F&S sciencePub Date : 2025-02-01DOI: 10.1016/j.xfss.2024.10.005
David Huang M.D. , Emily Flynn Ph.D , Ana Almonte-Loya B.S. , Brittany Davidson B.S. , Meagan Chan D.N.P. , Amber Casillas B.S. , Juan C. Irwin M.D., Ph.D. , Gabriela K. Fragiadakis Ph.D. , Hakan Cakmak M.D. , Alexis J. Combes Ph.D. , Marcelle I. Cedars M.D. , Marina Sirota Ph.D. , Linda C. Giudice M.D., Ph.D.
{"title":"A positive ReceptivaDx result for BCL6 does not correlate with abnormal ERA results or decreased expression of receptivity-associated markers: two sides of the endometrial receptivity coin in fertility evaluation and treatment","authors":"David Huang M.D. , Emily Flynn Ph.D , Ana Almonte-Loya B.S. , Brittany Davidson B.S. , Meagan Chan D.N.P. , Amber Casillas B.S. , Juan C. Irwin M.D., Ph.D. , Gabriela K. Fragiadakis Ph.D. , Hakan Cakmak M.D. , Alexis J. Combes Ph.D. , Marcelle I. Cedars M.D. , Marina Sirota Ph.D. , Linda C. Giudice M.D., Ph.D.","doi":"10.1016/j.xfss.2024.10.005","DOIUrl":"10.1016/j.xfss.2024.10.005","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate if a positive result on ReceptivaDx for evaluation of B-cell lymphoma 6 (BCL6), a proposed marker of progesterone resistance associated with impaired uterine receptivity, correlates with a suboptimal profile of receptivity-associated markers in the window of implantation using the endometrial receptivity array and single-nucleus transcriptomic analysis.</div></div><div><h3>Design</h3><div>Retrospective clinical cohort study; pilot study of single-nucleus RNA sequencing of prospectively collected window of implantation endometrium undergoing ReceptivaDx BCL6 evaluation.</div></div><div><h3>Subjects</h3><div>Patients with infertility who underwent endometrial biopsy for concurrent endometrial receptivity array analysis (ERA; Igenomix, Valencia, Spain) and BCL6 immunostaining (ReceptivaDx; Cicero Diagnostics, Inc., Huntington Beach, CA).</div></div><div><h3>Exposure</h3><div>Positive BCL6 result on ReceptivaDx (histologic score >1.4).</div></div><div><h3>Main Outcome Measures</h3><div>Prereceptive ERA result; relative expression levels of endometrial receptivity-associated epithelial genes by single-nucleus sequencing.</div></div><div><h3>Results</h3><div>One hundred and seventy-two patients with concurrent ERA and ReceptivaDx evaluation were included in the analysis: 40 were BCL6-positive and 132 were BCL6-negative. One patient (2.5%) in the BCL6-positive group had a prereceptive ERA result, compared with 29 patients (22.0%) in the BCL6-negative group (<em>P</em><.01). BCL6 positivity was associated with decreased odds of a prereceptive ERA result (odds ratio, 0.09; 95% confidence interval, 0.01–0.69; <em>P</em>=.02). Single-nucleus transcriptomic analysis of 5,718 epithelial cell nuclei from four individuals showed significant cell type-specific transcriptomic changes associated with a positive ReceptivaDx BCL6 result in both natural cycle (NC) and programmed cycle (PC) endometrium: there were 2,801 significantly differentially expressed genes comparing NC BCL6-positive with -negative, and 1,062 differentially expressed genes comparing PC BCL6-positive with -negative. Of the 34 receptivity-associated epithelial markers evaluated, 16 were significantly upregulated in NC BCL6-positive vs. -negative endometrium epithelial nuclei. In PC epithelial nuclei, 12 of the 34 receptivity-associated genes were significantly upregulated, whereas only one was significantly downregulated in BCL6-positive vs. -negative endometrium.</div></div><div><h3>Conclusions</h3><div>A positive ReceptivaDx BCL6 result does not correlate with a prereceptive ERA. Epithelial cells from BCL6-positive endometrium did not show significantly decreased expression in most of the receptivity markers evaluated. These findings demonstrate discordance between the interpretation of “endometrial receptivity” by ReceptivaDx and ERA, and highlight the need for further validation of endometrial evaluation methods in fertility treatment.</div></d","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"6 1","pages":"Pages 55-64"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482284","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}
F&S sciencePub Date : 2025-02-01DOI: 10.1016/j.xfss.2024.10.003
Ana Lobo de Almeida M.Sc. , Ana Gonçalves M.Sc. , Alberto Barros M.D., Ph.D. , Mário Sousa M.D., Ph.D. , Rosália Sá M.D., Ph.D.
{"title":"Bleomycin in vitro exposure decreases markers of human male gamete competence","authors":"Ana Lobo de Almeida M.Sc. , Ana Gonçalves M.Sc. , Alberto Barros M.D., Ph.D. , Mário Sousa M.D., Ph.D. , Rosália Sá M.D., Ph.D.","doi":"10.1016/j.xfss.2024.10.003","DOIUrl":"10.1016/j.xfss.2024.10.003","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the in vitro impact of bleomycin on human sperm deoxyribonucleic acid (DNA) integrity, functionality, and morphology, with the aim of elucidating the underlying mechanism and anticipating potential repercussions on patients’ reproductive function.</div></div><div><h3>Design</h3><div>Controlled laboratory-based in vitro investigation.</div></div><div><h3>Subjects</h3><div>Surplus human ejaculate donated for research by 45 reproductive-age participants exhibiting normozoospermic sperm parameters after clinical semen analysis. None of the participants had received a cancer diagnosis or undergone radiotherapy, chemotherapy, or both.</div></div><div><h3>Exposure</h3><div>After clinical semen analysis, sperm samples were centrifuged, diluted in sperm preparation medium, and exposed to bleomycin (100 μg/mL) for 2 hours at 37 °C in a humidified incubator with 5% CO<sub>2</sub>.</div></div><div><h3>Main Outcome Measures</h3><div>In vitro human sperm competence was evaluated by comparing raw sperm, sperm incubated with sperm preparation medium, and sperm exposed to bleomycin. Competence indicators included sperm motility, vitality, DNA and acrosome integrity, and mitochondrial membrane potential. Transmisson electron microscopy was employed to correlate the ultrastructural morphological findings with functional assays.</div></div><div><h3>Results</h3><div>Exposure to bleomycin for 2 hours in vitro significantly decreased sperm vitality, motility, and chromatin condensation compared with raw and control sperm. It also significantly increased sperm DNA fragmentation and the proportion of sperm with low mitochondrial membrane potential. Additionally, bleomycin significantly retarded the acrosomal response compared with control but did not affect the formation of intracellular and extracellular reactive oxygen species. Bleomycin-induced ultrastructural morphological changes supported the detected functional alterations.</div></div><div><h3>Conclusions</h3><div>Bleomycin negatively impacts male gamete competency in humans. Healthcare professionals should vigilantly monitor and further investigate the gonadotoxicity effects of bleomycin, in addition to its recognized lung toxicity. Meanwhile, it is recommended that patients with cancer undergoing bleomycin-containing chemotherapy regimens receive guidance on fertility preservation strategies.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"6 1","pages":"Pages 5-15"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407307","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}
F&S sciencePub Date : 2025-02-01DOI: 10.1016/j.xfss.2024.11.001
Simon Alesi B.Med.Sc. (Hons) , Helena Teede Ph.D. , Joanne Enticott Ph.D. , Kushan De Silva Ph.D. , Aya Mousa Ph.D.
{"title":"Blood-based inflammatory markers in female infertility: evidence from Mendelian randomization analysis","authors":"Simon Alesi B.Med.Sc. (Hons) , Helena Teede Ph.D. , Joanne Enticott Ph.D. , Kushan De Silva Ph.D. , Aya Mousa Ph.D.","doi":"10.1016/j.xfss.2024.11.001","DOIUrl":"10.1016/j.xfss.2024.11.001","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate causal associations between blood-based inflammatory markers and female infertility using Mendelian randomization (MR).</div></div><div><h3>Design</h3><div>Mendelian randomization using genome-wide association study data.</div></div><div><h3>Subjects</h3><div>Large female-only cohorts of European ancestry.</div></div><div><h3>Exposure</h3><div>Blood-based inflammatory markers (C-reactive protein, interleukins, monocyte chemoattractant protein-1, tumor necrosis factor-α, interferon-γ).</div></div><div><h3>Main Outcome Measures</h3><div>Anovulatory infertility (1,054 cases and 117,098 controls); female infertility of other/unspecified origin (5,667 cases and 117,098 controls); and medical treatment for female infertility (2,706 cases and 120,873 controls). Total causal effects were assessed using univariable two-sample methods including inverse variance weighted (IVW) as the primary analysis, as well as other secondary analyses (MR-Egger, weighted median, etc.), with relevant quality assessments.</div></div><div><h3>Results</h3><div>Interleukin-8 demonstrated a positive association with anovulatory infertility via IVW (odds ratio, 95% confidence interval; 1.51, 1.04–2.21) and weighted median (1.64, 1.05–2.57) methods. Monocyte chemoattractant protein-1 was associated with anovulatory infertility via MR-Egger (2.06, 1.13–3.77). Inverse associations were found for interleukins-12 and -18 via IVW, with higher interleukin-12 being associated with lower medical treatment for female infertility (0.75, 0.59–0.94), whereas higher interleukin-18 was associated with lower female infertility of other/unspecified origin (0.90, 0.83–0.97).</div></div><div><h3>Conclusions</h3><div>This is the first study to examine causal relationships between inflammation and female infertility using MR. Monocyte chemoattractant protein-1 and interleukin-8 are implicated in anovulatory infertility; however, only the relationship with interleukin-8 was evident in the primary analysis. Interleukins-12 and -18 demonstrated inverse associations with infertility outcomes. Further research is needed to uncover the mechanistic functions of these markers to confirm causality and examine their therapeutic potential for female infertility.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"6 1","pages":"Pages 85-98"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142633943","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}
F&S sciencePub Date : 2024-11-01DOI: 10.1016/j.xfss.2024.08.002
Alexander M. Quaas M.D., Ph.D. , Alan S. Penzias M.D. , Eli Y. Adashi M.D., M.S.
{"title":"Embryonic aneuploidy — the true “last barrier in assisted reproductive technology”?","authors":"Alexander M. Quaas M.D., Ph.D. , Alan S. Penzias M.D. , Eli Y. Adashi M.D., M.S.","doi":"10.1016/j.xfss.2024.08.002","DOIUrl":"10.1016/j.xfss.2024.08.002","url":null,"abstract":"<div><div>Human embryonic aneuploidy may represent one of the final frontiers in assisted reproductive technology, primarily secondary to oocyte aneuploidy. Mammalian oocytes possess unique characteristics predisposing them to much higher rates of aneuploidy than sperm or most somatic cells. Some of these characteristics are age-independent, whereas others result from reproductive aging and environmental toxicity. A detailed understanding of these properties may lead to novel diagnostic and therapeutic tools designed to detect and prevent oocyte and embryonic aneuploidy to overcome this ultimate barrier to success in assisted reproductive technology.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"5 4","pages":"Pages 303-305"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914744","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":"Engineered uterine primary myometrial cells with high-mobility group AT-hook 2 overexpression display a leiomyoma-like transcriptional and epigenomic phenotype","authors":"Priyanka Saini Ph.D. , Austin G. Holmes Ph.D. , Jian-Jun Wei M.D. , J. Brandon Parker Ph.D. , Debabrata Chakravarti Ph.D.","doi":"10.1016/j.xfss.2024.07.008","DOIUrl":"10.1016/j.xfss.2024.07.008","url":null,"abstract":"<div><h3>Objective</h3><div>To determine if engineered high-mobility group AT-hook 2 (HMGA2) overexpressing uterine primary myometrial cells recapitulate the transcriptional and epigenomic features of HMGA2-subtype leiomyomas.</div></div><div><h3>Design</h3><div>Isolated primary, “normal” myometrial cells from three patients were engineered to overexpress HMGA2 to determine how HMGA2 establishes transcriptomic and epigenomic features of HMGA2-overexpressing leiomyoma.</div></div><div><h3>Setting</h3><div>Academic research laboratory.</div></div><div><h3>Patient(s)</h3><div>Primary myometrial cells were isolated from normal myometrium obtained from three patients undergoing hysterectomy.</div></div><div><h3>Intervention(s)</h3><div>Not applicable.</div></div><div><h3>Main Outcome Measure(s)</h3><div>Determined genome-wide transcriptomic and epigenomic features of engineered HMGA2-overexpressing uterine primary myometrial cells.</div></div><div><h3>Result(s)</h3><div>Engineered HMGA2-V5-overexpressing primary myometrial cells approximated the HMGA2 expression level observed in HMGA2-overexpression subtype leiomyoma. High-mobility group AT-hook 2-V5 expression resulted in differential expression of 1,612 genes (false discovery rate [FDR] < 0.05) that were found to be enriched in pathways associated with leiomyoma formation, including extracellular matrix organization. Comparative gene expression analysis between HMGA2-V5 engineered primary cells and HMGA2-overexpression subtype leiomyoma revealed significant overlap of differentially expressed genes. Mechanistically, HMGA2-V5 overexpression resulted in 41,323 regions with differential H3K27ac deposition (FDR < 0.05) and 205,605 regions of altered chromatin accessibility (FDR < 0.05). Transcription factor binding site analysis implicated the AP-1 family of transcription factors.</div></div><div><h3>Conclusion(s)</h3><div>High-mobility group AT-hook 2 overexpression induces leiomyoma-like transcriptomic and epigenomic modulations in myometrial cells.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"5 4","pages":"Pages 352-368"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794185","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}
F&S sciencePub Date : 2024-11-01DOI: 10.1016/j.xfss.2024.08.004
Virpi Töhönen Ph.D. , Per Antonson Ph.D. , Nageswara Rao Boggavarapu Ph.D. , Heba Ali M.Sc. , Leticia Apolinario Motaholi Ph.D. , Jan-Åke Gustafsson Ph.D. , Mukesh Varshney Ph.D. , Kenny A. Rodriguez-Wallberg Ph.D. , Shintaro Katayama Ph.D. , Ivan Nalvarte Ph.D. , Jose Inzunza Ph.D.
{"title":"Transcriptomic profiling of the oocyte-cumulus-granulosa cell complex from estrogen receptor β knockout mice","authors":"Virpi Töhönen Ph.D. , Per Antonson Ph.D. , Nageswara Rao Boggavarapu Ph.D. , Heba Ali M.Sc. , Leticia Apolinario Motaholi Ph.D. , Jan-Åke Gustafsson Ph.D. , Mukesh Varshney Ph.D. , Kenny A. Rodriguez-Wallberg Ph.D. , Shintaro Katayama Ph.D. , Ivan Nalvarte Ph.D. , Jose Inzunza Ph.D.","doi":"10.1016/j.xfss.2024.08.004","DOIUrl":"10.1016/j.xfss.2024.08.004","url":null,"abstract":"<div><h3>Objective</h3><div>To study the role of estrogen receptor β in follicle development and maturation and the response to gonadotropin stimulation aiming at superovulation.</div></div><div><h3>Design</h3><div>Experimental study and transcriptomic analysis.</div></div><div><h3>Setting</h3><div>Karolinka Institutet, medical university.</div></div><div><h3>Animal(s)</h3><div>Healthy wild-type (WT) and estrogen receptor β knockout (<em>Esr</em>2-KO) female mice undergoing superovulation at 4 weeks, 7 weeks, and 6 months of age.</div></div><div><h3>Intervention(s)</h3><div>Not applicable.</div></div><div><h3>Main Outcome Measure(s)</h3><div>Oocyte yield after superovulation, transcriptomic profiling of cumulus-granulosa cell complexes and oocytes, and immunohistochemical analyses.</div></div><div><h3>Result(s)</h3><div>Superovulation of estrogen receptor β (ERβ) knockout mice resulted in reduced oocyte yield at 6 months of age compared with WT mice, but younger mice had similar yields. RNA-seq analysis of cumulus cells from superovulated WT and <em>Esr</em>2-KO mice identified genes and pathways associated with among others adhesion, proliferation, Wnt-signaling, and placed ERβ in bipotential granulosa cell cluster. Loss of ERβ increased expression of the other estrogen receptors <em>Esr1</em> and <em>Gper1</em>.</div></div><div><h3>Conclusion(s)</h3><div>Our results show that ERβ has an important role in regulating ovulation in response to exogenous gonadotropins in 6-month-old mice, but not in younger mice. Our transcriptomic and immunohistochemical observations suggest a dysregulation of the granulosa cell communication and lack of tight coordination between granulosa cell replication and antrum expansion. A significant upregulation of other estrogen receptors may support a compensatory mechanism sustaining fertility during younger age in <em>Esr2</em>-KO mice.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"5 4","pages":"Pages 306-317"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Tertiary lymphoid structures in endometriosis","authors":"Katherine B. Zutautas M.Sc. , Priyanka Yolmo B.Tech. , Minqi Xu M.D. , Timothy Childs M.D. , Madhuri Koti D.V.M., Ph.D. , Chandrakant Tayade D.V.M., Ph.D.","doi":"10.1016/j.xfss.2024.10.001","DOIUrl":"10.1016/j.xfss.2024.10.001","url":null,"abstract":"<div><h3>Objective</h3><div>To determine whether tertiary lymphoid structures (TLSs), which reflect organized immune cell aggregates present in non-lymphoid tissues, are consistent features of endometriosis lesions.</div></div><div><h3>Design</h3><div>Detailed histopathological analysis of endometrial and lesion tissue from patients with endometriosis and controls was performed. Multiplex immunofluorescence on select samples was then conducted to identify canonical cell populations present within TLSs: CD3<sup>+</sup> and CD8<sup>+</sup> T-cells, CD79a<sup>+</sup> B-cells, CD208<sup>+</sup> dendritic cells, CD21<sup>+</sup> follicular dendritic cells, and PNAd<sup>+</sup> high endothelial venules.</div></div><div><h3>Patient(s)</h3><div>Patients with histologically confirmed endometriosis (N = 113; 44.3 ± 6.0) and control individuals (N = 110; 44.6 ± 7.1).</div></div><div><h3>Intervention</h3><div>Not applicable.</div></div><div><h3>Main Outcome Measure(s)</h3><div>Detection of TLSs as characterized by the presence of all canonical cell types that constitute TLS and structure morphology.</div></div><div><h3>Result(s)</h3><div>Of the selected samples (N = 18; 6 ectopic/eutopic/control), mature TLSs were identified in 3 ectopic tissue samples present on the ovary and fallopian tube, with immature TLSs (lacking follicular dendritic cell networks and high endothelial venules) present throughout eutopic and control endometrial samples.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate the presence of TLSs across various endometriosis phenotypes, prompting further research into their significance within disease pathophysiology and the prognostic implications for patients.</div></div>","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"5 4","pages":"Pages 335-341"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382619","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}
F&S sciencePub Date : 2024-11-01DOI: 10.1016/j.xfss.2024.09.001
{"title":"Corrigendum for Bhatt S, Butola A, Acuña S, Hansen DH, Tinguely JC, Nystad M, et al. Characterizing the consistency of motion of spermatozoa through nanoscale motion tracing. F S Sci 2024;5:215–24.","authors":"","doi":"10.1016/j.xfss.2024.09.001","DOIUrl":"10.1016/j.xfss.2024.09.001","url":null,"abstract":"","PeriodicalId":73012,"journal":{"name":"F&S science","volume":"5 4","pages":"Page 404"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}