{"title":"Membrane Androgen Receptor(S) and their Role in Prostate Cancer:A Review","authors":"J. Singh, G. Bhattacharjee","doi":"10.18519/JER/2016/V20/165440","DOIUrl":"https://doi.org/10.18519/JER/2016/V20/165440","url":null,"abstract":"Androgen, a steroid hormone, typically mediates its action by binding to the cytosolic Androgen Receptor (AR), via the classical or genomic pathway. Androgens can also act through a non-classical or non-genomic pathway interacting with receptors present on the plasma membrane of cells. Although the identity of the nuclear AR is well established, the identity of the membrane AR is still not clear. Through independent studies, three proteins have been identified that are present on plasma membranes of prostate cells and can mediate androgen signalling, viz, GPRC6A, AR8 and ZIP9. Although these proteins can mediate androgen signalling, the membrane receptor which is used most frequently and specifically for mediating androgen action in prostate cells is not confirmed. Recent research has shown that the non-genomic androgen signalling plays a key role in progression of prostate cancer (PCa). In this review, the potential of these three proteins for their ability to act as the membrane AR has been analysed. The use of membrane AR as a novel target for the treatment of PCa has also been discussed.","PeriodicalId":15664,"journal":{"name":"Journal of Endocrinology and Reproduction","volume":"109 1","pages":"76-82"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76664211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Elangovan, M. Aruldhas, S. Suganya, P. Rajesh, E. Suthagar, A. Navin, N. Shobana, B. Sankar, R. Ilangovan
{"title":"Gestational Exposure to Di(2-ethylhexyl)phthalate Modifies the Expression Pattern of Genes Controlling Thyroid Hormone Biosynthesis in Puberal Rat Progeny","authors":"S. Elangovan, M. Aruldhas, S. Suganya, P. Rajesh, E. Suthagar, A. Navin, N. Shobana, B. Sankar, R. Ilangovan","doi":"10.18519/JER/2016/V20/165442","DOIUrl":"https://doi.org/10.18519/JER/2016/V20/165442","url":null,"abstract":"Di(2-ethylhexyl) phthalate (DEHP), a plasticizer, is known to disrupt thyroid functions but the underlying molecular mechanism remains obscure. The present study was conducted testing the hypothesis that gestational exposure to DEHP would modify the expression of specific genes controlling biosynthesis and action of thyroid hormones in the male progeny at puberal age. Pregnant rats were administered with DEHP [1, 10 and 100 mg (in olive oil)/Kg b.wt./day] from embryonic day 9 to 21 through oral route. The pups were sacrificed on post-natal day 60. Enzyme Immuno-Assay (EIA) revealed a dose-dependent decrease in serum 3,5,3’ triiodothyronine (T 3 ) and L-thyroxine (T 4 ) titres in DEHP-treated rats. Real-time RT-PCR and western blot analyses of thyroidal genes revealed decreased expression level of sodium/iodide symporter (Nis) and thyroid hormone receptor α (Trα) , whereas the expression of thyroid stimulating hormone receptor (Tshr) , thyroid hormone receptor β (Trβ) and pendrin (Pds) increased. While western blot detection showed decreased expression level of thyroperoxidase (Tpo) , RTPCR data pointed out augmented expression. Western blot detection of transcriptional factors showed decreased expression levels of fork-headbox e1 (Foxe1) and hematopoietically expressed homeobox (Hhex), whereas thyroid transcription factor-1 (Ttf-1) and paired-box domain 8 (Pax8) increased. Our study demonstrates, for the first time, that gestational exposure to DEHP affects the expression of genes controlling thyroid hormone synthesis in puberal rat progeny, and the hypothyroid state in these rats may be linked to decreased expression of Nis, Tpo , Foxe1 and Hhex.","PeriodicalId":15664,"journal":{"name":"Journal of Endocrinology and Reproduction","volume":"20 1","pages":"92-101"},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81716929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Seasonal Changes in the Secretory Activity of Seminal Vesicles of the Indian Fruit Bat Rousettus leschenaulti (Desmarest 1820)","authors":"A. Nerkar, M. P. Gujar, S. Bande, M. M. Gadegone","doi":"10.18519/jer/2015/v19/131676","DOIUrl":"https://doi.org/10.18519/jer/2015/v19/131676","url":null,"abstract":"The epithelium of the seminal vesicles of Rousettus leschenaultia shows cyclical pattern in the secretory activity during the reproductive cycle. During the sexually quiescent phase, the seminal vesicles are regressed; the cytoplasm of the epithelial cells contains coarse secretory granules and the lumina of the tubules are empty. The secretion is in the form of secretory blebs in this species of bat. The formation of secretory blebs from the columnar epithelial cells is initiated during the recrudescent phase and is at its peak during the active breeding phase. These secretory blebs are discharged into the lumen of the tubules. Lumina of the tubules are filled with secretory blebs during the recrudescent and active breeding phases. Later on these blebs disintegrate and dissolve to form a homogenous material in the lumen of the tubules. Thus, the mode of secretion in the seminal vesicle of Rousettus is apocrine. The functional significance of the secretion of the seminal vesicles in reproduction of male bat is discussed.","PeriodicalId":15664,"journal":{"name":"Journal of Endocrinology and Reproduction","volume":"26 1","pages":"64-68"},"PeriodicalIF":0.0,"publicationDate":"2016-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88588023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Thyroid Gland in Regulation of Annual Reproduction and Oxidative Metabolism of a Tropical Bird, Perdicula Asiatica :Role of Melatonin and Environmental Factors","authors":"V. Verma, S. Yadav, C. Haldar, R. Tripathi","doi":"10.18519/jer/2015/v19/131678","DOIUrl":"https://doi.org/10.18519/jer/2015/v19/131678","url":null,"abstract":"As a transducer of the environmental factors the pineal gland, together with the metabolically active thyroid gland, plays a major role in control of reproduction during different times of the year, in response to the changing environmental conditions of the tropical zone unlike in the temperate zone. Our avian model P. asiatica is a long day breeder. It is reproductively active during summer and quiescent during winter months. In this study we investigated the role of thyroid gland super-imposed by melatonin in the regulation of the annual male reproduction in this bird. The metabolically active thyroid gland presented a functional parallelism with the testicular activity suggesting that thyroid hormone is essential for reproductive activity and related metabolic energy for avian species. Our data also suggest an inhibitory effect of melatonin on thyroid gland function [weight, thyroxine (T3/ T4) level and thymidine kinase activity, THK] both during active and inactive phases of the reproductive cycle. However, this inhibitory effect was less evident during the active phase. The low level of melatonin during the reproductively active phase might be due to long days of summer which prevented the birds from being hyperthyroidic. Therefore, we suggest that the level of melatonin serves as a physiological check to control the seasonal reproductive activities of gonads and thyroid which synergistically play most important physiological roles in energy metabolism of these seasonally breeding bird P. asiatica .","PeriodicalId":15664,"journal":{"name":"Journal of Endocrinology and Reproduction","volume":"48 1","pages":"69-80"},"PeriodicalIF":0.0,"publicationDate":"2016-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75810303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Nerkar, K. R. Apkaje, V. G. Jamgade, M. M. Gadegone
{"title":"Secretion of Mucins in the Fallopian Tube Epithelium of the Bat Taphozous kachhensis Dobson","authors":"A. Nerkar, K. R. Apkaje, V. G. Jamgade, M. M. Gadegone","doi":"10.18519/JER/2015/V19/131675","DOIUrl":"https://doi.org/10.18519/JER/2015/V19/131675","url":null,"abstract":"Taphozous kachhensis is one of the largest Indian microchiropteran bats with a prominent gular pouch on the ventral side of the lower jaw. This is a seasonally monoestrous species and breeds once in a year. The Fallopian tube epithelium of T. kachhensis in both the segments, ampullary and isthumic, is lined by two cell types: ciliated and non-ciliated (secretory). The Fallopian tube shows alterations in its muco-subtances during estrus and pregnancy. The ciliated cells elaborate large quantity of glycogen, while non-ciliated cells elaborate high amounts of glycogen and neutral and acid mucins during estrus. Mucins are localized in the cytoplasm as well as cytoplasmic blebs. Glycogen and other muco-substances in non-ciliated cells decrease during pregnancy and the ciliated cells show a small amount of glycogen only. The concentration of muco-substances is highest during estrus, and the cytoplasmic blebs are numerous and prominent and are filled with secretion during this stage.","PeriodicalId":15664,"journal":{"name":"Journal of Endocrinology and Reproduction","volume":"59 1","pages":"57-63"},"PeriodicalIF":0.0,"publicationDate":"2016-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74303689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Aspects of Male Reproductive Toxic Effects of Quassia amara L.: Histopathological and Ultrastructural Study in Mouse","authors":"K. Faisal, R. Girija, M. A. Akbarsha","doi":"10.18519/jer/2015/v19/131679","DOIUrl":"https://doi.org/10.18519/jer/2015/v19/131679","url":null,"abstract":"Quassia amara is a Brazilian medicinal plant traditionally used as an herbal remedy for a variety of diseases. Quassin is the major secondary chemical compound in it, which is under investigation as an anti-malarial compound. There are preliminary studies implicating Q. amara in male reproductive toxicity. Hence, this elaborate study was undertaken to find the male reproductive toxic effects of Q. amara and quassin. Methanolic extract of Q. amara bark and quassin were administered to male mice for 35 days. The cauda epididymidal sperm, testis and epididymis were subjected to analysis adopting light and transmission electron microscopy. Sperm counts, motility and viability decreased. The incidence of sperm with abnormal morphologies increased. There was premature loss of germ cells from the seminiferous tubules, which correlated with Sertoli cell pathology. The Leydig cells were vacuolated, suggesting a hypo-androgen status. The epididymis indicated severe histopathological changes, including reflection of a mitogenic/tumorigenic effect of Q. amara . Thus, this study indicates that Q. amara , when applied as a therapeutic, could be severely toxic to male reproductive mechanisms and the principal mechanism of action appears to be through Leydig cells. Quassin, the major secondary metabolite responsible for the therapeutic potential of Q. amara , is also the one causative of the male reproductive toxic effects. Thus, this study substantiates the claim that Q. amara is toxic to male reproductive system.","PeriodicalId":15664,"journal":{"name":"Journal of Endocrinology and Reproduction","volume":"63 1","pages":"81-89"},"PeriodicalIF":0.0,"publicationDate":"2016-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88898295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A Compendium of Nuclear Receptors: The Superfamily of Ligand-Modulated Transcription Factors","authors":"A. K. Dash, R. Tyagi","doi":"10.18519/JER/2016/V20/149824","DOIUrl":"https://doi.org/10.18519/JER/2016/V20/149824","url":null,"abstract":"The ‘Nuclear Receptor Super-family’ is a group of ligand-modulated transcription factors with 48 members identified in human genome. Members of this family of receptors are now established to be involved in regulation of a plethora of physiological processes in the paradigms of development, reproduction, metabolism and homeostasis. Also, in the myriads of patho-physiological processes, these receptors have consistently exhibited enormous potential as targets for the treatment of diseases such as cancers, osteoporosis, diabetes, obesity, coronary heart disease, asthma, hypertension, thyroid conditions and multiple other metabolic disorders. In recent times, it is estimated that about 15% of the clinical drugs, used in treatments of different ailments, target nuclear receptors. These receptors include steroid/thyroid hormone receptors and orphan/adopted receptors that function as intra-cellular transcription factors to regulate expression of several hundreds of genes in response to their cognate ligands. Interestingly, nuclear receptors are also being assigned a novel role in serving as ‘epigenetic marks’ for the retention and transmission of cellular ‘transcriptional memory’. These receptors function primarily either as homodimers or heterodimers with Retinoid X Receptor (RXR) or sometimes as monomers. Being ‘drug responsive’ these receptors offer attractive targets for drug discovery since their activities can be favorably modulated by interacting ligands. However, many of the newly discovered members of this family of receptors remain incompletely understood, both in terms of physiological roles and activating ligands. In brief, nuclear receptors represent enormous potential for drug discovery and are continuously being examined to unravel the mysteries underlying their mechanisms of action. It has been well-over three decades since the cloning of steroid/nuclear receptors in the 1980s. Therefore, it’s only appropriate to prepare a comprehensive review that provides a compendium of facts and events from receptor cloning and characterization to establishment of receptor domain structures, physiological functioning and consequences of receptor malfunctioning. This review is expected to serve as a refreshing compendium of nuclear receptors for both, the beginners, as well as experts working in the areas of nuclear receptor biology.","PeriodicalId":15664,"journal":{"name":"Journal of Endocrinology and Reproduction","volume":"16 1","pages":"1-27"},"PeriodicalIF":0.0,"publicationDate":"2016-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73987105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mifepristone (RU486) Induces Polycystic Ovarian Syndrome in Female Wistar Rats with Features Analogous to Humans","authors":"M. Yakubu, F. J. Olawepo, L. Olayaki, O. Ibrahim","doi":"10.18311/JER/2015/V19/86061","DOIUrl":"https://doi.org/10.18311/JER/2015/V19/86061","url":null,"abstract":"Numerous inducers of polycystic ovarian syndrome (PCOS) at different doses have been proposed in several experimental animals but there is no consensus on an appropriate dose(s) that should ideally reproduce the key biochemical and clinical features of PCOS similar to those of humans. Therefore, this study was aimed at investigating an appropriate dose(s) for the induction of PCOS in female Wistar rats. Twenty-four female albino rats (190.00 ± 13.00 g) with 4-5 days of estrus cyclicity were completely randomized into 4 groups (A - D) of six animals each. Animals in group A (control) were subcutaneously administered 0.2 ml of pure olive oil, while those in groups B, C and D were subcutaneously administered same volume corresponding to 5.0, 7.5 and 10.0 mg of mifepristone in olive oil for 9 days starting from the day of estrus (Day 1). The estrus cycle, serum testosterone (T), estradiol (E), prolactin (Pr), follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), insulin (Is), weight of the animals, fasting blood glucose (FBS) and ovarian morphology were monitored/evaluated/examined. The 5.0 mg of mifepristone extended the estrus stage for four days, increased (p<0.05) the levels of serum E, P, Pr, FSH, T, triacylglycerides (TAG), and total cholesterol (TC) as well as decreased the concentrations of LH and high density lipoprotein-cholesterol (HDL-C). There was no significant difference (p<0.05) in the Is concentration, animal body weights and FBS at day 10 in rats administered 5.0 mg of mifepristone. The 7.5 mg of mifepristone produced irregular estrus cycle, increased Pr, TAG, T, and TC concentrations and FBS whereas it decreased E, P, HDL-C, and LH. The Is, FSH and body weights of the animals were not significantly altered at 7.5 mg of mifepristone. The 10.0 mg of mifepristone produced irregular estrus cycle, increased the levels of E, TAG, Is, LH, T as well as decreased the levels of P and HDL-C. The levels of Pr, FSH, TC, body weights and FBS were not significantly altered at this dose. There was no ovarian follicular growth and atresia in the 5.0 and 7.5 mg mifepristone-treated rats whereas the 10 mg of mifepristone produced these histopathological features. Overall, the study concluded that subcutaneous administration of mifepristone (RU486) induces polycystic ovarian syndrome in rats through deprivation of progesterone with the 10 mg producing majority of the key biochemical and clinical features associated with PCOS in humans. The study, therefore, recommends the subcutaneous administration of mifepristone (RU486) on daily basis for 9 days as a good model for inducing PCOS in animals.","PeriodicalId":15664,"journal":{"name":"Journal of Endocrinology and Reproduction","volume":"19 1","pages":"40-51"},"PeriodicalIF":0.0,"publicationDate":"2015-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90388871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. A. Devi, R. Binitha, S. Soorya, B. Amrutha, F. Sunny
{"title":"Oxidative Stress Responses of a Freshwater Teleost, Anabas testudineus , to an Endocrine Disruptor, Bisphenol A","authors":"C. A. Devi, R. Binitha, S. Soorya, B. Amrutha, F. Sunny","doi":"10.18519/JER/2015/V19/86045","DOIUrl":"https://doi.org/10.18519/JER/2015/V19/86045","url":null,"abstract":"Bisphenol-A (BPA), an industrial chemical used to manufacture polycarbonate plastic, is considered as a potent estrogenic endocrine disruptor. A majority of xenobiotics exert their toxic effect by causing generation of reactive oxygen species, leading to oxidative stress. Reports regarding oxidative stress responses to BPA in fish are scanty. From this viewpoint, in the present study, a freshwater fish, Anabas testudineus , was exposed to sub-lethal concentrations of BPA (2.5, 5.0,&7.5 mg/l), for different time periods (7, 15&30 days). Four major enzymes of the fish's antioxidant defense system viz., catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (Se-GPx), and glutathione-S-transferase (GST), and the non-enzymatic antioxidant glutathione (GSH) were chosen as biomarkers to examine the effects of BPA. The activities of SOD, GPx and GSH were elevated to significant levels, while CAT and GST activities were decreased significantly suggesting oxidative stress in BPAexposed fish. Reactive oxygen species are known to cause DNA fragmentation. Hence, DNA fragmentation assay was also done. The severity of DNA fragmentation in fish exposed to 7.5 mg/L BPA (30days) was remarkably increased (p<0.05 vs control) and this was revealed in gel electrophoresis analysis also. The results clearly show that BPA is a pollutant with oxidative potential, also with a potential for DNA fragmentation. The potential risks of this compound to nature and human populations are significant since the production of BPA related compounds is increasing dramatically each year.","PeriodicalId":15664,"journal":{"name":"Journal of Endocrinology and Reproduction","volume":"5 1","pages":"7-19"},"PeriodicalIF":0.0,"publicationDate":"2015-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77728357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cross Talk between Protein Kinase A and Androgen Signaling Pathway","authors":"Manisha Dagar, G. Bhattacharjee","doi":"10.18519/JER/2015/V19/86041","DOIUrl":"https://doi.org/10.18519/JER/2015/V19/86041","url":null,"abstract":"Protein kinases are enzymes that add phosphate group to proteins to modify their function. These proteins regulate signal transduction pathways, essential for many biological processes such as cell cycle, cell signaling, protein and enzyme regulation, etc. There are 518 protein kinases, divided in to 7 main families. Protein kinase A (PKA) is a member of AGC family of protein kinases. It is activated by activation of G protein-coupled receptors (GPCR) and plays an important role in many cellular pathways including androgen signaling. Steroid hormones such as androgens primarily function through a genomic pathway, binding to cytosolic androgen receptors (AR) and initiating changes in transcription of target genes. Androgens also functions through a non-genomic pathway which is rapid and mediated by membrane receptors. It manifests its effects by activation of cellular signal transduction pathways such as PKA, Protein kinase C, and mitogen activated kinase, and does not involve transcription. In this review, we have analyzed the interaction between androgen signaling pathways and PKA, and have highlighted how each of these pathways complements and strengthens the function of the other. PKA plays an important role in complete activation of nuclear AR and in turn PKA can be activated by androgens. The complex interaction between the two pathways plays a critical role in development and progression of prostate cancer (PCa). Though the exact role of each pathway is not completely understood yet simultaneous inhibition of both pathways could prove to be beneficial for PCa patients.","PeriodicalId":15664,"journal":{"name":"Journal of Endocrinology and Reproduction","volume":"37 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2015-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90198971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}