194 results on '"Nef S"'
Search Results
2. BIOLOGICAL SESSION“THE IMPORTANCE OF G. GAMOW'S IDEAS FOR BIOLOGY OF THE 21st CENTURY” AT THE XXІI GAMOW INTERNATIONAL ASTRONOMICAL CONFERENCE-SCHOOL IN ODESA (25 AUGUST, 2022)
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Alqudah, A.M., primary, Artemenko A.Yu., A.Yu., additional, Awal R., R., additional, Banson, A., additional, Вlagodarova, O.M., additional, Boerner, А, additional, Wang, F., additional, Volkov R.A., R.A., additional, Wingen, L., additional, Goram, R., additional, Gorodna, O., additional, Gretsky, I.O., additional, Griffiths, S., additional, Hrytsak, L.R., additional, Gromyko, O.M., additional, Gromozova, O.M., additional, Doneva, D., additional, Drobyk, N.M, additional, Zelinska, N., additional, Kartseva, T., additional, Kolisnyk, Kh. M., additional, Collier, S., additional, Kusz-Zamelczyk, K., additional, Lovegrove, A., additional, Lauber-Biason, A., additional, Leverington-Waite M., M., additional, Livshits, L., additional, Luzhetskyy, A.M., additional, Mayorova, O.Yu., additional, Martyniuk, V.S., additional, Misheva, S., additional, Myronovskyi, M.L, additional, Monczak, Yu., additional, Nef, S., additional, Novikov, A.V., additional, Aleksandrov, V., additional, Orford, S., additional, Popovych, Yu.A., additional, Prokopiak, M.Z., additional, Riche, A, additional, Roshka N.M., N.M., additional, Segrè, G., additional, Sirokha, D., additional, Tynkevich, Y.O., additional, Tistechok, S.I., additional, Fedorenko, V.O., additional, Philp Ch., Ch., additional, Hawkesford, M., additional, Tseysler, Yu.V., additional, Chayut, N., additional, Chebotar, S.V., additional, Cheng Sh., Sh., additional, Chorney, I.I., additional, Steuernagel, B., additional, Shewry, P., additional, and Jaruzelska, J., additional
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- 2022
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3. TRIM28-dependent SUMOylation protects the adult ovary from activation of the testicular pathway
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Rossitto, M, Dejardin, S, Rands, CM, Le Gras, S, Migale, R, Rafiee, M-R, Neirijnck, Y, Pruvost, A, Nguyen, AL, Bossis, G, Cammas, F, Le Gallic, L, Wilhelm, D, Lovell-Badge, R, Boizet-Bonhoure, B, Nef, S, Poulat, F, Rossitto, M, Dejardin, S, Rands, CM, Le Gras, S, Migale, R, Rafiee, M-R, Neirijnck, Y, Pruvost, A, Nguyen, AL, Bossis, G, Cammas, F, Le Gallic, L, Wilhelm, D, Lovell-Badge, R, Boizet-Bonhoure, B, Nef, S, and Poulat, F
- Abstract
Gonadal sexual fate in mammals is determined during embryonic development and must be actively maintained in adulthood. In the mouse ovary, oestrogen receptors and FOXL2 protect ovarian granulosa cells from transdifferentiation into Sertoli cells, their testicular counterpart. However, the mechanism underlying their protective effect is unknown. Here, we show that TRIM28 is required to prevent female-to-male sex reversal of the mouse ovary after birth. We found that upon loss of Trim28, ovarian granulosa cells transdifferentiate to Sertoli cells through an intermediate cell type, different from gonadal embryonic progenitors. TRIM28 is recruited on chromatin in the proximity of FOXL2 to maintain the ovarian pathway and to repress testicular-specific genes. The role of TRIM28 in ovarian maintenance depends on its E3-SUMO ligase activity that regulates the sex-specific SUMOylation profile of ovarian-specific genes. Our study identifies TRIM28 as a key factor in protecting the adult ovary from the testicular pathway.
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- 2022
4. Semen quality of young men in Switzerland: a nationwide cross‐sectional population‐based study
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Rahban, R, Priskorn, L, Senn, A, Stettler, E, Galli, F, Vargas, J, Van den Bergh, M, Fusconi, A, Garlantezec, R, Jensen, T K, Multigner, L, Skakkebæk, N E, Germond, M, Jørgensen, N, Nef, S, Bouchardy, C, Herrmann, C, Mousavi, M, Bulliard, J‐L, Maspoli, M, Bordoni, A, Konzelmann, I, Blanc‐Moya, R, Rohrmann, S, University of Zurich, and Nef, S
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2748 Urology ,2712 Endocrinology, Diabetes and Metabolism ,610 Medicine & health ,10060 Epidemiology, Biostatistics and Prevention Institute (EBPI) ,2743 Reproductive Medicine ,1310 Endocrinology - Published
- 2019
5. Maternal occupational exposure to endocrine-disrupting chemicals during pregnancy and semen parameters in adulthood: results of a nationwide cross-sectional study among Swiss conscripts
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Istvan, M, primary, Rahban, R, additional, Dananche, B, additional, Senn, A, additional, Stettler, E, additional, Multigner, L, additional, Nef, S, additional, and Garlantezec, R, additional
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- 2021
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6. O-228 The SSRI antidepressant Sertraline inhibits CatSper calcium channels in human sperm
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Rahban, R, primary, Rehfeld, A, additional, Schiffer, C, additional, Brenker, C, additional, Palme, D. Louise Egeberg, additional, Wang, T, additional, Lorenz, J, additional, Almstrup, K, additional, Skakkebaek, N E, additional, Strünker, T, additional, and Nef, S, additional
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- 2021
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7. The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice.
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Yenugu, S, Bagheri-Fam, S, Chen, H, Wilson, S, Ayers, K, Hughes, J, Sloan-Bena, F, Calvel, P, Robevska, G, Puisac, B, Kusz-Zamelczyk, K, Gimelli, S, Spik, A, Jaruzelska, J, Warenik-Szymankiewicz, A, Faradz, S, Nef, S, Pié, J, Thomas, P, Sinclair, A, Wilhelm, D, Yenugu, S, Bagheri-Fam, S, Chen, H, Wilson, S, Ayers, K, Hughes, J, Sloan-Bena, F, Calvel, P, Robevska, G, Puisac, B, Kusz-Zamelczyk, K, Gimelli, S, Spik, A, Jaruzelska, J, Warenik-Szymankiewicz, A, Faradz, S, Nef, S, Pié, J, Thomas, P, Sinclair, A, and Wilhelm, D
- Abstract
Disorders/differences of sex development (DSD) cause profound psychological and reproductive consequences for the affected individuals, however, most are still unexplained at the molecular level. Here, we present a novel gene, 3-hydroxy-3-methylglutaryl coenzyme A synthase 2 (HMGCS2), encoding a metabolic enzyme in the liver important for energy production from fatty acids, that shows an unusual expression pattern in developing fetal mouse gonads. Shortly after gonadal sex determination it is up-regulated in the developing testes following a very similar spatial and temporal pattern as the male-determining gene Sry in Sertoli cells before switching to ovarian enriched expression. To test if Hmgcs2 is important for gonad development in mammals, we pursued two lines of investigations. Firstly, we generated Hmgcs2-null mice using CRISPR/Cas9 and found that these mice had gonads that developed normally even on a sensitized background. Secondly, we screened 46,XY DSD patients with gonadal dysgenesis and identified two unrelated patients with a deletion and a deleterious missense variant in HMGCS2 respectively. However, both variants were heterozygous, suggesting that HMGCS2 might not be the causative gene. Analysis of a larger number of patients in the future might shed more light into the possible association of HMGCS2 with human gonadal development.
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- 2020
8. DNA methylation profiling of the fibrinogen gene landscape in human cells and during mouse and zebrafish development: OC 06.2
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Neerman-Arbez, M, Vorjohann, S, Pitetti, J-L, Nef, S, Gonelle-Gispert, C, Buhler, L, and Fish, R J
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- 2013
9. Semen quality of young men in Switzerland:a nationwide cross-sectional population-based study
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Rahban, R., Priskorn, L., Senn, A., Stettler, E., Galli, F., Vargas, J., Van den Bergh, M., Fusconi, A., Garlantezec, R., Jensen, T. K., Multigner, L., Skakkebæk, N. E., Germond, M., Jørgensen, N., Nef, S., Rahban, R., Priskorn, L., Senn, A., Stettler, E., Galli, F., Vargas, J., Van den Bergh, M., Fusconi, A., Garlantezec, R., Jensen, T. K., Multigner, L., Skakkebæk, N. E., Germond, M., Jørgensen, N., and Nef, S.
- Published
- 2019
10. Maternal occupational exposure to endocrine-disrupting chemicals during pregnancy and semen parameters in adulthood: results of a nationwide cross-sectional study among Swiss conscripts.
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Istvan, M, Rahban, R, Dananche, B, Senn, A, Stettler, E, Multigner, L, Nef, S, and Garlantézec, R
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OCCUPATIONAL exposure ,MATERNAL exposure ,SEMEN ,SEMEN analysis ,GENITALIA ,RESEARCH ,POLLUTANTS ,CROSS-sectional method ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,JOB Descriptive Index ,BIOTIC communities - Abstract
Study Question: Is there a relationship between maternal occupational exposure to endocrine-disrupting chemicals (EDCs) during pregnancy and the semen quality of their sons?Summary Answer: Our results suggest an association between maternal occupational exposure to potential EDCs, especially to pesticides, phthalates and heavy metals, and a decrease in several semen parameters.What Is Known Already: Sexual differentiation, development and proper functioning of the reproductive system are largely dependent on steroid hormones. Although there is some animal evidence, studies on maternal exposure to EDCs during pregnancy and its effect on the semen quality of sons are scarce and none have focused on maternal occupational exposure.Study Design, Size, Duration: A cross-sectional study aiming to evaluate semen quality was carried out among Swiss conscripts aged 18 to 22 years between 2005 and 2017.Participants/materials, Setting, Methods: Conscript and parent questionnaires were completed prior to the collection of a semen sample. Semen parameters were categorised according to the guidelines of the World Health Organization (WHO). Data on maternal employment during pregnancy were provided by the parent questionnaire. Maternal occupational exposure to potential EDC categories was defined using a job-exposure matrix (JEM). Logistic regressions were used to analyse the relationship between maternal occupational exposure to EDCs and each semen parameter adjusted for potential confounding factors. Results are presented using odds ratios and 95% confidence intervals.Main Results and the Role Of Chance: In total, 1,737 conscripts provided a conscript and parent questionnaire, as well as a semen sample; among these 1,045 of their mothers worked during pregnancy. Our study suggests an association between occupational exposure of mothers during pregnancy to potential EDCs and low semen volume and total sperm count, particularly for exposure to pesticides (OR 2.07, 95% CI 1.11-3.86 and OR 2.14, 95% CI 1.05-4.35), phthalates (OR 1.92, 95% CI 1.10-3.37 and OR 1.89, 95% CI 1.01-3.55), and heavy metals (OR 2.02, 95% CI 1.14-3.60 and OR 2.29, 95% CI 1.21-4.35). Maternal occupational exposure to heavy metals was additionally associated with a low sperm concentration (OR 1.89, 95% CI 1.06-3.37).Limitations, Reasons For Caution: Several limitations should be noted, such as the indirect method for maternal occupational exposure assessment during the pregnancy (JEM) and the cross-sectional design of the study.Wider Implications Of the Findings: Our observations reinforce the need to inform pregnant women of potential hazards during pregnancy that could impair their child's fertility. Additional studies are needed to confirm the involvement of EDCs.Study Funding/competing Interest(s): This work was supported by the Swiss Centre for Applied Human Toxicology: SCAHT and the 'Fondation privée des Hôpitaux Universitaires de Genève'. The collection of human biological material used for this study was supported by the FABER Foundation, the Swiss National Science Foundation (SNSF): NFP 50 'Endocrine Disruptors: Relevance to Humans, Animals and Ecosystems', the Medical Services of the Swiss Army (DDPS) and Medisupport. The authors declare they have no competing financial interests.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]- Published
- 2021
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11. Semen quality of young men in Switzerland: a nationwide cross‐sectional population‐based study.
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Rahban, R., Priskorn, L., Senn, A., Stettler, E., Galli, F., Vargas, J., Van den Bergh, M., Fusconi, A., Garlantezec, R., Jensen, T. K., Multigner, L., Skakkebæk, N. E., Germond, M., Jørgensen, N., Nef, S., Bouchardy, C., Herrmann, C., Mousavi, M., Bulliard, J.‐L., and Maspoli, M.
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SEMEN analysis ,YOUNG men ,MALE reproductive health ,DRAFT (Military service) ,CROSS-sectional method - Abstract
Background: Sperm counts have been steadily decreasing over the past five decades with regional differences in the Western world. The reasons behind these trends are complex, but numerous insights indicate that environmental and lifestyle factors are important players. Objective: To evaluate semen quality and male reproductive health in Switzerland. Materials and methods: A nationwide cross‐sectional study was conducted on 2523 young men coming from all regions of Switzerland, recruited during military conscription. Semen volume, sperm concentration, motility, and morphology were analyzed. Anatomy of the genital area and testicular volume was recorded. Testicular cancer incidence rates in the general population were retrieved from Swiss regional registries. Results: Median sperm concentration adjusted for period of sexual abstinence was 48 million/mL. Comparing with the 5th percentile of the WHO reference values for fertile men, 17% of men had sperm concentration below 15 million/mL, 25% had less than 40% motile spermatozoa, and 43% had less than 4% normal forms. Disparities in semen quality among geographic regions, urbanization rates, and linguistic areas were limited. A larger proportion of men with poor semen quality had been exposed in utero to maternal smoking. Furthermore, testicular cancer incidence rates in the Swiss general population increased significantly between 1980 and 2014. Discussion: For the first time, a systematic sampling among young men has confirmed that semen quality is affected on a national level. The median sperm concentration measured is among the lowest observed in Europe. No specific geographical differences could be identified. Further studies are needed to determine to what extent the fertility of Swiss men is compromised and to evaluate the impact of environmental and lifestyle factors. Conclusion: A significant proportion of Swiss young men display suboptimal semen quality with only 38% having sperm concentration, motility, and morphology values that met WHO semen reference criteria. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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12. Étude de la différenciation testiculaire par single cell RNA seq
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Nef, S., primary
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- 2015
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13. P0956 : MIR-22 deficiency exacerbates systemic and hepatic metabolic disorders associated with diet-induced obesity in mice
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Berthomieu, A.-S., primary, Portius, D., additional, Abegg, D., additional, Rantakari, P., additional, Zhang, F.-P., additional, Poutanen, M., additional, Picard, D., additional, Nef, S., additional, Adibekian, A., additional, and Foti, M., additional
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- 2015
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14. Loss of Function Mutation in the Palmitoyl-Transferase HHAT Leads to Syndromic 46,XY Disorder of Sex Development by Impeding Hedgehog Protein Palmitoylation and Signaling
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Mundlos, S, Callier, P, Calvel, P, Matevossian, A, Makrythanasis, P, Bernard, P, Kurosaka, H, Vannier, A, Thauvin-Robinet, C, Borel, C, Mazaud-Guittot, V, Rolland, A, Desdoits-Lethimonier, C, Guipponi, M, Zimmermann, C, Stevant, I, Kuhne, F, Conne, B, Santoni, F, Lambert, S, Huet, F, Mugneret, F, Jaruzelska, J, Faivre, L, Wilhelm, D, Jegou, B, Trainor, PA, Resh, MD, Antonarakis, SE, Nef, S, Mundlos, S, Callier, P, Calvel, P, Matevossian, A, Makrythanasis, P, Bernard, P, Kurosaka, H, Vannier, A, Thauvin-Robinet, C, Borel, C, Mazaud-Guittot, V, Rolland, A, Desdoits-Lethimonier, C, Guipponi, M, Zimmermann, C, Stevant, I, Kuhne, F, Conne, B, Santoni, F, Lambert, S, Huet, F, Mugneret, F, Jaruzelska, J, Faivre, L, Wilhelm, D, Jegou, B, Trainor, PA, Resh, MD, Antonarakis, SE, and Nef, S
- Abstract
The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene. This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development.
- Published
- 2014
15. Insulin and IGF1 Receptors Are Essential for XX and XY Gonadal Differentiation and Adrenal Development in Mice
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Yao, H, Pitetti, J-L, Calvel, P, Romero, Y, Conne, B, Vy, T, Papaioannou, MD, Schaad, O, Docquier, M, Herrera, PL, Wilhelm, D, Nef, S, Yao, H, Pitetti, J-L, Calvel, P, Romero, Y, Conne, B, Vy, T, Papaioannou, MD, Schaad, O, Docquier, M, Herrera, PL, Wilhelm, D, and Nef, S
- Abstract
Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. These findings indicate that prior to sex determination somatic progenitors in Insr;Igf1r mutant gonads are not lineage primed and thus incapable of upregulating/repressing the male and female genetic programs required for cell fate restriction. In consequence, embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that Insr;Igf1r mutant gonads, irrespective of genetic sex, remained in an extended undifferentiated state, before the ovarian differentiation program ultimately is initiated at around E16.5.
- Published
- 2013
16. 1288 miR-21 DEFICIENCY IMPROVES GLUCOSE TOLERANCE AND HEPATIC LIPID CATABOLISM IN MICE FED A HIGH-FAT DIET
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Ramadori, P., primary, Fournier, M., additional, Portius, D., additional, Maeder, C., additional, Romero, Y., additional, Nef, S., additional, and Foti, M., additional
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- 2013
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17. A phytoestrogen-rich diet increases energy expenditure and decreases adiposity in mice
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Cederroth, C.R. (Christopher), Vinciguerra, M. (Manlio), Kühne, L.C. (Liesbeth), Madani, R. (Rime), Doerge, D.R. (Daniel), Visser, T.J. (Theo), Foti, M. (Michelangelo), Rohner-Jeanrenaud, F. (Francoise), Vassalli, J.-D. (Jean-Dominique), Nef, S. (Serge), Cederroth, C.R. (Christopher), Vinciguerra, M. (Manlio), Kühne, L.C. (Liesbeth), Madani, R. (Rime), Doerge, D.R. (Daniel), Visser, T.J. (Theo), Foti, M. (Michelangelo), Rohner-Jeanrenaud, F. (Francoise), Vassalli, J.-D. (Jean-Dominique), and Nef, S. (Serge)
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- 2007
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18. The Glucocorticoid-Induced Leucine Zipper (GILZ) Is Essential for Spermatogonial Survival and Spermatogenesis
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Romero, Y., primary, Vuandaba, M., additional, Suarez, P., additional, Grey, C., additional, Calvel, P., additional, Conne, B., additional, Pearce, D., additional, de Massy, B., additional, Hummler, E., additional, and Nef, S., additional
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- 2012
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19. microRNAs in the Testis: Building Up Male Fertility
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Papaioannou, M. D., primary and Nef, S., additional
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- 2009
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20. Insulin Receptor and IGF1R Are Not Required for Oocyte Growth, Differentiation, and Maturation in Mice
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Pitetti, J.L., primary, Torre, D., additional, Conne, B., additional, Papaioannou, M.D., additional, Cederroth, C.R., additional, Xuan, S., additional, Kahn, R., additional, Parada, L.F., additional, Vassalli, J.D., additional, Efstratiadis, A., additional, and Nef, S., additional
- Published
- 2009
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21. Altered regulation of brain-derived neurotrophic factor protein in hippocampus following slice preparation
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Danzer, S.C, primary, Pan, E, additional, Nef, S, additional, Parada, L.F, additional, and McNamara, J.O, additional
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- 2004
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22. In vivo role of truncated trkb receptors during sensory ganglion neurogenesis
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Luikart, B.W, primary, Nef, S, additional, Shipman, T, additional, and Parada, L.F, additional
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- 2003
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23. mKlf7, a potential transcriptional regulator of TrkA nerve growth factor receptor expression in sensory and sympathetic neurons
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Lei, L., primary, Ma, L., additional, Nef, S., additional, Thai, T., additional, and Parada, L.F., additional
- Published
- 2001
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24. cpp32 messenger RNA neosynthesis is induced by fatal axotomy and is not regulated by athanatal Bcl-2 over-expression
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Guarin, E, primary, Seuret, P, additional, Nef, S, additional, de Bilbao, F, additional, Nef, P, additional, and Dubois-Dauphin, M, additional
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- 1999
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25. Direct modulation of calmodulin targets by the neuronal calcium sensor NCS-1.
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Schaad, N C, primary, De Castro, E, additional, Nef, S, additional, Hegi, S, additional, Hinrichsen, R, additional, Martone, M E, additional, Ellisman, M H, additional, Sikkink, R, additional, Rusnak, F, additional, Sygush, J, additional, and Nef, P, additional
- Published
- 1996
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26. Regulation of Rhodopsin Phosphorylation by a Family of Neuronal Calcium Sensors
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Decastro, E., primary, Nef, S., additional, Fiumelli, H., additional, Lenz, S.E., additional, Kawamura, S., additional, and Nef, P., additional
- Published
- 1995
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27. Identification of a neuronal calcium sensor (NCS-1) possibly involved in the regulation of receptor phosphorylation
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Nef, S., primary, Fiumelli, H., additional, de Castro, E., additional, Raest, M.-B., additional, and Nef, P., additional
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- 1995
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28. Hormones in male sexual development.
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Nef, S and Parada, L F
- Abstract
Classical embryology has provided a clear view of the timing and hormonal cues that govern sexual differentiation. Molecular biology has added important details to this picture. The cloning of SRY, MIS, and INSL3 provide insight into the molecular signals that provide important cues at the cellular level. Continued understanding of these pathways may provide the necessary information to one day reverse defects of sexual differentiation.
- Published
- 2000
29. Olfaction in birds: differential embryonic expression of nine putative odorant receptor genes in the avian olfactory system
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Nef, S., Allaman, I., Fiumelli, H., Castro, E. De, and Nef, P.
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- 1996
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30. In vitro differentiation of mouse pluripotent stem cells into corticosteroid-producing adrenocortical cells.
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Oikonomakos I, Tedesco M, Motamedi FJ, Peitzsch M, Nef S, Bornstein SR, Schedl A, Steenblock C, and Neirijnck Y
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- Animals, Mice, Adrenal Cortex cytology, Adrenal Cortex metabolism, Adrenocorticotropic Hormone metabolism, Adrenocorticotropic Hormone pharmacology, Steroidogenic Factor 1 metabolism, Steroidogenic Factor 1 genetics, Adrenal Cortex Hormones metabolism, Mouse Embryonic Stem Cells metabolism, Mouse Embryonic Stem Cells cytology, Angiotensin II pharmacology, Cells, Cultured, Cyclic AMP-Dependent Protein Kinases metabolism, Fibronectins metabolism, Cell Differentiation, Pluripotent Stem Cells metabolism, Pluripotent Stem Cells cytology
- Abstract
Directed differentiation of pluripotent stem cells into specialized cell types represents an invaluable tool for a wide range of applications. Here, we have exploited single-cell transcriptomic data to develop a stepwise in vitro differentiation system from mouse embryonic stem cells into adrenocortical cells. We show that during development, the adrenal primordium is embedded in an extracellular matrix containing tenascin and fibronectin. Culturing cells on fibronectin during differentiation increased the expression of the steroidogenic marker NR5A1. Furthermore, 3D cultures in the presence of protein kinase A (PKA)-pathway activators led to the formation of aggregates composed of different cell types expressing adrenal progenitor or steroidogenic markers, including the adrenocortical-specific enzyme CYP21A1. Importantly, in-vitro-differentiated cells responded to adrenocorticotropic hormone (ACTH) and angiotensin II with the production of glucocorticoids and mineralocorticoids, respectively, thus confirming the specificity of differentiation toward the adrenal lineage., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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31. Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse.
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Muroňová J, Kherraf ZE, Giordani E, Lambert E, Eckert S, Cazin C, Amiri-Yekta A, Court M, Chevalier G, Martinez G, Neirijnck Y, Kühne F, Wehrli L, Klena N, Hamel V, De Macedo L, Escoffier J, Guichard P, Coutton C, Mustapha SFB, Kharouf M, Bouin AP, Zouari R, Thierry-Mieg N, Nef S, Geimer S, Loeuillet C, Ray PF, and Arnoult C
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- Animals, Humans, Male, Mice, Centrioles, Mice, Knockout, Microtubule-Associated Proteins genetics, Semen, Abnormalities, Multiple, Infertility, Male genetics
- Abstract
From a cohort of 167 infertile patients suffering from multiple morphological abnormalities of the flagellum (MMAF), pathogenic bi-allelic mutations were identified in the CCDC146 gene. In somatic cells, CCDC146 is located at the centrosome and at multiple microtubule-related organelles during mitotic division, suggesting that it is a microtubule-associated protein (MAP). To decipher the molecular pathogenesis of infertility associated with CCDC146 mutations, a Ccdc146 knock-out (KO) mouse line was created. KO male mice were infertile, and sperm exhibited a phenotype identical to CCDC146 mutated patients. CCDC146 expression starts during late spermiogenesis. In the spermatozoon, the protein is conserved but is not localized to centrioles, unlike in somatic cells, rather it is present in the axoneme at the level of microtubule doublets. Expansion microscopy associated with the use of the detergent sarkosyl to solubilize microtubule doublets suggests that the protein may be a microtubule inner protein (MIP). At the subcellular level, the absence of CCDC146 impacted all microtubule-based organelles such as the manchette, the head-tail coupling apparatus (HTCA), and the axoneme. Through this study, a new genetic cause of infertility and a new factor in the formation and/or structure of the sperm axoneme were characterized., Competing Interests: JM, ZK, EG, EL, SE, CC, AA, MC, GC, GM, YN, FK, LW, NK, VH, LD, JE, PG, CC, SM, MK, AB, RZ, NT, SN, SG, CL, PR, CA No competing interests declared, (© 2023, Muroňová, Kherraf et al.)
- Published
- 2024
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32. Gonadotropin axis and semen quality in young Swiss men after cannabis consumption: Effect of chronicity and modulation by cannabidiol.
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Zufferey F, Buitrago E, Rahban R, Senn A, Stettler E, Rudaz S, Nef S, Donzé N, Thomas A, and Rossier MF
- Subjects
- Humans, Male, Semen Analysis, Dronabinol pharmacology, Switzerland, Seeds, Prolactin, Cannabis, Cannabidiol pharmacology
- Abstract
Background: While cannabis is the most widely used recreational drug in the world, the effects of phytocannabinoids on semen parameters and reproductive hormones remain controversial. Cannabinoid receptors are activated by these compounds at each level of the hypothalamus-pituitary-gonadotropic axis., Objectives: To assess the impact of the consumption of Δ-9-tetrahydrocannabinol and cannabidiol on semen parameters, as well as on male reproductive hormone and endocannabinoid levels, in a cohort of young Swiss men., Materials and Methods: The individuals in a Swiss cohort were divided according to their cannabis consumption. In the cannabis user group, we determined the delay between the last intake of cannabis and sample collection, the chronicity of use and the presence of cannabidiol in the consumed product. Urinary Δ-9-tetrahydrocannabinol metabolites were quantified via gas chromatography-mass spectrometry. Blood phytocannabinoids, endocannabinoids and male steroids were determined via liquid chromatography-mass spectrometry/mass spectrometry, and other hypothalamus-pituitary-gonadotropic axis hormones were determined via immunoassays. Semen parameters such as sperm concentration and motility were recorded using computer-assisted sperm analysis., Results: Anandamide, N-palmitoyl ethanolamide, androgens, estradiol and sex hormone binding globulin levels were all higher in cannabis users, particularly in chronic, recent and cannabidiol-positive consumers. Gonadotropin levels were not significantly different in these user subpopulations, whereas prolactin and albumin concentrations were lower. In addition, cannabis users had a more basic semen pH and a higher percentage of spermatozoa with progressive motility. However, the two latter observations seem to be related to a shorter period of sexual abstinence in this group rather than to the use of cannabis., Conclusions: Because both cannabidiol and Δ-9-tetrahydrocannabinol are frequently used by men of reproductive age, it is highly relevant to elucidate the potential effects they may have on human reproductive health. This study demonstrates that the mode of cannabis consumption must be considered when evaluating the effect of cannabis on semen quality., (© 2023 American Society of Andrology and European Academy of Andrology.)
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- 2024
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33. Loss of NR5A1 in mouse Sertoli cells after sex determination changes cellular identity and induces cell death by anoikis.
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Souali-Crespo S, Condrea D, Vernet N, Féret B, Klopfenstein M, Grandgirard E, Alunni V, Cerciat M, Jung M, Mayere C, Nef S, Mark M, Chalmel F, and Ghyselinck NB
- Subjects
- Animals, Male, Mice, Cell Death genetics, Testis metabolism, Anoikis genetics, Sertoli Cells metabolism
- Abstract
To investigate the role of the nuclear receptor NR5A1 in the testis after sex determination, we analyzed mice lacking NR5A1 in Sertoli cells (SCs) from embryonic day (E) 13.5 onwards. Ablation of Nr5a1 impaired the expression of genes characteristic of SC identity (e.g. Sox9 and Amh), caused SC death from E14.5 onwards through a Trp53-independent mechanism related to anoikis, and induced disorganization of the testis cords. Together, these effects caused germ cells to enter meiosis and die. Single-cell RNA-sequencing experiments revealed that NR5A1-deficient SCs changed their molecular identity: some acquired a 'pre-granulosa-like' cell identity, whereas other reverted to a 'supporting progenitor-like' cell identity, most of them being 'intersex' because they expressed both testicular and ovarian genes. Fetal Leydig cells (LCs) did not display significant changes, indicating that SCs are not required beyond E14.5 for their emergence or maintenance. In contrast, adult LCs were absent from postnatal testes. In addition, adult mutant males displayed persistence of Müllerian duct derivatives, decreased anogenital distance and reduced penis length, which could be explained by the loss of AMH and testosterone synthesis due to SC failure., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)
- Published
- 2023
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34. Association between self-reported mobile phone use and the semen quality of young men.
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Rahban R, Senn A, Nef S, and Rӧӧsli M
- Subjects
- Male, Humans, Adolescent, Young Adult, Adult, Semen, Sperm Motility, Prospective Studies, Self Report, Cross-Sectional Studies, Spermatozoa, Sperm Count, Semen Analysis, Cell Phone Use
- Abstract
Objectives: To investigate the association between mobile phone exposure and semen parameters., Design: A nationwide cross-sectional study., Setting: Andrology laboratories in close proximity to 6 army recruitment centers., Patients: In total, 2886 men from the general Swiss population, 18-22 years old, were recruited between 2005 and 2018 during military conscription., Intervention: Participants delivered a semen sample and completed a questionnaire on health and lifestyle, including the number of hours they spent using their mobile phones and where they placed them when not in use., Main Outcome Measures: Using logistic and multiple linear regression models, adjusted odds ratios and β coefficients were determined, respectively. The association between mobile phone exposure and semen parameters such as volume, sperm concentration, total sperm count (TSC), motility, and morphology was then evaluated., Results: A total of 2759 men answered the question concerning their mobile phone use, and 2764 gave details on the position of their mobile phone when not in use. In the adjusted linear model, a higher frequency of mobile phone use (>20 times per day) was associated with a lower sperm concentration (adjusted β: -0.152; 95% confidence interval: -0.316; 0.011) and a lower TSC (adjusted β: -0.271; 95% confidence interval: -0.515; -0.027). In the adjusted logistic regression model, this translates to a 30% and 21% increased risk for sperm concentration and TSC to be below the World Health Organization reference values for fertile men, respectively. This inverse association was found to be more pronounced in the first study period (2005-2007) and gradually decreased with time (2008-2011 and 2012-2018). No consistent associations were observed between mobile phone use and sperm motility or sperm morphology. Keeping a mobile phone in the pants pocket was not found to be associated with lower semen parameters., Conclusion: This large population-based study suggests that higher mobile phone use is associated with lower sperm concentration and TSC. The observed time trend of decreasing association is in line with the transition to new technologies and the corresponding decrease in mobile phone output power. Prospective studies with improved exposure assessment are needed to confirm whether the observed associations are causal., Competing Interests: Declaration of interests R.R. has nothing to disclose. A.S. has nothing to disclose. S.N. reports funding from Swiss Center for Applied Human Toxicology (SCAHT) and University of Geneva for the submitted work. M.R. reports funding from the Federal Office for the Environment, Federal Office for Health, the World Health Organization, and the Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail, France, outside of the submitted work; as well as consulting fees from the Swedish Radiation Authority., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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35. The -KTS splice variant of WT1 is essential for ovarian determination in mice.
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Gregoire EP, De Cian MC, Migale R, Perea-Gomez A, Schaub S, Bellido-Carreras N, Stévant I, Mayère C, Neirijnck Y, Loubat A, Rivaud P, Sopena ML, Lachambre S, Linssen MM, Hohenstein P, Lovell-Badge R, Nef S, Chalmel F, Schedl A, and Chaboissier MC
- Subjects
- Animals, Female, Male, Mice, Sex-Determining Region Y Protein genetics, Sex-Determining Region Y Protein metabolism, Testis growth & development, Protein Isoforms, Ovary growth & development, Sex Determination Processes genetics, WT1 Proteins genetics, WT1 Proteins metabolism
- Abstract
Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pregranulosa cells that govern testis and ovary development, respectively. Although the Y-linked testis-determining gene Sry has been identified, the ovarian-determining factor remains unknown. In this study, we identified -KTS, a major, alternatively spliced isoform of the Wilms tumor suppressor WT1, as a key determinant of female sex determination. Loss of - KTS variants blocked gonadal differentiation in mice, whereas increased expression, as found in Frasier syndrome, induced precocious differentiation of ovaries independently of their genetic sex. In XY embryos, this antagonized Sry expression, resulting in male-to-female sex reversal. Our results identify -KTS as an ovarian-determining factor and demonstrate that its time of activation is critical in gonadal sex differentiation.
- Published
- 2023
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36. The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm.
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Wehrli L, Galdadas I, Voirol L, Smieško M, Cambet Y, Jaquet V, Guerrier S, Gervasio FL, Nef S, and Rahban R
- Abstract
The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca
2+ concentration ([Ca2+ ]i ) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput screening (HTS) assay to measure changes in [Ca2+ ]i in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca2+ ]i and reduced the P4-induced Ca2+ influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and P4-inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm acrosome reaction (AR) and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiologically relevant concentrations within the nanomolar range. Like P4, most tested steroids did not significantly affect the AR while stanozolol and estropipate slightly increased sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen in silico for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and if bound to CatSper prior to P4, could impair the timely CatSper activation necessary for proper fertilization to occur., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wehrli, Galdadas, Voirol, Smieško, Cambet, Jaquet, Guerrier, Gervasio, Nef and Rahban.)- Published
- 2023
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37. Low-polarity untargeted metabolomic profiling as a tool to gain insight into seminal fluid.
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Olesti E, Boccard J, Rahban R, Girel S, Moskaleva NE, Zufferey F, Rossier MF, Nef S, Rudaz S, and González-Ruiz V
- Subjects
- Humans, Male, Metabolomics methods, Spermatozoa metabolism, Sperm Count, Semen Analysis, Semen metabolism
- Abstract
Introduction: A decrease in sperm cell count has been observed along the last several decades, especially in the most developed regions of the world. The use of metabolomics to study the composition of the seminal fluid is a promising approach to gain access to the molecular mechanisms underlying this fact., Objectives: In the present work, we aimed at relating metabolomic profiles of young healthy men to their semen quality parameters obtained from conventional microscopic analysis., Methods: An untargeted metabolomics approach focusing on low- to mid-polarity compounds was used to analyze a subset of seminal fluid samples from a cohort of over 2700 young healthy men., Results: Our results show that a broad metabolic profiling comprising several families of compounds (including acyl-carnitines, steroids, and other lipids) can contribute to effectively distinguish samples provided by individuals exhibiting low or high absolute sperm counts., Conclusion: A number of metabolites involved in sexual development and function, signaling, and energy metabolism were highlighted as being distinctive of samples coming from either group, proving untargeted metabolomics as a promising tool to better understand the pathophysiological processes responsible for male fertility impairment., (© 2023. The Author(s).)
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- 2023
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38. Single-cell transcriptomic profiling redefines the origin and specification of early adrenogonadal progenitors.
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Neirijnck Y, Sararols P, Kühne F, Mayère C, Weerasinghe Arachchige LC, Regard V, Nef S, and Schedl A
- Subjects
- Mice, Animals, Cell Lineage genetics, Cell Differentiation genetics, Gene Expression Profiling, Mammals, Transcriptome genetics, Gonads metabolism
- Abstract
Adrenal cortex and gonads represent the two major steroidogenic organs in mammals. Both tissues are considered to share a common developmental origin characterized by the expression of Nr5a1/Sf1. The precise origin of adrenogonadal progenitors and the processes driving differentiation toward the adrenal or gonadal fate remain, however, elusive. Here, we provide a comprehensive single-cell transcriptomic atlas of early mouse adrenogonadal development including 52 cell types belonging to twelve major cell lineages. Trajectory reconstruction reveals that adrenogonadal cells emerge from the lateral plate rather than the intermediate mesoderm. Surprisingly, we find that gonadal and adrenal fates have already diverged prior to Nr5a1 expression. Finally, lineage separation into gonadal and adrenal fates involves canonical versus non-canonical Wnt signaling and differential expression of Hox patterning genes. Thus, our study provides important insights into the molecular programs of adrenal and gonadal fate choice and will be a valuable resource for further research into adrenogonadal ontogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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39. The RNA binding protein DND1 is elevated in a subpopulation of pro-spermatogonia and targets chromatin modifiers and translational machinery during late gestation.
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Ruthig VA, Hatkevich T, Hardy J, Friedersdorf MB, Mayère C, Nef S, Keene JD, and Capel B
- Subjects
- Animals, Female, Male, Mice, Pregnancy, Chromatin metabolism, Neoplasm Proteins genetics, RNA-Binding Proteins genetics, Spermatogonia metabolism, Zebrafish genetics, Zebrafish metabolism
- Abstract
DND1 is essential to maintain germ cell identity. Loss of Dnd1 function results in germ cell differentiation to teratomas in some inbred strains of mice or to somatic fates in zebrafish. Using our knock-in mouse line in which a functional fusion protein between DND1 and GFP is expressed from the endogenous locus (Dnd1GFP), we distinguished two male germ cell (MGC) populations during late gestation cell cycle arrest (G0), consistent with recent reports of heterogeneity among MGCs. Most MGCs express lower levels of DND1-GFP (DND1-GFP-lo), but some MGCs express elevated levels of DND1-GFP (DND1-GFP-hi). A RNA-seq time course confirmed high Dnd1 transcript levels in DND1-GFP-hi cells along with 5-10-fold higher levels for multiple epigenetic regulators. Using antibodies against DND1-GFP for RNA immunoprecipitation (RIP)-sequencing, we identified multiple epigenetic and translational regulators that are binding targets of DND1 during G0 including DNA methyltransferases (Dnmts), histone deacetylases (Hdacs), Tudor domain proteins (Tdrds), actin dependent regulators (Smarcs), and a group of ribosomal and Golgi proteins. These data suggest that in DND1-GFP-hi cells, DND1 hosts coordinating mRNA regulons that consist of functionally related and localized groups of epigenetic enzymes and translational components., Competing Interests: The authors have no competing interests to disclose., (Copyright: © 2023 Ruthig et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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40. Mutations in STARD8 (DLC3) May Cause 46,XY Gonadal Dysgenesis.
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Sirokha D, Rayevsky A, Gorodna O, Kalynovskyi V, Zelinska N, Samson O, Kwiatkowska K, Nef S, Jaruzelska J, Kusz-Zamelczyk K, and Livshits L
- Abstract
Introduction: 46,XY gonadal dysgenesis is a condition that is characterised by undeveloped testes in individuals with a male karyotype. Mutations in many genes that underlie this condition have been identified; however, there are still a considerable number of patients with an unknown genetic background. Recently, a mutation in the STARD8 X-linked gene in two sisters with 46,XY gonadal dysgenesis has been reported. It was localised within the START domain, whose homologue in Drosophila is responsible for maintaining testes integrity during their development., Methods: We analysed the potential pathogenicity of another STARD8 mutation, p.R887C, that was identified in a patient with 46,XY asymmetric gonadal dysgenesis. For this purpose, molecular dynamics simulations were performed., Results: These simulations revealed the full rearrangement of the helix containing the p.R887C substitution upstream from the START domain, which may cause STARD8 protein dysfunction and contribute to 46,XY gonadal dysgenesis. A comparison of the phenotypes of the three described 46,XY gonadal dysgenesis patients that harbour STARD8 mutations indicated that alterations of this gene can result in a partial or complete gonadal dysgenesis phenotype., Conclusion: Based on these and previous results, it is reasonable to include STARD8 in gene panels for 46,XY gonadal dysgenesis., (© 2024 S. Karger AG, Basel.)
- Published
- 2023
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41. A conserved function of Human DLC3 and Drosophila Cv-c in testis development.
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Sotillos S, von der Decken I, Domenech Mercadé I, Srinivasan S, Sirokha D, Livshits L, Vanni S, Nef S, Biason-Lauber A, Rodríguez Gutiérrez D, and Castelli-Gair Hombría J
- Subjects
- Animals, Humans, Male, Drosophila, Germ Cells, GTPase-Activating Proteins genetics, Sex Differentiation, Testis, Drosophila Proteins genetics, Gonadal Dysgenesis
- Abstract
The identification of genes affecting gonad development is essential to understand the mechanisms causing Variations/Differences in Sex Development (DSD). Recently, a DLC3 mutation was associated with male gonadal dysgenesis in 46,XY DSD patients. We have studied the requirement of Cv-c, the Drosophila ortholog of DLC3, in Drosophila gonad development, as well as the functional capacity of DLC3 human variants to rescue cv-c gonad defects. We show that Cv-c is required to maintain testis integrity during fly development. We find that Cv-c and human DLC3 can perform the same function in fly embryos, as flies carrying wild type but not patient DLC3 variations can rescue gonadal dysgenesis, suggesting functional conservation. We also demonstrate that the StART domain mediates Cv-c's function in the male gonad independently from the GAP domain's activity. This work demonstrates a role for DLC3/Cv-c in male gonadogenesis and highlights a novel StART domain mediated function required to organize the gonadal mesoderm and maintain its interaction with the germ cells during testis development., Competing Interests: SS, Iv, ID, SS, DS, LL, SV, SN, AB, DR, JC No competing interests declared, (© 2022, Sotillos et al.)
- Published
- 2022
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42. TRIM28-dependent SUMOylation protects the adult ovary from activation of the testicular pathway.
- Author
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Rossitto M, Déjardin S, Rands CM, Le Gras S, Migale R, Rafiee MR, Neirijnck Y, Pruvost A, Nguyen AL, Bossis G, Cammas F, Le Gallic L, Wilhelm D, Lovell-Badge R, Boizet-Bonhoure B, Nef S, and Poulat F
- Subjects
- Animals, Female, Male, Mammals metabolism, Mice, Sertoli Cells metabolism, Testis metabolism, Transcription Factors genetics, Transcription Factors metabolism, Tripartite Motif-Containing Protein 28 genetics, Tripartite Motif-Containing Protein 28 metabolism, Ovary metabolism, Sumoylation
- Abstract
Gonadal sexual fate in mammals is determined during embryonic development and must be actively maintained in adulthood. In the mouse ovary, oestrogen receptors and FOXL2 protect ovarian granulosa cells from transdifferentiation into Sertoli cells, their testicular counterpart. However, the mechanism underlying their protective effect is unknown. Here, we show that TRIM28 is required to prevent female-to-male sex reversal of the mouse ovary after birth. We found that upon loss of Trim28, ovarian granulosa cells transdifferentiate to Sertoli cells through an intermediate cell type, different from gonadal embryonic progenitors. TRIM28 is recruited on chromatin in the proximity of FOXL2 to maintain the ovarian pathway and to repress testicular-specific genes. The role of TRIM28 in ovarian maintenance depends on its E3-SUMO ligase activity that regulates the sex-specific SUMOylation profile of ovarian-specific genes. Our study identifies TRIM28 as a key factor in protecting the adult ovary from the testicular pathway., (© 2022. The Author(s).)
- Published
- 2022
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43. Deciphering the origins and fates of steroidogenic lineages in the mouse testis.
- Author
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Ademi H, Djari C, Mayère C, Neirijnck Y, Sararols P, Rands CM, Stévant I, Conne B, and Nef S
- Subjects
- Androgens, Animals, Cell Differentiation, Fetus, Male, Mice, Leydig Cells, Testis
- Abstract
Leydig cells (LCs) are the major androgen-producing cells in the testis. They arise from steroidogenic progenitors (SPs), whose origins, maintenance, and differentiation dynamics remain largely unknown. Single-cell transcriptomics reveal that the mouse steroidogenic lineage is specified as early as embryonic day 12.5 (E12.5) and has a dual mesonephric and coelomic origin. SPs specifically express the Wnt5a gene and evolve rapidly. At E12.5 and E13.5, they give rise first to an intermediate population of pre-LCs, and finally to fetal LCs. At E16.5, SPs possess the characteristics of the dormant progenitors at the origin of adult LCs and are also transcriptionally closely related to peritubular myoid cells (PMCs). In agreement with our in silico analysis, in vivo lineage tracing indicates that Wnt5a-expressing cells are bona fide progenitors of PMCs as well as fetal and adult LCs, contributing to most of the LCs present in the fetal and adult testis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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44. Origin, specification and differentiation of a rare supporting-like lineage in the developing mouse gonad.
- Author
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Mayère C, Regard V, Perea-Gomez A, Bunce C, Neirijnck Y, Djari C, Bellido-Carreras N, Sararols P, Reeves R, Greenaway S, Simon M, Siggers P, Condrea D, Kühne F, Gantar I, Tang F, Stévant I, Batti L, Ghyselinck NB, Wilhelm D, Greenfield A, Capel B, Chaboissier MC, and Nef S
- Abstract
Gonadal sex determination represents a unique model for studying cell fate decisions. However, a complete understanding of the different cell lineages forming the developing testis and ovary remains elusive. Here, we investigated the origin, specification, and subsequent sex-specific differentiation of a previously uncharacterized population of supporting-like cells (SLCs) in the developing mouse gonads. The SLC lineage is closely related to the coelomic epithelium and specified as early as E10.5, making it the first somatic lineage to be specified in the bipotential gonad. SLC progenitors are localized within the genital ridge at the interface with the mesonephros and initially coexpress Wnt4 and Sox9 . SLCs become sexually dimorphic around E12.5, progressively acquire a more Sertoli- or pregranulosa-like identity and contribute to the formation of the rete testis and rete ovarii. Last, we found that WNT4 is a crucial regulator of the SLC lineage and is required for normal development of the rete testis.
- Published
- 2022
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45. Oligogenic heterozygous inheritance of sperm abnormalities in mouse.
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Martinez G, Coutton C, Loeuillet C, Cazin C, Muroňová J, Boguenet M, Lambert E, Dhellemmes M, Chevalier G, Hograindleur JP, Vilpreux C, Neirijnck Y, Kherraf ZE, Escoffier J, Nef S, Ray PF, and Arnoult C
- Subjects
- Humans, Male, Multifactorial Inheritance, Mutation, Sperm Tail, Spermatozoa, Abnormalities, Multiple genetics, Asthenozoospermia genetics, Infertility, Male genetics
- Abstract
Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects - the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man., Competing Interests: GM, CC, CL, CC, JM, MB, EL, MD, GC, JH, CV, YN, ZK, JE, SN, PR, CA No competing interests declared, (© 2022, Martinez et al.)
- Published
- 2022
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46. Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors.
- Author
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Graf M, Interlandi M, Moreno N, Holdhof D, Göbel C, Melcher V, Mertins J, Albert TK, Kastrati D, Alfert A, Holsten T, de Faria F, Meisterernst M, Rossig C, Warmuth-Metz M, Nowak J, Meyer Zu Hörste G, Mayère C, Nef S, Johann P, Frühwald MC, Dugas M, Schüller U, and Kerl K
- Subjects
- Animals, Germ Cells pathology, Humans, Mice, SMARCB1 Protein genetics, Single-Cell Analysis, Transcriptome, Rhabdoid Tumor genetics, Rhabdoid Tumor pathology
- Abstract
Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease., (© 2022. The Author(s).)
- Published
- 2022
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47. Loss of NEDD4 causes complete XY gonadal sex reversal in mice.
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Windley SP, Mayère C, McGovern AE, Harvey NL, Nef S, Schwarz Q, Kumar S, and Wilhelm D
- Subjects
- Animals, Cell Differentiation physiology, Female, Gene Expression Regulation, Developmental, Male, Mammals, Mice, Mice, Knockout, Ovary metabolism, SOX9 Transcription Factor metabolism, Testis metabolism, 46, XX Testicular Disorders of Sex Development, Gonads, Nedd4 Ubiquitin Protein Ligases metabolism
- Abstract
Gonadogenesis is the process wherein two morphologically distinct organs, the testis and the ovary, arise from a common precursor. In mammals, maleness is driven by the expression of Sry. SRY subsequently upregulates the related family member Sox9 which is responsible for initiating testis differentiation while repressing factors critical to ovarian development such as FOXL2 and β-catenin. Here, we report a hitherto uncharacterised role for the ubiquitin-protein ligase NEDD4 in this process. XY Nedd4-deficient mice exhibit complete male-to-female gonadal sex reversal shown by the ectopic upregulation of Foxl2 expression at the time of gonadal sex determination as well as insufficient upregulation of Sox9. This sex reversal extends to germ cells with ectopic expression of SYCP3 in XY Nedd4-/- germ cells and significantly higher Sycp3 transcripts in XY and XX Nedd4-deficient mice when compared to both XY and XX controls. Further, Nedd4-/- mice exhibit reduced gonadal precursor cell formation and gonadal size as a result of reduced proliferation within the developing gonad as well as reduced Nr5a1 expression. Together, these results establish an essential role for NEDD4 in XY gonadal sex determination and development and suggest a potential role for NEDD4 in orchestrating these cell fate decisions through the suppression of the female pathway to ensure proper testis differentiation., (© 2022. Crown.)
- Published
- 2022
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48. Combined Use of Whole Exome Sequencing and CRISPR/Cas9 to Study the Etiology of Non-Obstructive Azoospermia: Demonstration of the Dispensable Role of the Testis-Specific Genes C1orf185 and CCT6B .
- Author
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Cazin C, Neirijnck Y, Loeuillet C, Wehrli L, Kühne F, Lordey I, Mustapha SFB, Bouker A, Zouari R, Thierry-Mieg N, Nef S, Arnoult C, Ray PF, and Kherraf ZE
- Subjects
- Azoospermia physiopathology, Humans, Male, Azoospermia etiology, CRISPR-Cas Systems genetics, Chaperonin Containing TCP-1 genetics, Testis metabolism, Exome Sequencing methods
- Abstract
The genetic landscape of male infertility is highly complex. It is estimated that at least 4000 genes are involved in human spermatogenesis, but only few have so far been extensively studied. In this study, we investigated by whole exome sequencing two cases of idiopathic non-obstructive azoospermia (NOA) due to severe hypospermatogenesis. After variant filtering and prioritizing, we retained for each patient a homozygous loss-of-function (LoF) variant in a testis-specific gene, C1orf185 (c.250C>T; p.Gln84Ter) and CCT6B (c.615-2A>G), respectively. Both variants are rare according to the gnomAD database and absent from our local control cohort ( n = 445). To verify the implication of these candidate genes in NOA, we used the CRISPR/Cas9 system to invalidate the mouse orthologs 4930522H14Rik and Cct6b and produced two knockout (KO) mouse lines. Sperm and testis parameters of homozygous KO adult male mice were analyzed and compared with those of wild-type animals. We showed that homozygous KO males were fertile and displayed normal sperm parameters and a functional spermatogenesis. Overall, these results demonstrate that not all genes highly and specifically expressed in the testes are essential for spermatogenesis, and in particular, we conclude that bi-allelic variants of C1orf185 and CCT6B are most likely not to be involved in NOA and male fertility.
- Published
- 2021
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49. A Novel WT1 Mutation Identified in a 46,XX Testicular/Ovotesticular DSD Patient Results in the Retention of Intron 9.
- Author
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Sirokha D, Gorodna O, Vitrenko Y, Zelinska N, Ploski R, Nef S, Jaruzelska J, Kusz-Zamelczyk K, and Livshits L
- Abstract
The 46,XX testicular DSD (disorder/difference of sexual development) and 46,XX ovotesticular DSD (46,XX TDSD and 46,XX OTDSD) phenotypes are caused by genetic rearrangements or point mutations resulting in imbalance between components of the two antagonistic, pro-testicular and pro-ovarian pathways; however, the genetic causes of 46,XX TDSD/OTDSD are not fully understood, and molecular diagnosis for many patients with the conditions is unavailable. Only recently few mutations in the WT1 ( WT1 transcription factor; 11p13) gene were described in a group of 46,XX TDSD and 46,XX OTDSD individuals. The WT1 protein contains a DNA/RNA binding domain consisting of four zinc fingers (ZnF) and a three-amino acid (KTS) motif that is present or absent, as a result of alternative splicing, between ZnF3 and ZnF4 (±KTS isoforms). Here, we present a patient with 46,XX TDSD/OTDSD in whom whole exome sequencing revealed a heterozygous de novo WT1 c.1437A>G mutation within an alternative donor splice site which is used for -KTS WT1 isoform formation. So far, no mutation in this splice site has been identified in any patient group. We demonstrated that the mutation results in the retention of intron 9 in the mature mRNA of the 46,XX TDSD/OTDSD patient. In cases when the erroneous mRNA is translated, exclusively the expression of a truncated WT1 +KTS protein lacking ZnF4 and no -KTS protein occurs from the mutated allele of the patient. We discuss potential mechanisms and pathways which can be disturbed upon two conditions: Absence of Zn4F and altered +KTS/-KTS ratio.
- Published
- 2021
- Full Text
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50. The antidepressant Sertraline inhibits CatSper Ca2+ channels in human sperm.
- Author
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Rahban R, Rehfeld A, Schiffer C, Brenker C, Egeberg Palme DL, Wang T, Lorenz J, Almstrup K, Skakkebaek NE, Strünker T, and Nef S
- Subjects
- Antidepressive Agents metabolism, Antidepressive Agents pharmacology, Calcium Channels metabolism, Calcium Signaling, Humans, Male, Progesterone pharmacology, Sperm Motility, Spermatozoa metabolism, Calcium metabolism, Sertraline metabolism, Sertraline pharmacology
- Abstract
Study Question: Do selective serotonin reuptake inhibitor (SSRI) antidepressants affect the function of human sperm?, Summary Answer: The SSRI antidepressant Sertraline (e.g. Zoloft) inhibits the sperm-specific Ca2+ channel CatSper and affects human sperm function in vitro., What Is Known Already: In human sperm, CatSper translates changes of the chemical microenvironment into changes of the intracellular Ca2+ concentration ([Ca2+]i) and swimming behavior. CatSper is promiscuously activated by oviductal ligands, but also by synthetic chemicals that might disturb the fertilization process. It is well known that SSRIs have off-target actions on Ca2+, Na+ and K+ channels in somatic cells. Whether SSRIs affect the activity of CatSper is, however, unknown., Study Design, Size, Duration: We studied the action of the seven drugs belonging to the most commonly prescribed class of antidepressants, SSRIs, on resting [Ca2+]i and Ca2+ influx via CatSper in human sperm. The SSRI Sertraline was selected for in-depth analysis of its action on steroid-, prostaglandin-, pH- and voltage-activation of human CatSper. Moreover, the action of Sertraline on sperm acrosomal exocytosis and penetration into viscous media was evaluated., Participants/materials, Setting, Methods: The activity of CatSper was investigated in sperm of healthy volunteers, using kinetic Ca2+ fluorimetry and patch-clamp recordings. Acrosomal exocytosis was investigated using Pisum sativum agglutinin and image cytometry. Sperm penetration in viscous media was evaluated using the Kremer test., Main Results and the Role of Chance: Several SSRIs affected [Ca2+]i and attenuated ligand-induced Ca2+ influx via CatSper. In particular, the SSRI Sertraline almost completely suppressed Ca2+ influx via CatSper. Remarkably, the drug was about four-fold more potent to suppress prostaglandin- versus steroid-induced Ca2+ influx. Sertraline also suppressed alkaline- and voltage-activation of CatSper, indicating that the drug directly inhibits the channel. Finally, Sertraline impaired ligand-induced acrosome reaction and sperm penetration into viscous media., Limitations, Reasons for Caution: This is an in vitro study. Future studies have to assess the physiological relevance in vivo., Wider Implications of the Findings: The off-target action of Sertraline on CatSper in human sperm might impair the fertilization process. In a research setting, Sertraline may be used to selectively inhibit prostaglandin-induced Ca2+ influx., Study Funding/competing Interest(s): This work was supported by the Swiss Centre for Applied Human Toxicology (SCAHT), the Département de l'Instruction Publique of the State of Geneva, the German Research Foundation (CRU326), the Interdisciplinary Center for Clinical Research, Münster (IZKF; Str/014/21), the Innovation Fund Denmark (grant numbers 14-2013-4) and the EDMaRC research grant from the Kirsten and Freddy Johansen's Foundation. The authors declare that no conflict of interest could be perceived as prejudicing the impartiality of the research reported., Trial Registration Number: NA., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)
- Published
- 2021
- Full Text
- View/download PDF
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