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Primiparous mares produce smaller and lighter foals than in subsequent pregnancies. In most studies, their placenta is also smaller, more efficient and presents structural alterations, but maternal age is a confounding factor. This study aimed to characterize the effects of maternal parity using the mare's first two pregnancies or by comparing young mares with different parities over the same gestation year. The same young mares (4–6-year-old over the study) foaled for the first time in 2018 (primiparous in 2018, P18, n=10) and for the second time in 2020 (multiparous in 2020, M20, n=10). In 2020, another group of young mares foaled for the first time (primiparous in 2020, P20, n=18). All mares were inseminated with the semen of the same stallion and were fed identically over the study. To assess the effect of primiparity, M20 were compared to P18 (effect on the same mare), or P20 (effect in the same year). Placentas were recovered at foaling, measured, weighed and sampled close to the umbilical cord. Stereology was performed using MercartorPro software on HES-stained paraffin-embedded samples and analyzed using a linear model for paired samples or not and permutations with R software. Paired-end RNA-sequencing was performed (Illumina, NextSeq500) on 6 randomly chosen snap-frozen placentas/group. Differential expression was analyzed (DESeq2) using a false discovery rate (FDR) <0.05 cutoff. Gene Set Enrichment Analysis was performed on differential expressed genes using PANTHER overrepresentation test with GOBP database. Placental weight and surface were reduced and the efficiency (foal weight/placental surface, in kg/m2) was increased in primiparous mares in both comparisons (p<0.05). Volume was not modified by parity between the consecutives gestations but reduced in P20 vs M20 (p<0.05). Only the volume of allantoic stroma was significantly reduced in P18 vs M20 (p<0.05), whereas hemotrophic trophoblast and microcotyledonary vessels' volume tended to be reduced in P20 vs M20 placentas (p<0.1). In consecutive gestations, 118 genes were differentially expressed in placenta while in the same year, only 2 genes (IL4R and FFAR, interleukin-4 and free fatty acid receptors) were differentially expressed (FDR <0.05). Among the 118 genes differentially expressed between consecutive pregnancies, apelin signaling, angiogenesis and catalytic activity were overrepresented. All genes involved in these pathways were under-expressed in P18 mares. Both the apelin (normalized enrichment score, NES=-2.16, FDR <0.05) and its receptor (NES=-2.48, FDR <0.05) were less expressed in the placenta of P18 vs M20. This is also observed in intrauterine growth retardation in humans. Although placental morphology was lightly affected in both analyses, the inter-individual variability seemed to hide parity effects for transcriptomic analysis. Consecutive gestations, however, demonstrate that the smaller placental and foal size in primiparous mares seems to originate from reduced vascularization. [ABSTRACT FROM AUTHOR]

The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D+CD27+ B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD+CD27− and memory IgD−CD27+ B cells and develop in an AKT-dependent manner from their precursors in vitro , underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans. [Display omitted] • AKT signaling in B cells drives MZ B cell development • FoxO1 inactivation is necessary for MZ B cell development • AKT is also distinctively increased in human IgD+CD27+ MZ B cells • CD148 is expressed at higher levels in MZ B cells than FO B cells in mice and humans Cox et al. show that AKT activation biases B cell development toward marginal zone (MZ) B cells with innate functions. CD148 is identified as a receptor indicative of AKT signaling level in B cells, expressed at higher levels in MZ than FO B cells in mice and humans. [ABSTRACT FROM AUTHOR]

Abstract: TRIM proteins have recently emerged as novel players in antiviral defense. TRIM proteins contain a tri-partite motif, composed of a RING zinc finger, one or two B-boxes and a coiled-coil domain. Many members of this large protein family of E3 ubiquitin ligases catalyze the attachment of ubiquitin to a substrate protein, an activity dependent on the RING domain. We earlier made a full description of the TRIM gene family in zebrafish and pufferfish and identified three multigene TRIM subsets, a feature unique to fish. To determine their biological role, we further characterized members of the finTRIM subset. FinTRIM gene expression was studied during development and in multiple tissues in adult rainbow trout. Upregulation of a large number of finTRIM upon viral stimulation suggests they are involved in antiviral immunity. We also demonstrate that two finTRIM members display E3 ubiquitin ligase activity, indicating that finTRIMs could regulate antiviral signaling through ubiquitination. [Copyright &y& Elsevier]

The negative in utero effects of bisphenol A (BPA) on female reproduction are of concern since the ovarian reserve of primordial follicles is constituted during the fetal period. This time-window is difficult to access, particularly in humans. Animal models and explant culture systems are, therefore, vital tools for investigating EDC impacts on primordial germ cells (PGCs). Here, we investigated the effects of BPA on prophase I meiosis in the fetal sheep ovary. We established an in vitro model of early gametogenesis through retinoic acid (RA)-induced differentiation of sheep PGCs that progressed through meiosis. Using this system, we demonstrated that BPA (3 ×10-7 M & 3 ×10-5 M) exposure for 20 days disrupted meiotic initiation and completion in sheep oogonia and induced transcriptomic modifications of exposed explants. After exposure to the lowest concentrations of BPA (3 ×10-7 M), only 2 probes were significantly up-regulated corresponding to NR2F1 and TMEM167A transcripts. In contrast, after exposure to 3 × 10-5 M BPA, 446 probes were deregulated, 225 were down- and 221 were up-regulated following microarray analysis. Gene Ontology (GO) annotations of differentially expressed genes revealed that pathways mainly affected were involved in cell-cycle phase transition, meiosis and spindle assembly. Differences in key gene expression within each pathway were validated by qRT-PCR. This study provides a novel model for direct examination of the molecular pathways of environmental toxicants on early female gametogenesis and novel insights into the mechanisms by which BPA affects meiosis I. BPA exposure could thereby disrupt ovarian reserve formation by inhibiting meiotic progression of oocytes I and consequently by increasing atresia of primordial follicles containing defective oocytes. • Development of a meiosis targeting culture model of the fetal ovary in sheep. • BPA reduced the expression of meiotic marker genes in exposed explants. • BPA altered expression of genes involved in cell cycle transition, meiosis, and spindle formation. • Long-term effects could result in a reduction of the ovarian reserve and an increased frequency of aneuploidy. [ABSTRACT FROM AUTHOR]

The placenta controls exchanges between the mother and the fetus and therefore fetal development and growth. The maternal environment can lead to disturbance of placental functions, with consequences on the health of the offspring. Since the rabbit placenta is very close to that of humans, rabbit models can provide biomedical data to study human placental function. Yet, to limit the use of animal experiments and to investigate the mechanistic aspects of placental function, we developed a new cell culture model in which rabbit trophoblast cells are differentiated from rabbit trophoblast stem cells. Rabbit trophoblast stems cells were derived from blastocysts and differentiated onto a collagen gel and in the presence of a flow of culture medium to mimic maternal blood flow. Transcriptome analysis was performed on the stem and differentiated cells. Our culture model allows the differentiation of trophoblast stem cells. In particular, the fluid shear stress enhances microvilli formation on the differentiated cell surface, lipid droplets formation and fusion of cytotrophoblasts into syncytiotrophoblasts. In addition, the transcriptome analysis confirms the early trophoblast identity of the derived stem cells and reveals upregulation of signaling pathways involved in trophoblast differentiation. Thereby, the culture model allows mimicking the in vivo conditions in which maternal blood flow exerts a shear stress on trophoblast cells that influences their phenotype. General significance: Our culture model can be used to study the differentiation of trophoblast stem cells into cytotrophoblasts and syncytiotrophoblasts, as well as the trophoblast function in physiological and pathological conditions. • Derivation and differentiation of rabbit trophoblastic stem cells • Collagen and flow enhance syncytium formation and lipid droplet accumulation • The transcriptome of rabbit trophoblastic cells was explored during differentiation • The cell culture model allows exploring trophoblast cell differentiation and function [ABSTRACT FROM AUTHOR]

Abstract: Embolization with microspheres is widely applied to treat uterine fibroids. However, the foreign body reaction that could result from the degradation of the microspheres remains to be evaluated to adequately appreciate the tissular tolerance to such biomaterials. We compared herein the in situ degradation of PMMA microspheres coated with polyphosphazene (PMMA-PPms) and trisacryl gelatin microspheres (TGms) and we thoroughly investigated the induced local inflammatory responses, at 1 and 4 weeks after uterine artery embolization in sheep, by using immunohistochemistry and microarray analyses. PMMA-PPms underwent an acute and partial degradation that was associated with the early recruitment of phagocytic cells (CD172a+ and MHCII+), and with the up-regulated expression of genes involved in the movement of phagocytes (ALOX5AP, CXCL2, CXCL5, IL8, PTGS2, YARS). By contrast, TGms were not degraded and triggered a different inflammation profile including the recruitment of FBR Giant Cells and T-lymphocytes (CD4+) and the increased expression of genes involved in lymphocyte activation (CXCL10, IL2RG, IRAK4, MALT1). Our results indicate that, in contrast to a non-degradable microsphere such as TGms which is associated to a poorly inflammatory foreign body reaction that rapidly resolves, PMMA-PPms, which is partially degradable, rapidly recruits and activates inflammatory phagocytes, thus delaying the resolution of the foreign body reaction. [ABSTRACT FROM AUTHOR]