304. DECIDUAL HtrA3 NEGATIVELY REGULATES TROPHOBLAST INVASION

2010 ◽  
Vol 22 (9) ◽  
pp. 104
Author(s):  
H. Singh ◽  
S. Makino ◽  
Y. Endo ◽  
G. Nie
Keyword(s):  
Western Blotting ◽  
Protease Activity ◽  
Specific Inhibitor ◽  
First Trimester ◽  
Dominant Negative ◽  
Trophoblast Invasion ◽  
Wild Type ◽  
Placental Development ◽  
Endometrial Stromal Cells ◽  
Decidual Cells

Controlled trophoblast invasion cell into the maternal decidua (interstitial invasion) is important for placental development. Abnormalities in the invasion process may lead to pregnancy complications. Decidua secrets many factors to control trophoblast invasion. Serine protease HtrA3 is highly expressed in the decidual cells in the late secretory phase of the menstrual cycle and throughout pregnancy. It is highly expressed in first trimester in most trophoblast cell types, but not in the invading interstitial trophoblast. HtrA3 and its family members are down-regulated in a number of cancers and are proposed as tumor suppressors. We hypothesized that HtrA3 is an inhibitor of trophoblast invasion. The current study aimed to investigate whether HtrA3 secreted by decidual cells regulates trophoblast invasion. Human endometrial stromal cells (HESC) were decidualised with estradial, medroxyprogesterone acetate and cyclic AMP. Real-time RT-PCR, western blotting and immunocytochemistry demonstrated that decidualisation increased HtrA3 mRNA and protein expression. HtrA3 was also detected by western blotting in the conditioned media (CM) of decidualised HESC (96h), confirming its secretory nature. For functional studies, wild type and protease inactive mutant HtrA3 were produced using wheat germ cell-free technology. The mutant has negligible protease activity and significantly inhibited the wild type protease activity, supporting its dominant-negative inhibition and utility as a specific inhibitor of the wild type protein. CM of decidualised HESC suppressed invasion of trophoblast HTR-8 cells, whereas inhibition of HtrA3 in the decidual HESC CM by exogeneous addition of HtrA3 mutant increased trophoblast HTR-8 cell invasion. These results strongly support our hypothesis that decidual HtrA3 negatively regulates trophobalst invasion.

scholarly journals Progesterone-Dependent Induction of Phospholipase C-Related Catalytically Inactive Protein 1 (PRIP-1) in Decidualizing Human Endometrial Stromal Cells

Endocrinology ◽  
2016 ◽  
Vol 157 (7) ◽  
pp. 2883-2893 ◽  
Author(s):  
Joanne Muter ◽  
Paul J. Brighton ◽  
Emma S. Lucas ◽  
Lauren Lacey ◽  
Anatoly Shmygol ◽  
...  
Keyword(s):  
Phospholipase C ◽  
Stromal Cells ◽  
Nuclear Translocation ◽  
Scaffold Protein ◽  
Trophoblast Invasion ◽  
Differentiation Markers ◽  
Endometrial Stromal Cells ◽  
Decidual Cells ◽  
Phosphoinositide 3 Kinase ◽  
Inactive Protein

Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells. In pregnancy, decidual cells form a protective matrix around the implanting embryo, enabling coordinated trophoblast invasion and formation of a functional placenta. Continuous progesterone (P4) signaling renders decidual cells resistant to various environmental stressors, whereas withdrawal inevitably triggers tissue breakdown and menstruation or miscarriage. Here, we show that PLCL1, coding phospholipase C (PLC)-related catalytically inactive protein 1 (PRIP-1), is highly induced in response to P4 signaling in decidualizing human endometrial stromal cells (HESCs). Knockdown experiments in undifferentiated HESCs revealed that PRIP-1 maintains basal phosphoinositide 3-kinase/Protein kinase B activity, which in turn prevents illicit nuclear translocation of the transcription factor forkhead box protein O1 and induction of the apoptotic activator BIM. By contrast, loss of this scaffold protein did not compromise survival of decidual cells. PRIP-1 knockdown did also not interfere with the responsiveness of HESCs to deciduogenic cues, although the overall expression of differentiation markers, such as PRL, IGFBP1, and WNT4, was blunted. Finally, we show that PRIP-1 in decidual cells uncouples PLC activation from intracellular Ca2+ release by attenuating inositol 1,4,5-trisphosphate signaling. In summary, PRIP-1 is a multifaceted P4-inducible scaffold protein that gates the activity of major signal transduction pathways in the endometrium. It prevents apoptosis of proliferating stromal cells and contributes to the relative autonomy of decidual cells by silencing PLC signaling downstream of Gq protein-coupled receptors.

scholarly journals MEF2 transcription factors in human placenta and involvement in cytotrophoblast invasion and differentiation

2018 ◽  
Vol 50 (1) ◽  
pp. 10-19 ◽  
Author(s):  
Lucy Li ◽  
Lewis P. Rubin ◽  
Xiaoming Gong
Keyword(s):  
Transcription Factors ◽  
Human Placenta ◽  
Cellular Proliferation ◽  
Cell Types ◽  
Dominant Negative ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Cytotrophoblast Cell ◽  
Adverse Pregnancy

Development of the human placenta and its trophoblast cell types is critical for a successful pregnancy. Defects in trophoblast invasion and differentiation are associated with adverse pregnancy outcomes, including preeclampsia. The members of myocyte enhancer factor-2 (MEF2) family of transcription factors are key regulators of cellular proliferation, differentiation, and invasion in various cell types and tissues and might play a similarly important role in regulating trophoblast proliferation, invasion, and differentiation during human placental development. In the present study, using human cytotrophoblast cell lines (HTR8/SVneo and BeWo) and primary human cytotrophoblasts (CTBs), we show that members of the MEF2 family are differentially expressed in human placental CTBs, with MEF2B and MEF2D being highly expressed in first trimester extravillous CTBs. Overexpression of MEF2D results in cytotrophoblast proliferation and enhances the invasion and migration of extravillous-like HTR8/SVneo cells. This invasive property is blocked by overexpression of a dominant negative MEF2 (dnMEF2). In contrast, MEF2A is the principal MEF2 isoform expressed in term CTBs, MEF2C and MEF2D being expressed more weakly, and MEF2B expression being undetected. Overexpression of MEF2A induces cytotrophoblast differentiation and syncytium formation in BeWo cells. During in vitro differentiation of primary CTBs, MEF2A expression is associated with CTB differentiation into syncytiotrophoblast. Additionally, the course of p38 MAPK and ERK5 activities parallels the increase in MEF2A expression. These findings suggest individual members of MEF2 family distinctively regulate cytotrophoblast proliferation, invasion, and differentiation. Dysregulation of expression of MEF2 family or of their upstream signaling pathways may be associated with placenta-related pregnancy disorders.

scholarly journals Effects of adiponectin on human trophoblast invasion

2010 ◽  
Vol 207 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Delphine Benaitreau ◽  
Esther Dos Santos ◽  
Marie-Christine Leneveu ◽  
Nadia Alfaidy ◽  
Jean-Jacques Feige ◽  
...  
Keyword(s):  
First Trimester ◽  
Extravillous Trophoblast ◽  
Trophoblast Invasion ◽  
Placental Development ◽  
Independent Manner ◽  
Human Trophoblast ◽  
Pathological Conditions ◽  
First Trimester Of Pregnancy ◽  
Insight Into

Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory, anti-atherogenic, and anti-proliferative effects. The expression of specific adiponectin receptors in the placenta and in the endometrium suggests a role for this cytokine in placental development, but this role has not yet been elucidated. The invasion of trophoblast cells during the first trimester of pregnancy being crucial to placentation process, we have studied adiponectin effects on human trophoblast invasive capacities. We found that adiponectin stimulated human trophoblast cell migration in HTR-8/SVneo cells in a dose-independent manner. In addition, adiponectin also significantly enhanced invasion of HTR-8/SVneo cells and of human extravillous trophoblast from first trimester placenta. These pro-invasive effects of adiponectin in human trophoblasts seem to be mediated in part via increased matrix metalloproteinases (MMP2 and MMP9) activities and via repression of TIMP2 mRNA expression. Our results suggest that adiponectin could be a positive regulator of the early invasion process by modulating the MMP/TIMP balance. Moreover, these results provide an insight into the role of adiponectin in pathological conditions characterized by insufficient or excessive trophoblast invasion.

scholarly journals Exometabolomic analysis of decidualizing human endometrial stromal and perivascular cells

2020 ◽  
Author(s):  
Sarah Harden ◽  
Jieliang Zhou ◽  
Maria Diniz-da-Costa ◽  
Emma S. Lucas ◽  
Liang Cui ◽  
...  
Keyword(s):  
Time Course ◽  
Embryo Implantation ◽  
Cellular Reprogramming ◽  
Trophoblast Invasion ◽  
Perivascular Cells ◽  
Endometrial Stromal Cells ◽  
Signalling Molecules ◽  
Spatiotemporal Information ◽  
Decidual Cells ◽  
Acid Metabolites

ABSTRACTDifferentiation of endometrial fibroblasts into specialized decidual cells controls embryo implantation and transforms the cycling endometrium into a semi-permanent, immune-protective matrix that accommodates the placenta throughout pregnancy. This process starts during the midluteal phase of the menstrual cycle with decidual transformation of perivascular cells (PVC) surrounding the terminal spiral arterioles and endometrial stromal cells (EnSC) underlying the luminal epithelium. Decidualization involves extensive cellular reprogramming and acquisition of a secretory phenotype, essential for coordinated placental trophoblast invasion. Secreted metabolites are an emerging class of signalling molecules. Here, we used liquid chromatography-mass spectrometry to characterise the dynamic changes in metabolite secretion (exometabolome) of primary PVC and EnSC decidualized over 8 days. We identified 79 annotated metabolites differentially secreted upon decidualization, including prostaglandin, sphingolipid, and hyaluronic acid metabolites. Secreted metabolites encompassed 21 metabolic pathways, most prominently glycerolipid and pyrimidine metabolism. Although temporal exometabolome changes were comparable between decidualizing PVC and EnSC, 32 metabolites were differentially secreted across the decidualization time-course. Further, targeted metabolomics demonstrated a conspicuous difference in xanthine secretion between decidualized PVC and EnSC. Taken together, our findings indicate that the metabolic footprints generated by different decidual subpopulations encode spatiotemporal information that may be important for optimal embryo implantation.

scholarly journals Temporal Changes of the Endothelin System in Human Cytotrophoblasts During the First Trimester of Pregnancy

2018 ◽  
pp. S247-S255 ◽  
Author(s):  
A. MAJALI-MARTINEZ ◽  
S. BARTH ◽  
U. LANG ◽  
G. DESOYE ◽  
M. CERVAR-ZIVKOVIC
Keyword(s):  
First Trimester ◽  
Temporal Changes ◽  
Trophoblast Invasion ◽  
Receptor Subtypes ◽  
Placental Development ◽  
Receptor System ◽  
Tissue Samples ◽  
Endothelin System ◽  
First Trimester Of Pregnancy ◽  
Proliferation And Invasion

The first trimester of pregnancy is characterized by continuous proliferation, invasion and differentiation of cytotrophoblasts. These processes are precisely controlled both, in space and time by molecules such as endothelin-1 (ET-1). ET-1 is expressed in human first trimester trophoblast and is known to stimulate cytotrophoblast proliferation through endothelin A and B receptor subtypes (ETA and ETB), and cytotrophoblast invasion through ETB. However, temporal changes of the ET system during the first trimester of pregnancy have not been previously studied. This study tested the hypothesis that ET-1 release, ETA and ETB expression are increased towards the end of the first trimester of pregnancy (weeks 10-12 vs. weeks 6-9), resulting in increased cytotrophoblast proliferation and invasion. Tissue samples were obtained from 17 surgical pregnancy interruptions (week 6-9: n=9; week 10-12: n=8). After cytotrophoblast isolation, the invasive and proliferative phenotypes were immune-separated by an α6-integrin antibody. Both proliferative and invasive cytotrophoblasts were cultured separately on plastic or Matrigel for 24 h. ET-1 release into the culture medium of both cytotrophoblast subtypes was measured by radioimmunoassay. ETA and ETB mRNA expression was measured by RT-PCR, and the ET-1 effect on cytotrophoblast proliferation and invasion was determined using proliferation and invasion assays, respectively. ET-1 release increased from early to late first trimester of pregnancy in both proliferative (1.8-4.5 fold) and invasive cytotrophoblasts (9.3-28 fold), especially when cultured on Matrigel. This was paralleled by less ETB mRNA on invasive cytotrophoblasts independent of the time period in first trimester, whereas ETA expression was similar on proliferative an invasive cytotrophoblasts. Proliferation and invasion of cytotrophoblasts under control conditions decreased from early to late first trimester. ET-1 stimulated both processes at both periods with the most pronounced effect (7-fold) on invasion in late first trimester. The ET-1/ET-receptor system changes between weeks 6-9 and 10-12 in pregnancy. Our data suggest an autocrine and endocrine ET-1 effect, which is stronger in late than in early first trimester of pregnancy paralleled by different stimulatory effects on trophoblast invasion and proliferation. In general, this suggests time as an additional effector of the critical processes governing placental development in the first trimester of human pregnancy.

scholarly journals Human Decidual Cells Activity in Women with Spontaneous Abortions of Probable CMV Aetiology During the First Trimester of Gestation. An Immunohistochemical Study with CMV-Associated Antigen

2004 ◽  
Vol 47 (3) ◽  
pp. 195-199 ◽  
Author(s):  
Demetrio Tamiolakis ◽  
Ioannis Venizelos ◽  
Maria Lambropoulou ◽  
Athanasia Kotini ◽  
Sophia Barbagadaki ◽  
...  
Keyword(s):  
Stromal Cells ◽  
First Trimester ◽  
Intrauterine Fetal Death ◽  
Spontaneous Abortions ◽  
Endometrial Stromal Cells ◽  
Chorionic Villi ◽  
Decidual Cells ◽  
Lymphoplasmacytic Infiltrate ◽  
Infected Cells ◽  
Mononuclear Infiltrate

Aim: To determine the expression of CMV-associated antigen in the human decidual endometrial stromal cells in spontaneous abortions with no evidence of maternal relapse during the first trimester of gestation. Experimental design: We examined 15 placentas resulting from intrauterine fetal death after spontaneous abortion during the 8th, 10th, and 12th week of gestation respectively, and in which CMV reactivation was ruled out from serological evaluation of the pregnant women at admission, versus equal controls after voluntary abortion following well-documented maternal viral recurrence. In addition, a panel of monoclonal antibodies for the identification of leukocytes (CD45/LCA), B-lymphocytes (CD20/L-26), and T-lymphocytes (CD45RO/UCHL1), was performed. All women received hormonal medication to support gestation, in the cases of spontaneous abortions. Results: Immunohistochemical examination using a specific antibody against cytomegalovirus showed large multinucleated infected cells with intranuclear inclusions, located primarily in the decidual stroma within a lymphoplasmacytic infiltrate in the cases of spontaneous abortions. No evidence of infection was observed in the chorionic villi. In the cases of voluntary abortions same findings were observed in the relevant areas, and a strong evidence of infection was observed in the chorionic villi. Conclusion: This study demonstrates 1) that the decidual endometrial stromal cells can express the CMV-associated antigen prior to serological manifestation of the viral replication, 2) the expression of the antigen is higher in cases of hormonal administration to support gestation. In these cases a mild mononuclear infiltrate of UCHL1 (T marker) positive cells, accompanies the CMV-associated antigen positive cells.

Impaired decidualization caused by downregulation of circadian clock gene BMAL1 contributes to human recurrent miscarriage†

2019 ◽  
Vol 101 (1) ◽  
pp. 138-147 ◽  
Author(s):  
Shijian Lv ◽  
Na Wang ◽  
Jin Ma ◽  
Wei-Ping Li ◽  
Zi-Jiang Chen ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Recurrent Miscarriage ◽  
First Trimester ◽  
Subsequent Pregnancy ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Trophoblast Invasion ◽  
Intrauterine Pregnancy ◽  
Endometrial Stromal Cells ◽  
Aryl Hydrocarbon

Abstract Recurrent miscarriage (RM) is characterized by two or more consecutive losses of a clinically established intrauterine pregnancy at early gestation. To date, the etiology of RM remains poorly understood. Impaired decidualization is thought to predispose women to subsequent pregnancy failure. The transcriptional factor brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL1) controls circadian rhythms and regulates a very large diversity of physiological processes. BMAL1 is essential for fertility. Here, we investigated the expression and function of BMAL1 in human decidualization and its relation with RM. A total of 39 decidua samples were collected. We also examined human endometrial stromal cells (HESCs) and primary endometrial stromal cells (ESCs), and primary decidual stromal cells (DSCs) isolated from decidua of first-trimester pregnancies. Compared to normal pregnant women, the expression of BMAL1 was reduced in the decidual tissues from individuals with RM. After in vitro induction of decidualization, the transcription of BMAL1 in both HESCs and primary ESCs was increased. This is in line with the relatively higher expression of BMAL1 in DSCs than in ESCs. Silencing of BMAL1 resulted in impaired decidualization. Moreover, levels of tissue inhibitors of metalloproteinases (TIMPs) increased significantly upon decidualization. Further experiments demonstrated that BMAL1 silencing curtails the ability of DSCs to restrict excessive trophoblast invasion via downregulation of TIMP3. Our study demonstrates a functional role for BMAL1 during decidualization: the downregulation of BMAL1 in RM leads to impaired decidualization and aberrant trophoblast invasion by regulating TIMP3 and consequently predisposing individuals for RM.

scholarly journals Adiponectin limits differentiation and trophoblast invasion in human endometrial cells

2017 ◽  
Vol 59 (3) ◽  
pp. 285-297 ◽  
Author(s):  
Fabien Duval ◽  
Esther Dos Santos ◽  
Hadia Moindjie ◽  
Valérie Serazin ◽  
Nelly Swierkowski-Blanchard ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Embryo Implantation ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Trophoblast Invasion ◽  
Human Escs ◽  
Trophoblastic Cell ◽  
Endometrial Stromal Cells ◽  
Human Trophoblast ◽  
Endometrial Cells ◽  
Decidual Cells

Successful human embryo implantation requires a proper differentiation of endometrial stromal cells (ESCs) into decidual cells, during a process called decidualization. ESCs express specific molecules, such as prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1) and connexin-43. Decidual cells are also involved in the control of trophoblast invasion, by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory and anti-proliferative effects. At the embryo–maternal interface, adiponectin promotes differentiation and invasion of human trophoblastic cells. We hypothesize that the effects of adiponectin on endometrium could counteract its pro-invasive effects previously described in the human trophoblast. In this context, we have firstly demonstrated that adiponectin downregulates IGFBP-1 and connexin-43 mRNA expressions, as well as prolactin secretion in ESCs, suggesting an anti-differentiative effect of adiponectin. Secondly, we found that invasive capacities of trophoblastic cell line HTR-8/SVneo are reduced in the presence of conditioned media from ESC cultured in the presence of adiponectin. Adiponectin’s anti-invasive action is associated with a decreased activity of MMP-2 and MMP-9, and an increased TIMP-3 mRNA expression in ESCs. Finally, adiponectin receptors (ADIPOR1 and ADIPOR2) knockdown abolishes the anti-differentiative and anti-invasive effects of adiponectin in human ESCs. Altogether, our results suggest that adiponectin reduces the decidualization process and inversely induces the production of endometrial factors that limit trophoblast invasion. Thus, through a dual control in trophoblast and endometrial cells, adiponectin appears as a pivotal actor of the embryo implantation process.

scholarly journals Exometabolomic Analysis of Decidualizing Human Endometrial Stromal and Perivascular Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Sarah L. Harden ◽  
Jieliang Zhou ◽  
Seley Gharanei ◽  
Maria Diniz-da-Costa ◽  
Emma S. Lucas ◽  
...  
Keyword(s):  
Time Course ◽  
Embryo Implantation ◽  
Cellular Reprogramming ◽  
Trophoblast Invasion ◽  
Perivascular Cells ◽  
Endometrial Stromal Cells ◽  
Time Resolved ◽  
Spatiotemporal Information ◽  
Decidual Cells ◽  
Purine Pathway

Differentiation of endometrial fibroblasts into specialized decidual cells controls embryo implantation and transforms the cycling endometrium into a semi-permanent, immune-protective matrix that accommodates the placenta throughout pregnancy. This process starts during the midluteal phase of the menstrual cycle with decidual transformation of perivascular cells (PVC) surrounding the terminal spiral arterioles and endometrial stromal cells (EnSC) underlying the luminal epithelium. Decidualization involves extensive cellular reprogramming and acquisition of a secretory phenotype, essential for coordinated placental trophoblast invasion. Secreted metabolites are an emerging class of signaling molecules, collectively known as the exometabolome. Here, we used liquid chromatography-mass spectrometry to characterize and analyze time-resolved changes in metabolite secretion (exometabolome) of primary PVC and EnSC decidualized over 8 days. PVC were isolated using positive selection of the cell surface marker SUSD2. We identified 79 annotated metabolites differentially secreted upon decidualization, including prostaglandin, sphingolipid, and hyaluronic acid metabolites. Secreted metabolites encompassed 21 metabolic pathways, most prominently glycerolipid and pyrimidine metabolism. Although temporal exometabolome changes were comparable between decidualizing PVC and EnSC, 32 metabolites were differentially secreted across the decidualization time-course. Further, targeted metabolomics demonstrated significant differences in secretion of purine pathway metabolites between decidualized PVC and EnSC. Taken together, our findings indicate that the metabolic footprints generated by different decidual subpopulations encode spatiotemporal information that may be important for optimal embryo implantation.

scholarly journals Spatio-temporal coordination at the maternal-fetal interface promotes trophoblast invasion and vascular remodeling in the first half of human pregnancy

2021 ◽  
Author(s):  
Shirley Greenbaum ◽  
Inna Averbukh ◽  
Erin Soon ◽  
Gabrielle Rizzuto ◽  
Alex Baranski ◽  
...  
Keyword(s):  
Gestational Age ◽  
Ion Beam ◽  
Cell Types ◽  
First Trimester ◽  
Machine Learning Algorithms ◽  
Cell Segmentation ◽  
Trophoblast Invasion ◽  
Decidual Cells ◽  
Spatio Temporal ◽  
Maternal Fetal Interface

AbstractBeginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels that lack smooth muscle and are partially lined with EVTs instead of vascular endothelium. Several mechanisms have been proposed to explain how EVTs coordinate with decidual cells to promote a tissue microenvironment conducive to spiral artery remodeling (SAR). However, it remains a matter of debate which immune and stromal cell types participate in these interactions, how this process evolves with respect to gestational age, and which anatomic routes are the predominate path of EVT invasion in humans. To elucidate this complex interplay, we used multiplexed ion beam imaging by time of flight with a 37-plex antibody panel to build the first spatio-temporal atlas of the human maternal-fetal interface in the first half of pregnancy at single-cell resolution. We analyzed ~500,000 cells and 588 spiral arteries within intact decidua from 66 patients between 6-20 weeks of gestation. Using custom machine learning algorithms for cell segmentation and classification, we evaluated the spatial distributions and phenotype of 20 maternal and five EVT populations with respect to gestational age and SAR. Gestational age substantially influenced the frequency of most maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, Galectin-9, and IDO-1 preferentially enriched at later time points. In contrast, SAR progression, and not gestational age, preferentially correlated with local invasion of EVTs. Lastly, by comparing spatial co-occurrence and phenotype of decidual interstitial, perivascular and intravascular EVTs with respect to SAR progression, we developed a statistical model suggesting an intravasation mechanism as the predominant route of EVT invasion in superficial decidua. Taken together, these results support a coordinated model of decidualization in which increasing gestational age drives a transition in maternal decidua towards a tolerogenic niche conducive to locally regulated, EVT-dependent SAR.

Sign in / Sign up

Export Citation Format

Share Document