), Estrogen receptor (ER)α expression is confined to the periductal stromal cells in the proximal region of the outgrowing ducts. Bone morphogenetic protein (BMP)-4 expression, initially high before prostate budding, declines rapidly after birth, thus releasing its inhibitory effects on ductal outgrowth. Shh is secreted by distal tip epithelial cells, activates ptc receptors on adjacent stromal cells, and participates in ductal outgrowth and prostatic differentiation. Fibroblast growth factor (FGF)-10 is expressed by distal mesenchymal cells and stimulates ductal outgrowth and branching. Nkx3.1 is expressed early by undifferentiated epithelial cells and is involved in prostate initiation and epithelial differentiation. Hoxb-13 is expressed in epithelial cells as they differentiate and is involved in maintaining a differentiated phenotype. Neonatal estrogen exposure alters the expression of these genes in a lobe-specific manner (right). ERα is up-regulated and expressed out to the distal tips of the outgrowing ducts. BMP-4 expression is maintained at high levels for up to 2 weeks, Shh and FGF-10 expression are reduced, Nkx3.1 is transiently suppressed, and Hoxb-13 is immediately and permanently suppressed. We gratefully acknowledge Oliver Putz, PhD, for the graphic representation of our data." @default.
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• W1562974583 date "2004-05-06" @default.
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• W1562974583 title "Estrogenic Regulation of Signaling Pathways and Homeobox Genes During Rat Prostate Development" @default.
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