Placental Research Articles

Epigenetic dynamics of partially methylated domains in human placenta and trophoblast stem cells.

The placenta is essential for nutrient exchange and hormone production between the mother and the developing fetus and serves as an invaluable model for epigenetic research. Most epigenetic studies of the human placenta have used whole placentas from term pregnancies and have identified the presence of partially methylated domains (PMDs). However, the origin of these domains, which are typically absent in most somatic cells, remains unclear in the placental context. Using whole-genome bisulfite sequencing and analysis of histone H3 modifications, we generated epigenetic profiles of human cytotrophoblasts during the first trimester and at term, as well as human trophoblast stem cells. Our study focused specifically on PMDs. We found that genomic regions likely to form PMDs are resistant to global DNA demethylation during trophectoderm reprogramming, and that PMDs arise through a slow methylation process within condensed chromatin near the nuclear lamina. In addition, we found significant differences in histone H3 modifications between PMDs in cytotrophoblasts and trophoblast stem cells. Our findings suggest that spatiotemporal genomic features shape megabase-scale DNA methylation patterns, including PMDs, in the human placenta and highlight distinct differences in PMDs between human cytotrophoblasts and trophoblast stem cells. These findings advance our understanding of placental biology and provide a basis for further research into human development and related diseases.

The Immunomodulatory Role of Regulatory T Cells in Preterm Birth and Associated Pregnancy Outcomes

Spontaneous preterm birth (sPTB), defined as live birth before 37 weeks of gestational age, is associated with immune dysregulation and pro-inflammatory conditions that profoundly impact newborn health. The question of immune integrity at the maternal-foetal interface is a focus of recent studies centring not only sPTB but the conditions often affiliated with this outcome. Regulatory T cells (Tregs) play a critical anti-inflammatory role in pregnancy, promoting foetal tolerance and placentation. Due to this gestational role, it is hypothesised that decreased or dysfunctional Tregs may be implicated in cases of sPTB. This review examines studies comparing Treg presence in healthy term pregnancies and those with sPTB-associated conditions. Conflicting findings across different conditions and within sPTB itself have been identified. However, notable findings from the research indicate increased proinflammatory cytokines in pregnancies suffering from premature rupture of membranes (pPROM), chorioamnionitis, infection, preeclampsia, and gestational diabetes (GDM). Additionally, reduced Treg levels were identified in preeclampsia, GDM, and pPROM as well as chorioamnionitis presenting with increased Treg dysfunctionality. Treg deficiencies may contribute to health issues in preterm newborns. Current sPTB treatments are limited, underscoring the potential of in utero therapies targeting inflammation, including T cell interventions. Future research aims to establish consensus on the role of Tregs in sPTB and associated conditions and advancing understanding of mechanisms leading to Treg deficiencies in adverse pregnancy outcomes.

CD4+ but not CD8+ T cells are required for protection against severe guinea pig cytomegalovirus infections.

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus and the leading cause of infectious disease related birth defects worldwide. How the immune response modulates the risk of intrauterine transmission of HCMV after maternal infection remains poorly understood. Maternal T cells likely play a critical role in preventing infection at the maternal-fetal interface and limiting spread across the placenta, but concerns exist that immune responses to infection may also cause placental dysfunction and adverse pregnancy outcomes. This study investigated the role of CD4+ and CD8+ T cells in a guinea pig model of primary cytomegalovirus infection. Monoclonal antibodies specific to guinea pig CD4 and CD8 were used to deplete T cells in non-pregnant and in pregnant guinea pigs after mid-gestation. CD4+ T cell depletion increased the severity of illness, caused significantly elevated viral loads, and increased the rate of congenital guinea pig cytomegalovirus (GPCMV) infection relative to animals treated with control antibody. CD8+ T cell depletion was comparably well tolerated and did not significantly affect the weight of infected guinea pigs or viral loads in their blood or tissue. However, significantly more viral genomes and transcripts were detected in the placenta and decidua of CD8+ T cell depleted dams post-infection. This study corroborates earlier findings made in nonhuman primates that maternal CD4+ T cells play a critical role in limiting the severity of primary CMV infection during pregnancy while also revealing that other innate and adaptive immune responses can compensate for an absent CD8+ T cell response in α-CD8-treated guinea pigs.

Definite Treatment Delay With Neoadjuvant Chemotherapy and Longitudinal Monitoring by Circulating Tumor DNA for Advanced Cervical Cancer During Pregnancy: A Case Series and Literature Review.

Previous studies mainly concentrate on neoadjuvant chemotherapy (NACT) for delivery delay in FIGO Stage IB1-IIIB cervical cancer during pregnancy to prevent early preterm delivery while not affecting maternal outcome. Here, we described two pregnant patients with FIGO Stage IIIC cervical cancer about their diagnosis, treatment, and outcome. Both patients underwent cesarean delivery, left enlarged lymph node dissection, and longitudinal monitoring by circulating tumor DNA. Our study suggested that pregnant patient was completely response to NACT, which was confirmed by ctDNA monitoring, followed by left pelvic enlarged lymph node dissection during cesarean section and adjuvant chemoradiotherapy postpartum. The infant grew normally, without any evidence of chemotherapy-related side effects after delivery. In pregnant women with advanced cervical cancer, longitudinal ctDNA monitoring might be able to evaluate maternal response to NACT and confirm if delivery delay to optimize fetal outcome would compacting the maternal outcomes or not. Cervical cancer may not transmit across the placental barrier and so it is safe for delayed delivery until fetal maturity in utero during pregnancy.

PM2.5 Induces Developmental Neurotoxicity in Cortical Organoids

There is mounting evidence implicating the potential neurotoxic effects of PM2.5 during brain development, as it has been observed to traverse both the placental barrier and the fetal blood-brain barrier. However, the current utilization of 2D cell culture and animal models falls short in providing an accurate representation of human brain development. Consequently, the precise mechanisms underlying PM2.5-induced developmental neurotoxicity in humans remain obscure. To address this research gap, we constructed three-dimensional (3D) cortical organoids that faithfully recapitulate the initial stages of human cerebral cortex development. Our goal is to investigate the mechanisms of PM2.5-induced neurotoxicity using 3D brain organoids that express cortical layer proteins. Our findings demonstrate that exposure to PM2.5 concentrations of 5 μg/mL and 50 μg/mL induces neuronal apoptosis and disrupts normal neural differentiation, thereby suggesting a detrimental impact on neurodevelopment. Furthermore, transcriptomic analysis revealed PM2.5 exposure induced aberrations in mitochondrial complex I functionality, which is reminiscent of Parkinson's syndrome, potentially mediated by misguided axon guidance and compromised synaptic maintenance. This study is a pioneering assessment of the neurotoxicity of PM2.5 pollution on human brain tissues based on 3D cortical organoids, and the results are of great significance in guiding the formulation of the next air pollution prevention and control policies in China to achieve the sustainable improvement of air quality and to formulate pollution abatement strategies that can maximize the benefits to public health.

Between Living and Non-living: Materiality of the Placentain Ming China.

This study explores materiality and material cultures of human placenta in Ming China (1368-1644), for it perfectly displays Chinese ambiguous attitudes towards the human body parts between living and non-living. For a long time, the Chinese had widely applied human body parts in medical treatments and ritual healings. Numerous evidences in relation to their collection, production, efficacy and application are widely recorded in medical works, in particular those found in materia medica. In the sixteenth century, the Bencao gangmu (Systemic Materia Medica, 1596) illustrates thirty-five "human body drugs." Of those, the placenta was believed effective for curing illnesses, nourishing the body and prolonging life. The questions to be answered include: how is the placenta perceived in medical and religious discourses? What is its "materiality" and "efficacy" when it becomes a drug? What ethical issues and moral concerns are involved with eating the placenta? Last but not least, how was the placenta ritually buried after childbirth in premodern China? In so doing, this essay aims to provide a better understanding of the placenta situated in both material and cosmological worlds. It helps us rethink the multiple relations of human body part to part, part to whole, and body to body.

Long-Term Implicit Epigenetic Stress Information in the Enteric Nervous System and its Contribution to Developing and Perpetuating IBS.

Psychiatric and mood disorders may play an important role in the development and persistence of irritable bowel syndrome (IBS). Previously, we hypothesized that stress-induced implicit memories may persist throughout life via epigenetic processes in the enteric nervous system (ENS), independent of the central nervous system (CNS). These epigenetic memories in the ENS may contribute to developing and perpetuating IBS. Here, we further elaborate on our earlier hypothesis. That is, during pregnancy, maternal prenatal stresses perturb the HPA axis and increase circulating cortisol levels, which can affect the maternal gut microbiota. Maternal cortisol can cross the placental barrier and increase cortisol-circulating levels in the fetus. This leads to dysregulation of the HPA axis, affecting the gut microbiota, microbial metabolites, and intestinal permeability in the fetus. Microbial metabolites, such as short-chain fatty acids (which also regulate the development of fetal ENS), can modulate a range of diseases by inducing epigenetic changes. These mentioned processes suggest that stress-related, implicit, long-term epigenetic memories may be programmed into the fetal ENS during pregnancy. Subsequently, this implicit epigenetic stress information from the fetal ENS could be conveyed to the CNS through the bidirectional microbiota-gut-brain axis (MGBA), leading to perturbed functional connectivity among various brain networks and the dysregulation of affective and pain processes.

A Mini Review of the Literature with a Special Focus on India on the Prevalence of Indian Traditional Medicine (ITM) use During Pregnancy

Background: Although pregnancy has been an integral part of women’s lives for millennia, not all women have found the process comfortable. About 65 percent of women in India consume Indian traditional herbs during pregnancy. Herbal medicines are used nowadays by up to half of the world's population. Phytomedicines isolated from plants contain a wide variety of bioactive components that can have both negative and positive effects. Many herbal plants, such as Sage (Salvia fruticosa), golden cotula (Matricaria aurea), anise (P. anisum), peppermint (Mentha aquatica), and cumin (Cuminum cyminum), etc., are used in pregnancy. To minimize the adverse effects, the use of Indian traditional medicine can be the best possible alternative. Objective: Regarding the usage of herbal medicines in India, there are large research gaps and a lack of a regulatory framework. This article aims to highlight the most common traditional Indian remedies used by pregnant women, along with their uses and any possible interactions between herbal remedies and prescription drugs. Method: Several databases, including the WHO guidelines, PubMed, Bentham Science, Elsevier, Springer Nature, Wiley, and Research Gate, were used to compile the data for the article following a thorough analysis of the various research findings connected to pregnancy and herbs for pregnancy care. Result: An overview of the use of herbal medicine is given in this review, along with information on its limitations and general safety. The prevalence of herbal medicine use during pregnancy in India is then discussed, along with the uses, adverse effects, side effects, and efficacy of the most popular herbal medications. Conclusion: The use of herbal medicine during pregnancy is a common phenomenon. The outcomes of this study showed Indian Traditional medicines are known to have numerous advantages that can be helpful during or after pregnancy, including raising milk production, reducing nausea, easing labor pains, reducing morning sickness, or reducing flatulence, however, some herbal remedies have the potential to be teratogenic, poisonous, and abortive, especially during the first trimester of pregnancy because the active components of some medicinal plants can cross the placental barrier and get to the foetus. To determine the safety of taking herbal medications, studies, especially clinical trial trials, must be conducted.

Analysis of the relationship between neonatal birth weight and meconium metabolites based on birth cohort metabolomics

Neonatal birth weight is a crucial indicator of intrauterine growth and development with important implications for child development and adult health. The birth weight of a newborn is closely linked to the nutrition and health of the mother during pregnancy as well as genetic factors. Therefore, assessing the metabolic status of the fetus in utero is greatly significant for understanding the mechanisms responsible for abnormal birth weight. While previous studies often analyzed the impact of maternal metabolism on fetal development using umbilical cord blood from pregnant women, such blood may not accurately reflect the actual intrauterine environment owing to the barrier function of the placenta; moreover, obtaining biological samples during the fetal period is challenging. Meconium, the first feces excreted by a newborn, provides ideal biological material for studying maternal and infant health. Metabolomics can reveal metabolic changes in living organisms by analyzing small molecules in biological samples; hence studying meconium samples using metabolomics technology is expected to reveal fetal metabolic changes during pregnancy, thereby providing new insights into fetal nutritional intake, growth, and development, as well as metabolic pathways related to birth weight. To gain a deeper understanding of the metabolic changes associated with birth weight, this study collected metabolomic data from the meconium of 484 newborns in the established Xiaogan birth cohort using an untargeted metabolomics technique based on liquid chromatography-high resolution mass spectrometry (LC-HRMS) and analyzed the association between meconium metabolites and birth weight. This cohort exhibited incidence rates of low birth weight (<2500 g) and macrosomia (>4000 g) of 3.3% and 7.2%, respectively, which were roughly equivalent to the national average. Orthogonal partial least squares discriminant analysis revealed significant differences between the meconium metabolomes of the low birth weight and macrosomic groups when compared to the normal weight group. We discovered significant distinctions between the differential metabolites of newborns of low birth weight and those of normal weight, as well as between macrosomic and normal weight newborns that point to disparate biological pathways. Newborns with low birth weight exhibited significantly lower levels of critical amino acids, such as glutamate and proline, compared to the normal weight group, which may be associated with placental dysfunction and maternal nutritional deficiencies. Conversely, the meconium of macrosomic newborns contained significantly elevated levels of hormone metabolites such as estrone that reflected the pathophysiological state associated with maternal metabolic diseases or excessive placental hormone levels. Our study suggests that the metabolomic profile of the meconium reflects the metabolic pathways and regulatory mechanisms at play during fetal growth and development, and offers potential metabolic biomarkers and directions for future in-depth research into diseases related to fetal development. However, this study was based solely on the Xiaogan birth cohort, which was limited to specific regions and populations. A multicenter, multiethnic, and multiregional study is expected to help validate the universality of our research findings.

COVID-19 and Its Potential Impact on Children Born to Mothers Infected During Pregnancy: A Comprehensive Review

Pregnancy is a vulnerable period of time during which pregnant people are prone to infections like COVID-19, which can increase risks for both the mother and fetus. These infections may lead to complications such as preterm birth, developmental delays, and congenital abnormalities. While COVID-19 poses additional risks like placental dysfunction and neonatal infections, studies on long-term effects remain limited. Ongoing research and monitoring are essential to understand and mitigate potential cognitive and developmental challenges in children born to mothers infected with COVID-19. This review aims to guide clinicians in managing these risks throughout childhood. Maternal COVID-19 infection during pregnancy can have significant implications for fetal development, even if the newborn is not infected at birth. The release of inflammatory cytokines may cross the placental barrier, potentially disrupting fetal brain development and increasing the risk of long-term cognitive and behavioral issues, such as ADHD or autism. Placental dysfunction, caused by inflammation or thrombosis, can lead to intrauterine growth restriction (IUGR), preterm birth, or hypoxia, affecting both neurological and respiratory health in newborns. Furthermore, a compromised fetal immune system can increase susceptibility to autoimmune conditions and infections. The early diagnosis and management of infections during pregnancy are crucial in mitigating risks to both the mother and fetus. Swift intervention can prevent complications like preterm birth and long-term developmental challenges, ensuring better health outcomes for both the mother and child. Long-term monitoring of children born to mothers infected with COVID-19 is necessary to understand the full extent of the virus’s impact. This review evaluates the long-term systemic effects of maternal COVID-19 infection during pregnancy on fetuses, newborns, and children, focusing beyond vertical transmission. It highlights the broader impacts on fetal development, offering insights to help clinicians manage potential issues that may arise later in life.

Optimization of an Affordable and Efficient Skin Allograft Composite with Excellent Biomechanical and Biological Properties Suitable for the Regeneration of Deep Skin Wounds: A Preclinical Study.

Deep skin wounds require grafting with a skin substitute for treatment. Despite many attempts in the development of an affordable and efficient skin substitute, the repair of deep skin wounds still remains challenging. In the current study, we present a 3D sponge composite made from human placenta (a disposable organ) and sodium alginate with exceptional properties for skin tissue engineering applications. Toward this goal, different proportions of alginate (Alg) and decellularized placenta scaffold (DPS) were composited and freeze-dried to generate a 3D sponge with the desired biomechanical and biological features. Comprehensive in vitro, in ovo, and in vivo characterizations were performed to assess the morphology, physical structure, mechanical behaviors, angiogenic potential, and wound healing properties of the composites. Through these analyses, the scaffold with optimal proportions of Alg (50%) and DPS (50%) was found to have superior properties. The optimized scaffold (Alg50/DPS50) was applied to the full-thickness wounds created in rats. Our data revealed that the addition of DPS to the Alg solution caused a significant improvement in the mechanical characteristics of the scaffold. Remarkably, the fabricated composite scaffold exhibited mechanical properties similar to those of native skin tissue. When implanted into the full-thickness wounds, the Alg50/DPS50 composite scaffold promoted angiogenesis, re-epithelialization, and granulation tissue formation, as compared to the group without a scaffold. Overall, our findings underscore the potential value of this hybrid scaffold for enhancing skin wound healing and suggest an Alg50/DPS50 composite for clinical investigations.

An unexpected late paroxyclaenid (Mammalia, Cimolesta) out of Europe: dental evidence from the Oligocene of the Bugti Hills, Pakistan

AbstractEight isolated mammal molars were discovered in lower Oligocene deposits of the Bugti Hills, Pakistan (Paali Nala, DB‐C2; lower Chitarwata Formation). Because of their unusual morphology, these molars have long remained enigmatic. Extensive comparisons with fossil eutherian and metatherian mammals and the recent description of new paroxyclaenids (Mammalia, Cimolesta) from the lower Eocene (Ypresian) of Europe have highlighted the plausible affinities of these teeth from the Oligocene of Pakistan and suggest a referral to Paroxyclaenidae. The dental morphology of this taxon is singular among Paroxyclaenidae, and as such it allows us to propose here a new species and a new genus: Welcommoides gurki. The occurrence of a paroxyclaenid in the Oligocene of Pakistan remains somewhat unexpected inasmuch as these mammals have so far been known only from the Eocene of Europe. At c. 4.2 kg, W. gurki is the largest paroxyclaenid ever discovered, and is assigned to the subfamily Merialinae, which became extinct in Europe around the Ypresian–Lutetian transition, long before the occurrence of this new taxon from Pakistan. Welcommoides has a suite of unusual characters compared with merialines, suggesting that this South Asian lineage had diverged for some time from its European Ypresian counterparts. Such a hypothesis is supported by the faunal similarities between European and Indian subcontinent faunas during the Ypresian. Moreover, our discovery strengthens support for the hypothesis that low latitudes of South Asia were a tropical refugium, at least during the first steps of the global climatic deterioration started at the Eocene–Oligocene transition.

Effects of oxycodone on placental lineages: Evidence from the transcriptome profile of mouse trophoblast giant cells

Pregnant women are often prescribed or abuse opioid drugs. The placenta is likely the key to understanding how opioids cause adverse pregnancy outcomes. Maternal oxycodone (OXY) exposure of pregnant mice leads to disturbances in the layer of invasive parietal trophoblast giant cells (pTGC) that forms the interface between the placenta and uterus. These cells are analogous to extravillous trophoblasts of the human placenta. They are crucial to coordinating the metabolic needs of the conceptus with those of the mother and are primary participants in the placenta-brain axis. Their large nuclear size, however, has precluded both single-cell (sc) and single-nucleus (sn) RNA-seq analyses beyond embryonic day (E) 8.5. Here, we compared the transcriptomes of placentas from pregnant mice exposed to OXY with unexposed controls at E12.5, with particular emphasis on the pTGC. The nonfluidic Parse snRNA-seq approach permitted characterization of the nuclear transcriptomes of all the major placental cell lineages and their presumed progenitors at E12.5. OXY exposure had a negligible effect on components of the placental labyrinth, including the two syncytial cell layers, but caused transcriptomic changes consistent with metabolic stress throughout the spongiotrophoblast. Most notably, there was loss of the majority of pTGC, whose normal gene expression is consistent with elevated energy demand relating to biosynthesis of multiple secretory products, especially hormones, and endoduplication of DNA. This unusual sensitivity of pTGC presumably puts the pregnancy and future health of the offspring at particular risk to OXY exposure.

Human decidua basalis mesenchymal stem/stromal cells enhance anticancer properties of human natural killer cells, in vitro

IntroductionMesenchymal stem cells/stromal cells from the Decidua Basalis of the human placenta (DBMSCs) express wide range of effector molecules that modulate the functions of their target cells. These properties make them potential candidate for use in cellular therapy. In this study, we have investigated the consequences of interaction between DBMSCs and natural killer (NK) cells for both cell types.MethodsDBMSCs were cultured with IL-2-activated and resting non-activated NK cells isolated from healthy human peripheral blood and various functional assays were performed including, NK cell proliferation and cytolytic activities. Flow cytometry and microscopic studies were performed to examine the expression of NK cell receptors that mediate these cytolytic activities against DBMSCs. Moreover, the mechanism underlying these effects was also investigated.ResultsOur findings revealed that, co-culture of DBMSCs and NK cells resulted in inhibition of proliferation of resting NK cells, while proliferation of IL-2 activated NK cells was increased. Contrarily, treatment of DBMSC’s with comparatively high numbers of IL-2 activated NK cells, resulted in their lysis, whereas treatment with low numbers resulted in reduction in their proliferation. Cytolytic activity of NK cells against DBMSCs was mediated by several activating NK cell receptors. In spite of the expression of HLA class I molecules by DBMSCs, they were still lysed by NK cells, excluding their involvement in cytolytic activity. In addition, preconditioning NK cells by DBMSCs, enhanced their ability to suppress tumor cell proliferation and in severe cases resulted in their partial lysis. Lysis and decrease of tumor cell proliferation is associated with increased expression of important molecules involved in anticancer activities.DiscussionWe conclude that DBMSCs exhibit dualfunctions on NK cells that enhance their anticancer therapeutic potential.

Histological Change of Placenta in Diabetic Pregnant Women in Comparison to Normal Pregnant Women

Background: The placenta is a foeto-maternal organ and its alterations is directly related to the disease’s length and severity. The human placenta experiences a number of functional and structural pathologic alterations when complicated by metabolic disorder such as diabetes mellitus. Methods: This cross-sectional comparative study was conducted over a period of threeyears from January 2019 to December 2021 at the Department of Anatomy, Rajshahi Medical College, Rajshahi, in collaboration with the Department of Obstetrics and Gynaecology, Rajshahi Medical College Hospital and Diabetic Hospital Rajshahi, Bangladesh. The study was carried out on 70 pregnant women, among them 35 diabetics and 35 non-diabetics. The fibrinoid necrosis, syncytial knot and immature villi of the placenta were studied in diabetic and non-diabetic pregnant women. SPSS software, version-24 was used for data analysis, with a p-value &lt; 0.05 indicating statistically significance for all tests. Results: The diabetic and non-diabetic pregnant women groups were almost identical in terms of attachment of umbilical cord to placenta with marginal attachment being more often found in either group (p = 0.829). Histological examination of placenta showed that fibrinoid necrosis was common in placenta of diabetic mothers than that of the normal mothers (p &lt; 0.001). Syncytial knot and immature villi were higher in the former group than those in the latter group, here p values were also less than .001. Conclusion: Histological findings (fibrinoid necrosis, syncytial knot and immature villi) were more in placenta of diabetic mother and they were highly significant different between the groups. EWMCJ Vol. 12, No. 1&amp;2, January-July 2024: 27-33

Prenatal Opioid and Alcohol Exposures: Association with Altered Placental Serotonin Transporter Structure and/or Expression

Fetal exposures to many drugs of abuse, e.g., opioids and alcohol (EtOH), are associated with adverse neurodevelopmental problems in early childhood, including abnormalities in activity of the serotonin (5HT) transporter (SERT), which transports 5HT across the placenta. Little is known about the effects of these drugs on SERT expression. Pregnant women who used EtOH or opioids were compared to gestational age-matched controls using a structured questionnaire to determine prenatal substance exposure. Following elective pregnancy termination, placental membranous vesicles and exosomes were prepared from first and second trimester human placentas. Changes in EtOH- or opioid-exposed placental SERT expression and modifications were assessed by quantitative western blot. Novel SERT isoforms were sequenced and analyzed. Opioid-exposed but not EtOH-exposed maternal placentas showed SERT cleavage and formation of new SERT fragments (isoforms). Alcohol-exposed cases showed reduced SERT levels. Antibodies to the N-terminal SERT region did not recognize either of the two cleavage products, while antibodies to the central and C-terminal regions recognized both bands. The secondary band seen in the opioid group may represent a hypophosphorylated SERT fragment. These changes in SERT modifications and expression may result in altered fetal brain serotonergic neurotransmission, which could have neurodevelopmental implications.

Aromatase as a novel target of parabens in human and rat placentas: 3D-quantitative structure-activity relationship and docking analysis

Aromatase (CYP19A1), a pivotal enzyme in the biosynthesis of estradiol from testosterone, is predominantly expressed in reproductive tissues including placentas. This study investigated the effects of paraben acid and nine parabens on the activity of human and rat CYP19A1 using microsomes derived from human and rat placentas and on estradiol secretion in human choriocarcinoma BeWo cells. The results showed that propyl, butyl, hexyl, heptyl, and nonyl parabens significantly inhibited human CYP19A1 activity, with IC50 values of 66.37, 61.08, 55.65, 48.26, and 27.24 μM, respectively. In BeWo cells, these parabens notably diminished estradiol secretion at concentrations of 100 μM. Similarly, rat CYP19A1 was inhibited by these parabens, with IC50 values of 98.07, 70.10, 41.30, 27.93, and 6.33 μM for propyl, butyl, hexyl, heptyl, and nonyl parabens, respectively. Kinetic analysis identified these compounds as mixed inhibitors. Bivariate correlation analysis revealed a negative correlation between the partition coefficient value, molecular weight, the number of carbon atoms in the alcohol moiety, as well as heavy atom number and IC50 values. Three-dimensional quantitative structure-activity relationship analysis highlighted the critical role of hydrophobic regions in determining inhibitory potency. Docking studies suggested that parabens interact with the heme-iron binding site of both human and rat CYP19A1. This study elucidates the inhibitory effects of various parabens on CYP19A1 and their binding mechanisms, thereby providing a deeper understanding of their potential impact on estrogen biosynthesis.

The post-cranial anatomy and functional morphology of Conoryctes comma (Mammalia: Taeniodonta) from the Paleocene of North America.

Conoryctes comma is a member of the enigmatic group Taeniodonta, Paleogene mammals that have been found only in North America. Taeniodonts were part of the first wave of placental mammal diversification after the end-Cretaceous extinction. The lack of postcranial elements has limited the understanding of the anatomy and locomotion of Conoryctes, and how it compared to other taeniodonts. We here describe the postcranial anatomy and functional morphology of Conoryctes, based largely on nine new specimens found in the San Juan Basin, New Mexico, USA. The specimens include elements of the axial column, such as the axis, sacrum, and ribs; the humerus, ulna, radius, and part of the manus; the innominate, femur, tibia, and part of the pes, including the tarsals. Conoryctes was a medium-sized mammal, with a robust humerus, radius, and femur, and with anatomical similarities to other conoryctid taeniodonts and Onychodectes. The tarsal elements of Conoryctes show characteristics of the "leptictimorph astragalocalcaneal morphology" as seen in other Paleogene mammals, such as Escavadodon, Palaeanodon, and Procerberus. Anatomical features of the forelimb and hindlimb of Conoryctes indicate that it was a scratch-digging animal with powerful forearm muscles and well-stabilized digits, features that may have helped it adapt to the subtropical forests of the San Juan Basin, approximately 63 million years ago. This corroborates the previous hypothesis that digging adaptations are seen in all members of Taeniodonta for which the postcranial elements are known, and that digging ability was present in the common ancestor of the clade and potentially central to their radiation after the environmental destruction of the end-Cretaceous extinction.

Senescent Syncytiotrophoblast Secretion During Early Onset Preeclampsia.

Preeclampsia is a severe hypertensive disorder in pregnancy that causes preterm delivery, maternal and fetal morbidity, mortality, and life-long sequelae. Understanding the pathogenesis of preeclampsia is a critical first step toward protecting mother and child from this syndrome and increased risk of cardiovascular disease later in life. However, effective early predictive tests and therapies for preeclampsia are scarce. To identify novel markers and signaling pathways for early onset preeclampsia, we profiled human maternal-fetal interface units (fetal villi and maternal decidua) from early onset preeclampsia and healthy controls using single-nucleus RNA sequencing combined with spatial transcriptomics. The placental syncytiotrophoblast is in direct contact with maternal blood and forms the barrier between fetal and maternal circulation. We identified different transcriptomic states of the endocrine syncytiotrophoblast nuclei with patterns of dysregulation associated with a senescence-associated secretory phenotype and a spatial dysregulation of senescence in the placental trophoblast layer. Elevated senescence markers were validated in placental tissues of clinical multicenter cohorts. Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester. We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis. This indicates that increased syncytiotrophoblast senescence appears weeks before clinical manifestation of early onset preeclampsia, suggesting that the dysregulated preeclamptic placenta starts with higher cell maturation resulting in premature and increased senescence-associated secretory phenotype release. These senescence-associated secretory phenotype markers may serve as an additional early diagnostic tool for this syndrome.

Nursing and midwifery simulation training with a newly developed low-cost high-fidelity placenta simulator: a collaboration between Italy and Ethiopia

BackgroundSimulation training provides safe environment for skill acquisition and retention. This study addresses a critical challenge in Africa – umbilical cord and placenta management after childbirth – aiming to bridge theoretical learning with practical experiences through simulation. We realized a new low-cost high-fidelity simulator of placenta and umbilical cord. We conducted a needs-based training course for nursing and midwifery students at St. Luke Hospital of Wolisso, Ethiopia, to validate our new simulator and compare its acceptability and teaching effectiveness with other two simulators (conventional low-fidelity model and human placenta).MethodsWe surveyed St. Luke Hospital medical experts to obtain their feedback on the new simulator’s face, content, and usability. We carried out a simulation training course for 67 students who received theoretical lectures and simulation courses being divided into three groups according to the simulator used. We assessed the simulators’ user acceptability using the Technology Acceptance Model (TAM) and compared the final objective evaluations by tutors between groups.ResultsExperts confirmed the new simulator’s fidelity, material quality, and usability. Students training on the new simulator demonstrated higher objective scores and perceived it as more useful and user-friendly compared to human placenta, while there was no difference between conventional simulator and human placenta in the TAM items.ConclusionWe validated a new high-fidelity simulator developed by the Sant’Anna School of Advanced Studies in Pisa, Italy, using the TAM scale and robust statistical methods, thanks to a successful collaboration with St. Luke’s Hospital in a simulation training course where students achieved higher objective scores and perceived the simulator as more useful and easier to use than a real human placenta, suggesting significant educational benefits and potential for future research.